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Sample records for experimental autoimmune encephalomyelitis1

  1. Interferon-¿ regulates oxidative stress during experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Espejo, C.; Penkowa, Milena; Saez-Torres, I.

    2002-01-01

    Neurobiology, experimental autoimmune encephalomyelitis IFN-d, multiple sclerosis, neurodegeneration, oxidative stress......Neurobiology, experimental autoimmune encephalomyelitis IFN-d, multiple sclerosis, neurodegeneration, oxidative stress...

  2. Experimental models of autoimmune inflammatory ocular diseases

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    Fabio Gasparin

    2012-04-01

    Full Text Available Ocular inflammation is one of the leading causes of blindness and loss of vision. Human uveitis is a complex and heterogeneous group of diseases characterized by inflammation of intraocular tissues. The eye may be the only organ involved, or uveitis may be part of a systemic disease. A significant number of cases are of unknown etiology and are labeled idiopathic. Animal models have been developed to the study of the physiopathogenesis of autoimmune uveitis due to the difficulty in obtaining human eye inflamed tissues for experiments. Most of those models are induced by injection of specific photoreceptors proteins (e.g., S-antigen, interphotoreceptor retinoid-binding protein, rhodopsin, recoverin, phosducin. Non-retinal antigens, including melanin-associated proteins and myelin basic protein, are also good inducers of uveitis in animals. Understanding the basic mechanisms and pathogenesis of autoimmune ocular diseases are essential for the development of new treatment approaches and therapeutic agents. The present review describes the main experimental models of autoimmune ocular inflammatory diseases.

  3. Costimulatory signal blockade in murine relapsing experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Schaub, M; Issazadeh-Navikas, Shohreh; Stadlbauer, T H

    1999-01-01

    Blockade of the CD28-B7 or CD40L-CD40 T cell costimulatory signals prevents induction of experimental autoimmune encephalomyelitis (EAE). However, the effect of simultaneous blockade of these signals in EAE is unknown. We show that administration of either MR1 (to block CD40L) or CTLA4Ig (to block...

  4. Beneficial effects of blueberries in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Xin, Junping; Feinstein, Douglas L; Hejna, Matthew J; Lorens, Stanley A; McGuire, Susan O

    2012-06-13

    Experimental autoimmune encephalomyelitis (EAE) is an animal model of autoimmune disease that presents with pathological and clinical features similar to those of multiple sclerosis (MS) including inflammation and neurodegeneration. This study investigated whether blueberries, which possess immunomodulatory, anti-inflammatory, and neuroprotective properties, could provide protection in EAE. Dietary supplementation with 1% whole, freeze-dried blueberries reduced disease incidence by >50% in a chronic EAE model (p blueberries, which are easily administered orally and well-tolerated, may provide benefit to MS patients.

  5. Immunomodulation of experimental autoimmune encephalomyelitis by helminth ova immunization.

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    Sewell, Diane; Qing, Zhu; Reinke, Emily; Elliot, David; Weinstock, Joel; Sandor, Matyas; Fabry, Zsuzsa

    2003-01-01

    Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS) characterized by chronic inflammatory demyelination of the central nervous system (CNS). The pathology of EAE involves autoimmune CD4(+) T(h)1 cells. There is a striking inverse correlation between the occurrence of parasitic and autoimmune diseases. We demonstrate that in mice with Schistosoma mansoni ova immunization, the severity of EAE is reduced as measured by decreased clinical scores and CNS cellular infiltrates. Disease suppression is associated with immune deviation in the periphery and the CNS, demonstrated by decreased IFN-gamma and increased IL-4, transforming growth factor-beta and IL-10 levels in the periphery, and increased frequency of IL-4 producing neuroantigen-specific T cells in the brain. S. mansoni helminth ova treatment influenced the course of EAE in wild-type mice, but not in STAT6-deficient animals. This indicates that STAT6 plays a critical role in regulating the ameliorating effect of S. mansoni ova treatment on the autoimmune response, and provides the direct link between helminth treatment, T(h)2 environment and improved EAE. As some intestinal helminthic infections induce minimal pathology, they might offer a safe and inexpensive therapy to prevent and/or ameliorate MS.

  6. T cells in multiple sclerosis and experimental autoimmune encephalomyelitis.

    LENUS (Irish Health Repository)

    Fletcher, J M

    2012-02-01

    Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS), which involves autoimmune responses to myelin antigens. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have provided convincing evidence that T cells specific for self-antigens mediate pathology in these diseases. Until recently, T helper type 1 (Th1) cells were thought to be the main effector T cells responsible for the autoimmune inflammation. However more recent studies have highlighted an important pathogenic role for CD4(+) T cells that secrete interleukin (IL)-17, termed Th17, but also IL-17-secreting gammadelta T cells in EAE as well as other autoimmune and chronic inflammatory conditions. This has prompted intensive study of the induction, function and regulation of IL-17-producing T cells in MS and EAE. In this paper, we review the contribution of Th1, Th17, gammadelta, CD8(+) and regulatory T cells as well as the possible development of new therapeutic approaches for MS based on manipulating these T cell subtypes.

  7. Individual behavioral characteristics of wild-type rats predict susceptibility to experimental autoimmune encephalomyelitis

    NARCIS (Netherlands)

    Kavelaars, A; Heijnen, CJ; Tennekes, R; Bruggink, JE; Koolhaas, JM

    1999-01-01

    Neuroendocrine-immune interactions are thought to be important in determining susceptibility to autoimmune disease. Animal studies have revealed that differences in susceptibility to experimental autoimmune encephalomyelitis (EAE) are related to:reactivity in the hypothalamo-pituitary-adrenal axis.

  8. Introducing Autoimmunity at the Synapse by a Novel Animal Model of Experimental Autoimmune Myasthenia Gravis.

    Science.gov (United States)

    Wang, Jianwen; Xiao, Yatao; Zhang, Kejing; Luo, Benyan; Shen, Chengyong

    2018-02-06

    The neuromuscular junction (NMJ) is a peripheral synapse between motor neurons and skeletal muscle fibers that controls muscle contraction. The NMJ is the target of various disorders including myasthenia gravis (MG), an autoimmune disease in which auto-antibodies (auto-Abs) attack the synapse, and thus cause muscle weakness in patients. There are multiple auto-Abs in the MG patient sera, but not all the Abs are proven to be pathogenic, which increases the difficulties in clinical diagnoses and treatments. To establish the causative roles of auto-Abs in MG pathogenesis, the experimental autoimmune MG (EAMG) induced by the active immunization of auto-antigens (auto-Ags) or the passive transfer of auto-Abs is required. These models simulate many features of the human disease. To date, there are three kinds of EAMG models reported, of which AChR-EAMG and MuSK-EAMG are well characterized, while the recent LRP4-EAMG is much less studied. Here, we report a current summary of LRP4-EAMG and its pathogenic mechanisms. The features of LRP4-EAMG are more similar to those of AChR-EAMG, indicating a similar clinical treatment for LRP4- and AChR-positive MG patients, compared to MuSK-positive MG patients. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

  9. IL17 Mediates Pelvic Pain in Experimental Autoimmune Prostatitis (EAP.

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    Stephen F Murphy

    Full Text Available Chronic pelvic pain syndrome (CPPS is the most common form of prostatitis, accounting for 90-95% of all diagnoses. It is a complex multi-symptom syndrome with unknown etiology and limited effective treatments. Previous investigations highlight roles for inflammatory mediators in disease progression by correlating levels of cytokines and chemokines with patient reported symptom scores. It is hypothesized that alteration of adaptive immune mechanisms results in autoimmunity and subsequent development of pain. Mouse models of CPPS have been developed to delineate these immune mechanisms driving pain in humans. Using the experimental autoimmune prostatitis (EAP in C57BL/6 mice model of CPPS we examined the role of CD4+T-cell subsets in the development and maintenance of prostate pain, by tactile allodynia behavioral testing and flow cytometry. In tandem with increased CD4+IL17A+ T-cells upon EAP induction, prophylactic treatment with an anti-IL17 antibody one-day prior to EAP induction prevented the onset of pelvic pain. Therapeutic blockade of IL17 did not reverse pain symptoms indicating that IL17 is essential for development but not maintenance of chronic pain in EAP. Furthermore we identified a cytokine, IL7, to be associated with increased symptom severity in CPPS patients and is increased in patient prostatic secretions and the prostates of EAP mice. IL7 is fundamental to development of IL17 producing cells and plays a role in maturation of auto-reactive T-cells, it is also associated with autoimmune disorders including multiple sclerosis and type-1 diabetes. More recently a growing body of research has pointed to IL17's role in development of neuropathic and chronic pain. This report presents novel data on the role of CD4+IL17+ T-cells in development and maintenance of pain in EAP and CPPS.

  10. Experimental Models of Autoimmune Demyelinating Diseases in Nonhuman Primates.

    Science.gov (United States)

    Stimmer, Lev; Fovet, Claire-Maëlle; Serguera, Ché

    2017-01-01

    Human idiopathic inflammatory demyelinating diseases (IIDD) are a heterogeneous group of autoimmune inflammatory and demyelinating disorders of the central nervous system (CNS). These include multiple sclerosis (MS), the most common chronic IIDD, but also rarer disorders such as acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (NMO). Great efforts have been made to understand the pathophysiology of MS, leading to the development of a few effective treatments. Nonetheless, IIDD still require a better understanding of the causes and underlying mechanisms to implement more effective therapies and diagnostic methods. Experimental autoimmune encephalomyelitis (EAE) is a commonly used animal model to study the pathophysiology of IIDD. EAE is principally induced through immunization with myelin antigens combined with immune-activating adjuvants. Nonhuman primates (NHP), the phylogenetically closest relatives of humans, challenged by similar microorganisms as other primates may recapitulate comparable immune responses to that of humans. In this review, the authors describe EAE models in 3 NHP species: rhesus macaques ( Macaca mulatta), cynomolgus macaques ( Macaca fascicularis), and common marmosets ( Callithrix jacchus), evaluating their respective contribution to the understanding of human IIDD. EAE in NHP is a heterogeneous disease, including acute monophasic and chronic polyphasic forms. This diversity makes it a versatile model to use in translational research. This clinical variability also creates an opportunity to explore multiple facets of immune-mediated mechanisms of neuro-inflammation and demyelination as well as intrinsic protective mechanisms. Here, the authors review current insights into the pathogenesis and immunopathological mechanisms implicated in the development of EAE in NHP.

  11. Experimental autoimmune encephalomyelitis from a tissue energy perspective.

    Science.gov (United States)

    Desai, Roshni A; Smith, Kenneth J

    2017-01-01

    Increasing evidence suggests a key role for tissue energy failure in the pathophysiology of multiple sclerosis (MS). Studies in experimental autoimmune encephalomyelitis (EAE), a commonly used model of MS, have been instrumental in illuminating the mechanisms that may be involved in compromising energy production. In this article, we review recent advances in EAE research focussing on factors that conspire to impair tissue energy metabolism, such as tissue hypoxia, mitochondrial dysfunction, production of reactive oxygen/nitrogen species, and sodium dysregulation, which are directly affected by energy insufficiency, and promote cellular damage. A greater understanding of how inflammation affects tissue energy balance may lead to novel and effective therapeutic strategies that ultimately will benefit not only people affected by MS but also people affected by the wide range of other neurological disorders in which neuroinflammation plays an important role.

  12. Preventive Treatment with Methylprednisolone Paradoxically Exacerbates Experimental Autoimmune Encephalomyelitis

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    Simone Wüst

    2012-01-01

    Full Text Available Glucocorticoids (GCs represent the standard treatment for acute disease bouts in multiple sclerosis (MS patients, for which methylprednisolone (MP pulse therapy is the most frequently used protocol. Here, we compared the efficacy of therapeutic and preventive MP application in MOG35-55-induced experimental autoimmune encephalomyelitis (EAE in C57Bl/6 mice. When administered briefly after the onset of the disease, MP efficiently ameliorated EAE in a dose-dependent manner. Surprisingly, MP administration around the time of immunization was contraindicated as it even increased leukocyte infiltration into the CNS and worsened the disease symptoms. Our analyses suggest that in the latter case an incomplete depletion of peripheral T cells by MP triggers homeostatic proliferation, which presumably results in an enhanced priming of autoreactive T cells and causes an aggravated disease course. Thus, the timing and selection of a particular GC derivative require careful consideration in MS therapy.

  13. B-Cell Depletion Attenuates White and Gray Matter Pathology in Marmoset Experimental Autoimmune Encephalomyelitis

    NARCIS (Netherlands)

    Kap, Yolanda S.; Bauer, Jan; van Driel, Nikki; Bleeker, Wim K.; Parren, Paul W. H. I.; Kooi, Evert-Jan; Geurts, Jeroen J. G.; Laman, Jon D.; Craigen, Jenny L.; Blezer, Erwin; 't Hart, Bert A.

    2011-01-01

    This study investigated the effect of CD20-positive B-cell depletion on central nervous system (CNS) white and gray matter pathology in experimental autoimmune encephalomyelitis in common marmosets, a relevant preclinical model of multiple sclerosis. Experimental autoimmune encephalomyelitis was

  14. Lactobacillus helveticus SBT2171 Attenuates Experimental Autoimmune Encephalomyelitis in Mice

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    Maya Yamashita

    2018-01-01

    Full Text Available We recently reported that Lactobacillus helveticus SBT2171 (LH2171 inhibited the proliferation and inflammatory cytokine production of primary immune cells in vitro, and alleviated collagen-induced arthritis (CIA in mice, a model of human rheumatoid arthritis (RA. In this study, we newly investigated whether LH2171 could relieve the severity of experimental autoimmune encephalomyelitis (EAE, a murine model of multiple sclerosis (MS, which is an autoimmune disease, but develop the symptoms by different mechanisms from RA. In MS and EAE, main cause of the disease is the abnormality in CD4+ T cell immunity, whereas in RA and CIA, is that in antibody-mediated immunity. The intraperitoneal administration of LH2171 significantly decreased the incidence and clinical score of EAE in mice. LH2171 also reduced the numbers of pathogenic immune cells, especially Th17 cells, in the spinal cord at the peak stage of disease severity. Interestingly, before the onset of EAE, LH2171 administration remarkably decreased the ratio of Th17 cells to CD4+ T cells in the inguinal lymph nodes (LNs, where pathogenic immune cells are activated to infiltrate the central nervous system, including the spinal cord. Furthermore, the expression of interleukin (IL-6, an inflammatory cytokine essential for Th17 differentiation, decreased in the LNs of LH2171-administered mice. Moreover, LH2171 significantly inhibited IL-6 production in vitro from both DC2.4 and RAW264.7 cells, model cell lines of antigen-presenting cells. These findings suggest that LH2171 might down-regulate IL-6 production and the subsequent Th17 differentiation and spinal cord infiltration, consequently alleviating EAE symptoms.

  15. Cytoskeletal protein carbonylation and degradation in experimental autoimmune encephalomyelitis

    Science.gov (United States)

    Smerjac, Suzanne M.; Bizzozero, Oscar A.

    2013-01-01

    Protein carbonylation, the non-enzymatic addition of aldehydes or ketones to specific amino acid residues, has been implicated in the pathophysiology of multiple sclerosis (MS). In this study we investigated whether protein carbonyls (PCOs) also accumulate in the spinal cord of Lewis rats with acute experimental autoimmune encephalomyelitis (EAE). Western blots analysis after derivatization with dinitrophenyl hydrazine (oxyblot) showed elevated protein carbonylation at the time of maximal clinical disability. During the same period glutathione levels were substantially reduced, suggesting a causal relationship between these two markers. In contrast, lipid peroxidation products accumulated in EAE spinal cord well before the appearance of neurological symptoms. Carbonyl staining was not restricted to inflammatory lesions but present throughout the spinal cord particularly in neuronal cell bodies and axons. By 2-dimensional-oxyblot we identified several cytoskeletal proteins, including β-actin, GFAP and the neurofilament proteins as the major targets of carbonylation. These findings were confirmed by pull-down experiments, which also showed an increase in the number of carbonylated β-actin molecules and a decrease in that of oxidized neurofilament proteins in EAE. These data suggest the possibility that oxidation targets neurofilament proteins for degradation, which may contribute to axonal pathology observed in MS and EAE. PMID:18088377

  16. Lapachol, a compound targeting pyrimidine metabolism, ameliorates experimental autoimmune arthritis.

    Science.gov (United States)

    Peres, Raphael S; Santos, Gabriela B; Cecilio, Nerry T; Jabor, Valquíria A P; Niehues, Michael; Torres, Bruna G S; Buqui, Gabriela; Silva, Carlos H T P; Costa, Teresa Dalla; Lopes, Norberto P; Nonato, Maria C; Ramalho, Fernando S; Louzada-Júnior, Paulo; Cunha, Thiago M; Cunha, Fernando Q; Emery, Flavio S; Alves-Filho, Jose C

    2017-03-07

    The inhibition of pyrimidine biosynthesis by blocking the dihydroorotate dehydrogenase (DHODH) activity, the prime target of leflunomide (LEF), has been proven to be an effective strategy for rheumatoid arthritis (RA) treatment. However, a considerable proportion of RA patients are refractory to LEF. Here, we investigated lapachol (LAP), a natural naphthoquinone, as a potential DHODH inhibitor and addressed its immunosuppressive properties. Molecular flexible docking studies and bioactivity assays were performed to determine the ability of LAP to interact and inhibit DHODH. In vitro studies were conducted to assess the antiproliferative effect of LAP using isolated lymphocytes. Finally, collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA) models were employed to address the anti-arthritic effects of LAP. We found that LAP is a potent DHODH inhibitor which had a remarkable ability to inhibit both human and murine lymphocyte proliferation in vitro. Importantly, uridine supplementation abrogated the antiproliferative effect of LAP, supporting that the pyrimidine metabolic pathway is the target of LAP. In vivo, LAP treatment markedly reduced CIA and AIA progression as evidenced by the reduction in clinical score, articular tissue damage, and inflammation. Our findings propose a binding model of interaction and support the ability of LAP to inhibit DHODH, decreasing lymphocyte proliferation and attenuating the severity of experimental autoimmune arthritis. Therefore, LAP could be considered as a potential immunosuppressive lead candidate with potential therapeutic implications for RA.

  17. Modulation of experimental autoimmune encephalomyelitis by endogenous Annexin A1

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    Flower Rod J

    2009-11-01

    Full Text Available Abstract Background Autoimmune diseases, like multiple sclerosis, are triggered by uncontrolled activation of cells of the immune system against self-antigen present, for instance, in the central nervous system. We have reported novel biological functions for Annexin A1, an effector of endogenous anti-inflammation, to produce positive actions on the adaptive immune system by reducing the threshold of T cell activation. In this study, we investigated the potential modulatory role of Annexin A1 in the development of experimental autoimmune encephalomyelitis, a model of multiple sclerosis. Methods Male control C57/BL6 and AnxA1 null mice were immunized subcutaneously with an emulsion consisting of 300 μg of MOG35-55 in PBS combined with an equal volume of CFA. Lymph node cells obtained from mice immunized with MOG33-55 for 14 days were re-stimulated in vitro with MOG33-55 (100 μg/ml for 4 days and the Th1/Th17 cytokine profile measured by ELISA. Spinal cords were processed either to isolate the infiltrated T cells or fixed and stained with haematoxylin and eosin. Statistical analyses were performed using two-tailed, unpaired Student's t tests or ANOVA. Results Our results show a direct correlation between Annexin A1 expression and severity of EAE. Analysis of MOG35-55-induced EAE development in Annexin A1 null mice showed decreased signs of the disease compared to wild type mice. This defect was significant at the peak of the disease and accompanied by reduced infiltration of T cells in the spinal cord. Finally, analysis of the T cell recall response in vitro following stimulation with MOG35-55 showed a decrease proliferation of Annexin A1 null T cells, with a significantly reduced Th1/Th17 phenotype, compared to wild type cells. Conclusion Together these findings suggest that Annexin A1 null mice have an impaired capacity to develop EAE. Furthermore strategies aiming at reducing Annexin A1 functions or expression in T cells might represent a

  18. Metallothionein I+II expression and their role in experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Penkowa, M; Hidalgo, J

    2000-01-01

    We examined the expression and roles of neuroprotective metallothionein-I+II (MT-I+II) in the rat CNS in experimental autoimmune encephalomyelitis (EAE), an animal model for the human autoimmune disease, multiple sclerosis (MS). EAE caused significant macrophage activation, T-lymphocyte infiltrat...

  19. Immunomodulatory effects of helminths and protozoa in multiple sclerosis and experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Hasseldam, Henrik; Hansen, C S; Johansen, F F

    2013-01-01

    one of the reasons for the disease-dampening effects, reported in numerous studies investigating parasite infections and autoimmunity. This review will focus on recent advances in the field of parasites as beneficial immunomodulators, in multiple sclerosis and the animal model experimental autoimmune...

  20. Citrullination of central nervous system proteins during the development of experimental autoimmune encephalomyelitis.

    NARCIS (Netherlands)

    Raijmakers, R.; Vogelzangs, J.H.P.; Croxford, J.L.; Wesseling, P.; Venrooij, W.J.W. van; Pruijn, G.J.M.

    2005-01-01

    Immunization of mammals with central nervous system (CNS)-derived proteins or peptides induces experimental autoimmune encephalomyelitis (EAE), a disease resembling the human autoimmune disease multiple sclerosis (MS). Both diseases are accompanied by destruction of a part of the of the myelin

  1. Minocycline effects on the cerebrospinal fluid proteome of experimental autoimmune encephalomyelitis rats

    NARCIS (Netherlands)

    Stoop, M.P.; Rosenling, T.; Attali, A.; Meesters, R.J.; Stingl, C.; Dekker, L.J.; Aken, H. van; Suidgeest, E.; Hintzen, R.Q.; Tuinstra, T.; Gool, A.J. van; Luider, T.M.; Bischoff, R.

    2012-01-01

    To identify response biomarkers for pharmaceutical treatment of multiple sclerosis, we induced experimental autoimmune encephalomyelitis (EAE) in rats and treated symptomatic animals with minocycline. Cerebrospinal fluid (CSF) samples were collected 14 days after EAE induction at the peak of

  2. Minocycline Effects on the Cerebrospinal Fluid Proteome of Experimental Autoimmune Encephalomyelitis Rats

    NARCIS (Netherlands)

    Stoop, Marcel P.; Rosenling, Therese; Attali, Amos; Meesters, Roland J. W.; Stingl, Christoph; Dekker, Lennard J.; van Aken, Hans; Suidgeest, Ernst; Hintzen, Rogier Q.; Tuinstra, Tinka; van Gool, Alain; Luider, Theo M.; Bischoff, Rainer

    2012-01-01

    To identify response biomarkers for pharmaceutical treatment of multiple sclerosis, we induced experimental autoimmune encephalomyelitis (EAE) in rats and treated symptomatic animals with minocycline. Cerebrospinal fluid (CSF) samples were collected 14 days after EAE induction at the peak of

  3. Beneficial role of rapamycin in experimental autoimmune myositis.

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    Nicolas Prevel

    Full Text Available We developed an experimental autoimmune myositis (EAM mouse model of polymyositis where we outlined the role of regulatory T (Treg cells. Rapamycin, this immunosuppressant drug used to prevent rejection in organ transplantation, is known to spare Treg. Our aim was to test the efficacy of rapamycin in vivo in this EAM model and to investigate the effects of the drug on different immune cell sub-populations.EAM is induced by 3 injections of myosin emulsified in CFA. Mice received rapamycin during 25 days starting one day before myosin immunization (preventive treatment, or during 10 days following the last myosin immunization (curative treatment.Under preventive or curative treatment, an increase of muscle strength was observed with a parallel decrease of muscle inflammation, both being well correlated (R(2 = -0.645, p<0.0001. Rapamycin induced a general decrease in muscle of CD4 and CD8 T cells in lymphoid tissues, but spared B cells. Among T cells, the frequency of Treg was increased in rapamycin treated mice in draining lymph nodes (16.9 ± 2.2% vs. 9.3 ± 1.4%, p<0.001, which were mostly activated regulatory T cells (CD62L(lowCD44(high: 58.1 ± 5.78% vs. 33.1 ± 7%, treated vs. untreated, p<0.001. In rapamycin treated mice, inhibition of proliferation (Ki-67(+ is more important in effector T cells compared to Tregs cells (p<0.05. Furthermore, during preventive treatment, rapamycin increased the levels of KLF2 transcript in CD44(low CD62L(high naive T cell and in CD62L(low CD44(high activated T cell.Rapamycin showed efficacy both as curative and preventive treatment in our murine model of experimental myositis, in which it induced an increase of muscle strength with a parallel decrease in muscle inflammation. Rapamycin administration was also associated with a decrease in the frequency of effector T cells, an increase in Tregs, and, when administered as preventive treatment, an upregulation of KFL2 in naive and activated T cells.

  4. Genetic dissection of experimental autoimmune neuroinflammatory diseases in rats

    OpenAIRE

    Dahlman, Ingrid

    1999-01-01

    Multiple Sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) causing neurological deficits. The disease has a complex etiology comprising multiple unidentified susceptibility genes and environmental influences. Certain human leukocyte antigen (HLA) class 11 alleles are associated with an increased risk of developing MS, which provides important circumstantial evidence for a T-cell mediated autoimmune pathogenesis of the dise...

  5. Suppression of experimental autoimmune encephalomyelitis by ultraviolet light is not mediated by isomerization of urocanic acid.

    Science.gov (United States)

    Irving, Amy A; Marling, Steven J; Plum, Lori A; DeLuca, Hector F

    2017-01-05

    Ultraviolet B irradiation confers strong resistance against experimental autoimmune encephalomyelitis, a model of multiple sclerosis. This protection by ultraviolet B is independent of vitamin D production but causes isomerization of urocanic acid, a naturally occurring immunosuppressant. To determine whether UCA isomerization from trans to cis is responsible for the protection against experimental autoimmune encephalomyelitis afforded by ultraviolet B, trans- or cis-urocanic acid was administered to animals and their disease progression was monitored. Disease incidence was reduced by 74% in animals exposed to ultraviolet B, and skin cis-urocanic acid levels increased greater than 30%. However, increasing skin cis-urocanic acid levels independent of ultraviolet B was unable to alter disease onset or progression. It is unlikely that urocanic acid isomerization is responsible for the ultraviolet B-mediated suppression of experimental autoimmune encephalomyelitis. Additional work is needed to investigate alternative mechanisms by which UVB suppresses disease.

  6. Increased demyelination and axonal damage in metallothionein I+II-deficient mice during experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Penkowa, M; Espejo, C; Martínez-Cáceres, E M

    2003-01-01

    Metallothioneins I+II (MT-I+II) are antioxidant, neuroprotective factors. We previously showed that MT-I+II deficiency during experimental autoimmune encephalomyelitis (EAE) leads to increased disease incidence and clinical symptoms. Moreover, the inflammatory response of macrophages and T cells,...

  7. The experimental autoimmune encephalomyelitis model for proteomic biomarker studies : From rat to human

    NARCIS (Netherlands)

    Rosenling, Therese; Attali, Amos; Luider, Theo M.; Bischoff, Rainer

    2011-01-01

    Multiple sclerosis (MScl) is defined by central nervous system (CNS) inflammation, demyelination and axonal damage. Some of the disease mechanisms are known but the cause of this complex disorder stays an enigma. Experimental autoimmune encephalomyelitis (EAE) is an animal model mimicking many

  8. Differential effects of B7-1 blockade in the rat experimental autoimmune encephalomyelitis model

    DEFF Research Database (Denmark)

    Gallon, L; Chandraker, A; Issazadeh-Navikas, Shohreh

    1997-01-01

    Blocking the CD28-B7 T cell costimulatory activation pathway protects animals from developing experimental autoimmune encephalomyelitis (EAE). In the mouse EAE model, selective blockade of B7-1 by specific mAbs has been shown to protect animals from EAE. In the Lewis rat model, we have shown that...

  9. Prevention of murine experimental autoimmune orchitis by recombinant human interleukin-6

    DEFF Research Database (Denmark)

    Li, Lu; Itoh, Masahiro; Ablake, Maila

    2002-01-01

    We studied the effect of exogenously administered recombinant human interleukin (IL)-6 on the development of experimental autoimmune orchitis (EAO) in C3H/Hej mice. IL-6 significantly reduced histological signs of EAO and appearance of delayed type hypersensitivity against the immunizing testicul...

  10. Neuroprotection without immunomodulation is not sufficient to reduce first relapse severity in experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Hasseldam, Henrik; Johansen, Flemming Fryd

    2010-01-01

    relapse and related this to demyelination, axonal degeneration and relapse severity. METHODS: Experimental autoimmune encephalomyelitis was induced in Dark Agouti rats and treatment with R(+)WIN55,212-2 was initiated at symptom debut. The animals were scored clinically throughout the experiment...

  11. Experimental autoimmune encephalomyelitis in the common marmoset: a novel animal model for multiple sclerosis

    NARCIS (Netherlands)

    H.P.M. Brok (Herbert)

    2002-01-01

    textabstractMultiple sclerosis (MS) is a major cause of disability in young adults affecting approximately 15,000 people in The Netberlands. Critical aspects of the disease have been modeled by experimental autoimmune encephalomyelitis (EAE) in animals. The vast majority of investigators use rats

  12. Prevention of murine experimental autoimmune orchitis by recombinant human interleukin-6

    DEFF Research Database (Denmark)

    Li, Lu; Itoh, Masahiro; Ablake, Maila

    2002-01-01

    We studied the effect of exogenously administered recombinant human interleukin (IL)-6 on the development of experimental autoimmune orchitis (EAO) in C3H/Hej mice. IL-6 significantly reduced histological signs of EAO and appearance of delayed type hypersensitivity against the immunizing testicular...

  13. Bone marrow-derived versus parenchymal sources of inducible nitric oxide synthase in experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Zehntner, Simone P; Bourbonniere, Lyne; Hassan-Zahraee, Mina

    2004-01-01

    The role of nitric oxide (NO) in central nervous system (CNS) inflammation is uncertain. Whereas experimental autoimmune encephalomyelitis (EAE) is exacerbated in mice deficient in inducible nitric oxide synthase (iNOS), inhibitor studies have suggested a pro-inflammatory role for NO. These discr...

  14. Soluble mannosylated myelin peptide inhibits the encephalitogenicity of autoreactive T cells during experimental autoimmune encephalomyelitis

    NARCIS (Netherlands)

    Kel, J.; Oldenampsen, J.; Luca, M.; Drijfhout, J.W.; Koning, F.; Nagelkerken, L.

    2007-01-01

    We have previously shown that immunization with a mannosylated myelin peptide in complete adjuvant induces tolerance instead of disease in experimental autoimmune encephalomyelitis (EAE), a rodent model for multiple sclerosis. In this report we demonstrate that treatment with a soluble mannosylated

  15. IgG1 deficiency exacerbates experimental autoimmune myasthenia gravis in BALB/c mice

    OpenAIRE

    Huda, Ruksana; Strait, Richard T.; Tüzün, Erdem; Finkelman, Fred D.; Christadoss, Premkumar

    2015-01-01

    Myasthenia gravis is an autoimmune disease characterized by muscle weakness due to neuromuscular junction (NMJ) damage by anti-acetylcholine receptor (AChR) auto-antibodies and complement. In experimental autoimmune myasthenia gravis (EAMG), which is induced by immunization with Torpedo AChR in CFA, anti-AChR IgG2b and IgG1 are the predominant isotypes in the circulation. Complement activation by isotypes such as IgG2b plays a crucial role in EAMG pathogenesis; this suggested the possibility ...

  16. Treatment with N-acetyl-seryl-aspartyl-lysyl-proline prevents experimental autoimmune myocarditis in rats.

    Science.gov (United States)

    Nakagawa, Pablo; Liu, Yunhe; Liao, Tang-Dong; Chen, Xiaojuan; González, Germán E; Bobbitt, Kevin R; Smolarek, Derek; Peterson, Ed L; Kedl, Ross; Yang, Xiao-Ping; Rhaleb, Nour-Eddine; Carretero, Oscar A

    2012-11-01

    Myocarditis is commonly associated with cardiotropic infections and has been linked to development of autoimmunity. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring tetrapeptide that prevents inflammation and fibrosis in hypertension and other cardiovascular diseases; however, its effect on autoimmune-mediated cardiac diseases remains unknown. We studied the effects of Ac-SDKP in experimental autoimmune myocarditis (EAM), a model of T cell-mediated autoimmune disease. This study was conducted to test the hypothesis that Ac-SDKP prevents autoimmune myocardial injury by modulating the immune responses. Lewis rats were immunized with porcine cardiac myosin and treated with Ac-SDKP or vehicle. In EAM, Ac-SDKP prevented both systolic and diastolic cardiac dysfunction, remodeling as shown by hypertrophy and fibrosis, and cell-mediated immune responses without affecting myosin-specific autoantibodies or antigen-specific T cell responses. In addition, Ac-SDKP reduced cardiac infiltration by macrophages, dendritic cells, and T cells, pro-inflammatory cytokines [interleukin (IL)-1α, tumor necrosis factor-α, IL-2, IL-17] and chemokines (cytokine-induced neutrophil chemoattractant-1, interferon-γ-induced protein 10), cell adhesion molecules (intercellular adhesion molecule-1, L-selectin), and matrix metalloproteinases (MMP). Ac-SDKP prevents autoimmune cardiac dysfunction and remodeling without reducing the production of autoantibodies or T cell responses to cardiac myosin. The protective effects of Ac-SDKP in autoimmune myocardial injury are most likely mediated by inhibition of 1) innate and adaptive immune cell infiltration and 2) expression of proinflammatory mediators such as cytokines, chemokines, adhesion molecules, and MMPs.

  17. Proteasome inhibitors as experimental therapeutics of autoimmune diseases

    NARCIS (Netherlands)

    Verbrugge, C.S.E.; Scheper, R.J.; Lems, W.F.; de Gruijl, T.D.; Jansen, G.

    2015-01-01

    Current treatment strategies for rheumatoid arthritis (RA) consisting of disease-modifying anti-rheumatic drugs or biological agents are not always effective, hence driving the demand for new experimental therapeutics. The antiproliferative capacity of proteasome inhibitors (PIs) has received

  18. Pain hypersensitivity in rats with experimental autoimmune neuritis, an animal model of human inflammatory demyelinating neuropathy.

    Science.gov (United States)

    Moalem-Taylor, Gila; Allbutt, Haydn N; Iordanova, Mihaela D; Tracey, David J

    2007-07-01

    Experimental autoimmune neuritis (EAN) is a T cell mediated autoimmune disease of the peripheral nervous system that serves as an animal model of the acute inflammatory demyelinating polyradiculoneuropathy in Guillain-Barre syndrome (GBS). Although pain is a common symptom of GBS occurring in 55-85% of cases, it is often overlooked and the underlying mechanisms are poorly understood. Here we examined whether animals with EAN exhibit signs of neuropathic pain including hyperalgesia and allodynia, and assessed their peripheral nerve autoimmune inflammation. We immunized Lewis rats with peripheral myelin P2 peptide (amino acids 57-81) emulsified with complete Freund's adjuvant, or with adjuvant only as control. P2-immunized rats developed mild to modest monophasic EAN with disease onset at day 8, peak at days 15-17, and full recovery by day 28 following immunization. Rats with EAN showed a significant decrease in withdrawal latency to thermal stimuli and withdrawal threshold to mechanical stimuli, in both hindpaws and forepaws, during the course of the disease. We observed a significant infiltration of T cells bearing alphabeta receptors, and a significant increase in antigen-presenting cells expressing MHC class II as well as macrophages, in EAN-affected rats. Our results demonstrate that animals with active EAN develop significant thermal hyperalgesia and mechanical allodynia, accompanied by pronounced autoimmune inflammation in peripheral nerves. These findings suggest that EAN is a useful model for the pain seen in many GBS patients, and may facilitate study of neuroimmune mechanisms underlying pain in autoimmune neuropathies.

  19. Co-delivery of autoantigen and dexamethasone in incomplete Freund's adjuvant ameliorates experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Northrup, Laura; Griffin, J Daniel; Christopher, Matthew A; Antunez, Lorena R; Hartwell, Brittany L; Pickens, Chad J; Berkland, Cory

    2017-11-28

    Current therapies for autoimmune diseases focus on treating the symptoms rather than the underlying disease cause. A major setback in improving current therapeutics for autoimmunity is the lack of antigen specificity. Successful antigen-specific immunotherapy (ASIT) would allow for improved treatment of autoimmune diseases. In this work, dexamethasone was co-delivered with autoantigen (PLP) in vivo to create effective ASIT for the treatment of experimental autoimmune encephalomyelitis (EAE). Using an emulsion of incomplete Freund's adjuvant (IFA) as a co-delivery vehicle, it was discovered that the controlled release of autoantigen was important for the suppression of clinical disease symptoms. Analysis of the immune response via cytokines revealed that dexamethasone was important for shifting the immune response away from inflammation. Co-delivery of both autoantigen and dexamethasone increased B-cell populations and antibody production, signifying an increased humoral immune response. Overall, this data indicated that the co-delivery of PLP and dexamethasone with a water-in-oil emulsion is effective in treating a murine autoimmune model. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Accelerated Course of Experimental Autoimmune Encephalomyelitis in PD-1-Deficient Central Nervous System Myelin Mutants

    Science.gov (United States)

    Kroner, Antje; Schwab, Nicholas; Ip, Chi Wang; Ortler, Sonja; Göbel, Kerstin; Nave, Klaus-Armin; Mäurer, Mathias; Martini, Rudolf; Wiendl, Heinz

    2009-01-01

    It is assumed that the onset and course of autoimmune inflammatory central nervous system (CNS) disorders (eg, multiple sclerosis) are influenced by factors that afflict immune regulation as well as CNS vulnerability. We challenged this concept experimentally by investigating how genetic alterations that affect myelin (primary oligodendrocyte damage in PLPtg mice) and/or T-cell regulation (deficiency of PD-1) influence both the onset and course of an experimental autoimmune CNS inflammatory disease [MOG35-55-induced experimental autoimmune encephalomyelitis (EAE)]. We observed that double pathology was associated with a significantly earlier onset of disease, a slight increase in the neurological score, an increase in the number of infiltrating cells, and enhanced axonal degeneration compared with wild-type mice and the respective, single mutant controls. Double-mutant PLPtg/PD-1−/− mice showed an increased production of interferon-γ by CNS immune cells at the peak of disease. Neither PD-1 deficiency nor oligodendropathy led to detectable spread of antigenic MHC class I- or class II-restricted epitopes during EAE. However, absence of PD-1 clearly increased the propensity of T lymphocytes to expand, and the number of clonal expansions reliably reflected the severity of the EAE disease course. Our data show that the interplay between immune dysregulation and myelinopathy results in a stable exacerbation of actively induced autoimmune CNS inflammation, suggesting that the combination of several pathological issues contributes significantly to disease susceptibility or relapses in human disease. PMID:19443704

  1. RGC-32 Promotes Th17 Cell Differentiation and Enhances Experimental Autoimmune Encephalomyelitis.

    Science.gov (United States)

    Rus, Violeta; Nguyen, Vinh; Tatomir, Alexandru; Lees, Jason R; Mekala, Armugam P; Boodhoo, Dallas; Tegla, Cosmin A; Luzina, Irina G; Antony, Paul A; Cudrici, Cornelia D; Badea, Tudor C; Rus, Horea G

    2017-05-15

    Th17 cells play a critical role in autoimmune diseases, including multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Response gene to complement (RGC)-32 is a cell cycle regulator and a downstream target of TGF-β that mediates its profibrotic activity. In this study, we report that RGC-32 is preferentially upregulated during Th17 cell differentiation. RGC-32(-/-) mice have normal Th1, Th2, and regulatory T cell differentiation but show defective Th17 differentiation in vitro. The impaired Th17 differentiation is associated with defects in IFN regulatory factor 4, B cell-activating transcription factor, retinoic acid-related orphan receptor γt, and SMAD2 activation. In vivo, RGC-32(-/-) mice display an attenuated experimental autoimmune encephalomyelitis phenotype accompanied by decreased CNS inflammation and reduced frequency of IL-17- and GM-CSF-producing CD4(+) T cells. Collectively, our results identify RGC-32 as a novel regulator of Th17 cell differentiation in vitro and in vivo and suggest that RGC-32 is a potential therapeutic target in multiple sclerosis and other Th17-mediated autoimmune diseases. Copyright © 2017 by The American Association of Immunologists, Inc.

  2. Dimethyl Fumarate Ameliorates Lewis Rat Experimental Autoimmune Neuritis and Mediates Axonal Protection

    Science.gov (United States)

    Pitarokoili, Kalliopi; Ambrosius, Björn; Meyer, Daniela; Schrewe, Lisa; Gold, Ralf

    2015-01-01

    Background Dimethyl fumarate is an immunomodulatory and neuroprotective drug, approved recently for the treatment of relapsing-remitting multiple sclerosis. In view of the limited therapeutic options for human acute and chronic polyneuritis, we used the animal model of experimental autoimmune neuritis in the Lewis rat to study the effects of dimethyl fumarate on autoimmune inflammation and neuroprotection in the peripheral nervous system. Methods and Findings Experimental autoimmune neuritis was induced by immunization with the neuritogenic peptide (amino acids 53–78) of P2 myelin protein. Preventive treatment with dimethyl fumarate given at 45 mg/kg twice daily by oral gavage significantly ameliorated clinical neuritis by reducing demyelination and axonal degeneration in the nerve conduction studies. Histology revealed a significantly lower degree of inflammatory infiltrates in the sciatic nerves. In addition, we detected a reduction of early signs of axonal degeneration through a reduction of amyloid precursor protein expressed in axons of the peripheral nerves. This reduction correlated with an increase of nuclear factor (erythroid derived 2)-related factor 2 positive axons, supporting the neuroprotective potential of dimethyl fumarate. Furthermore, nuclear factor (erythroid derived 2)-related factor 2 expression in Schwann cells was only rarely detected and there was no increase of Schwann cells death during EAN. Conclusions We conclude that immunmodulatory and neuroprotective dimethyl fumarate may represent an innovative therapeutic option in human autoimmune neuropathies. PMID:26618510

  3. Dimethyl Fumarate Ameliorates Lewis Rat Experimental Autoimmune Neuritis and Mediates Axonal Protection.

    Directory of Open Access Journals (Sweden)

    Kalliopi Pitarokoili

    Full Text Available Dimethyl fumarate is an immunomodulatory and neuroprotective drug, approved recently for the treatment of relapsing-remitting multiple sclerosis. In view of the limited therapeutic options for human acute and chronic polyneuritis, we used the animal model of experimental autoimmune neuritis in the Lewis rat to study the effects of dimethyl fumarate on autoimmune inflammation and neuroprotection in the peripheral nervous system.Experimental autoimmune neuritis was induced by immunization with the neuritogenic peptide (amino acids 53-78 of P2 myelin protein. Preventive treatment with dimethyl fumarate given at 45 mg/kg twice daily by oral gavage significantly ameliorated clinical neuritis by reducing demyelination and axonal degeneration in the nerve conduction studies. Histology revealed a significantly lower degree of inflammatory infiltrates in the sciatic nerves. In addition, we detected a reduction of early signs of axonal degeneration through a reduction of amyloid precursor protein expressed in axons of the peripheral nerves. This reduction correlated with an increase of nuclear factor (erythroid derived 2-related factor 2 positive axons, supporting the neuroprotective potential of dimethyl fumarate. Furthermore, nuclear factor (erythroid derived 2-related factor 2 expression in Schwann cells was only rarely detected and there was no increase of Schwann cells death during EAN.We conclude that immunomodulatory and neuroprotective dimethyl fumarate may represent an innovative therapeutic option in human autoimmune neuropathies.

  4. A modified vaccination technique for the prevention and treatment of an experimental autoimmune kidney disease.

    Science.gov (United States)

    Barabas, Arpad Zsigmond; Cole, Chad Douglas; Barabas, Arpad David; Lafreniere, Rene

    2007-09-01

    The main purpose of this article is to introduce a promising new vaccination technique and to outline its efficacy and safety as demonstrated in an experimental autoimmune kidney disease. We have found that antigen (AG)-specific downregulation and/or upregulation of immune responses can be achieved by injections of immune complexes (ICs) which contain prepackaged information. This result is attained with the new vaccination method, a method developed in our laboratory which we have called "modified vaccination technique" (MVT). This MVT not only enables the prevention of pathogenic autoimmune events leading to the development of an experimental autoimmune kidney disease; it also allows, with equal effectiveness, therapeutic intervention to terminate the disease. With an injected IC containing predetermined immune response-inducing components, the process effectuates a specific antibody information transfer conferring advantages that go beyond its prophylactic and therapeutic applicability. Its specificity can induce a precise immune response to correct mishaps, for example, in conditions where the immune system overreacts to an autologous antigen or fails to recognize unwanted self (as in autoimmune disorders, cancer, etc.) Preformed ICs are nontoxic and nonirritant, evoke a predetermined antibody response without the use of adjuvants, cause no disturbance in the overall regulatory function of the immune system, and produce no side effects. We firmly believe that proper implementation of the MVT will be able to induce and maintain specific preventive and/or curative responses in a way that is both natural and more effective in patients with chronic ailments presently treatable only with drugs.

  5. Metallothionein treatment reduces proinflammatory cytokines IL-6 and TNF-alpha and apoptotic cell death during experimental autoimmune encephalomyelitis (EAE)

    DEFF Research Database (Denmark)

    Penkowa, M; Hidalgo, J

    2001-01-01

    Experimental autoimmune encephalomyelitis (EAE) is an animal model for the human autoimmune disease multiple sclerosis (MS). Proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are considered important for induction and pathogenesis of EAE/MS disease...

  6. Regulatory T cell induction during Plasmodium chabaudi infection modifies the clinical course of experimental autoimmune encephalomyelitis.

    Directory of Open Access Journals (Sweden)

    Alessandro S Farias

    Full Text Available BACKGROUND: Experimental autoimmune encephalomyelitis (EAE is used as an animal model for human multiple sclerosis (MS, which is an inflammatory demyelinating autoimmune disease of the central nervous system characterized by activation of Th1 and/or Th17 cells. Human autoimmune diseases can be either exacerbated or suppressed by infectious agents. Recent studies have shown that regulatory T cells play a crucial role in the escape mechanism of Plasmodium spp. both in humans and in experimental models. These cells suppress the Th1 response against the parasite and prevent its elimination. Regulatory T cells have been largely associated with protection or amelioration in several autoimmune diseases, mainly by their capacity to suppress proinflammatory response. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we verified that CD4(+CD25(+ regulatory T cells (T regs generated during malaria infection (6 days after EAE induction interfere with the evolution of EAE. We observed a positive correlation between the reduction of EAE clinical symptoms and an increase of parasitemia levels. Suppression of the disease was also accompanied by a decrease in the expression of IL-17 and IFN-γ and increases in the expression of IL-10 and TGF-β1 relative to EAE control mice. The adoptive transfer of CD4(+CD25(+ cells from P. chabaudi-infected mice reduced the clinical evolution of EAE, confirming the role of these T regs. CONCLUSIONS/SIGNIFICANCE: These data corroborate previous findings showing that infections interfere with the prevalence and evolution of autoimmune diseases by inducing regulatory T cells, which regulate EAE in an apparently non-specific manner.

  7. A Nonsecosteroidal Vitamin D Receptor Modulator Ameliorates Experimental Autoimmune Encephalomyelitis without Causing Hypercalcemia

    Directory of Open Access Journals (Sweden)

    Songqing Na

    2011-01-01

    Full Text Available Vitamin D receptor (VDR agonists are currently the agents of choice for the treatment of psoriasis, a skin inflammatory indication that is believed to involve an autoimmune component. 1,25-dihydroxyvitamin D3 [1,25-(OH2D3], the biologically active metabolite of vitamin D, has shown efficacy in animal autoimmune disease models of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and type I diabetes. However, the side effect of 1,25-(OH2D3 and its synthetic secosteroidal analogs is hypercalcemia, which is a major impediment in their clinical development for autoimmune diseases. Hypercalcemia develops as a result of the action of VDR agonists on the intestine. Here, we describe the identification of a VDR modulator (VDRM compound A that was transcriptionally less active in intestinal cells and as a result exhibited less calcemic activity in vivo than 1,25-(OH2D3. Cytokine analysis indicated that the VDRM not only modulated the T-helper cell balance from Th1 to Th2 effector function but also inhibited Th17 differentiation. Finally, we demonstrate that the oral administration of compound A inhibited the induction and progress of experimental autoimmune encephalomyelitis in mice without causing hypercalcemia.

  8. Synergistic effect of rapamycin and cyclosporin A in the treatment of experimental autoimmune uveoretinitis.

    Science.gov (United States)

    Martin, D F; DeBarge, L R; Nussenblatt, R B; Chan, C C; Roberge, F G

    1995-01-15

    Immunosuppressive drugs currently available for the treatment of autoimmune diseases display a narrow therapeutic window between efficacy and toxic side effects. The use of combinations of drugs that have a synergistic effect may expand this window and reduce the risk of toxicity. We evaluated the combination effect of rapamycin (Rapa) and cyclosporin A (CsA) in an autoimmune disease model of the eye. The dose-effect relationship of Rapa with CsA was measured in vitro on the inhibition of proliferation of retinal S-Ag-primed lymphocytes. A median effect analysis was performed and a combination index (CI) calculated for 50% inhibition of proliferation. Rapa and CsA were markedly synergistic over a wide dose range (lowest CI = 0.31). Calculated dose reduction factors indicated that Rapa could be reduced nine-fold and CsA reduced five-fold when these drugs were used in combination. These reduced doses were tested in vivo for the treatment of experimental autoimmune uveoretinitis (EAU). Twelve of 15 rats treated with CsA, 2 mg/kg/day, developed EAU with a median severity of 2.5. Fourteen of 15 rats treated with Rapa, 0.01 mg/kg/day, developed EAU with a median severity of 3.25. Complete inhibition of EAU was achieved in all 15 animals treated with the combination of Rapa and CsA (combined vs CsA alone, p toxicity of these drugs for the treatment of autoimmune uveitis.

  9. Teriflunomide Attenuates Immunopathological Changes in the Dark Agouti Rat Model of Experimental Autoimmune Encephalomyelitis

    OpenAIRE

    Ringheim, Garth E.; Lan eLee; Lynn eLaws-Ricker; Thomas eDelohery; Li eLiu; Donghui eZhang; Nicholas eColletti; Soos, Timothy J.; Kendra eSchroeder; Barbara eFanelli; Nian eTian; Arendt, Christopher W; Deborah eIglesias-Bregna; Margaret ePetty; Zhongqi eJi

    2013-01-01

    Teriflunomide is an oral disease-modifying therapy recently approved in several locations for relapsing-remitting multiple sclerosis. To gain insight into the effects of teriflunomide, immunocyte population changes were measured during progression of experimental autoimmune encephalomyelitis in Dark Agouti rats. Treatment with teriflunomide attenuated levels of spinal cord-infiltrating T cells, natural killer cells, macrophages, and neutrophils. Teriflunomide also mitigated the disease-induce...

  10. Proinflammatory effects of exogenously administered IL-10 in experimental autoimmune orchitis

    DEFF Research Database (Denmark)

    Kaneko, Tetsushi; Itoh, Masahiro; Nakamura, Yoichi

    2003-01-01

    We studied the effects of exogenously administered recombinant murine interleukin (IL)-10 on the development of experimental autoimmune orchitis (EAO) in C3H/He mice. IL-10 significantly augments histological signs of EAO when administered for 6 consecutive days from days 15 to 20 after primary i...... immunisations with testicular germ cells. These data demonstrate that IL-10, in addition to its well-known antiinflammatory property, also has proinflammatory functions capable of up-regulating testicular immunoinflammatory processes in vivo....

  11. Proinflammatory effects of exogenously administered IL-10 in experimental autoimmune orchitis

    DEFF Research Database (Denmark)

    Kaneko, Tetsushi; Itoh, Masahiro; Nakamura, Yoichi

    2003-01-01

    We studied the effects of exogenously administered recombinant murine interleukin (IL)-10 on the development of experimental autoimmune orchitis (EAO) in C3H/He mice. IL-10 significantly augments histological signs of EAO when administered for 6 consecutive days from days 15 to 20 after primary...... immunisations with testicular germ cells. These data demonstrate that IL-10, in addition to its well-known antiinflammatory property, also has proinflammatory functions capable of up-regulating testicular immunoinflammatory processes in vivo....

  12. Mast Cells in the Pathogenesis of Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Rosetta Pedotti

    2012-11-01

    Full Text Available Mast cells (MCs are best known as key immune players in immunoglobulin E (IgE-dependent allergic reactions. In recent years, several lines of evidence have suggested that MCs might play an important role in several pathological conditions, including autoimmune disorders such as multiple sclerosis (MS and experimental autoimmune encephalomyelitis (EAE, an animal model for MS. Since their first description in MS plaques in the late 1800s, much effort has been put into elucidating the contribution of MCs to the development of central nervous system (CNS autoimmunity. Mouse models of MC-deficiency have provided a valuable experimental tool for dissecting MC involvement in MS and EAE. However, to date there is still major controversy concerning the function of MCs in these diseases. Indeed, although MCs have been classically proposed as having a detrimental and pro-inflammatory role, recent literature has questioned and resized the contribution of MCs to the pathology of MS and EAE. In this review, we will present the main evidence obtained in MS and EAE on this topic, and discuss the critical and controversial aspects of such evidence.

  13. Immunomodulatory effects of helminths and protozoa in multiple sclerosis and experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Hasseldam, H; Hansen, C S; Johansen, F F

    2013-01-01

    Multiple sclerosis is a chronic inflammatory CNS disease, which affects about 1 in 1000 individuals in the western world. During the last couple of decades, epidemiological data have accumulated, pointing towards increases in incidence. This has been suggested to be linked to the relatively high hygiene standards that exist in the western world, with reduced exposure to various pathogens, including parasites, as a consequence. Parasites are known to employ various immunomodulatory and anti-inflammatory strategies, which enable them to evade destruction by the immune system. This is most likely one of the reasons for the disease-dampening effects, reported in numerous studies investigating parasite infections and autoimmunity. This review will focus on recent advances in the field of parasites as beneficial immunomodulators, in multiple sclerosis and the animal model experimental autoimmune encephalomyelitis. © 2012 Blackwell Publishing Ltd.

  14. Amelioration of Experimental Autoimmune Encephalomyelitis by Isogarcinol Extracted from Garcinia mangostana L. Mangosteen.

    Science.gov (United States)

    Wang, Mengqi; Xie, Yufei; Zhong, Youxiu; Cen, Juren; Wang, Lei; Liu, Yuanyuan; Zhu, Ying; Tong, Li; Wei, Qun

    2016-11-30

    Isogarcinol is a new natural immunosuppressant that was extracted from Garcinia mangostana L. in our laboratory. Knowledge of its effects on treatable diseases and its mechanism of action is still very limited. In this study, we explored the therapeutic effect of isogarcinol in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). Treatment with oral 100 mg/kg isogarcinol markedly ameliorated clinical scores, alleviated inflammation and demyelination of the spinal cord, and reduced intracranial lesions in EAE mice. The percentages of Th cells and macrophages were also strongly reduced. Isogarcinol appeared to act by inhibiting T helper (Th) 1 and Th17 cell differentiation via the janus kinase/signal transducers and activators of transcription pathway and by impairing macrophage function. Our data suggest that isogarcinol has the potential to be an effective therapeutic agent of low toxicity for treating MS and other autoimmune diseases.

  15. Modulation of Multiple Sclerosis and Its Animal Model Experimental Autoimmune Encephalomyelitis by Food and Gut Microbiota

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    Ward J. van den Hoogen

    2017-09-01

    Full Text Available Multiple sclerosis (MS is an autoimmune neurological disease characterized by chronic inflammation of the central nervous system (CNS, leading to demyelination, axonal damage, and symptoms such as fatigue and disability. Although the cause of MS is not known, the infiltration of peripherally activated immune cells into the CNS has a key pathogenic role. Accumulating evidence supports an important role of diet and gut microbiota in immune-mediated diseases. Preclinical as well as clinical studies suggest a role for gut microbiota and dietary components in MS. Here, we review these recent studies on gut microbiota and dietary interventions in MS and its animal model experimental autoimmune encephalomyelitis. We also propose directions for future research.

  16. Role of passive T-cell death in chronic experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Issazadeh-Navikas, Shohreh; Abdallah, K; Chitnis, T

    2000-01-01

    The mechanisms of chronic disease and recovery from relapses in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, are unknown. Deletion of myelin-specific lymphocytes by apoptosis may play a role in termination of the inflammatory response. One pathway....... We found that mice transgenic for Bcl-x(L) have an earlier onset and a more chronic form of EAE induced by myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 compared with wild-type littermate mice. This was not due to an expanded autoreactive cell repertoire. Primed peripheral lymphocytes from...... that the passive cell death pathway is important in the pathogenesis of chronic EAE. These findings have implications for understanding the pathogenesis of multiple sclerosis and other autoimmune diseases....

  17. Galectin isolated from parasite inhibits remission of experimental autoimmune encephalomyelitis by up-regulating autoantibody.

    Science.gov (United States)

    Bing, S J; Ha, D; Ahn, G; Cho, J; Kim, A; Park, S K; Yu, H S; Jee, Y

    2015-06-01

    Recently, parasite infections or parasite-derived products have been suggested as a therapeutic strategy with suppression of immunopathology, which involves the induction of regulatory T cells or/and T helper type 2 (Th2) responses. In a recent study, researchers reported that constructed recombinant galectin (rTl-gal) isolated from an adult worm of the gastrointestinal nematode parasite Toxascaris leonina attenuated clinical symptoms of inflammatory bowel disease in mice treated with dextran sulphate sodium. Noting the role of rTl-gal in inflammatory disease, we attempted to investigate the effect of the parasite via its rTl-gal on neuronal autoimmune disease using experimental autoimmune encephalomyelitis (EAE), a mouse inflammatory and demyelinating autoimmune disease model of human multiple sclerosis. In this model, rTl-gal-treated experimental autoimmune encephalomyelitis (EAE) mice failed to recover after the peak of the disease, leading to persistent central nervous system (CNS) damage, such as demyelination, gliosis and axonal damage. Further, rTl-gal-treated EAE mice markedly increased the number of CD45R/B220(+) B cells in both infiltrated inflammation and the periphery, along with the increased production of autoantibody [anti-myelin oligodendrocyte glycoprotein (MOG)35-55 ] in serum at chronic stage. Upon antigen restimulation, rTl-gal treatment affected the release of overall cytokines, especially interferon (IFN)-γ and tumour necrosis factor (TNF)-α. Our results suggest that galectin isolated from a gastrointestinal parasite can deliver a harmful effect to EAE contrary to its beneficial effect on inflammatory bowel disease. © 2015 British Society for Immunology.

  18. Intraperitoneal Infusion of Mesenchymal Stem/Stromal Cells Prevents Experimental Autoimmune Uveitis in Mice

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    Joo Youn Oh

    2014-01-01

    Full Text Available Autoimmune uveitis is one of the leading causes of blindness. We here investigated whether intraperitoneal administration of human mesenchymal stem/stromal cells (hMSCs might prevent development of experimental autoimmune uveitis (EAU in mice. Time course study showed that the number of IFN-γ- or IL-17-expressing CD4+ T cells was increased in draining lymph nodes (DLNs on the postimmunization day 7 and decreased thereafter. The retinal structure was severely disrupted on day 21. An intraperitoneal injection of hMSCs at the time of immunization protected the retina from damage and suppressed the levels of proinflammatory cytokines in the eye. Analysis of DLNs on day 7 showed that hMSCs decreased the number of Th1 and Th17 cells. The hMSCs did not reduce the levels of IL-1β, IL-6, IL-12, and IL-23 which are the cytokines that drive Th1/Th17 differentiation. Also, hMSCs did not induce CD4+CD25+Foxp3+ cells. However, hMSCs increased the level of an immunoregulatory cytokine IL-10 and the population of IL-10-expressing B220+CD19+ cells. Together, data demonstrate that hMSCs attenuate EAU by suppressing Th1/Th17 cells and induce IL-10-expressing B220+CD19+ cells. Our results support suggestions that hMSCs may offer a therapy for autoimmune diseases mediated by Th1/Th17 responses.

  19. Administration of Mycobacterium leprae rHsp65 aggravates experimental autoimmune uveitis in mice.

    Directory of Open Access Journals (Sweden)

    Eliana B Marengo

    Full Text Available The 60 kDa heat shock protein family, Hsp60, constitutes an abundant and highly conserved class of molecules that are highly expressed in chronic-inflammatory and autoimmune processes. Experimental autoimmune uveitis [EAU] is a T cell mediated intraocular inflammatory disease that resembles human uveitis. Mycobacterial and homologous Hsp60 peptides induces uveitis in rats, however their participation in aggravating the disease is poorly known. We here evaluate the effects of the Mycobacterium leprae Hsp65 in the development/progression of EAU and the autoimmune response against the eye through the induction of the endogenous disequilibrium by enhancing the entropy of the immunobiological system with the addition of homologous Hsp. B10.RIII mice were immunized subcutaneously with interphotoreceptor retinoid-binding protein [IRBP], followed by intraperitoneally inoculation of M. leprae recombinant Hsp65 [rHsp65]. We evaluated the proliferative response, cytokine production and the percentage of CD4(+IL-17(+, CD4(+IFN-gamma(+ and CD4(+Foxp3(+ cells ex vivo, by flow cytometry. Disease severity was determined by eye histological examination and serum levels of anti-IRBP and anti-Hsp60/65 measured by ELISA. EAU scores increased in the Hsp65 group and were associated with an expansion of CD4(+IFN-gamma(+ and CD4(+IL-17(+ T cells, corroborating with higher levels of IFN-gamma. Our data indicate that rHsp65 is one of the managers with a significant impact over the immune response during autoimmunity, skewing it to a pathogenic state, promoting both Th1 and Th17 commitment. It seems comprehensible that the specificity and primary function of Hsp60 molecules can be considered as a potential pathogenic factor acting as a whistleblower announcing chronic-inflammatory diseases progression.

  20. Recombinant IgG2a Fc (M045) multimers effectively suppress experimental autoimmune myasthenia gravis.

    Science.gov (United States)

    Thiruppathi, Muthusamy; Sheng, Jian Rong; Li, Liangcheng; Prabhakar, Bellur S; Meriggioli, Matthew N

    2014-08-01

    Myasthenia gravis (MG) is an autoimmune disorder caused by target-specific pathogenic antibodies directed toward postsynaptic neuromuscular junction (NMJ) proteins, most commonly the skeletal muscle nicotinic acetylcholine receptor (AChR). In MG, high-affinity anti-AChR Abs binding to the NMJ lead to loss of functional AChRs, culminating in neuromuscular transmission failure and myasthenic symptoms. Intravenous immune globulin (IVIg) has broad therapeutic application in the treatment of a range of autoimmune diseases, including MG, although its mechanism of action is not clear. Recently, the anti-inflammatory and anti-autoimmune activities of IVIg have been attributed to the IgG Fc domains. Soluble immune aggregates bearing intact Fc fragments have been shown to be effective treatment for a number of autoimmune disorders in mice, and fully recombinant multimeric Fc molecules have been shown to be effective in treating collagen-induced arthritis, murine immune thrombocytopenic purpura, and experimental inflammatory neuritis. In this study, a murine model of MG (EAMG) was used to study the effectiveness of this novel recombinant polyvalent IgG2a Fc (M045) in treating established myasthenia, with a direct comparison to treatment with IVIg. M045 treatment had profound effects on the clinical course of EAMG, accompanied by down-modulation of pathogenic antibody responses. These effects were associated with reduced B cell activation and T cell proliferative responses to AChR, an expansion in the population of FoxP3(+) regulatory T cells, and enhanced production of suppressive cytokines, such as IL-10. Treatment was at least as effective as IVIg in suppressing EAMG, even at doses 25-30 fold lower. Multimeric Fc molecules offer the advantages of being recombinant, homogenous, available in unlimited quantity, free of risk from infection and effective at significantly reduced protein loads, and may represent a viable therapeutic alternative to polyclonal IVIg. Copyright

  1. Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids.

    Science.gov (United States)

    Pryce, Gareth; Riddall, Dieter R; Selwood, David L; Giovannoni, Gavin; Baker, David

    2015-06-01

    Multiple sclerosis (MS) is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system. Compounds within cannabis, notably Δ9-tetrahydrocannabinol (Δ9-THC) can limit the inappropriate neurotransmissions that cause MS-related problems and medicinal cannabis is now licenced for the treatment of MS symptoms. However, the biology indicates that the endocannabinoid system may offer the potential to control other aspects of disease. Although there is limited evidence that the cannabinoids from cannabis are having significant immunosuppressive activities that will influence relapsing autoimmunity, we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability. Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis (EAE) in ABH mice, possibly via blockade of voltage-gated sodium channels. In addition, whilst non-sedating doses of Δ9-THC do not inhibit relapsing autoimmunity, they dose-dependently inhibit the accumulation of disability during EAE. They also appear to slow down clinical progression during MS in humans. Although a 3 year, phase III clinical trial did not detect a beneficial effect of oral Δ9-THC in progressive MS, a planned subgroup analysis of people with less disability who progressed more rapidly, demonstrated a significant slowing of progression by oral Δ9-THC compared to placebo. Whilst this may support the experimental and biological evidence for a neuroprotective effect by the endocannabinoid system in MS, it remains to be established whether this will be formally demonstrated in further trials of Δ9-THC/cannabis in progressive MS.

  2. Teriflunomide attenuates immunopathological changes in the Dark Agouti rat model of experimental autoimmune encephalomyelitis

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    Garth E. Ringheim

    2013-10-01

    Full Text Available Teriflunomide is an oral disease-modifying therapy recently approved in several locations for relapsing forms of multiple sclerosis. To gain insight into the effects of teriflunomide, immunocyte population changes were measured during progression of experimental autoimmune encephalomyelitis in Dark Agouti rats. Treatment with teriflunomide attenuated levels of spinal cord-infiltrating T cells, natural killer cells, macrophages, and neutrophils. Teriflunomide also mitigated the disease-induced changes in immune cell populations in the blood and spleen suggesting an inhibitory effect on pathogenic immune responses.

  3. Teriflunomide attenuates immunopathological changes in the dark agouti rat model of experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Ringheim, Garth E; Lee, Lan; Laws-Ricker, Lynn; Delohery, Tomas; Liu, Li; Zhang, Donghui; Colletti, Nicholas; Soos, Timothy J; Schroeder, Kendra; Fanelli, Barbara; Tian, Nian; Arendt, Christopher W; Iglesias-Bregna, Deborah; Petty, Margaret; Ji, Zhongqi; Qian, George; Gaur, Rajula; Weinstock, Daniel; Cavallo, Jean; Telsinskas, Juventas; McMonagle-Strucko, Kathleen

    2013-01-01

    Teriflunomide is an oral disease-modifying therapy recently approved in several locations for relapsing-remitting multiple sclerosis. To gain insight into the effects of teriflunomide, immunocyte population changes were measured during progression of experimental autoimmune encephalomyelitis in Dark Agouti rats. Treatment with teriflunomide attenuated levels of spinal cord-infiltrating T cells, natural killer cells, macrophages, and neutrophils. Teriflunomide also mitigated the disease-induced changes in immune cell populations in the blood and spleen suggesting an inhibitory effect on pathogenic immune responses.

  4. Therapeutic effect of nucleoside analogs on experimental autoimmune encephalomyelitis in dark agouti rats

    Directory of Open Access Journals (Sweden)

    Stojkov Danijela

    2006-01-01

    Full Text Available Experimental autoimmune encephalomyelitis (EAE is a commonly used animal model of the human neurological disorder multiple sclerosis. The purpose of the present study was to investigate the effect of combined treatment with two nucleoside analogs, ribavirin and tiazofurin, on development of EAE actively induced in highly susceptible dark agouti rats. The obtained results showed that ribavirin and tiazofurin applied either separately or in combination from the onset of the firstsymptoms of EAE after its induction (therapeutic treatment significantly suppressed EAE’s clinical symptoms. However, the most pronounced effect was gained with combined treatment, probably as a result of synergistic/additive action.

  5. Key metalloproteinases are expressed by specific cell types in experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Toft-Hansen, Henrik; Nuttall, Robert K; Edwards, Dylan R

    2004-01-01

    animal model, experimental autoimmune encephalomyelitis (EAE). We used real-time RT-PCR to profile the expression of all 22 known mouse MMPs, seven ADAMs, and all four known TIMPs in spinal cord from SJL/J mice and mice with adoptively transferred myelin basic protein (MBP)-specific EAE. A significant...... and >3-fold alteration in expression was observed for MMP-8, MMP-10, MMP-12, ADAM-12, and TIMP-1, which were up-regulated, and for MMP-15, which was down-regulated. Expression levels correlated with disease course, with all but ADAM-12 returning toward control levels in remission. To examine potential...

  6. Chemokine expression in GKO mice (lacking interferon-gamma) with experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Glabinski, A R; Krakowski, M; Han, Y

    1999-01-01

    Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease of the central nervous system (CNS) considered to be an animal model for multiple sclerosis (MS). The detailed mechanism that specifies accumulation of inflammatory cells within the CNS in these conditions remains a subject...... in the CNS of mice with an intact IFN-gamma gene and EAE, was strikingly absent. In vitro experiments confirmed that IFNgamma selectively stimulates astrocytes for IP-10 expression. These results indicate that IP-10 is dependent upon IFN-gamma for its upregulation during this model disease, and document...

  7. Regulatory T Cell Dysfunction Acquiesces to BTLA+ Regulatory B Cells Subsequent Oral Intervention of Experimental Autoimmune Encephalomyelitis

    OpenAIRE

    Huarte, Eduardo; Jun, SangMu; Rynda-Apple, Agnieszka; Golden, Sara; Jackiw, Larissa; Hoffman, Carol; Maddaloni, Massimo; Pascual, David W.

    2016-01-01

    Regulatory T cells (Tregs) induced during autoimmunity often become quiescent and unable to resolve disease, suggesting inadequate activation. Resolution of established experimental autoimmune encephalomyelitis (EAE) can be achieved with myelin oligodendrocyte glycoprotein (MOG) fused to reovirus protein ��1 (MOG-p��1) which activates Tregs, restoring protection, but requiring other regulatory cells to revitalize them. B cells have a dichotomous role in both the pathogenesis and recovery from...

  8. Prophylactic effect of probiotics on the development of experimental autoimmune myasthenia gravis.

    Directory of Open Access Journals (Sweden)

    Chang-Suk Chae

    Full Text Available Probiotics are live bacteria that confer health benefits to the host physiology. Although protective role of probiotics have been reported in diverse diseases, no information is available whether probiotics can modulate neuromuscular immune disorders. We have recently demonstrated that IRT5 probiotics, a mixture of 5 probiotics, could suppress diverse experimental disorders in mice model. In this study we further investigated whether IRT5 probiotics could modulate the progression of experimental autoimmune myasthenia gravis (EAMG. Myasthenia gravis (MG is a T cell dependent antibody mediated autoimmune disorder in which acetylcholine receptor (AChR at the neuromuscular junction is the major auto-antigen. Oral administration of IRT5 probiotics significantly reduced clinical symptoms of EAMG such as weight loss, body trembling and grip strength. Prophylactic effect of IRT5 probiotics on EMAG is mediated by down-regulation of effector function of AChR-reactive T cells and B cells. Administration of IRT5 probiotics decreased AChR-reactive lymphocyte proliferation, anti-AChR reactive IgG levels and inflammatory cytokine levels such as IFN-γ, TNF-α, IL-6 and IL-17. Down-regulation of inflammatory mediators in AChR-reactive lymphocytes by IRT5 probiotics is mediated by the generation of regulatory dendritic cells (rDCs that express increased levels of IL-10, TGF-β, arginase 1 and aldh1a2. Furthermore, DCs isolated from IRT5 probiotics-fed group effectively converted CD4(+ T cells into CD4(+Foxp3(+ regulatory T cells compared with control DCs. Our data suggest that IRT5 probiotics could be applicable to modulate antibody mediated autoimmune diseases including myasthenia gravis.

  9. The cardioprotector dexrazoxane augments therapeutic efficacy of mitoxantrone in experimental autoimmune encephalomyelitis

    Science.gov (United States)

    WEILBACH, F X; CHAN, A; TOYKA, K V; GOLD, R

    2004-01-01

    The present study investigates the immunological effects of a combination treatment of mitoxantrone and the cardioprotector dexrazoxane in experimental autoimmune encephalomyelitis (EAE). Mitoxantrone, an anthracycline-derived immunosuppressive drug has been approved recently for treatment of very active multiple sclerosis (MS). Its prolonged use is limited due to its cardiotoxic properties. Dexrazoxane (DZR (S)-(+)-1,2-bis (3,5.dioxopiperazinyl)propane, ICRF-187) is an iron III chelator which in animal models and in cancer patients reduces anthracycline and mitoxantrone induced cardiotoxicity when given immediately before these agents. We examined the immunological effects of dexrazoxane in combination with mitoxantrone in experimental autoimmune encephalomyelitis (EAE) in Lewis rats. EAE was induced by active immunization with myelin basic protein (MBP) or by adoptive transfer of MBP specific T cells (AT-EAE). The clinical course, spinal cord pathology, activity of metalloproteinases (MMP-2 and MMP-9) and T cell apoptosis were assessed. Monotherapy with DZR ameliorated slightly the course of actively induced EAE and AT-EAE. The combination of DZR and mitoxantrone was superior to mitoxantrone given alone. Clinical amelioration ran in parallel with the marked reduction of inflammatory infiltration which was nearly abolished by the combination treatment. DZR did not affect the activity of metalloproteinase 9 and did not increase the proportion of apoptotic lymph node cells ex vivo or T cells in situ. We conclude that in addition to its cardioprotective role, DZR augments mitoxantrone-mediated immunosuppressive effects in animal models of human central nervous system (CNS) autoimmune disease. Clinical trials in MS patients are warranted to evaluate the unexpected immunosuppressive efficacy of DZR as add-on treatment. PMID:14678264

  10. Prophylactic Effect of Probiotics on the Development of Experimental Autoimmune Myasthenia Gravis

    Science.gov (United States)

    Chae, Chang-Suk; Kwon, Ho-Keun; Hwang, Ji-Sun; Kim, Jung-Eun; Im, Sin-Hyeog

    2012-01-01

    Probiotics are live bacteria that confer health benefits to the host physiology. Although protective role of probiotics have been reported in diverse diseases, no information is available whether probiotics can modulate neuromuscular immune disorders. We have recently demonstrated that IRT5 probiotics, a mixture of 5 probiotics, could suppress diverse experimental disorders in mice model. In this study we further investigated whether IRT5 probiotics could modulate the progression of experimental autoimmune myasthenia gravis (EAMG). Myasthenia gravis (MG) is a T cell dependent antibody mediated autoimmune disorder in which acetylcholine receptor (AChR) at the neuromuscular junction is the major auto-antigen. Oral administration of IRT5 probiotics significantly reduced clinical symptoms of EAMG such as weight loss, body trembling and grip strength. Prophylactic effect of IRT5 probiotics on EMAG is mediated by down-regulation of effector function of AChR-reactive T cells and B cells. Administration of IRT5 probiotics decreased AChR-reactive lymphocyte proliferation, anti-AChR reactive IgG levels and inflammatory cytokine levels such as IFN-γ, TNF-α, IL-6 and IL-17. Down-regulation of inflammatory mediators in AChR-reactive lymphocytes by IRT5 probiotics is mediated by the generation of regulatory dendritic cells (rDCs) that express increased levels of IL-10, TGF-β, arginase 1 and aldh1a2. Furthermore, DCs isolated from IRT5 probiotics-fed group effectively converted CD4+ T cells into CD4+Foxp3+ regulatory T cells compared with control DCs. Our data suggest that IRT5 probiotics could be applicable to modulate antibody mediated autoimmune diseases including myasthenia gravis. PMID:23284891

  11. Time-Dependent Progression of Demyelination and Axonal Pathology in MP4-Induced Experimental Autoimmune Encephalomyelitis.

    Directory of Open Access Journals (Sweden)

    Johanna Prinz

    Full Text Available Multiple sclerosis (MS is an autoimmune disease of the central nervous system (CNS characterized by inflammation, demyelination and axonal pathology. Myelin basic protein/proteolipid protein (MBP-PLP fusion protein MP4 is capable of inducing chronic experimental autoimmune encephalomyelitis (EAE in susceptible mouse strains mirroring diverse histopathological and immunological hallmarks of MS. Lack of human tissue underscores the importance of animal models to study the pathology of MS.Twenty-two female C57BL/6 (B6 mice were immunized with MP4 and the clinical development of experimental autoimmune encephalomyelitis (EAE was observed. Methylene blue-stained semi-thin and ultra-thin sections of the lumbar spinal cord were assessed at the peak of acute EAE, three months (chronic EAE and six months after onset of EAE (long-term EAE. The extent of lesional area and inflammation were analyzed in semi-thin sections on a light microscopic level. The magnitude of demyelination and axonal damage were determined using electron microscopy. Emphasis was put on the ventrolateral tract (VLT of the spinal cord.B6 mice demonstrated increasing demyelination and severe axonal pathology in the course of MP4-induced EAE. Additionally, mitochondrial swelling and a decrease in the nearest neighbor neurofilament distance (NNND as early signs of axonal damage were evident with the onset of EAE. In semi-thin sections we observed the maximum of lesional area in the chronic state of EAE while inflammation was found to a similar extent in acute and chronic EAE. In contrast to the well-established myelin oligodendrocyte glycoprotein (MOG model, disease stages of MP4-induced EAE could not be distinguished by assessing the extent of parenchymal edema or the grade of inflammation.Our results complement our previous ultrastructural studies of B6 EAE models and suggest that B6 mice immunized with different antigens constitute useful instruments to study the diverse

  12. Prophylactic effect of probiotics on the development of experimental autoimmune myasthenia gravis.

    Science.gov (United States)

    Chae, Chang-Suk; Kwon, Ho-Keun; Hwang, Ji-Sun; Kim, Jung-Eun; Im, Sin-Hyeog

    2012-01-01

    Probiotics are live bacteria that confer health benefits to the host physiology. Although protective role of probiotics have been reported in diverse diseases, no information is available whether probiotics can modulate neuromuscular immune disorders. We have recently demonstrated that IRT5 probiotics, a mixture of 5 probiotics, could suppress diverse experimental disorders in mice model. In this study we further investigated whether IRT5 probiotics could modulate the progression of experimental autoimmune myasthenia gravis (EAMG). Myasthenia gravis (MG) is a T cell dependent antibody mediated autoimmune disorder in which acetylcholine receptor (AChR) at the neuromuscular junction is the major auto-antigen. Oral administration of IRT5 probiotics significantly reduced clinical symptoms of EAMG such as weight loss, body trembling and grip strength. Prophylactic effect of IRT5 probiotics on EMAG is mediated by down-regulation of effector function of AChR-reactive T cells and B cells. Administration of IRT5 probiotics decreased AChR-reactive lymphocyte proliferation, anti-AChR reactive IgG levels and inflammatory cytokine levels such as IFN-γ, TNF-α, IL-6 and IL-17. Down-regulation of inflammatory mediators in AChR-reactive lymphocytes by IRT5 probiotics is mediated by the generation of regulatory dendritic cells (rDCs) that express increased levels of IL-10, TGF-β, arginase 1 and aldh1a2. Furthermore, DCs isolated from IRT5 probiotics-fed group effectively converted CD4(+) T cells into CD4(+)Foxp3(+) regulatory T cells compared with control DCs. Our data suggest that IRT5 probiotics could be applicable to modulate antibody mediated autoimmune diseases including myasthenia gravis.

  13. Locus coeruleus damage and noradrenaline reductions in multiple sclerosis and experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Polak, Paul E; Kalinin, Sergey; Feinstein, Douglas L

    2011-03-01

    The endogenous neurotransmitter noradrenaline exerts anti-inflammatory and neuroprotective effects in vitro and in vivo. Several studies report that noradrenaline levels are altered in the central nervous system of patients with multiple sclerosis and rodents with experimental autoimmune encephalomyelitis, which could contribute to pathology. Since the major source of noradrenaline are neurons in the locus coeruleus, we hypothesized that alterations in noradrenaline levels are a consequence of stress or damage to locus coeruleus neurons. In C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide 35-55 to develop chronic disease, cortical and spinal cord levels of noradrenaline were significantly reduced versus control mice. Immunohistochemical staining revealed increased astrocyte activation in the ventral portion of the locus coeruleus in immunized mice. The immunized mice showed neuronal damage in the locus coeruleus detected by a reduction of average cell size of tyrosine hydroxylase stained neurons. Analysis of the locus coeruleus of multiple sclerosis and control brains showed a significant increase in astrocyte activation, a reduction in noradrenaline levels, and neuronal stress indicated by hypertrophy of tyrosine hydroxylase stained cell bodies. However, the magnitude of these changes was not correlated with extent of demyelination or of cellular infiltrates. Together these findings demonstrate the presence of inflammation and neuronal stress in multiple sclerosis as well as in experimental autoimmune encephalomyelitis. Since reduced noradrenaline levels could be permissive for increased inflammation and neuronal damage, these results suggest that methods to raise noradrenaline levels or increase locus coeruleus function may be of benefit in treating multiple sclerosis.

  14. Minocycline up-regulates the expression of brain-derived neurotrophic factor and nerve growth factor in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Chen, Xiaohong; Ma, Lili; Jiang, Ying; Chen, Shaoqiong; Zhu, Cansheng; Liu, Mei; Ma, Xiaomeng; Zhu, Dongliang; Liu, Yingying; Peng, Fuhua; Wang, Qing; Pi, Rongbiao

    2012-07-05

    Previous evidence demonstrated that minocycline could ameliorate clinical severity of experimental autoimmune encephalomyelitis and exhibit several anti-inflammatory and neuroprotective activities. However, few studies have been carried out to assess its effects on the expression of neurotrophins in experimental autoimmune encephalomyelitis or multiple sclerosis. Here we investigated the alteration of brain-derived neurotrophic factor and nerve growth factor in the sera, cerebral cortex, and lumbar spinal cord of experimental autoimmune encephalomyelitis C57 BL/6 mice in vivo as well as the splenocytes culture supernatants in vitro after minocycline administration. Our results demonstrated that minocycline could up-regulate the expression of brain-derived neurotrophic factor and nerve growth factor both in peripheral (sera and splenocytes culture supernatants) and target organs (cerebral cortex and lumber spinal cord) of mice with experimental autoimmune encephalomyelitis. These data suggest that up-regulation of neurotrophins in experimental autoimmune encephalomyelitis may be a novel neuroprotective mechanism of minocycline. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Rotarod motor performance and advanced spinal cord lesion image analysis refine assessment of neurodegeneration in experimental autoimmune encephalomyelitis

    NARCIS (Netherlands)

    R. van den Berg (Robert); J.D. Laman (Jon); M. van Meurs (Marjan); R.Q. Hintzen (Rogier); C.C. Hoogenraad (Casper)

    2016-01-01

    markdownabstract_Background_ Experimental autoimmune encephalomyelitis (EAE) is a commonly used experimental model for multiple sclerosis (MS). Experience with this model mainly comes from the field of immunology, while data on its use in studying the neurodegenerative aspects of MS is scarce.

  16. Probenecid Application Prevents Clinical Symptoms and Inflammation in Experimental Autoimmune Encephalomyelitis.

    Science.gov (United States)

    Hainz, Nadine; Wolf, Sandra; Tschernig, Thomas; Meier, Carola

    2016-02-01

    Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Neurological impairments are caused by axonal damage due to demyelination and neuroinflammation within the central nervous system. T cells mediate the neuroinflammation. The activation of T cells is induced by the release of adenosine triphosphate and involves purinergic receptors as well as pannexin (Panx) proteins. As Panx1 is expressed on T cells, we here propose that application of probenecid, a known Panx inhibitor, will prevent the onset of clinical symptoms in a mouse model of MS, the experimental autoimmune encephalomyelitis (EAE) model. EAE-induced mice received daily injections of probenecid. Disease scores, T cell numbers, and microglia activation were compared between experimental groups. Probenecid treatment resulted in lower disease scores as compared to EAE animals. Probenecid-treated animals also displayed fewer inflammatory lesions. Microglia activation was not altered by treatment. In conclusion, probenecid prevented the onset of EAE.

  17. Disparate Effects of Mesenchymal Stem Cells in Experimental Autoimmune Encephalomyelitis and Cuprizone-Induced Demyelination.

    Directory of Open Access Journals (Sweden)

    Justin D Glenn

    Full Text Available Mesenchymal stem cells (MSCs are pleiotropic cells with potential therapeutic benefits for a wide range of diseases. Because of their immunomodulatory properties they have been utilized to treat autoimmune diseases such as multiple sclerosis (MS, which is characterized by demyelination. The microenvironment surrounding MSCs is thought to affect their differentiation and phenotype, which could in turn affect the efficacy. We thus sought to dissect the potential for differential impact of MSCs on central nervous system (CNS disease in T cell mediated and non-T cell mediated settings using the MOG35-55 experimental autoimmune encephalomyelitis (EAE and cuprizone-mediated demyelination models, respectively. As the pathogeneses of MS and EAE are thought to be mediated by IFNγ-producing (TH1 and IL-17A-producing (TH17 effector CD4+ T cells, we investigated the effect of MSCs on the development of these two key pathogenic cell groups. Although MSCs suppressed the activation and effector function of TH17 cells, they did not affect TH1 activation, but enhanced TH1 effector function and ultimately produced no effect on EAE. In the non- T cell mediated cuprizone model of demyelination, MSC administration had a positive effect, with an overall increase in myelin abundance in the brain of MSC-treated mice compared to controls. These results highlight the potential variability of MSCs as a biologic therapeutic tool in the treatment of autoimmune disease and the need for further investigation into the multifaceted functions of MSCs in diverse microenvironments and the mechanisms behind the diversity.

  18. Alpha-tocopherol ameliorates experimental autoimmune encephalomyelitis through the regulation of Th1 cells

    Directory of Open Access Journals (Sweden)

    Haikuo Xue

    2016-05-01

    Full Text Available Objective(s: Multiple sclerosis (MS is a serious neurological autoimmune disease, it commonly affects young adults. Vitamin E (Vit E is an important component of human diet with antioxidant activity, which protects the body’s biological systems. In order to assess the effect of Vit E treatment on this autoimmune disease, we established experimental autoimmune encephalomyelitis (EAE, the animal model of MS, and treated EAE with α-tocopherol (AT which is the main content of Vit E. Materials and Methods:Twenty C57BL/6 adult female mice were used and divided into two groups randomly. EAE was induced with myelin oligodendrocyte glycoprotein (MOG, and one group was treated with AT, at a dose of 100 mg/kg on the 3th day post-immunization with MOG, the other group was treated with 1% alcohol. Mice were euthanized on day 14, post-immunization, spleens were removed for assessing splenocytes proliferation and cytokine profile, and spinal cords were dissected to assess the infiltration of inflammatory cells in spinal cord. Results:AT was able to attenuate the severity of EAE and delay the disease progression. H&E staining and fast blue staining indicated that AT reduced the inflammation and the demyelination reaction in the spinal cord. Treatment with AT significantly decreased the proliferation of splenocytes. AT also inhibited the production of IFN-γ (Th1 cytokine, though the other cytokines were only affected slightly. Conclusion:According to the results, AT ameliorated EAE, through suppressing the proliferation of T cells and the Th1 response. AT may be used as a potential treatment for MS.

  19. Epitope-Specific Tolerance Modes Differentially Specify Susceptibility to Proteolipid Protein-Induced Experimental Autoimmune Encephalomyelitis

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    Lei Wang

    2017-11-01

    Full Text Available Immunization with myelin components can elicit experimental autoimmune encephalomyelitis (EAE. EAE susceptibility varies between mouse strains, depending on the antigen employed. BL/6 mice are largely resistant to EAE induction with proteolipid protein (PLP, probably a reflection of antigen-specific tolerance. However, the extent and mechanism(s of tolerance to PLP remain unclear. Here, we identified three PLP epitopes in PLP-deficient BL/6 mice. PLP-sufficient mice did not respond against two of these, whereas tolerance was “leaky” for an epitope with weak predicted MHCII binding, and only this epitope was encephalitogenic. In TCR transgenic mice, the “EAE-susceptibility-associated” epitope was “ignored” by specific CD4 T cells, whereas the “resistance-associated” epitope induced clonal deletion and Treg induction in the thymus. Central tolerance was autoimmune regulator dependent and required expression and presentation of PLP by thymic epithelial cells (TECs. TEC-specific ablation of PLP revealed that peripheral tolerance, mediated by dendritic cells through recessive tolerance mechanisms (deletion and anergy, could largely compensate for a lack of central tolerance. However, adoptive EAE was exacerbated in mice lacking PLP in TECs, pointing toward a non-redundant role of the thymus in dominant tolerance to PLP. Our findings reveal multiple layers of tolerance to a central nervous system autoantigen that vary among epitopes and thereby specify disease susceptibility. Understanding how different modalities of tolerance apply to distinct T cell epitopes of a target in autoimmunity has implications for antigen-specific strategies to therapeutically interfere with unwanted immune reactions against self.

  20. Proteomic Profiling Analysis Reveals a Link between Experimental Autoimmune Uveitis and Complement Activation in Rats.

    Science.gov (United States)

    Guo, D D; Hu, B; Tang, H Y; Sun, Y Y; Liu, B; Tian, Q M; Bi, H S

    2017-05-01

    Uveitis is an autoimmune disease that usually damages the vision function, leading to poor visual quality in patients. As an autoimmune ocular inflammatory disease, the pathogenesis of uveitis is associated with abnormal expression of some proteins and aberrant regulation of multiple signalling pathways. Nevertheless, the detailed mechanism remains unclear. In this study, we induced an experimental autoimmune uveitis (EAU) model in rats. We determined the levels of C3a and membrane attack complex C5b-9 (soluble C5b-9, sC5b-9) in both plasma and aqueous humour, identified the differentially expressed proteins in plasma by liquid chromatography-tandem mass spectrometry and employed bioinformatics algorithms to analyse differentially expressed proteins in EAU rat plasma. The results demonstrate that there were 168 differentially expressed plasma proteins in EAU rats versus control subjects. The levels of sC5b-9 and C3a were elevated in the plasmas and aqueous humours of EAU rats. Gene ontology enrichment analysis showed that the differentially expressed proteins in EAU rat plasma were mainly involved in metabolic and immune processes. Kyoto encyclopedia of genes and genomes (KEGG) pathway annotation, database for annotation, visualization and integrated discovery (DAVID) and protein-protein interaction analyses revealed that the differentially expressed proteins in EAU rat plasmas were closely associated with complement and coagulation cascades, metabolic pathways, NF-kappa B, PI3K-Akt, Toll-like receptors and autophagy. Overall, the differentially expressed proteins in EAU rat plasmas are mainly involved in the complement and coagulation cascades. The pathogenesis of uveitis closely correlates with complement activation. © 2017 The Foundation for the Scandinavian Journal of Immunology.

  1. Identification of gene expression patterns crucially involved in experimental autoimmune encephalomyelitis and multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Martin M. Herrmann

    2016-10-01

    Full Text Available After encounter with a central nervous system (CNS-derived autoantigen, lymphocytes leave the lymph nodes and enter the CNS. This event leads only rarely to subsequent tissue damage. Genes relevant to CNS pathology after cell infiltration are largely undefined. Myelin-oligodendrocyte-glycoprotein (MOG-induced experimental autoimmune encephalomyelitis (EAE is an animal model of multiple sclerosis (MS, a chronic autoimmune disease of the CNS that results in disability. To assess genes that are involved in encephalitogenicity and subsequent tissue damage mediated by CNS-infiltrating cells, we performed a DNA microarray analysis from cells derived from lymph nodes and eluted from CNS in LEW.1AV1 (RT1av1 rats immunized with MOG 91-108. The data was compared to immunizations with adjuvant alone or naive rats and to immunizations with the immunogenic but not encephalitogenic MOG 73-90 peptide. Here, we show involvement of Cd38, Cxcr4 and Akt and confirm these findings by the use of Cd38-knockout (B6.129P2-Cd38tm1Lnd/J mice, S1P-receptor modulation during EAE and quantitative expression analysis in individuals with MS. The hereby-defined underlying pathways indicate cellular activation and migration pathways mediated by G-protein-coupled receptors as crucial events in CNS tissue damage. These pathways can be further explored for novel therapeutic interventions.

  2. Traditional Chinese medicine Yisui Tongjing relieved neural severity in experimental autoimmune neuritis rat model.

    Science.gov (United States)

    Zhang, Erli; Li, Mingquan; Zhao, Jianjun; Dong, Yuxiang; Yang, Xueqin; Huang, Jingbo

    2016-01-01

    To study the effect of Yisui Tongjing (YSTJ) prescription on motor nerve conduction velocity (MNCV) and microstructure of the sciatic nerve in experimental autoimmune neuritis (EAN) rats, the Guillain-Barré syndrome classic animal models. In this study, we established an EAN model in Lewis rats by immunization. We evaluated the potential clinical application of a traditional Chinese medicine YSTJ by intragastric administration and compared its effect with immunoglobulin. The sciatic MNCV was measured by electrophysiology experiment. Hematoxylin-eosin staining and transmission electron microscope analysis were used to determine the pathologically morphological changes before and after YSTJ application. We found that application of YSTJ could significantly alleviate the clinical signs in EAN rats. The treatment also increased MNCV in the sciatic nerve compared to that in the untreated nerve. Demyelination in the sciatic nerve in EAN rats was significantly ameliorated, and newly generated myelinated nerve fibers were observed with treatment of high dose of YSTJ. This study showed that the traditional Chinese medicine YSTJ was likely to serve as a therapeutic medicine in autoimmune neuropathies, providing an effective and economic means to the treatment of Guillain-Barré syndrome.

  3. Treg cell resistance to apoptosis in DNA vaccination for experimental autoimmune encephalomyelitis treatment.

    Directory of Open Access Journals (Sweden)

    Youmin Kang

    Full Text Available BACKGROUND: Regulatory T (Treg cells can be induced with DNA vaccinations and protect mice from the development of experimental autoimmune encephalomyelitis (EAE, a mouse model of multiple sclerosis (MS. Tacrolimus (FK506 has been shown to have functions on inducing immunosuppression and augmenting apoptosis of pathologic T cells in autoimmune disease. Here we examined the therapeutic effect of DNA vaccine in conjunction with FK506 on EAE. METHODOLOGY/PRINCIPAL FINDINGS: After EAE induction, C57BL/6 mice were treated with DNA vaccine in conjunction with FK506. Functional Treg cells were induced in treated EAE mice and suppressed Th1 and Th17 cell responses. Infiltrated CD4 T cells were reduced while Treg cells were induced in spinal cords of treated EAE mice. Remarkably, the activated CD4 T cells augmented apoptosis, but the induced Treg cells resisted apoptosis in treated EAE mice, resulting in alleviation of clinical EAE severity. CONCLUSIONS/SIGNIFICANCE: DNA vaccine in conjunction with FK506 treatment ameliorates EAE by enhancing apoptosis of CD4 T cells and resisting apoptosis of induced Treg cells. Our findings implicate the potential of tolerogenic DNA vaccines for treating MS.

  4. Ginsenoside Rd ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice.

    Science.gov (United States)

    Zhu, Dongliang; Liu, Mei; Yang, Yaowu; Ma, Lili; Jiang, Ying; Zhou, Linli; Huang, Qiling; Pi, Rongbiao; Chen, Xiaohong

    2014-09-01

    Multiple sclerosis (MS) is a common disabling autoimmune disease without an effective treatment in young adults. Ginsenoside Rd, extracted from Panax notoginseng, has multiple pharmacological effects and potential therapeutic applications in diseases of the central nervous system. In this study, we explore the efficacy of ginsenoside Rd in experimental autoimmune encephalomyelitis (EAE), an established model of MS. EAE was induced by myelin oligodendrocyte glycoprotein 35-55-amino-acid peptide. Ginsenoside Rd (10-80 mg/kg/day) or vehicle was intraperitoneally administered on the disease onset day, and the therapy persisted throughout the experiments. The dose of 40 mg/kg/day of ginsenoside Rd was selected as optimal. Ginsenoside Rd effectively ameliorated the clinical severity in EAE mice, reduced the permeability of the blood-brain barrier, regulated the secretion of interferon-gamma and interleukin-4, promoted the Th2 shift in vivo (cerebral cortex) and in vitro (splenocytes culture supernatants), and prevented the reduction in expression of brain-derived neurotrophic factor and nerve growth factor in both cerebral cortex and lumbar spinal cord of EAE mice. This study establishes the potency of ginsenoside Rd in inhibiting the clinical course of EAE. These findings suggest that ginsenoside Rd could be a promising agent for amelioration of neuroimmune dysfunction diseases such as MS. © 2014 Wiley Periodicals, Inc.

  5. Gestational Hypothyroidism Increases the Severity of Experimental Autoimmune Encephalomyelitis in Adult Offspring

    Science.gov (United States)

    Albornoz, Eduardo A.; Carreño, Leandro J.; Cortes, Claudia M.; Gonzalez, Pablo A.; Cisternas, Pablo A.; Cautivo, Kelly M.; Catalán, Tamara P.; Opazo, M. Cecilia; Eugenin, Eliseo A.; Berman, Joan W.; Bueno, Susan M.; Kalergis, Alexis M.

    2013-01-01

    Background: Maternal thyroid hormones play a fundamental role in appropriate fetal development during gestation. Offspring that have been gestated under maternal hypothyroidism suffer cognitive impairment. Thyroid hormone deficiency during gestation can significantly impact the central nervous system by altering the migration, differentiation, and function of neurons, oligodendrocytes, and astrocytes. Given that gestational hypothyroidism alters the immune cell ratio in offspring, it is possible that this condition could result in higher sensitivity for the development of autoimmune diseases. Methods: Adult mice gestated under hypothyroidism were induced with experimental autoimmune encephalomyelitis (EAE). Twenty-one days after EAE induction, the disease score, myelin content, immune cell infiltration, and oligodendrocyte death were evaluated. Results: We observed that mice gestated under hypothyroidism showed higher EAE scores after disease induction during adulthood compared to mice gestated in euthyroidism. In addition, spinal cord sections of mice gestated under hypothyroidism that suffered EAE in adulthood showed higher demyelination, CD4+ and CD8+ infiltration, and increased oligodendrocyte death. Conclusions: These results show for the first time that a deficiency in maternal thyroid hormones during gestation can influence the outcome of a central nervous system inflammatory disease, such as EAE, in their offspring. These data strongly support evaluating thyroid hormones in pregnant women and treating hypothyroidism during pregnancy to prevent increased susceptibility to inflammatory diseases in the central nervous system of offspring. PMID:23777566

  6. Tuftsin promotes an anti-inflammatory switch and attenuates symptoms in experimental autoimmune encephalomyelitis.

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    Muzhou Wu

    Full Text Available Multiple sclerosis (MS is a demyelinating autoimmune disease mediated by infiltration of T cells into the central nervous system after compromise of the blood-brain barrier. We have previously shown that administration of tuftsin, a macrophage/microglial activator, dramatically improves the clinical course of experimental autoimmune encephalomyelitis (EAE, a well-established animal model for MS. Tuftsin administration correlates with upregulation of the immunosuppressive Helper-2 T cell (Th2 cytokine transcription factor GATA-3. We now show that tuftsin-mediated microglial activation results in shifting microglia to an anti-inflammatory phenotype. Moreover, the T cell phenotype is shifted towards immunoprotection after exposure to tuftsin-treated activated microglia; specifically, downregulation of pro-inflammatory Th1 responses is triggered in conjunction with upregulation of Th2-specific responses and expansion of immunosuppressive regulatory T cells (Tregs. Finally, tuftsin-shifted T cells, delivered into animals via adoptive transfer, reverse the pathology observed in mice with established EAE. Taken together, our findings demonstrate that tuftsin decreases the proinflammatory environment of EAE and may represent a therapeutic opportunity for treatment of MS.

  7. Carboxypeptidase N-deficient mice present with polymorphic disease phenotypes on induction of experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Hu, Xianzhen; Wetsel, Rick A; Ramos, Theresa N; Mueller-Ortiz, Stacey L; Schoeb, Trenton R; Barnum, Scott R

    2014-02-01

    Carboxypeptidase N (CPN) is a member of the carboxypeptidase family of enzymes that cleave carboxy-terminal lysine and arginine residues from a large number of biologically active peptides and proteins. These enzymes are best known for their roles in modulating the activity of kinins, complement anaphylatoxins and coagulation proteins. Although CPN makes important contributions to acute inflammatory events, little is known about its role in autoimmune disease. In this study we used CPN(-/-) mice in experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. Unexpectedly, we observed several EAE disease phenotypes in CPN(-/-) mice compared to wild type mice. The majority of CPN(-/-) mice died within five to seven days after disease induction, before displaying clinical signs of disease. The remaining mice presented with either mild EAE or did not develop EAE. In addition, CPN(-/-) mice injected with complete or incomplete Freund's adjuvant died within the same time frame and in similar numbers as those induced for EAE. Overall, the course of EAE in CPN(-/-) mice was significantly delayed and attenuated compared to wild type mice. Spinal cord histopathology in CPN(-/-) mice revealed meningeal, but not parenchymal leukocyte infiltration, and minimal demyelination. Our results indicate that CPN plays an important role in EAE development and progression and suggests that multiple CPN ligands contribute to the disease phenotypes we observed. Copyright © 2013 Elsevier GmbH. All rights reserved.

  8. Helminth Products Potently Modulate Experimental Autoimmune Encephalomyelitis by Downregulating Neuroinflammation and Promoting a Suppressive Microenvironment

    Directory of Open Access Journals (Sweden)

    Alberto N. Peón

    2017-01-01

    Full Text Available A negative correlation between the geographical distribution of autoimmune diseases and helminth infections has been largely associated in the last few years with a possible role for such type of parasites in the regulation of inflammatory diseases, suggesting new pathways for drug development. However, few helminth-derived immunomodulators have been tested in experimental autoimmune encephalomyelitis (EAE, an animal model of the human disease multiple sclerosis (MS. The immunomodulatory activities of Taenia crassiceps excreted/secreted products (TcES that may suppress EAE development were sought for. Interestingly, it was discovered that TcES was able to suppress EAE development with more potency than dexamethasone; moreover, TcES treatment was still effective even when inoculated at later stages after the onset of EAE. Importantly, the TcES treatment was able to induce a range of Th2-type cytokines, while suppressing Th1 and Th17 responses. Both the polyclonal and the antigen-specific proliferative responses of lymphocytes were also inhibited in EAE-ill mice receiving TcES in association with a potent recruitment of suppressor cell populations. Peritoneal inoculation of TcES was able to direct the normal inflammatory cell traffic to the site of injection, thus modulating CNS infiltration, which may work along with Th2 immune polarization and lymphocyte activation impairment to downregulate EAE development.

  9. IgG glycan hydrolysis by EndoS inhibits experimental autoimmune encephalomyelitis

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    Benkhoucha Mahdia

    2012-09-01

    Full Text Available Abstract Studies in experimental autoimmune encephalomyelitis (EAE, a mouse model of multiple sclerosis, have shown that B cells markedly influence the course of the disease, although whether their effects are protective or pathological is a matter of debate. EndoS hydrolysis of the IgG glycan has profound effects on IgG effector functions, such as complement activation and Fc receptor binding, suggesting that the enzyme could be used as an immunomodulatory therapeutic agent against IgG-mediated diseases. We demonstrate here that EndoS has a protective effect in myelin oligodendrocyte glycoprotein peptide amino acid 35–55 (MOG35-55-induced EAE, a chronic neuroinflammatory demyelinating disorder of the central nervous system (CNS in which humoral immune responses are thought to play only a minor role. EndoS treatment in chronic MOG35-55-EAE did not impair encephalitogenic T cell priming and recruitment into the CNS of mice, consistent with a primary role of EndoS in controlling IgG effector functions. In contrast, reduced EAE severity coincided with poor serum complement activation and deposition within the spinal cord, suggesting that EndoS treatment impairs B cell effector function. These results identify EndoS as a potential therapeutic agent against antibody-mediated CNS autoimmune disorders.

  10. 5-Androstenediol Ameliorates Pleurisy, Septic Shock, and Experimental Autoimmune Encephalomyelitis in Mice

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    Ferdinando Nicoletti

    2010-01-01

    Full Text Available Androstenediol (androst-5-ene-3β,17β-diol; 5-AED, a natural adrenal steroid, has been shown to suppress experimental autoimmune encephalomyelitis (EAE in female SJL/J mice. We here report that 5-AED limits inflammation and proinflammatory cytokines including TNFα in murine models of carrageenan-induced pleurisy and lippopolysaccaride- (LPS induced septic shock. 5-AED binds to and transactivates sex steroid receptors with the same general rank order of potency (ERβ > ERα ≫ AR. 5-AED provides benefit in EAE in a dose-dependent fashion, even when treatment is delayed until onset of disease. The minimally effective dose may be as low as 4 mg/kg in mice. However, benefit was not observed when 5-AED was given in soluble formulation, leading to a short half-life and rapid clearance. These observations suggest that treatment with 5-AED limits the production of pro-inflammatory cytokines in these animal models and, ultimately, when formulated and administered properly, may be beneficial for patients with multiple sclerosis and other Th1-driven autoimmune diseases.

  11. GM-CSF is not essential for experimental autoimmune encephalomyelitis but promotes brain-targeted disease.

    Science.gov (United States)

    Pierson, Emily R; Goverman, Joan M

    2017-04-06

    Experimental autoimmune encephalomyelitis (EAE) has been used as an animal model of multiple sclerosis to identify pathogenic cytokines that could be therapeutic targets. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is the only cytokine reported to be essential for EAE. We investigated the role of GM-CSF in EAE in C3HeB/FeJ mice that uniquely exhibit extensive brain and spinal cord inflammation. Unexpectedly, GM-CSF-deficient C3HeB/FeJ mice were fully susceptible to EAE because IL-17 activity compensated for the loss of GM-CSF during induction of spinal cord-targeted disease. In contrast, both GM-CSF and IL-17 were needed to fully overcome the inhibitory influence of IFN-γ on the induction of inflammation in the brain. Both GM-CSF and IL-17 independently promoted neutrophil accumulation in the brain, which was essential for brain-targeted disease. These results identify a GM-CSF/IL-17/IFN-γ axis that regulates inflammation in the central nervous system and suggest that a combination of cytokine-neutralizing therapies may be needed to dampen central nervous system autoimmunity.

  12. Major histocompatibility complex-controlled protective influences on experimental autoimmune encephalomyelitis are peptide specific

    DEFF Research Database (Denmark)

    Issazadeh-Navikas, Shohreh; Kjellén, P; Olsson, T

    1997-01-01

    The myelin basic protein (MBP) peptide 63-88-induced experimental autoimmune encephalomyelitis (EAE) and its associated T cell cytokine profile are influenced by the rat major histocompatibility complex (MHC). There is an allele-specific protective influence of the MHC class I region, whereas...... the MHC class II region display either disease-protective or -promoting effects. To investigate if the MHC-associated protection is dependent on certain combinations of MBP peptide and MHC molecules, we have now used another peptide (MBP 89-101). A broader and different set of rat MHC alleles were......-101 peptide, except in LEW.1N (RT1 pi) rats which were relatively resistant. Only this strain responded with additional Th2-like and transforming growth factor-beta responses to the peptide in vitro. In vivo depletion of CD8+ cells aggravated the disease in this strain. We conclude that both MHC...

  13. Genetic variants of CC chemokine genes in experimental autoimmune encephalomyelitis, multiple sclerosis and rheumatoid arthritis

    DEFF Research Database (Denmark)

    Ockinger, J; Stridh, P; Beyeen, A D

    2010-01-01

    Multiple sclerosis (MS) is a complex disorder of the central nervous system, causing inflammation, demyelination and axonal damage. A limited number of genetic risk factors for MS have been identified, but the etiology of the disease remains largely unknown. For the identification of genes...... regulating neuroinflammation we used a rat model of MS, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), and carried out a linkage analysis in an advanced intercross line (AIL). We thereby redefine the Eae18b locus to a 0.88 Mb region, including a cluster...... of chemokine genes. Further, we show differential expression of Ccl2, Ccl11 and Ccl11 during EAE in rat strains with opposite susceptibility to EAE, regulated by genotype in Eae18b. The human homologous genes were tested for association to MS in 3841 cases and 4046 controls from four Nordic countries...

  14. Genetic variants of CC chemokine genes in experimental autoimmune encephalomyelitis, multiple sclerosis and rheumatoid arthritis

    DEFF Research Database (Denmark)

    Ockinger, J; Stridh, P; Beyeen, A D

    2010-01-01

    Multiple sclerosis (MS) is a complex disorder of the central nervous system, causing inflammation, demyelination and axonal damage. A limited number of genetic risk factors for MS have been identified, but the etiology of the disease remains largely unknown. For the identification of genes...... regulating neuroinflammation we used a rat model of MS, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), and carried out a linkage analysis in an advanced intercross line (AIL). We thereby redefine the Eae18b locus to a 0.88 Mb region, including a cluster....... A haplotype in CCL2 and rs3136682 in CCL1 show a protective association to MS, whereas a haplotype in CCL13 is disease predisposing. In the HLA-DRB1* 15 positive subgroup, we also identified an association to a risk haplotype in CCL2, suggesting an influence from the human leukocyte antigen (HLA) locus. We...

  15. Microwave and magnetic (M2) proteomics of the experimental autoimmune encephalomyelitis animal model of multiple sclerosis

    Science.gov (United States)

    Raphael, Itay; Mahesula, Swetha; Kalsaria, Karan; Kotagiri, Venkat; Purkar, Anjali B.; Anjanappa, Manjushree; Shah, Darshit; Pericherla, Vidya; Jadhav, Yeshwant Lal Avinash; Raghunathan, Rekha; Vaynberg, Michael; Noriega, David; Grimaldo, Nazul H.; Wenk, Carola; Gelfond, Jonathan A.L.; Forsthuber, Thomas G.; Haskins, William E.

    2013-01-01

    We hypothesized that quantitative MS/MS-based proteomics at multiple time points, incorporating rapid microwave and magnetic (M2) sample preparation, could enable relative protein expression to be correlated to disease progression in the experimental autoimmune encephalomyelitis (EAE) animal model of multiple sclerosis. To test our hypothesis, microwave-assisted reduction/alkylation/digestion of proteins from brain tissue lysates bound to C8 magnetic beads and microwave-assisted isobaric chemical labeling were performed of released peptides, in 90 s prior to unbiased proteomic analysis. Disease progression in EAE was assessed by scoring clinical EAE disease severity and confirmed by histopathologic evaluation for central nervous system inflammation. Decoding the expression of 283 top-ranked proteins (p proteomics is a rapid method to quantify putative prognostic/predictive protein biomarkers and therapeutic targets of disease progression in the EAE animal model of multiple sclerosis. PMID:23161666

  16. Microwave and magnetic (M(2) ) proteomics of the experimental autoimmune encephalomyelitis animal model of multiple sclerosis.

    Science.gov (United States)

    Raphael, Itay; Mahesula, Swetha; Kalsaria, Karan; Kotagiri, Venkat; Purkar, Anjali B; Anjanappa, Manjushree; Shah, Darshit; Pericherla, Vidya; Jadhav, Yeshwant Lal Avinash; Raghunathan, Rekha; Vaynberg, Michael; Noriega, David; Grimaldo, Nazul H; Wenk, Carola; Gelfond, Jonathan A L; Forsthuber, Thomas G; Haskins, William E

    2012-12-01

    We hypothesized that quantitative MS/MS-based proteomics at multiple time points, incorporating rapid microwave and magnetic (M(2) ) sample preparation, could enable relative protein expression to be correlated to disease progression in the experimental autoimmune encephalomyelitis (EAE) animal model of multiple sclerosis. To test our hypothesis, microwave-assisted reduction/alkylation/digestion of proteins from brain tissue lysates bound to C8 magnetic beads and microwave-assisted isobaric chemical labeling were performed of released peptides, in 90 s prior to unbiased proteomic analysis. Disease progression in EAE was assessed by scoring clinical EAE disease severity and confirmed by histopathologic evaluation for central nervous system inflammation. Decoding the expression of 283 top-ranked proteins (p proteomics is a rapid method to quantify putative prognostic/predictive protein biomarkers and therapeutic targets of disease progression in the EAE animal model of multiple sclerosis. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Teige, Ingrid; Treschow, Alexandra; Teige, Anna

    2003-01-01

    Since the basic mechanisms behind the beneficial effects of IFN-beta in multiple sclerosis (MS) patients are still obscure, here we have investigated the effects of IFN-beta gene disruption on the commonly used animal model for MS, experimental autoimmune encephalomyelitis (EAE). We show that IFN......-beta knockout (KO) mice are more susceptible to EAE than their wild-type (wt) littermates; they develop more severe and chronic neurological symptoms with more extensive CNS inflammation and demyelination. However, there was no discrepancy observed between wt and KO mice regarding the capacity of T cells...... to proliferate or produce IFN-gamma in response to recall Ag. Consequently, we addressed the effect of IFN-beta on encephalitogenic T cell development and the disease initiation phase by passive transfer of autoreactive T cells from KO or wt littermates to both groups of mice. Interestingly, IFN-beta KO mice...

  18. Rituximab therapy reduces organ-specific T cell responses and ameliorates experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Monson, Nancy L; Cravens, Petra; Hussain, Rehana; Harp, Christopher T; Cummings, Matthew; de Pilar Martin, Maria; Ben, Li-Hong; Do, Julie; Lyons, Jeri-Anne; Lovette-Racke, Amy; Cross, Anne H; Racke, Michael K; Stüve, Olaf; Shlomchik, Mark; Eagar, Todd N

    2011-02-16

    Recent clinical trials have established B cell depletion by the anti-CD20 chimeric antibody Rituximab as a beneficial therapy for patients with relapsing-remitting multiple sclerosis (MS). The impact of Rituximab on T cell responses remains largely unexplored. In the experimental autoimmune encephalomyelitis (EAE) model of MS in mice that express human CD20, Rituximab administration rapidly depleted peripheral B cells and strongly reduced EAE severity. B cell depletion was also associated with diminished Delayed Type Hypersensitivity (DTH) and a reduction in T cell proliferation and IL-17 production during recall immune response experiments. While Rituximab is not considered a broad immunosuppressant, our results indicate a role for B cells as a therapeutic cellular target in regulating encephalitogenic T cell responses in specific tissues.

  19. Rituximab therapy reduces organ-specific T cell responses and ameliorates experimental autoimmune encephalomyelitis.

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    Nancy L Monson

    Full Text Available Recent clinical trials have established B cell depletion by the anti-CD20 chimeric antibody Rituximab as a beneficial therapy for patients with relapsing-remitting multiple sclerosis (MS. The impact of Rituximab on T cell responses remains largely unexplored. In the experimental autoimmune encephalomyelitis (EAE model of MS in mice that express human CD20, Rituximab administration rapidly depleted peripheral B cells and strongly reduced EAE severity. B cell depletion was also associated with diminished Delayed Type Hypersensitivity (DTH and a reduction in T cell proliferation and IL-17 production during recall immune response experiments. While Rituximab is not considered a broad immunosuppressant, our results indicate a role for B cells as a therapeutic cellular target in regulating encephalitogenic T cell responses in specific tissues.

  20. Effect and Mechanism of QiShenYiQi Pill on Experimental Autoimmune Myocarditis Rats

    Science.gov (United States)

    Lv, Shichao; Wu, Meifang; Li, Meng; Wang, Qiang; Xu, Ling; Wang, Xiaojing; Zhang, Junping

    2016-01-01

    Background To observe the effect of QiShenYiQi pill (QSYQ) on experimental autoimmune myocarditis rats, and to explore its mechanism of action. Material/methods Lewis rats underwent the injection of myocardial myosin mixed with Freund’s complete adjuvant were randomized into 3 groups: model, valsartan, and QSYQ groups. Rats injected with phosphate-buffered saline (PBS) mixed with Freund’s complete adjuvant were used as the control group. Rats were euthanized at 4 and 8 weeks, and we weighed rat body mass, heart mass, and left ventricular mass. Myocardium sections were stained with hematoxylin and eosin (H&E) and Masson trichrome. Myocardial TGF-β1 and CTGF protein expression was detected by immunohistochemistry, and myocardial TGF-β1 and CTGF mRNA expression was detected by real-time qPCR. Results QSYQ reduced HMI and LVMI, as well as the histological score of hearts and CVF, which further decreased over time, and its effect was significantly greater than that of valsartan at 4 and 8 weeks. After 4 weeks, QSYQ inhibited the protein and mRNA expression of TGF-β1 and CTGF, and its effect on lowering CTGF was significantly greater than that of valsartan. In addition, after 8 weeks, QSYQ also inhibited the protein and mRNA expression of CTGF, whereas there was no significant difference in the expression of myocardial TGF-β1. Conclusions This study provides evidence that QSYQ can improve cardiac remodeling of experimental autoimmune myocarditis rats. It also effectively improved the degree of myocardial fibrosis, which is related to the mechanism of regulation of TGF-β1 CTGF. PMID:26946470

  1. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS)

    Science.gov (United States)

    Constantinescu, Cris S; Farooqi, Nasr; O'Brien, Kate; Gran, Bruno

    2011-01-01

    Experimental autoimmune encephalomyelitis (EAE) is the most commonly used experimental model for the human inflammatory demyelinating disease, multiple sclerosis (MS). EAE is a complex condition in which the interaction between a variety of immunopathological and neuropathological mechanisms leads to an approximation of the key pathological features of MS: inflammation, demyelination, axonal loss and gliosis. The counter-regulatory mechanisms of resolution of inflammation and remyelination also occur in EAE, which, therefore can also serve as a model for these processes. Moreover, EAE is often used as a model of cell-mediated organ-specific autoimmune conditions in general. EAE has a complex neuropharmacology, and many of the drugs that are in current or imminent use in MS have been developed, tested or validated on the basis of EAE studies. There is great heterogeneity in the susceptibility to the induction, the method of induction and the response to various immunological or neuropharmacological interventions, many of which are reviewed here. This makes EAE a very versatile system to use in translational neuro- and immunopharmacology, but the model needs to be tailored to the scientific question being asked. While creating difficulties and underscoring the inherent weaknesses of this model of MS in straightforward translation from EAE to the human disease, this variability also creates an opportunity to explore multiple facets of the immune and neural mechanisms of immune-mediated neuroinflammation and demyelination as well as intrinsic protective mechanisms. This allows the eventual development and preclinical testing of a wide range of potential therapeutic interventions. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21371012

  2. Carvedilol Inhibits Matrix Metalloproteinase-2 Activation in Experimental Autoimmune Myocarditis: Possibilities of Cardioprotective Application.

    Science.gov (United States)

    Skrzypiec-Spring, Monika; Haczkiewicz, Katarzyna; Sapa, Agnieszka; Piasecki, Tomasz; Kwiatkowska, Joanna; Ceremuga, Ireneusz; Wozniak, Mieczyslaw; Biczysko, Wieslawa; Kobierzycki, Christopher; Dziegiel, Piotr; Podhorska-Okolow, Marzenna; Szelag, Adam

    2017-01-01

    Acute myocarditis is a potentially lethal inflammatory heart disease that frequently precedes the development of dilated cardiomyopathy and subsequent heart failure. At present, there is no effective standardized therapy for acute myocarditis, besides the optimal care of heart failure and arrhythmias in accordance with evidence-based guidelines and specific etiology-driven therapy for infectious myocarditis. Carvedilol has been shown to be cardioprotective by reducing cardiac pro-inflammatory cytokines present in oxidative stress in certain heart diseases. However, effects of carvedilol administration in acute myocarditis with its impact on matrix metalloproteinases' (MMPs) activation have not been elucidated. Carvedilol in 3 doses (2, 10, and 30 mg/kg) was given daily to 3 study groups of rats (n = 8) with experimental autoimmune myocarditis by gastric gavage for 3 weeks. In comparison to untreated rats (n = 8) with induced myocarditis, carvedilol significantly prevented the left ventricle enlargement and/or systolic dysfunction depending on the dose in study groups. Performed zymography showed enhanced MMP-2 activity in untreated rats, while carvedilol administration reduced alterations. This was accompanied by prevention of troponin I release and myofilaments degradation in cardiac muscle tissue. Additionally, severe inflammatory cell infiltration was detected in the nontreated group. Carvedilol in all doses tested, had no impact on severity of inflammation. The severity of inflammation did not differ between study groups and in relation to the untreated group. The protective effects of carvedilol on heart function observed in the acute phase of experimental autoimmune myocarditis seem to be associated with its ability to decrease MMP-2 activity and subsequently prevent degradation of myofilaments and release of troponin I while not related to suppression of inflammation.

  3. Treatment with metallothionein prevents demyelination and axonal damage and increases oligodendrocyte precursors and tissue repair during experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Penkowa, Milena; Hidalgo, Juan

    2003-01-01

    Experimental autoimmune encephalomyelitis (EAE) is an animal model for the human demyelinating disease multiple sclerosis (MS). EAE and MS are characterized by significant inflammation, demyelination, neuroglial damage, and cell death. Metallothionein-I and -II (MT-I + II) are antiinflammatory an...

  4. Altered inflammatory response and increased neurodegeneration in metallothionein I+II deficient mice during experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Penkowa, M; Espejo, C; Martínez-Cáceres, E M

    2001-01-01

    Metallothionein-I+II (MT-I+II) are antioxidant, neuroprotective proteins, and in this report we have examined their roles during experimental autoimmune encephalomyelitis (EAE) by comparing MT-I+II-knock-out (MTKO) and wild-type mice. We herewith show that EAE susceptibility is higher in MTKO mic...

  5. Kinetics of expression of costimulatory molecules and their ligands in murine relapsing experimental autoimmune encephalomyelitis in vivo

    DEFF Research Database (Denmark)

    Issazadeh-Navikas, Shohreh; Navikas, V; Schaub, M

    1998-01-01

    We studied the kinetics of expression of costimulatory molecules and cytokines in the central nervous system (CNS) in murine relapsing experimental autoimmune encephalomyelitis (EAE). During the natural course of EAE, B7-2 expression in the CNS correlated with clinical signs, while B7-1 was exclu...

  6. Correlation of gut microbiota composition with resistance to experimental autoimmune encephalomyelitis in rats

    Directory of Open Access Journals (Sweden)

    Suzana Stanisavljevic

    2016-12-01

    Full Text Available Multiple sclerosis is a chronic inflammatory disease of the central nervous system (CNS. It is widely accepted that autoimmune response against the antigens of the CNS is the essential pathogenic force in the disease. It has recently become increasingly appreciated that activated encephalitogenic cells tend to migrate towards gut associated lymphoid tissues (GALT and that interrupted balance between regulatory and inflammatory immunity within the GALT might have decisive role in the initiation and propagation of the CNS autoimmunity. Gut microbiota composition and function has the major impact on the balance in the GALT. Thus, our aim was to perform analyses of gut microbiota in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis. Albino Oxford (AO rats that are highly resistant to EAE induction and Dark Agouti (DA rats that develop EAE after mild immunization were compared for gut microbiota composition in different phases after EAE induction. Microbial analyses of the genus Lactobacillus and related lactic acid bacteria showed higher diversity of Lactobacillus spp. in EAE-resistant AO rats, while some members of Firmicutes and Proteobacteria (Undibacterium oligocarboniphilum were detected only in faeces of DA rats at the peak of the disease (between 13 and 16 days after induction. Interestingly, Turicibacter sp. that was found exclusively in non-immunized AO, but not in DA rats in our previous study was detected in DA rats that remained healthy 16 days after induction. Similar observation was obtained for the members of Lachnospiraceae. As dominant presence of the members of Lachnospiraceae family in gut microbial community has been linked with mild symptoms of various diseases, it is tempting to assume that Turicibacter sp. and Lachnospiraceae contribute to the prevention of EAE development and the alleviation of the disease symptoms. Further, production of a typical regulatory cytokine interleukin-10 was

  7. A cannabigerol derivative suppresses immune responses and protects mice from experimental autoimmune encephalomyelitis.

    Directory of Open Access Journals (Sweden)

    Francisco J Carrillo-Salinas

    Full Text Available Phytocannabinoids that do not produce psychotropic effects are considered of special interest as novel therapeutic agents in CNS diseases. A cannabigerol quinone, the compound VCE-003, has been shown to alleviate symptoms in a viral model of multiple sclerosis (MS. Hence, we studied T cells and macrophages as targets for VCE-003 and its efficacy in an autoimmune model of MS. Proliferation, cell cycle, expression of activation markers was assessed by FACs in human primary T cells, and cytokine and chemokine production was evaluated. Transcription was studied in Jurkat cells and RAW264.7 cells were used to study the effects of VCE-003 on IL-17-induced macrophage polarization to a M1 phenotype. Experimental autoimmune encephalomyelitis (EAE was induced by myelin oligodendrocyte glycoprotein (MOG₃₅₋₅₅ immunization and spinal cord pathology was assessed by immunohistochemistry. Neurological impairment was evaluated using disease scores. We show here that VCE-003 inhibits CD3/CD28-induced proliferation, cell cycle progression and the expression of the IL-2Rα and ICAM-1 activation markers in human primary T cells. VCE-003 inhibits the secretion of Th1/Th17 cytokines and chemokines in primary murine T cells, and it reduces the transcriptional activity of the IL-2, IL-17 and TNFα promoters induced by CD3/CD28. In addition, VCE-003 and JWH-133, a selective CB2 agonist, dampened the IL-17-induced polarization of macrophages to a pro-inflammatory M1 profile. VCE-003 also prevented LPS-induced iNOS expression in microglia. VCE-003 ameliorates the neurological defects and the severity of MOG-induced EAE in mice through CB2 and PPARγ receptor activation. A reduction in cell infiltrates, mainly CD4+ T cells, was observed, and Th1 and Th17 responses were inhibited in the spinal cord of VCE-003-treated mice, accompanied by weaker microglial activation, structural preservation of myelin sheets and reduced axonal damage. This study highlights the

  8. Leukemia inhibitory factor protects axons in experimental autoimmune encephalomyelitis via an oligodendrocyte-independent mechanism.

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    Melissa M Gresle

    Full Text Available Leukemia inhibitory factor (LIF and Ciliary Neurotrophic factor (CNTF are members of the interleukin-6 family of cytokines, defined by use of the gp130 molecule as an obligate receptor. In the murine experimental autoimmune encephalomyelitis (EAE model, antagonism of LIF and genetic deletion of CNTF worsen disease. The potential mechanism of action of these cytokines in EAE is complex, as gp130 is expressed by all neural cells, and could involve immuno-modulation, reduction of oligodendrocyte injury, neuronal protection, or a combination of these actions. In this study we aim to investigate whether the beneficial effects of CNTF/LIF signalling in EAE are associated with axonal protection; and whether this requires signalling through oligodendrocytes. We induced MOG₃₅₋₅₅ EAE in CNTF, LIF and double knockout mice. On a CNTF null background, LIF knockout was associated with increased EAE severity (EAE grade 2.1±0.14 vs 2.6±0.19; P<0.05. These mice also showed increased axonal damage relative to LIF heterozygous mice, as indicated by decreased optic nerve parallel diffusivity on MRI (1540±207 µm²-/s vs 1310±175 µm²-/s; P<0.05, and optic nerve (-12.5% and spinal cord (-16% axon densities; and increased serum neurofilament-H levels (2.5 fold increase. No differences in inflammatory cell numbers or peripheral auto-immune T-cell priming were evident. Oligodendrocyte-targeted gp130 knockout mice showed that disruption of CNTF/LIF signalling in these cells has no effect on acute EAE severity. These studies demonstrate that endogenous CNTF and LIF act centrally to protect axons from acute inflammatory destruction via an oligodendrocyte-independent mechanism.

  9. P2Y2R deficiency attenuates experimental autoimmune uveitis development.

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    Lia Judice M Relvas

    Full Text Available We aimed to study the role of the nucleotide receptor P2Y2R in the development of experimental autoimmune uveitis (EAU. EAU was induced in P2Y2+/+ and P2Y2-/- mice by immunization with IRBP peptide or by adoptive transfer of in vitro restimulated semi-purified IRBP-specific enriched T lymphocytes from spleens and lymph nodes isolated from native C57Bl/6 or P2Y2+/+ and P2Y2-/- immunized mice. Clinical and histological scores were used to grade disease severity. Splenocytes and lymph node cell phenotypes were analyzed using flow cytometry. Semi-purified lymphocytes and MACS-purified CD4+ T lymphocytes from P2Y2+/+ and P2Y2-/- immunized mice were tested for proliferation and cytokine secretion. Our data show that clinical and histological scores were significantly decreased in IRBP-immunized P2Y2-/- mice as in P2Y2-/- mice adoptively transfered with enriched T lymphocytes from C57Bl/6 IRBP-immunized mice. In parallel, naïve C57Bl/6 mice adoptively transferred with T lymphocytes from P2Y2-/- IRBP-immunized mice also showed significantly less disease. No differences in term of spleen and lymph node cell recruitment or phenotype appeared between P2Y2-/- and P2Y2+/+ immunized mice. However, once restimulated in vitro with IRBP, P2Y2-/- T cells proliferate less and secrete less cytokines than the P2Y2+/+ one. We further found that antigen-presenting cells of P2Y2-/- immunized mice were responsible for this proliferation defect. Together our data show that P2Y2-/- mice are less susceptible to mount an autoimmune response against IRBP. Those results are in accordance with the danger model, which makes a link between autoreactive lymphocyte activation, cell migration and the release of danger signals such as extracellular nucleotides.

  10. Astragaloside IV attenuates experimental autoimmune encephalomyelitis of mice by counteracting oxidative stress at multiple levels.

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    Yixin He

    Full Text Available Multiple sclerosis (MS is a chronic autoimmune neuroinflammatory disease found mostly in young adults in the western world. Oxidative stress induced neuronal apoptosis plays an important role in the pathogenesis of MS. In current study, astragaloside IV (ASI, a natural saponin molecule isolated from Astragalus membranceus, given at 20 mg/kg daily attenuated the severity of experimental autoimmune encephalomyelitis (EAE in mice significantly. Further studies disclosed that ASI treatment inhibited the increase of ROS and pro-inflammatory cytokine levels, down-regulation of SOD and GSH-Px activities, and elevation of iNOS, p53 and phosphorylated tau in central nervous system (CNS as well as the leakage of BBB of EAE mice. Meanwhile, the decreased ratio of Bcl-2/Bax was reversed by ASI. Moreover, ASI regulated T-cell differentiation and infiltration into CNS. In neuroblast SH-SY5Y cells, ASI dose-dependently reduced cellular ROS level and phosphorylation of tau in response to hydrogen peroxide challenge by modulation of Bcl-2/Bax ratio. ASI also inhibited activation of microglia both in vivo and in vitro. iNOS up-regulation induced by IFNγ stimulation was abolished by ASI dose-dependently in BV-2 cells. In summary, ASI prevented the severity of EAE progression possibly by counterbalancing oxidative stress and its effects via reduction of cellular ROS level, enhancement of antioxidant defense system, increase of anti-apoptotic and anti-inflammatory pathways, as well as modulation of T-cell differentiation and infiltration into CNS. The study suggested ASI may be effective for clinical therapy/prevention of MS.

  11. TH1 and TH17 cells promote crescent formation in experimental autoimmune glomerulonephritis.

    Science.gov (United States)

    Hünemörder, Stefanie; Treder, Julia; Ahrens, Stefanie; Schumacher, Valéa; Paust, Hans-Joachim; Menter, Thomas; Matthys, Patrick; Kamradt, Thomas; Meyer-Schwesinger, Catherine; Panzer, Ulf; Hopfer, Helmut; Mittrücker, Hans-Willi

    2015-09-01

    Autoimmunity against the Goodpasture antigen α3IV-NC1 results in crescentic glomerulonephritis (GN). Both antibodies and T cells directed against α3IV-NC1 have been implicated in disease development and progression. Using the model of experimental autoimmune glomerulonephritis (EAG) in DBA/1 mice, we aimed to characterize the frequency and function of α3IV-NC1-specific CD4(+) T cells in the kidneys. DBA/1 mice repeatedly immunized with human α3IV-NC1 developed necrotizing/crescentic GN. Kidneys with crescentic GN contained CD4(+) cells responding to α3IV-NC1 with the production of IFN-γ or IL-17A, demonstrating the accumulation of both α3IV-NC1-specific TH1 and TH17 cells. To test the functional relevance of TH1 and TH17 cells, EAG was induced in DBA/1 mice deficient in IFN-γR, IL-17A or IL-23p19. Mice of all knockout groups mounted α3IV-NC1 IgG, developed nephrotic range proteinuria, and IgG deposition to the glomerular basement membranes at levels similar to immunized wild-type mice. However, all knockout groups showed significantly fewer glomerular crescents and attenuated tubulointerstitial damage. Our results suggest that both α3IV-NC1-specific TH1 and TH17 cells accumulate in the kidneys and are crucial for the development of necrotizing/crescentic GN. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  12. Inhibitory effects of alprazolam on the development of acute experimental autoimmune encephalomyelitis in stressed rats.

    Science.gov (United States)

    Núñez-Iglesias, María J; Novío, Silvia; Almeida-Dias, Antonio; Freire-Garabal, Manuel

    2010-12-01

    The progression and development of multiple sclerosis (MS) has long been hypothesized to be associated with stress. Benzodiazepines have been observed to reduce negative consequences of stress on the immune system in experimental and clinical models, but there are no data on their effects on MS, or experimental autoimmune encephalomyelitis (EAE), a model for human MS. We designed experiments conducted to ascertain whether alprazolam could modify the clinical, histological and neuroendocrine manifestations of acute EAE in Lewis rats exposed to a chronic auditory stressor. EAE was induced by injection of an emulsion of MBP and complete Freund's adjuvant containing Mycobacterium tuberculosis H37Ra. Stress application and treatment with drugs (placebo or alprazolam) were initiated 5days before inoculation and continued daily for the duration of the experiment (days 14 or 34 postinoculation).Our results show significant increases in the severity of neurological signs, the histological lesions of the spinal cord (inflammation), and the corticosterone plasmatic levels in stressed rats compared to those non-stressed ones. Treatment with alprazolam reversed the adverse effects of stress. These findings could have clinical implications in patients suffering from MS treated with benzodiazepines, so besides the psychopharmacological properties of alprazolam against stress, it has beneficial consequences on EAE. Copyright © 2010 Elsevier Inc. All rights reserved.

  13. MS14, a Marine Herbal Medicine, an Immunosuppressive Drug in Experimental Autoimmune Encephalomyelitis.

    Science.gov (United States)

    Ebrahimi Kalan, Abbas; Soleimani Rad, Jafar; Kafami, Laya; Mohamadnezhad, Daryoush; Khaki, Amir Afshin; Mohammadi Roushandeh, Amaneh

    2014-07-01

    Cytokines are secreted signaling proteins which play essential roles in immune responses during experimental autoimmune encephalomyelitis (EAE), a demyelinating model that mimics many features of multiple sclerosis (MS). Interleukin 6 (IL-6) is a multifunctional cytokine produced by different cells, mediating inflammatory reactions and immune-mediated processes. Several studies have described immunosuppressive potentials of several herbal medicines. MS14 as an Iranian marine herbal medicine has anti-inflammatory and immunomodulatory activities. The present study investigated the immunosuppressive potential of MS14 as an herbal drug as well as the IL-6 level in EAE model. We hope it will be a new approach for neurologic diseases and autoimmune originated diseases therapy. The present experimental study was a collaboration between Department of Anatomical Sciences of Tabriz University of Medical Sciences and Shefa Neuroscience Research Center of Tehran. We used 30 C57BL/6 mice. The animals were immunized with myelin oligodendrocyte glycoprotein (MOG) to induce EAE and treated with MS14-containing (30%) diets. Subjects were selected by simple random sampling and then they were randomly allocated to two groups. EAE symptoms were assessed using the standard 10-point EAE scoring system from the seventh to the 35th day after immunization. Afterwards, the spleen was removed and its cells were cultured with or without MOG 35-55; then, the IL-6 level was analyzed by ELISA. In addition, histopathological studies were carried out for demyelination lesion evaluation in the spinal cord. MS14 significantly improved clinical symptoms of EAE compared with the control (P < 0.05). It also suppressed proliferative responses of T cells and decreased IL-6 expression (16.93 ± 2.7 vs. 21.4 ± 3.33) (P < 0.05). Our results strongly suggested that IL-6 as a potential molecule could have a role in neuroimmunology and neuroinflammation, which is in congruent with previous studies. Therefore

  14. Continued administration of ciliary neurotrophic factor protects mice from inflammatory pathology in experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Kuhlmann, Tanja; Remington, Leah; Cognet, Isabelle

    2006-01-01

    Multiple sclerosis is an inflammatory disease of the central nervous system that leads to loss of myelin and oligodendrocytes and damage to axons. We show that daily administration (days 8 to 24) of murine ciliary neurotrophic factor (CNTF), a neurotrophic factor that has been described as a surv......Multiple sclerosis is an inflammatory disease of the central nervous system that leads to loss of myelin and oligodendrocytes and damage to axons. We show that daily administration (days 8 to 24) of murine ciliary neurotrophic factor (CNTF), a neurotrophic factor that has been described...... as a survival and differentiation factor for neurons and oligodendrocytes, significantly ameliorates the clinical course of a mouse model of multiple sclerosis. In the acute phase of experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein peptide 35-55, treatment with CNTF did...... not change the peripheral immune response but did reduce the number of perivascular infiltrates and T cells and the level of diffuse microglial activation in spinal cord. Blood brain barrier permeability was significantly reduced in CNTF-treated animals. Beneficial effects of CNTF did not persist after...

  15. A DPP-4 inhibitor suppresses fibrosis and inflammation on experimental autoimmune myocarditis in mice.

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    Hiroyuki Hirakawa

    Full Text Available Myocarditis is a critical inflammatory disorder which causes life-threatening conditions. No specific or effective treatment has been established. DPP-4 inhibitors have salutary effects not only on type 2 diabetes but also on certain cardiovascular diseases. However, the role of a DPP-4 inhibitor on myocarditis has not been investigated. To clarify the effects of a DPP-4 inhibitor on myocarditis, we used an experimental autoimmune myocarditis (EAM model in Balb/c mice. EAM mice were assigned to the following groups: EAM mice group treated with a DPP-4 inhibitor (linagliptin (n = 19 and those untreated (n = 22. Pathological analysis revealed that the myocardial fibrosis area ratio in the treated group was significantly lower than in the untreated group. RT-PCR analysis demonstrated that the levels of mRNA expression of IL-2, TNF-α, IL-1β and IL-6 were significantly lower in the treated group than in the untreated group. Lymphocyte proliferation assay showed that treatment with the DPP-4 inhibitor had no effect on antigen-induced spleen cell proliferation. Administration of the DPP-4 inhibitor remarkably suppressed cardiac fibrosis and reduced inflammatory cytokine gene expression in EAM mice. Thus, the agents present in DPP-4 inhibitors may be useful to treat and/or prevent clinical myocarditis.

  16. Differential RNA Expression Profile of Skeletal Muscle Induced by Experimental Autoimmune Myasthenia Gravis in Rats

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    Henry Kaminski

    2016-11-01

    Full Text Available The differential susceptibility of skeletal muscle by myasthenia gravis (MG is not well understood. We utilized RNA expression profiling of extraocular muscle (EOM, diaphragm (DIA, and extensor digitorum (EDL of rats with experimental autoimmune MG (EAMG to evaluate the hypothesis that muscles respond differentially to injury produced by EAMG. EAMG was induced in female Lewis rats by immunization with acetylcholine receptor purified from the electric organ of the Torpedo. Six weeks later after rats had developed weakness and serum antibodies directed against the AChR, animals underwent euthanasia and RNA profiling performed on DIA, EDL, and EOM. Profiling results were validated by qPCR. Across the three muscles between the experiment and control groups, three hundred and fifty-nine probes (1.16% with greater than 2 fold changes in expression in 7 of 9 series pairwise comparisons from 31,090 probes were identified with approximately two-thirds being increased. The three muscles shared 16 genes with increased expression and 6 reduced expression. Functional annotation demonstrated that these common expression changes fell predominantly into categories of metabolism, stress response, and signaling. Evaluation of specific gene function indicated that EAMG led to a change to oxidative metabolism. Genes related to muscle regeneration and suppression of immune response were activated. Evidence of a differential immune response among muscles was not evident. Each muscle had a distinct RNA profile but with commonality in gene categories expressed that are focused on muscle repair, moderation of inflammation, and oxidative metabolism.

  17. Tryptase-PAR2 axis in experimental autoimmune prostatitis, a model for chronic pelvic pain syndrome.

    Science.gov (United States)

    Roman, Kenny; Done, Joseph D; Schaeffer, Anthony J; Murphy, Stephen F; Thumbikat, Praveen

    2014-07-01

    Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) affects up to 15% of the male population and is characterized by pelvic pain. Mast cells are implicated in the murine experimental autoimmune prostatitis (EAP) model as key to chronic pelvic pain development. The mast cell mediator tryptase-β and its cognate receptor protease-activated receptor 2 (PAR2) are involved in mediating pain in other visceral disease models. Prostatic secretions and urines from CP/CPPS patients were examined for the presence of mast cell degranulation products. Tryptase-β and PAR2 expression were examined in murine EAP. Pelvic pain and inflammation were assessed in the presence or absence of PAR2 expression and upon PAR2 neutralization. Tryptase-β and carboxypeptidase A3 were elevated in CP/CPPS compared to healthy volunteers. Tryptase-β was capable of inducing pelvic pain and was increased in EAP along with its receptor PAR2. PAR2 was required for the development of chronic pelvic pain in EAP. PAR2 signaling in dorsal root ganglia led to extracellular signal-regulated kinase (ERK)1/2 phosphorylation and calcium influx. PAR2 neutralization using antibodies attenuated chronic pelvic pain in EAP. The tryptase-PAR2 axis is an important mediator of pelvic pain in EAP and may play a role in the pathogenesis of CP/CPPS. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  18. Diazepam Inhibits Proliferation of Lymph Node Cells Isolated from Rats with Experimental Autoimmune Encephalomyelitis.

    Science.gov (United States)

    Fernández Hurst, Nicolás; Bibolini, Mario J; Roth, German A

    2015-01-01

    Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease with similarities to human multiple sclerosis involving peripheral activation of autoreactive T cells which infiltrate the central nervous system and react to self antigens leading to damage. In previous studies, we have demonstrated that treatment with diazepam decreases the incidence and histological signs associated with the disease and diminishes immunological responses. The aim of the present work was to evaluate direct effects of diazepam on isolated T cells involved in immune responses during the development of EAE. Animals were sensitized with whole myelin to induce EAE and sacrificed during the acute phase of the disease. In mononuclear cells isolated from popliteal lymph nodes, cell viability, apoptosis induction, proliferation and cytokine production were evaluated. Diazepam did not have a toxic or proapoptotic effect on the cells, at least up to the concentration of 25 μM, but proliferation, CD8+ T-cell activation and proinflammatory cytokine production were dose-dependently decreased. Diazepam has a direct inhibitory effect on the proliferation and activation of T lymphocytes isolated from the main lymphoid organ involved in disease onset and this could be one of the mechanisms that contribute to the beneficial effect previously observed with diazepam in vivo during EAE development. © 2015 S. Karger AG, Basel.

  19. Exogenous schwann cells migrate, remyelinate and promote clinical recovery in experimental auto-immune encephalomyelitis.

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    Violetta Zujovic

    Full Text Available Schwann cell (SC transplantation is currently being discussed as a strategy that may promote functional recovery in patients with multiple sclerosis (MS and other inflammatory demyelinating diseases of the central nervous system (CNS. However this assumes they will not only survive but also remyelinate demyelinated axons in the chronically inflamed CNS. To address this question we investigated the fate of transplanted SCs in myelin oligodendrocyte glycoprotein (MOG-induced experimental autoimmune encephalomyelitis (EAE in the Dark Agouti rat; an animal model that reproduces the complex inflammatory demyelinating immunopathology of MS. We now report that SCs expressing green fluorescent protein (GFP-SCs allografted after disease onset not only survive but also migrate to remyelinate lesions in the inflamed CNS. GFP-SCs were detected more frequently in the parenchyma after direct injection into the spinal cord, than via intra-thecal delivery into the cerebrospinal fluid. In both cases the transplanted cells intermingled with astrocytes in demyelinated lesions, aligned with axons and by twenty one days post transplantation had formed Pzero protein immunoreactive internodes. Strikingly, GFP-SCs transplantation was associated with marked decrease in clinical disease severity in terms of mortality; all GFP-SCs transplanted animals survived whilst 80% of controls died within 40 days of disease.

  20. Exogenous Schwann Cells Migrate, Remyelinate and Promote Clinical Recovery in Experimental Auto-Immune Encephalomyelitis

    Science.gov (United States)

    Zujovic, Violetta; Doucerain, Cédric; Hidalgo, Antoine; Bachelin, Corinne; Lachapelle, François; Weissert, Robert; Stadelmann, Christine; Linington, Chris; Evercooren, Anne Baron-Van

    2012-01-01

    Schwann cell (SC) transplantation is currently being discussed as a strategy that may promote functional recovery in patients with multiple sclerosis (MS) and other inflammatory demyelinating diseases of the central nervous system (CNS). However this assumes they will not only survive but also remyelinate demyelinated axons in the chronically inflamed CNS. To address this question we investigated the fate of transplanted SCs in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in the Dark Agouti rat; an animal model that reproduces the complex inflammatory demyelinating immunopathology of MS. We now report that SCs expressing green fluorescent protein (GFP-SCs) allografted after disease onset not only survive but also migrate to remyelinate lesions in the inflamed CNS. GFP-SCs were detected more frequently in the parenchyma after direct injection into the spinal cord, than via intra-thecal delivery into the cerebrospinal fluid. In both cases the transplanted cells intermingled with astrocytes in demyelinated lesions, aligned with axons and by twenty one days post transplantation had formed Pzero protein immunoreactive internodes. Strikingly, GFP-SCs transplantation was associated with marked decrease in clinical disease severity in terms of mortality; all GFP-SCs transplanted animals survived whilst 80% of controls died within 40 days of disease. PMID:22984406

  1. Lingo-1 inhibited by RNA interference promotes functional recovery of experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Wang, Chun-Juan; Qu, Chuan-Qiang; Zhang, Jie; Fu, Pei-Cai; Guo, Shou-Gang; Tang, Rong-Hua

    2014-12-01

    Lingo-1 is a negative regulator of myelination. Repairment of demyelinating diseases, such as multiple sclerosis (MS)/experimental autoimmune encephalomyelitis (EAE), requires activation of the myelination program. In this study, we observed the effect of RNA interference on Lingo-1 expression, and the impact of Lingo-1 suppression on functional recovery and myelination/remyelination in EAE mice. Lentiviral vectors encoding Lingo-1 short hairpin RNA (LV/Lingo-1-shRNA) were constructed to inhibit Lingo-1 expression. LV/Lingo-1-shRNA of different titers were transferred into myelin oligodendrocyte glycoprotein-induced EAE mice by intracerebroventricular (ICV) injection. Meanwhile, lentiviral vectors carrying nonsense gene sequence (LVCON053) were used as negative control. The Lingo-1 expression was detected and locomotor function was evaluated at different time points (on days 1,3,7,14,21, and 30 after ICV injection). Myelination was investigated by luxol fast blue (LFB) staining.LV/Lingo-1-shRNA administration via ICV injection could efficiently down-regulate the Lingo-1 mRNA and protein expression in EAE mice on days 7,14,21, and 30 (P RNA interference is, therefore, a promising approach for the treatment of demyelinating diseases, such as MS/EAE. © 2014 Wiley Periodicals, Inc.

  2. [Features of pathological changes in the non-myelin sheath of rats with experimental autoimmune encephalomyelitis].

    Science.gov (United States)

    Zhang, Jin-Feng; Huang, Rong; Yang, Yu-Jia; Xu, Jun; Jin, Shi-Jie

    2012-04-01

    To study the pathological changes in the non-myelin sheath by observing histological damages to the neurofilament protein and apoptosis of neurons in rats with experimental autoimmune encephalomyelitis (EAE). Forty-eight Wistar rats were randomly divided into two groups: control and EAE (24 rats in each group). Behavioral changes were observed. Inflammation reactions and demyelination were observed by hematoxylin eosin staining and LOYEZ staining.The level of neurofilament was detected by immunohistochemistry. Apoptosis of the neuron in the spinal cord was detected by TUNEL. Behavioral and histological results confirmed that the model of EAE rats was prepared successfully. In the EAE group, typical morphological features of axonal damage (sparsed axonal density, axonal distortion, axonal transection and even axonal disappearance) were found from the seventh day after immunization and the morphological changes were the most obvious on the fourteenth day. Neurofilament density in the EAE group was significantly lower than in the control group (P<0.01) at 7, 14 and 21 days after immunization. The neuronal apoptosis index in the EAE group at 7, 14 and 21 days after immunization was significantly higher than in the control group (P<0.01). In addition to inflammatory demyelination, axonal damage and neuronal apoptosis can be observed in the early stage of EAE. Pathological changes may be associated with neurological dysfunction.

  3. Protective influences on experimental autoimmune encephalomyelitis by MHC class I and class II alleles

    DEFF Research Database (Denmark)

    Mustafa, M; Vingsbo, C; Olsson, T

    1994-01-01

    Experimental autoimmune encephalomyelitis (EAE) is influenced by polymorphism of the MHC. We have previously found that Lewis rats with certain MHC haplotypes are susceptible to disease induced with the myelin basic protein (MBP) peptide 63-88, whereas Lewis rats with other MHC haplotypes...... are resistant. Interestingly, rats with the MHC u haplotype develop an immune response to the MBP 63-88, but do not get EAE. In this study we have used intra-MHC recombinant rat strains to compare the influences of the MHC u with the a haplotype. We discovered the following: 1) The class II region of the MHC...... a haplotype permits EAE and a Th1 type of immune response as measured by IFN-gamma production after in vitro challenge of in vivo-primed T cells with MBP 63-88. 2) The class II region of the u haplotype is associated with a disease-protective immune response characterized by production of not only IFN...

  4. Development of experimental autoimmune uveitis: efficient recruitment of monocytes is independent of CCR2.

    Science.gov (United States)

    Dagkalis, Athanasios; Wallace, Carol; Xu, Heping; Liebau, Sebastian; Manivannan, Ayyakkannu; Stone, Michael A; Mack, Matthias; Liversidge, Janet; Crane, Isabel J

    2009-09-01

    Macrophages are major contributors to the damage occurring in the retina in experimental autoimmune uveitis (EAU). CCR2 may be needed for efficient recruitment of monocytes to an inflammatory site, and the aim of this study was to determine whether this was the case in EAU. EAU was induced and graded in C57BL/6J and CCR2(-/-) mice. Macrophage infiltration and CCR2 expression were assessed using immunohistochemistry. Retinas were examined for MCP-1 expression using RT-PCR. Rolling and infiltration of labeled bone marrow monocytes at the inflamed retinal vasculature were examined by scanning laser ophthalmoscopy and confocal microscopy, respectively. Effect of CCR2 deletion or blockade by antibody and antagonist was determined. Expression of mRNA for MCP-1 increased as EAU developed and was localized to the retina. CCR2 was associated with infiltrating macrophages. However, EAU induced in CCR2(-/-) mice was not reduced in severity, and neither was the percentage of macrophages in the retina. CCR2(-/-) monocytes, 48 hours after adoptive transfer to mice with EAU, showed no significant difference in percentage rolling or infiltration into the retina compared to WT. CCR2-independent rolling of monocytes was confirmed by CCR2 neutralizing antibody and antagonist treatment. CCR2 does not have a primary role in the recruitment of monocytes to the inflammatory site across the blood-retina barrier in well-developed EAU. Therapeutics targeting CCR2 are unlikely to be of value in treating human posterior uveitis.

  5. Protecting axonal degeneration by increasing nicotinamide adenine dinucleotide levels in experimental autoimmune encephalomyelitis models.

    Science.gov (United States)

    Kaneko, Shinjiro; Wang, Jing; Kaneko, Marie; Yiu, Glenn; Hurrell, Joanna M; Chitnis, Tanuja; Khoury, Samia J; He, Zhigang

    2006-09-20

    Axonal damage is a major morphological alteration in the CNS of patients with multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the underlying mechanism for the axonal damage associated with MS/EAE and its contribution to the clinical symptoms remain unclear. The expression of a fusion protein, named "Wallerian degeneration slow" (Wld(S)), can protect axons from degeneration, likely through a beta-nicotinamide adenine dinucleotide (NAD)-dependent mechanism. In this study, we find that, when induced with EAE, Wld(S) mice showed a modest attenuation of behavioral deficits and axon loss, suggesting that EAE-associated axon damage may occur by a mechanism similar to Wallerian degeneration. Furthermore, nicotinamide (NAm), an NAD biosynthesis precursor, profoundly prevents the degeneration of demyelinated axons and improves the behavioral deficits in EAE models. Finally, we demonstrate that delayed NAm treatment is also beneficial to EAE models, pointing to the therapeutic potential of NAm as a protective agent for EAE and perhaps MS patients.

  6. A study of experimental autoimmune encephalomyelitis in dogs as a disease model for canine necrotizing encephalitis

    Science.gov (United States)

    Moon, Jong-Hyun; Jung, Hae-Won; Lee, Hee-Chun; Jeon, Joon-Hyeok; Kim, Na-Hyun; Sur, Jung-Hyang; Ha, Jeongim

    2015-01-01

    In the present study, the use of dogs with experimental autoimmune encephalomyelitis (EAE) as a disease model for necrotizing encephalitis (NE) was assessed. Twelve healthy dogs were included in this study. Canine forebrain tissues (8 g), including white and grey matter, were homogenized with 4 mL of phosphate-buffered saline for 5 min in an ice bath. The suspension was emulsified with the same volume of Freund's complete adjuvant containing 1 mg/mL of killed Mycobacterium tuberculosis H37Ra. Under sedation, each dog was injected subcutaneously with canine brain homogenate at four sites: two in the inguinal and two in the axillary regions. A second injection (booster) was administered to all the dogs using the same procedure 7 days after the first injection. Clinical assessment, magnetic resonance imaging, cerebrospinal fluid analyses, necropsies, and histopathological and immunohistochemical examinations were performed for the dogs with EAE. Out of the 12 animals, seven (58%) developed clinically manifest EAE at various times after immunization. Characteristics of canine EAE models were very similar to canine NE, suggesting that canine EAE can be a disease model for NE in dogs. PMID:25269720

  7. Fusion of metabolomics and proteomics data for biomarkers discovery: case study on the experimental autoimmune encephalomyelitis

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    Wijmenga Sybren S

    2011-06-01

    Full Text Available Abstract Background Analysis of Cerebrospinal Fluid (CSF samples holds great promise to diagnose neurological pathologies and gain insight into the molecular background of these pathologies. Proteomics and metabolomics methods provide invaluable information on the biomolecular content of CSF and thereby on the possible status of the central nervous system, including neurological pathologies. The combined information provides a more complete description of CSF content. Extracting the full combined information requires a combined analysis of different datasets i.e. fusion of the data. Results A novel fusion method is presented and applied to proteomics and metabolomics data from a pre-clinical model of multiple sclerosis: an Experimental Autoimmune Encephalomyelitis (EAE model in rats. The method follows a mid-level fusion architecture. The relevant information is extracted per platform using extended canonical variates analysis. The results are subsequently merged in order to be analyzed jointly. We find that the combined proteome and metabolome data allow for the efficient and reliable discrimination between healthy, peripherally inflamed rats, and rats at the onset of the EAE. The predicted accuracy reaches 89% on a test set. The important variables (metabolites and proteins in this model are known to be linked to EAE and/or multiple sclerosis. Conclusions Fusion of proteomics and metabolomics data is possible. The main issues of high-dimensionality and missing values are overcome. The outcome leads to higher accuracy in prediction and more exhaustive description of the disease profile. The biological interpretation of the involved variables validates our fusion approach.

  8. Mouse models of multiple sclerosis: experimental autoimmune encephalomyelitis and Theiler's virus-induced demyelinating disease.

    Science.gov (United States)

    McCarthy, Derrick P; Richards, Maureen H; Miller, Stephen D

    2012-01-01

    Experimental autoimmune encephalomyelitis (EAE) and Theiler's Murine Encephalitis Virus-Induced Demyelinating Disease (TMEV-IDD) are two clinically relevant murine models of multiple sclerosis (MS). Like MS, both are characterized by mononuclear cell infiltration into the CNS and demyelination. EAE is induced by either the administration of myelin protein or peptide in adjuvant or by the adoptive transfer of encephalitogenic T cell blasts into naïve recipients. The relative merits of each of these protocols are compared. Depending on the type of question being asked, different mouse strains and peptides are used. Different disease courses are observed with different strains and different peptides in active EAE. These variations are also addressed. Additionally, issues relevant to clinical grading of EAE in mice are discussed. In addition to EAE induction, useful references for other disease indicators such as DTH, in vitro proliferation, and immunohistochemistry are provided. TMEV-IDD is a useful model for understanding the possible viral etiology of MS. This section provides detailed information on the preparation of viral stocks and subsequent intracerebral infection of mice. Additionally, virus plaque assay and clinical disease assessment are discussed. Recently, recombinant TMEV strains have been created for the study of molecular mimicry which incorporate various 30 amino acid myelin epitopes within the leader region of TMEV.

  9. Modulation of fibronectin expression in the central nervous system of Lewis rats with experimental autoimmune encephalomyelitis

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    De-Carvalho M.C.A.

    1999-01-01

    Full Text Available Fibronectin (FN, a large family of plasma and extracellular matrix (ECM glycoproteins, plays an important role in leukocyte migration. In normal central nervous system (CNS, a fine and delicate mesh of FN is virtually restricted to the basal membrane of cerebral blood vessels and to the glial limitans externa. Experimental autoimmune encephalomyelitis (EAE, an inflammatory CNS demyelinating disease, was induced in Lewis rats with a spinal cord homogenate. During the preclinical phase and the onset of the disease, marked immunolabelling was observed on the endothelial luminal surface and basal lamina of spinal cord and brainstem microvasculature. In the paralytic phase, a discrete labelling was evident in blood vessels of spinal cord and brainstem associated or not with an inflammatory infiltrate. Conversely, intense immunolabelling was present in cerebral and cerebellar blood vessels, which were still free from inflammatory cuffs. Shortly after clinical recovery minimal labelling was observed in a few blood vessels. Brainstem and spinal cord returned to normal, but numerous inflammatory foci and demyelination were still evident near the ventricle walls, in the cerebral cortex and in the cerebellum. Intense expression of FN in brain vessels ascending from the spinal cord towards the encephalon preceded the appearance of inflammatory cells but faded away after the establishment of the inflammatory cuff. These results indicate an important role for FN in the pathogenesis of CNS inflammatory demyelinating events occurring during EAE.

  10. Combined treatment with ribavirin and tiazofurin attenuates response of glial cells in experimental autoimmune encephalomyelitis

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    Nedeljković Nadežda

    2012-01-01

    Full Text Available Experimental autoimmune encephalomyelitis (EAE is an animal model of multiple sclerosis (MS, a human inflammatory and demyelinating disease. Microglia and astrocytes are glial cells of the central nervous system (CNS that play a dual role in MS and EAE pathology. The aim of this study was to examine the effect of combined treatment with two nucleoside analogues, ribavirin and tiazofurin, on microglia and astrocytes in actively induced EAE. Therapeutic treatment with a combination of these two nucleoside analogues reduced disease severity, mononuclear cell infiltration and demyelination. The obtained histological results indicate that ribavirin and tiazofurin changed activated microglia into an inactive type and attenuated astrocyte reactivity at the end of the treatment period. Since reduction of reactive microgliosis and astrogliosis correlated with EAE suppression, the present study also suggests that the obtained beneficial effect of ribavirin and tiazofurin could be a consequence of their action inside as well as outside the CNS. [Acknowledgments. This work was supported by the Serbian Ministry of Education and Science, Project No: III41014.

  11. Treatment with Anti-EGF Ab Ameliorates Experimental Autoimmune Encephalomyelitis via Induction of Neurogenesis and Oligodendrogenesis

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    Yifat Amir-Levy

    2014-01-01

    Full Text Available Background. The neural stem cells (NSCs migrate to the damaged sites in multiple sclerosis (MS and in experimental autoimmune encephalomyelitis (EAE. However, the differentiation into neurons or oligodendrocytes is blocked. Epidermal growth factor (EGF stimulates NSC proliferation and mobilization to demyelinated lesions but also induces astrogenesis and glial scar. Objective. To examine the clinical and histopathological effects of EGF neutralization on EAE. Methods. EAE-induced SJL mice were intravenously treated with either anti-EGF neutralizing antibody (Ab or isotype control or PBS. On day 9 after immunization, 3 mice of each group were daily treated for 9 days with BrdU and then sacrificed for immunohistochemical analysis. Results. Treatment with anti-EGF Ab significantly ameliorated EAE symptoms during the second relapse. Anti-EGF Ab induced a shift from BrdU+GFAP+ NSCs to BrdU+DCX+ neuroblasts in the subventricular zone (SVZ, increased BrdU+NeuN+ neurons in the granular cell layer of the dentate gyrus, and increased BrdU+O4+ oligodendrocytes in the SVZ. There was no change in the inflammatory infiltrates in response to anti-EGF Ab. Conclusions. Therapy with anti-EGF Ab ameliorates EAE via induction of neurogenesis and oligodendrogenesis. No immunosuppressive effect was found. Further investigation is needed to support these notions of beneficial effect of anti-EGF Ab in MS.

  12. Treatment with Vitamin D/MOG Association Suppresses Experimental Autoimmune Encephalomyelitis.

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    Fernanda Chiuso-Minicucci

    Full Text Available Experimental autoimmune encephalomyelitis (EAE is an animal model to study multiple sclerosis (MS. Considering the tolerogenic effects of active vitamin D, we evaluated the therapeutic effect of myelin oligodendrocyte glycoprotein (MOG associated with active vitamin D in EAE development. EAE was induced in female C57BL/6 mice by immunization with MOG emulsified with Complete Freund's Adjuvant plus Mycobacterium tuberculosis. Animals also received two intraperitoneal doses of Bordetella pertussis toxin. One day after immunization, mice were treated with 0,1 μg of 1α,25-dihydroxyvitamin D3 (1,25(OH2D3 every other day during 15 days (on days 1, 3, 5, 7, 9, 11, 13 and 15. MOG (150 μg was co-administered on days 3 and 11. The administration of 1,25(OH2D3 or MOG determined significant reduction in EAE incidence and in clinical scores. When MOG was associated with 1,25(OH2D3 the animals did not develop EAE. Spleen and central nervous system (CNS cell cultures from this group produced less IL-6 and IL-17 upon stimulation with MOG in comparison to the EAE control group. In addition, this treatment inhibited dendritic cells maturation in the spleen and reduced inflammatory infiltration in the CNS. The association of MOG with 1,25(OH2D3 was able to control EAE development.

  13. SAP Suppresses the Development of Experimental Autoimmune Encephalomyelitis in C57BL6 Mice

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    Ji, Zhe; Ke, Zun-Ji; Geng, Jian-Guo

    2012-01-01

    Experimental autoimmune encephalomyelitis (EAE) is a CD4+ T cell-mediated disease of the CNS. Serum amyloid P component (SAP) is a highly conserved plasma protein named for its universal presence in amyloid deposits. Here we report SAP transgenic mice had unexpectedly attenuated EAE due to impaired encephalitogenic responses. Following induction with myelin oligodendroglial glycoprotein (MOG) peptide 35–55 in CFA, SAP transgenic mice showed reduced spinal cord inflammation with lower severity of EAE attacks as compared with control C57BL/6 mice. However in SAP-KO mice, the severity of EAE is enhanced. Adoptive transfer of Ag-restimulated T cells from wild-type to SAP transgenic mice or transfer of SAP transgenic Ag-restimulated T cells to control mice induced milder EAE. T cells from MOG-primed SAP transgenic mice showed weak proliferative responses. Furthermore, in SAP transgenic mice, there is little infiltration of CD45-positive cells in the spinal cord. In vitro, SAP suppressed the secretion of IL-2 stimulated by P-selectin, and blocked P-selectin binding to T cells. Moreover, SAP could change the affinity between α4-integrin and T cells. These data suggested that SAP could antagonize the development of the acute phase of inflammation accompanying EAE by modulating the function of P-selectin. PMID:21647172

  14. Serum Neuroinflammatory Disease-Induced Central Nervous System Proteins Predict Clinical Onset of Experimental Autoimmune Encephalomyelitis

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    Itay Raphael

    2017-07-01

    Full Text Available There is an urgent need in multiple sclerosis (MS patients to develop biomarkers and laboratory tests to improve early diagnosis, predict clinical relapses, and optimize treatment responses. In healthy individuals, the transport of proteins across the blood–brain barrier (BBB is tightly regulated, whereas, in MS, central nervous system (CNS inflammation results in damage to neuronal tissues, disruption of BBB integrity, and potential release of neuroinflammatory disease-induced CNS proteins (NDICPs into CSF and serum. Therefore, changes in serum NDICP abundance could serve as biomarkers of MS. Here, we sought to determine if changes in serum NDICPs are detectable prior to clinical onset of experimental autoimmune encephalomyelitis (EAE and, therefore, enable prediction of disease onset. Importantly, we show in longitudinal serum specimens from individual mice with EAE that pre-onset expression waves of synapsin-2, glutamine synthetase, enolase-2, and synaptotagmin-1 enable the prediction of clinical disease with high sensitivity and specificity. Moreover, we observed differences in serum NDICPs between active and passive immunization in EAE, suggesting hitherto not appreciated differences for disease induction mechanisms. Our studies provide the first evidence for enabling the prediction of clinical disease using serum NDICPs. The results provide proof-of-concept for the development of high-confidence serum NDICP expression waves and protein biomarker candidates for MS.

  15. Role of PU.1 Expression as an Inflammatory Marker in Experimental Autoimmune Uveoretinitis.

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    Umazume, Akihiko; Kezuka, Takeshi; Matsuda, Ryusaku; Usui, Yoshihiko; Takahashi, Hiroki; Yamakawa, Naoyuki; Yashiro, Takuya; Nishiyama, Chiharu; Goto, Hiroshi

    2017-04-27

    PU.1 is an Ets family transcription factor, which is essential for the development of immune system through generation of myeloid and lymphoid lineages. In this study, we investigated PU.1 expression in the retina of mice with experimental autoimmune uveoretinitis (EAU) and the association between PU.1 expression level and inflammation in EAU. IRBP 1-20 peptide-immunized mice were used. Quantitative PCR, ELISA analysis, cytometric bead array (CBA), assay and immunostaining were conducted using ocular tissues and lymph nodes. Quantitative PCR showed significant increases in mRNA levels of PU.1 in the retina at the peak of inflammation. Immunostaining of retina flat mounts revealed that most PU.1-positive cells were co-stained with anti-CD11c and anti-F4/80 antibodies. PU.1 knockdown in lymph node cells significantly suppressed IRBP-stimulated IFN-γ production measured by ELISA and IL-2 production measured by CBA. PU.1 may play crucial roles in the development and progression of inflammation in EAU.

  16. LINGO-1 antibody ameliorates myelin impairment and spatial memory deficits in experimental autoimmune encephalomyelitis mice.

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    Sun, Jun-Jun; Ren, Qing-Guo; Xu, Lin; Zhang, Zhi-Jun

    2015-09-18

    More than 50% of multiple sclerosis patients develop cognitive impairment. However, the underlying mechanisms are still unclear, and there is no effective treatment. LINGO-1 (LRR and Ig domain containing NOGO receptor interacting protein 1) has been identified as an inhibitor of oligodendrocyte differentiation and myelination. Using the experimental autoimmune encephalomyelitis (EAE) mouse model, we assessed cognitive function at early and late stages of EAE, determined brain expression of myelin basic protein (MBP) and investigated whether the LINGO-1 antibody could restore deficits in learning and memory and ameliorate any loss of MBP. We found that deficits in learning and memory occurred in late EAE and identified decreased expression of MBP in the parahippocampal cortex (PHC) and fimbria-fornix. Moreover, the LINGO-1 antibody significantly improved learning and memory in EAE and partially restored MBP in PHC. Furthermore, the LINGO-1 antibody activated the AKT/mTOR signaling pathway regulating myelin growth. Our results suggest that demyelination in the PHC and fimbria-fornix might contribute to cognitive deficits and the LINGO-1 antibody could ameliorate these deficits by promoting myelin growth in the PHC. Our research demonstrates that LINGO-1 antagonism may be an effective approach to the treatment of the cognitive impairment of multiple sclerosis patients.

  17. Experimental autoimmune myasthenia gravis may occur in the context of a polarized Th1- or Th2-type immune response in rats

    DEFF Research Database (Denmark)

    Saoudi, A; Bernard, I; Hoedemaekers, A

    1999-01-01

    Experimental autoimmune myasthenia gravis (EAMG) is a T cell-dependent, Ab-mediated autoimmune disease induced in rats by a single immunization with acetylcholine receptor (AChR). Although polarized Th1 responses have been shown to be crucial for the development of mouse EAMG, the role of Th cell...

  18. Arg deficiency does not influence the course of Myelin Oligodendrocyte Glycoprotein (MOG35-55)-induced experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Jacobsen, Freja Aksel; Hulst, Camilla; Bäckström, Thomas

    2016-01-01

    extensively studied in immune activation, roles for Arg are incompletely characterized. To investigate the role for Arg in experimental autoimmune encephalomyelitis, we studied disease development in Arg-/- mice. Methods: Arg-/- and Arg+/+ mice were generated from breeding of Arg+/- mice on the C57BL/6...... background. Mice were immunized with the myelin oligodendrocyte glycoprotein (MOG)35-55 peptide and disease development recorded. Lymphocyte phenotypes of wild type Arg+/+ and Arg-/- mice were studied by in vitro stimulation assays and flow cytometry. Results: The breeding of Arg+/+ and Arg-/- mice showed......Background: Inhibition of Abl kinases has an ameliorating effect on the rodent model for multiple sclerosis, experimental autoimmune encephalomyelitis, and arrests lymphocyte activation. The family of Abl kinases consists of the Abl1/Abl and Abl2/Arg tyrosine kinases. While the Abl kinase has been...

  19. Specific and strain-independent effects of dexamethasone in the prevention and treatment of experimental autoimmune encephalomyelitis in rodents

    DEFF Research Database (Denmark)

    Donia, M; Mangano, K; Quattrocchi, C

    2010-01-01

    Experimental autoimmune encephalomyelitis in rodents (EAE) is a generally accepted in vivo model for immunopathogenic mechanisms underlying multiple sclerosis (MS). There are, however, different forms of rodent EAE, and therapeutic regimens may affect these forms differently. We have therefore te...... predictors of drug efficacy in at least some variants of human MS. Better understanding of the clinical and immunopharmacologic features of these models might prove useful when testing new drug candidates for MS treatment....

  20. Autoimmune regulator (AIRE)-deficient CD8+CD28low regulatory T lymphocytes fail to control experimental colitis.

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    Pomié, Céline; Vicente, Rita; Vuddamalay, Yirajen; Lundgren, Brita Ardesjö; van der Hoek, Mark; Enault, Geneviève; Kagan, Jérémy; Fazilleau, Nicolas; Scott, Hamish S; Romagnoli, Paola; van Meerwijk, Joost P M

    2011-07-26

    Mutations in the gene encoding the transcription factor autoimmune regulator (AIRE) are responsible for autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome. AIRE directs expression of tissue-restricted antigens in the thymic medulla and in lymph node stromal cells and thereby substantially contributes to induction of immunological tolerance to self-antigens. Data from experimental mouse models showed that AIRE deficiency leads to impaired deletion of autospecific T-cell precursors. However, a potential role for AIRE in the function of regulatory T-cell populations, which are known to play a central role in prevention of immunopathology, has remained elusive. Regulatory T cells of CD8(+)CD28(low) phenotype efficiently control immune responses in experimental autoimmune and colitis models in mice. Here we show that CD8(+)CD28(low) regulatory T lymphocytes from AIRE-deficient mice are transcriptionally and phenotypically normal and exert efficient suppression of in vitro immune responses, but completely fail to prevent experimental colitis in vivo. Our data therefore demonstrate that AIRE plays an important role in the in vivo function of a naturally occurring regulatory T-cell population.

  1. Resistance to experimental autoimmune encephalomyelitis development in Lewis rats from a conventional animal facility

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    Sofia Fernanda Gonçalves Zorzella

    2007-12-01

    Full Text Available Experimental autoimmune encephalomyelitis (EAE is an inflammatory disease of the brain and spinal cord that is mediated by CD4+ T lymphocytes specific to myelin components. In this study we compared development of EAE in Lewis rats from two colonies, one kept in pathogen-free conditions (CEMIB colony and the other (Botucatu colony kept in a conventional animal facility. Female Lewis rats were immunized with 100 µl of an emulsion containing 50 µg of myelin, associated with incomplete Freund's adjuvant plus Mycobacterium butyricum. Animals were daily evaluated for clinical score and weight. CEMIB colony presented high EAE incidence with clinical scores that varied from three to four along with significant weight losses. A variable disease incidence was observed in the Botucatu colony with clinical scores not higher than one and no weight loss. Immunological and histopathological characteristics were also compared after 20 days of immunization. Significant amounts of IFN-gamma, TNF-alpha and IL-10 were induced by myelin in cultures from CEMIB animals but not from the Botucatu colony. Significantly higher levels of anti-myelin IgG1 were detected in the CEMIB colony. Clear histopathological differences were also found. Cervical spinal cord sections from CEMIB animals showed typical perivascular inflammatory foci whereas samples from the Botucatu colony showed a scanty inflammatory infiltration. Helminths were found in animals from Botucatu colony but not, as expected, in the CEMIB pathogen-free animals. As the animals maintained in a conventional animal facility developed a very discrete clinical, and histopathological EAE in comparison to the rats kept in pathogen-free conditions, we believe that environmental factors such as intestinal parasites could underlie this resistance to EAE development, supporting the applicability of the hygiene hypothesis to EAE.

  2. Mechanisms of action of cannabidiol in adoptively transferred experimental autoimmune encephalomyelitis.

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    González-García, Coral; Torres, Irene Moreno; García-Hernández, Ruth; Campos-Ruíz, Lucía; Esparragoza, Luis Rodríguez; Coronado, María José; Grande, Aranzazu García; García-Merino, Antonio; Sánchez López, Antonio J

    2017-12-01

    Cannabidiol (CBD) is one of the most important compounds in Cannabis sativa, lacks psychotropic effects, and possesses a high number of therapeutic properties including the amelioration of experimental autoimmune encephalomyelitis (EAE). The aim of this study was to analyse the relative efficacy of CBD in adoptively transferred EAE (at-EAE), a model that allows better delineation of the effector phase of EAE. Splenocytes and lymph nodes from mice with actively induced EAE were cultured in the presence of MOG 35-55 and IL-12 and inoculated intraperitoneally in recipient female C57BL/6J mice. The effects of CBD were evaluated using clinical scores and magnetic resonance imaging (MRI). In the central nervous system, the extent of cell infiltration, axonal damage, demyelination, microglial activation and cannabinoid receptors expression was assessed by immunohistochemistry. Lymph cell viability, apoptosis, oxidative stress and IL-6 production were measured in vitro. Preventive intraperitoneal treatment with CBD ameliorated the clinical signs of at-EAE, and this improvement was accompanied by a reduction of the apparent diffusion coefficient in the subiculum area of the brain. Inflammatory infiltration, axonal damage, and demyelination were reduced, and cannabinoid receptor expression was modulated. Incubation with CBD decreased encephalitogenic cell viability, increasing early apoptosis and reactive oxygen species (ROS) and decreasing IL-6 production. The reduction in viability was not mediated by CB 1 , CB 2 or GPR55 receptors. CBD markedly improved the clinical signs of at-EAE and reduced infiltration, demyelination and axonal damage. The CBD-mediated decrease in the viability of encephalitogenic cells involves ROS generation, apoptosis and a decrease in IL-6 production and may contribute to the therapeutic effect of this compound. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Effect of ether glycerol lipids on interleukin-1β release and experimental autoimmune encephalomyelitis.

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    Boomkamp, Stephanie D; Byun, Hoe-Sup; Ubhi, Satvir; Jiang, Hui-Rong; Pyne, Susan; Bittman, Robert; Pyne, Nigel J

    2016-01-01

    We have assessed the effect of two ether glycerol lipids, 77-6 ((2S, 3R)-4-(Tetradecyloxy)-2-amino-1,3-butanediol) and 56-5 ((S)-2-Amino-3-O-hexadecyl-1-propanol), which are substrates for sphingosine kinases, on inflammatory responses. Treatment of differentiated U937 macrophage-like cells with 77-6 but not 56-5 enhanced IL-1β release; either alone or in the presence of LPS. The stimulatory effect of sphingosine or 77-6 on LPS-stimulated IL-1β release was reduced by pretreatment of cells with the caspase-1 inhibitor, Ac-YVAD-CHO, thereby indicating a role for the inflammasome. The enhancement of LPS-stimulated IL-1β release in response to sphingosine, but not 77-6, was reduced by pretreatment of cells with the cathepsin B inhibitor, CA074Me, indicating a role for lysosomal destabilization in the effect of sphingosine. Administration of 56-5 to mice increased disease progression in an experimental autoimmune encephalomyelitis model and this was associated with a considerable increase in the infiltration of CD4(+) T-cells, CD11b(+) monocytes and F4/80(+) macrophages in the spinal cord. 56-5 and 77-6 were without effect on the degradation of myc-tagged sphingosine 1-phosphate 1 receptor in CCL39 cells. Therefore, the effect of 56-5 on EAE disease progression is likely to be independent of the inflammasome or the sphingosine 1-phosphate 1 receptor. However, 56-5 is chemically similar to platelet activating factor and the exacerbation of EAE disease progression might be linked to platelet activating factor receptor signaling. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. Cerebral biochemical pathways in experimental autoimmune encephalomyelitis and adjuvant arthritis: a comparative metabolomic study.

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    Norbert W Lutz

    Full Text Available Many diseases, including brain disorders, are associated with perturbations of tissue metabolism. However, an often overlooked issue is the impact that inflammations outside the brain may have on brain metabolism. Our main goal was to study similarities and differences between brain metabolite profiles of animals suffering from experimental autoimmune encephalomyelitis (EAE and adjuvant arthritis (AA in Lewis rat models. Our principal objective was the determination of molecular protagonists involved in the metabolism underlying these diseases. EAE was induced by intraplantar injection of complete Freund's adjuvant (CFA and spinal-cord homogenate (SC-H, whereas AA was induced by CFA only. Naive rats served as controls (n = 9 for each group. Two weeks after inoculation, animals were sacrificed, and brains were removed and processed for metabolomic analysis by NMR spectroscopy or for immunohistochemistry. Interestingly, both inflammatory diseases caused similar, though not identical, changes in metabolites involved in regulation of brain cell size and membrane production: among the osmolytes, taurine and the neuronal marker, N-acetylaspartate, were decreased, and the astrocyte marker, myo-inositol, slightly increased in both inoculated groups compared with controls. Also ethanolamine-containing phospholipids, sources of inflammatory agents, and several glycolytic metabolites were increased in both inoculated groups. By contrast, the amino acids, aspartate and isoleucine, were less concentrated in CFA/SC-H and control vs. CFA rats. Our results suggest that inflammatory brain metabolite profiles may indicate the existence of either cerebral (EAE or extra-cerebral (AA inflammation. These inflammatory processes may act through distinct pathways that converge toward similar brain metabolic profiles. Our findings open new avenues for future studies aimed at demonstrating whether brain metabolic effects provoked by AA are pain/stress-mediated and

  5. A novel pathogenic RBP-3 peptide reveals epitope spreading in persistent experimental autoimmune uveoretinitis.

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    Boldison, Joanne; Khera, Tarnjit K; Copland, David A; Stimpson, Madeleine L; Crawford, Gemma L; Dick, Andrew D; Nicholson, Lindsay B

    2015-10-01

    Experimental autoimmune uveoretinitis (EAU) in the C57BL/6J mouse is a model of non-infectious posterior segment intraocular inflammation that parallels clinical features of the human disease. The purpose of this study was to analyse the immune response to the four murine subunits of retinol binding protein-3 (RBP-3) to identify pathogenic epitopes to investigate the presence of intramolecular epitope spreading during the persistent inflammation phase observed in this model of EAU. Recombinant murine subunits of the RBP-3 protein were purified and used to immunize C57BL/6J mice to induce EAU. An overlapping peptide library was used to screen RBP-3 subunit 3 for immunogenicity and pathogenicity. Disease phenotype and characterization of pathogenic subunits and peptides was undertaken by topical endoscopic fundal imaging, immunohistochemistry, proliferation assays and flow cytometry. RBP-3 subunits 1, 2 and 3 induced EAU in the C57BL/6J mice, with subunit 3 eliciting the most destructive clinical disease. Within subunit 3 we identified a novel uveitogenic epitope, 629-643. The disease induced by this peptide was comparable to that produced by the uveitogenic 1-20 peptide. Following immunization, peptide-specific responses by CD4(+) and CD8(+) T-cell subsets were detected, and cells from both populations were present in the retinal inflammatory infiltrate. Intramolecular epitope spreading between 629-643 and 1-20 was detected in mice with clinical signs of disease. The 629-643 RBP-3 peptide is a major uveitogenic peptide for the induction of EAU in C57BL/6J mice and the persistent clinical disease induced with one peptide leads to epitope spreading. © 2015 John Wiley & Sons Ltd.

  6. Resveratrol defends blood-brain barrier integrity in experimental autoimmune encephalomyelitis mice.

    Science.gov (United States)

    Wang, Dong; Li, Shi-Ping; Fu, Jin-Sheng; Zhang, Sheng; Bai, Lin; Guo, Li

    2016-11-01

    The mouse autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS), is primarily characterized as dysfunction of the blood-brain barrier (BBB). Resveratrol exhibits anti-inflammatory, antioxidative, and neuroprotective activities. We investigated the beneficial effects of resveratrol in protecting the integrity of the BBB in EAE mice and observed improved clinical outcome in the EAE mice after resveratrol treatment. Evans blue (EB) extravasation was used to detect the disruption of BBB. Western blot were used to detected the tight junction proteins and adhesion molecules zonula occludens-1 (ZO-1), occludin, ICAM-1, and VCAM-1. Inflammatory factors inducible nitric oxide synthase (iNOS), IL-1β, and arginase 1 were evaluated by quantitative RT-PCR (qPCR) and IL-10 by ELISA. NADPH oxidase (NOX) levels were evaluated by qPCR, and its activity was analyzed by lucigenin-derived chemiluminescence. Resveratrol at doses of 25 and 50 mg/kg produced a dose-dependent decrease in EAE paralysis and EB leakage, ameliorated EAE-induced loss of tight junction proteins ZO-1, occludin, and claudin-5, as well as repressed the EAE-induced increase in adhesion proteins ICAM-1 and VCAM-1. In addition, resveratrol suppressed the EAE-induced overexpression of proinflammatory transcripts iNOS and IL-1β and upregulated the expression of anti-inflammatory transcripts arginase 1 and IL-10 cytokine in the brain. Furthermore, resveratrol downregulated the overexpressed NOX2 and NOX4 in the brain and suppressed NADPH activity. Resveratrol ameliorates the clinical severity of MS through maintaining the BBB integrity in EAE mice. Copyright © 2016 the American Physiological Society.

  7. Partial deficiency of sphingosine-1-phosphate lyase confers protection in experimental autoimmune encephalomyelitis.

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    Andreas Billich

    Full Text Available BACKGROUND: Sphingosine-1-phosphate (S1P regulates the egress of T cells from lymphoid organs; levels of S1P in the tissues are controlled by S1P lyase (Sgpl1. Hence, Sgpl1 offers a target to block T cell-dependent inflammatory processes. However, the involvement of Sgpl1 in models of disease has not been fully elucidated yet, since Sgpl1 KO mice have a short life-span. METHODOLOGY: We generated inducible Sgpl1 KO mice featuring partial reduction of Sgpl1 activity and analyzed them with respect to sphingolipid levels, T-cell distribution, and response in models of inflammation. PRINCIPAL FINDINGS: The partially Sgpl1 deficient mice are viable but feature profound reduction of peripheral T cells, similar to the constitutive KO mice. While thymic T cell development in these mice appears normal, mature T cells are retained in thymus and lymph nodes, leading to reduced T cell numbers in spleen and blood, with a skewing towards increased proportions of memory T cells and T regulatory cells. The therapeutic relevance of Sgpl1 is demonstrated by the fact that the inducible KO mice are protected in experimental autoimmune encephalomyelitis (EAE. T cell immigration into the CNS was found to be profoundly reduced. Since S1P levels in the brain of the animals are unchanged, we conclude that protection in EAE is due to the peripheral effect on T cells, leading to reduced CNS immigration, rather than on local effects in the CNS. SIGNIFICANCE: The data suggest Sgpl1 as a novel therapeutic target for the treatment of multiple sclerosis.

  8. Excess circulating alternatively activated myeloid (M2 cells accelerate ALS progression while inhibiting experimental autoimmune encephalomyelitis.

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    Ilan Vaknin

    Full Text Available Circulating immune cells including autoreactive T cells and monocytes have been documented as key players in maintaining, protecting and repairing the central nervous system (CNS in health and disease. Here, we hypothesized that neurodegenerative diseases might be associated, similarly to tumors, with increased levels of circulating peripheral myeloid derived suppressor cells (MDSCs, representing a subset of suppressor cells that often expand under pathological conditions and inhibit possible recruitment of helper T cells needed for fighting off the disease.We tested this working hypothesis in amyotrophic lateral sclerosis (ALS and its mouse model, which are characterized by a rapid progression once clinical symptoms are evident. Adaptive transfer of alternatively activated myeloid (M2 cells, which homed to the spleen and exhibited immune suppressive activity in G93A mutant superoxide dismutase-1 (mSOD1 mice at a stage before emergence of disease symptoms, resulted in earlier appearance of disease symptoms and shorter life expectancy. The same protocol mitigated the inflammation-induced disease model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE, which requires circulating T cells for disease induction. Analysis of whole peripheral blood samples obtained from 28 patients suffering from sporadic ALS (sALS, revealed a two-fold increase in the percentage of circulating MDSCs (LIN(-/LowHLA-DR(-CD33(+ compared to controls.Taken together, these results emphasize the distinct requirements for fighting the inflammatory neurodegenerative disease, multiple sclerosis, and the neurodegenerative disease, ALS, though both share a local inflammatory component. Moreover, the increased levels of circulating MDSCs in ALS patients indicates the operation of systemic mechanisms that might lead to an impairment of T cell reactivity needed to overcome the disease conditions within the CNS. This high level of suppressive immune cells might

  9. Immunomodulation of Experimental Autoimmune Encephalomyelitis by Oral Administration of Copolymer 1

    Science.gov (United States)

    Teitelbaum, Dvora; Arnon, Ruth; Sela, Michael

    1999-03-01

    The activity of copolymer 1 (Cop 1, Copax-one, glatiramer acetate) in suppressing experimental autoimmune encephalomyelitis (EAE) and in the treatment of multiple sclerosis patients when injected parenterally has been extensively demonstrated. In the present study we addressed the question of whether Cop 1 can induce oral tolerance to EAE similar to myelin basic protein (MBP). We now have demonstrated that oral Cop 1 inhibited EAE induction in both rats and mice. Furthermore, oral Cop 1 was more effective than oral MBP in suppressing EAE in rats. The beneficial effect of oral Cop 1 was found to be associated with specific inhibition of the proliferative and Th1 cytokine secretion responses to MBP of spleen cells from Cop 1-fed mice and rats. In all of these assays, oral Cop 1 was more effective than oral MBP. The tolerance induced by Cop 1 could be adoptively transferred with spleen cells from Cop 1-fed animals. Furthermore, Cop 1-specific T cell lines, which inhibit EAE induction in vivo, could be isolated from the above spleen cells. These T cell lines secrete the anti-inflammatory cytokines IL-10 and transforming growth factor type β , but not IL-4, in response to both Cop 1 and MBP. In conclusion, oral Cop 1 has a beneficial effect on the development of EAE that is associated with down-regulation of T cell immune responses to MBP and is mediated by Th2/3 type regulatory cells. These results suggest that oral administration of Cop 1 may modulate multiple sclerosis as well.

  10. Effects of 1, 25-Dihydroxyvitamin D3 on Experimental Autoimmune Myocarditis in Mice

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    Fen Hu

    2016-05-01

    Full Text Available Background/Aims: Myocarditis is an important inflammatory disease of the heart which causes life-threatening conditions. 1, 25(OH2 D3 has effects on multiple systems and diseases. The present study was aimed to investigate the effect of 1, 25(OH2 D3 on experimental autoimmune myocarditis (EAM, and explored the underlying mechanisms involved. Methods: EAM was induced by immunizing BALB/c mice with cardiac α-myosin heavy chain peptides (MyHC-α. 1, 25(OH2 D3 (1,000 ng/kg once or vehicle was administered intraperitoneally every other day during the entire experiment. On day 21, transthoracic echocardiography was performed and cardiac inflammatory infiltration was detected by hematoxylin and eosin (HE. The terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL assay, and Western blots for the expression of protein caspase-3 and cleaved-caspase3 were used to evaluate apoptosis. Transmission electron microscopy and Western blots for the expression of protein Beclin-1, LC3B, and P62 were used to evaluate autophagy. Results: The ratio of heart weight/body weight was significantly reduced in 1, 25(OH2 D3 -treated EAM mice, compared with vehicle -treated ones. 1, 25(OH2 D3 treatment improved cardiac function, diminished cell infiltration in cardiac, suppressed myocardial apoptosis, decreased the number of autophagosomes, and decreased the protein expression of Beclin-1, LC3-II and p62. Conclusions: The present results demonstrated that administration of 1, 25(OH2 D3 decreased EAM severity. 1, 25(OH2 D3 treatment may be a feasible therapeutic approach for EAM.

  11. Pain in experimental autoimmune encephalitis: a comparative study between different mouse models

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    Lu Jianning

    2012-10-01

    Full Text Available Abstract Background Pain can be one of the most severe symptoms associated with multiple sclerosis (MS and develops with varying levels and time courses. MS-related pain is difficult to treat, since very little is known about the mechanisms underlying its development. Animal models of experimental autoimmune encephalomyelitis (EAE mimic many aspects of MS and are well-suited to study underlying pathophysiological mechanisms. Yet, to date very little is known about the sensory abnormalities in different EAE models. We therefore aimed to thoroughly characterize pain behavior of the hindpaw in SJL and C57BL/6 mice immunized with PLP139-151 peptide or MOG35-55 peptide respectively. Moreover, we studied the activity of pain-related molecules and plasticity-related genes in the spinal cord and investigated functional changes in the peripheral nerves using electrophysiology. Methods We analyzed thermal and mechanical sensitivity of the hindpaw in both EAE models during the whole disease course. Qualitative and quantitative immunohistochemical analysis of pain-related molecules and plasticity-related genes was performed on spinal cord sections at different timepoints during the disease course. Moreover, we investigated functional changes in the peripheral nerves using electrophysiology. Results Mice in both EAE models developed thermal hyperalgesia during the chronic phase of the disease. However, whereas SJL mice developed marked mechanical allodynia over the chronic phase of the disease, C57BL/6 mice developed only minor mechanical allodynia over the onset and peak phase of the disease. Interestingly, the magnitude of glial changes in the spinal cord was stronger in SJL mice than in C57BL/6 mice and their time course matched the temporal profile of mechanical hypersensitivity. Conclusions Diverse EAE models bearing genetic, clinical and histopathological heterogeneity, show different profiles of sensory and pathological changes and thereby enable

  12. Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune myasthenia gravis.

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    Tüzün, Erdem; Scott, Benjamin G; Goluszko, Elzbieta; Higgs, Stephen; Christadoss, Premkumar

    2003-10-01

    Abs to acetylcholine receptor (AChR) and complement are the major constituents of pathogenic events causing neuromuscular junction destruction in both myasthenia gravis (MG) and experimental autoimmune MG (EAMG). To analyze the differential roles of the classical vs alternative complement pathways in EAMG induction, we immunized C3(-/-), C4(-/-), C3(+/-), and C4(+/-) mice and their control littermates (C3(+/+) and C4(+/+) mice) with AChR in CFA. C3(-/-) and C4(-/-) mice were resistant to disease, whereas mice heterozygous for C3 or C4 displayed intermediate susceptibility. Although C3(-/-) and C4(-/-) mice had anti-AChR Abs in their sera, anti-AChR IgG production by C3(-/-) mice was significantly suppressed. Both C3(-/-) and C4(-/-) mice had reduced levels of B cells and increased expression of apoptotis inducers (Fas ligand, CD69) and apoptotic cells in lymph nodes. Immunofluorescence studies showed that the neuromuscular junction of C3(-/-) and C4(-/-) mice lacked C3 or membrane attack complex deposits, despite having IgG deposits, thus providing in vivo evidence for the incapacity of anti-AChR IgGs to induce full-blown EAMG without the aid of complements. The data provide the first direct genetic evidence for the classical complement pathway in the induction of EAMG induced by AChR immunization. Accordingly, severe MG and other Ab- and complement-mediated diseases could be effectively treated by inhibiting C4, thus leaving the alternative complement pathway intact.

  13. Delayed onset of experimental autoimmune encephalomyelitis in Olig1 deficient mice.

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    Xiaoli Guo

    Full Text Available BACKGROUND: Olig1 is a basic helix-loop-helix (bHLH transcription factor that is essential for oligodendrogenesis and efficient remyelination. However, its role in neurodegenerative disorders has not been well-elucidated. METHODOLOGY/PRINCIPAL FINDINGS: Here we investigated the effects of Olig1 deficiency on experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS. We show that the mean disease onset of myelin oligodendrocyte glycoprotein (MOG-induced EAE in Olig1(-/- mice is significantly slower than wide-type (WT mice (19.8 ± 2.2 in Olig1(-/- mice and 9.5 ± 0.3 days in WT mice. In addition, 10% of Olig1(-/- mice did not develop EAE by the end of the observation periods (60 days. The severity of EAE, the extent of demyelination, and the activation of microglial cells and astrocytes in spinal cords, were significantly milder in Olig1(-/- mice compared with WT mice in the early stage. Moreover, the visual function, as assessed by the second-kernel of multifocal electroretinograms, was better preserved, and the number of degenerating axons in the optic nerve was significantly reduced in Olig1(-/- mice. Interestingly, Olig1 deficiency had no effect on T cell response capability, however, it reduced the expression of myelin proteins such as MOG, myelin basic protein (MBP and myelin-associated glycoprotein (MAG. The expression of Olig2 remained unchanged in the optic nerve and brain, and it was reduced in the spinal cord of Olig1(-/- mice. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the Olig1 signaling pathways may be involved in the incidence rate and the severity of neurological symptoms in MS.

  14. Immunopathological events initiated and maintained by pathogenic IgG autoantibodies in an experimental autoimmune kidney disease.

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    Barabas, Arpad Zsigmond; Cole, Chad Douglas; Lafreniere, Rene; Weir, Donald Mackay

    2012-11-01

    The experimental models of Heymann nephritis (HN) and slowly progressive Heymann nephritis (SPHN) give us rare opportunities to investigate the etiologies and pathogenesis of two immunopathological processes in rats leading to: (1) autoimmune disease, where the autoimmune disease HN and SPHN is initiated and maintained by cross-reactive pathogenic IgG autoantibodies (aabs) directed against the renal proximal convoluted tubules' brush border (BB) cells - where the nephritogenic antigen (ag) is produced and localized - damaging and releasing BB associated nephritogenic ag into the circulation which in turn contributes to continuation of the autoimmune disease; and (2) immune complex glomerulonephritis, where the glomerular injury is initiated, proceeding into a chronic progressive disease by depositing immune complexes (ICs) - made up of a glomerular epithelial cell produced endogenous nephritogenic ag and the developing pathogenic IgG aab directed against the nephritogenic ag, and complement components - on the epithelial side of the glomerular basement membrane. We also observed how the normally functioning immune system is able to avert autoimmune disease developments by circulating specific non-pathogenic IgM aabs clearing the system of intracytoplasmic ags released from cells at the end of their life spans or following damage by toxic agents. We also described how an autoimmune disease SPHN can be prevented and when present terminated by the implementation of a new vaccination technique we have developed and call modified vaccination technique. By increasing the specific IgM aab production against the native nephritogenic ag - by injecting ICs made up of: [nephritogenic ag X homologous anti-nephritogenic ag IgM ab] in slight ag excess into SPHN rats - pathogenic IgG aab producing native and modified nephritogenic ags were removed from the circulation and termination of the autoimmune disease causing immune events was achieved. Even though HN and SPHN are not

  15. Persistent activation of microglia is associated with neuronal dysfunction of callosal projecting pathways and multiple sclerosis-like lesions in relapsing--remitting experimental autoimmune encephalomyelitis

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    Rasmussen, Stine; Wang, Yue; Kivisäkk, Pia

    2007-01-01

    Cortical pathology, callosal atrophy and axonal loss are substrates of progression in multiple sclerosis (MS). Here we describe cortical, periventricular subcortical lesions and callosal demyelination in relapsing-remitting experimental autoimmune encephalomyelitis in SJL mice that are similar to...

  16. Impact of pregabalin treatment on synaptic plasticity and glial reactivity during the course of experimental autoimmune encephalomyelitis

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    Silva, Gleidy A A; Pradella, Fernando; Moraes, Adriel; Farias, Alessandro; dos Santos, Leonilda M B; de Oliveira, Alexandre L R

    2014-01-01

    Background Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease that affects young adults. It is characterized by generating a chronic demyelinating autoimmune inflammation in the central nervous system. An experimental model for studying MS is the experimental autoimmune encephalomyelitis (EAE), induced by immunization with antigenic proteins from myelin. Aims The present study investigated the evolution of EAE in pregabalin treated animals up to the remission phase. Methods and results The results demonstrated a delay in the onset of the disease with statistical differences at the 10th and the 16th day after immunization. Additionally, the walking track test (CatWalk) was used to evaluate different parameters related to motor function. Although no difference between groups was obtained for the foot print pressure, the regularity index was improved post treatment, indicating a better motor coordination. The immunohistochemical analysis of putative synapse preservation and glial reactivity revealed that pregabalin treatment improved the overall morphology of the spinal cord. A preservation of circuits was depicted and the glial reaction was downregulated during the course of the disease. qRT-PCR data did not show immunomodulatory effects of pregabalin, indicating that the positive effects were restricted to the CNS environment. Conclusions Overall, the present data indicate that pregabalin is efficient for reducing the seriousness of EAE, delaying its course as well as reducing synaptic loss and astroglial reaction. PMID:25365796

  17. Copaiba Oil Suppresses Inflammatory Cytokines in Splenocytes of C57Bl/6 Mice Induced with Experimental Autoimmune Encephalomyelitis (EAE

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    Débora S. Dias

    2014-08-01

    Full Text Available Experimental autoimmune encephalomyelitis (EAE is a murine autoimmune disease used to study multiple sclerosis. We have investigated the immunomodulatory effects of copaiba oil (100, 50 and 25 µg/mL on NO, H2O2, TNF-α, IFN-γ and IL-17 production in cultured cells from EAE-mice. Copaiba oil (100 µg/mL inhibited H2O2, NO, IFN-γ TNF-α and IL-17 production spontaneously or after ConA and MOG35–55 stimulation. It is suggested that copaiba oil acts on the mechanism of development of EAE by IFN-γ, IL-17 and TNF-α inhibition, modulating the immune response on both Th1 and Th17 cells.

  18. Epigallocatechin-3-gallate ameliorates experimental autoimmune encephalomyelitis by altering balance among CD4+ T cell subsets

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    Studies suggest that green tea component epigallocatechin-3-gallate (EGCG) may have a beneficial effect in reducing the pathogenesis of autoimmune diseases; however, the underlying mechanism(s) are not well understood. In this study, we determined the effect of EGCG on the development of experiment...

  19. Modulation of Multiple Sclerosis and its Animal Model experimental Autoimmune encephalomyelitis by Food and Gut Microbiota

    NARCIS (Netherlands)

    van den Hoogen, Ward J.; Laman, Jon D.; 't Hart, Bert A.

    2017-01-01

    Multiple sclerosis (MS) is an autoimmune neurological disease characterized by chronic inflammation of the central nervous system (CNS), leading to demyelination, axonal damage, and symptoms such as fatigue and disability. Although the cause of MS is not known, the infiltration of peripherally

  20. Effects of Japanese herbal medicine Sairei-to on murine experimental autoimmune uveitis.

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    Kaburaki, Toshikatsu; Zhang, Qi; Jin, Xiangyuan; Uchiyama, Masateru; Fujino, Yujiro; Nakahara, Hisae; Takamoto, Mitsuko; Otomo, Kazuyoshi; Niimi, Masanori

    2013-12-01

    It has been suggested thatSairei-to (TJ114), a traditional Japanese herbal medicine, has immunomodulatory activities. To evaluate the effects of TJ114 on uveitis, we examined the effectiveness of oral administration in a murine model of experimental autoimmune uveitis (EAU). Murine EAU was induced by subcutaneous injection of human inter-photoreceptor retinoid-binding protein (IRBP) peptide mixed with complete Freund's adjuvant. In the TJ114-treated group, 2 g/kg was administrated orally from 0 to 20 days after immunization. Clinical scoring, histopathological scoring of EAU, cell proliferation, cytokine assessment, and adoptive transfer experiment of splenic T cells into naïve mice were performed. EAU development occurred in 32 of 38 mice (86 %) in the untreated group and 12 of 33 (36 %) in the TJ114-treated group. The clinical scores for EAU in the vehicle-treated and TJ114-treated groups were 1.56 ± 1.65 and 0.59 ± 0.63 respectively, at 14 days after immunization (p < 0.01, Mann-Whitney U-test), and 2.26 ± 1.56 and 0.75 ± 1.31 respectively at 21 days (p < 0.001, Mann-Whitney U-test), while the histopathological scores at 21 days were 1.47 ± 1.42 and 0.54 ± 0.84 respectively (p < 0.01, Mann-Whitney U-test). Interferon (IFN)-γ and tumor necrosis factor (TNF)-α production by cervical lymph node cells obtained from the TJ114-treated group were significantly reduced as compared with those from the vehicle-treated group (p < 0.01, Student's unpaired t-test). Moreover, the levels of C-C motif chemokine 2 (CCL2) and IFN-γ were significantly reduced in splenocytes of TJ114-treated mice as compared with the vehicle-treated group (p < 0.01, Student's unpaired t-test). Mice that received adoptive transfer of splenic T cells from TJ114-treated EAU mice caused significantly lower severity of EAU compared to those that received from vehicle-treated EAU mice. Oral administration of TJ114 has an inhibitory effect on a murine model of EAU, possibly via reduction in

  1. Role of Anti-Osteopontin Antibodies in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

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    Clemente, Nausicaa; Comi, Cristoforo; Raineri, Davide; Cappellano, Giuseppe; Vecchio, Domizia; Orilieri, Elisabetta; Gigliotti, Casimiro L.; Boggio, Elena; Dianzani, Chiara; Sorosina, Melissa; Martinelli-Boneschi, Filippo; Caldano, Marzia; Bertolotto, Antonio; Ambrogio, Luca; Sblattero, Daniele; Cena, Tiziana; Leone, Maurizio; Dianzani, Umberto; Chiocchetti, Annalisa

    2017-01-01

    Osteopontin (OPN) is highly expressed in demyelinating lesions in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). OPN is cleaved by thrombin into N- (OPN-N) and C-terminal (OPN-C) fragments with different ligands and functions. In EAE, administering recombinant OPN induces relapses, whereas treatment with anti-OPN antibodies ameliorates the disease. Anti-OPN autoantibodies (autoAbs) are spontaneously produced during EAE but have never been detected in MS. The aim of the study was to evaluate anti-OPN autoAbs in the serum of MS patients, correlate them with disease course, and recapitulate the human findings in EAE. We performed ELISA in the serum of 122 patients collected cross-sectionally, and 50 patients with relapsing–remitting (RR) disease collected at diagnosis and followed longitudinally for 10 years. In the cross-sectional patients, the autoAb levels were higher in the RR patients than in the primary- and secondary-progressive MS and healthy control groups, and they were highest in the initial stages of the disease. In the longitudinal group, the levels at diagnosis directly correlated with the number of relapses during the following 10 years. Moreover, in patients with active disease, who underwent disease-modifying treatments, autoAbs were higher than in untreated patients and were associated with low MS severity score. The autoAb displayed neutralizing activity and mainly recognized OPN-C rather than OPN-N. To confirm the clinical effect of these autoAbs in vivo, EAE was induced using myelin oligodendrocyte glycoprotein MOG35–55 in C57BL/6 mice pre-vaccinated with ovalbumin (OVA)-linked OPN or OVA alone. We then evaluated the titer of antibodies to OPN, the clinical scores and in vitro cytokine secretion by spleen lymphocytes. Vaccination significantly induced antibodies against OPN during EAE, decreased disease severity, and the protective effect was correlated with decreased T cell secretion of interleukin 17 and

  2. Phosphodiesterase 5 inhibition at disease onset prevents experimental autoimmune encephalomyelitis progression through immunoregulatory and neuroprotective actions.

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    Pifarré, Paula; Gutierrez-Mecinas, María; Prado, Judith; Usero, Lorena; Roura-Mir, Carme; Giralt, Mercedes; Hidalgo, Juan; García, Agustina

    2014-01-01

    In addition to detrimental inflammation, widespread axon degeneration is an important feature of multiple sclerosis (MS) pathology and a major correlate for permanent clinical deficits. Thus, treatments that combine immunomodulatory and neuroprotective effects are beneficial for MS. Using myelin oligodendrocyte glycoprotein peptide 35-55 (MOG)-induced experimental autoimmune encephalomyelitis (EAE) as a model of MS, we recently showed that daily treatment with the phosphodiesterase 5 (PDE5) inhibitor sildenafil at peak disease rapidly ameliorates clinical symptoms and neuropathology (Pifarre et al., 2011). We have now investigated the immunomodulatory and neuroprotective actions of sildenafil treatment from the onset of EAE when the immune response prevails and show that early administration of the drug prevents disease progression. Ultrastructural analysis of spinal cord evidenced that sildenafil treatment preserves axons and myelin and increases the number of remyelinating axons. Immunostaining of oligodendrocytes at different stages of differentiation showed that sildenafil protects immature and mature myelinating oligodendrocytes. Brain-derived neurotrophic factor (BDNF), a recognized neuroprotectant in EAE, was up-regulated by sildenafil in immune and neural cells suggesting its implication in the beneficial effects of the drug. RNA microarray analysis of spinal cord revealed that sildenafil up-regulates YM-1, a marker of the alternative macrophage/microglial M2 phenotype that has neuroprotective and regenerative properties. Immunostaining confirmed up-regulation of YM-1 while the classical macrophage/microglial activation marker Iba-1 was down-regulated. Microarray analysis also showed a notable up-regulation of several members of the granzyme B cluster (GrBs). Immunostaining revealed expression of GrBs in Foxp3+-T regulatory cells (Tregs) suggesting a role for these proteases in sildenafil-induced suppression of T effector cells (Teffs). In vitro analysis of

  3. GM-CSF-Producing Th Cells in Rats Sensitive and Resistant to Experimental Autoimmune Encephalomyelitis.

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    Stojić-Vukanić, Zorica; Pilipović, Ivan; Vujnović, Ivana; Nacka-Aleksić, Mirjana; Petrović, Raisa; Arsenović-Ranin, Nevena; Dimitrijević, Mirjana; Leposavić, Gordana

    2016-01-01

    Given that granulocyte macrophage colony-stimulating factor (GM-CSF) is identified as the key factor to endow auto-reactive Th cells with the potential to induce neuroinflammation in experimental autoimmune encephalomyelitis (EAE) models, the frequency and phenotype of GM-CSF-producing (GM-CSF+) Th cells in draining lymph nodes (dLNs) and spinal cord (SC) of Albino Oxford (AO) and Dark Agouti (DA) rats immunized for EAE were examined. The generation of neuroantigen-specific GM-CSF+ Th lymphocytes was impaired in dLNs of AO rats (relatively resistant to EAE induction) compared with their DA counterparts (susceptible to EAE) reflecting impaired CD4+ lymphocyte proliferation and less supportive of GM-CSF+ Th cell differentiation dLN cytokine microenvironment. Immunophenotyping of GM-CSF+ Th cells showed their phenotypic heterogeneity in both strains and revealed lower frequency of IL-17+IFN-γ+, IL-17+IFN-γ-, and IL-17-IFN-γ+ cells accompanied by higher frequency of IL-17-IFN-γ- cells among them in AO than in DA rats. Compared with DA, in AO rats was also found (i) slightly lower surface density of CCR2 (drives accumulation of highly pathogenic GM-CSF+IFN-γ+ Th17 cells in SC) on GM-CSF+IFN-γ+ Th17 lymphocytes from dLNs, and (ii) diminished CCL2 mRNA expression in SC tissue, suggesting their impaired migration into the SC. Moreover, dLN and SC cytokine environments in AO rats were shown to be less supportive of GM-CSF+IFN-γ+ Th17 cell differentiation (judging by lower expression of mRNAs for IL-1β, IL-6 and IL-23/p19). In accordance with the (i) lower frequency of GM-CSF+ Th cells in dLNs and SC of AO rats and their lower GM-CSF production, and (ii) impaired CCL2 expression in the SC tissue, the proportion of proinflammatory monocytes among peripheral blood cells and their progeny (CD45hi cells) among the SC CD11b+ cells were reduced in AO compared with DA rats. Collectively, the results indicate that the strain specificities in efficacy of several mechanisms

  4. Arctigenin Suppress Th17 Cells and Ameliorates Experimental Autoimmune Encephalomyelitis Through AMPK and PPAR-γ/ROR-γt Signaling.

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    Li, Wen; Zhang, Zhihui; Zhang, Kai; Xue, Zhenyi; Li, Yan; Zhang, Zimu; Zhang, Lijuan; Gu, Chao; Zhang, Qi; Hao, Junwei; Da, Yurong; Yao, Zhi; Kong, Ying; Zhang, Rongxin

    2016-10-01

    Arctigenin is a herb compound extract from Arctium lappa and is reported to exhibit pharmacological properties, including neuronal protection and antidiabetic, antitumor, and antioxidant properties. However, the effects of arctigenin on autoimmune inflammatory diseases of the CNS, multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis (EAE) are still unclear. In this study, we demonstrated that arctigenin-treated mice are resistant to EAE; the clinical scores of arctigenin-treated mice are significantly reduced. Histochemical assays of spinal cord sections also showed that arctigenin reduces inflammation and demyelination in mice with EAE. Furthermore, the Th1 and Th17 cells in peripheral immune organs are inhibited by arctigenin in vivo. In addition, the Th1 cytokine IFN-γ and transcription factor T-bet, as well as the Th17 cytokines IL-17A, IL-17F, and transcription factor ROR-γt are significantly suppressed upon arctigenin treatment in vitro and in vivo. Interestedly, Th17 cells are obviously inhibited in CNS of mice with EAE, while Th1 cells do not significantly change. Besides, arctigenin significantly restrains the differentiation of Th17 cells. We further demonstrate that arctigenin activates AMPK and inhibits phosphorylated p38, in addition, upregulates PPAR-γ, and finally suppresses ROR-γt. These findings suggest that arctigenin may have anti-inflammatory and immunosuppressive properties via inhibiting Th17 cells, indicating that it could be a potential therapeutic drug for multiple sclerosis or other autoimmune inflammatory diseases.

  5. Comparative Effects of Human Neural Stem Cells and Oligodendrocyte Progenitor Cells on the Neurobehavioral Disorders of Experimental Autoimmune Encephalomyelitis Mice

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    Dae-Kwon Bae

    2016-01-01

    Full Text Available Since multiple sclerosis (MS is featured with widespread demyelination caused by autoimmune response, we investigated the recovery effects of F3.olig2 progenitors, established by transducing human neural stem cells (F3 NSCs with Olig2 transcription factor, in myelin oligodendrocyte glycoprotein- (MOG- induced experimental autoimmune encephalomyelitis (EAE model mice. Six days after EAE induction, F3 or F3.olig2 cells (1 × 106/mouse were intravenously transplanted. MOG-injected mice displayed severe neurobehavioral deficits which were remarkably attenuated and restored by cell transplantation, in which F3.olig2 cells were superior to its parental F3 cells. Transplanted cells migrated to the injured spinal cord, matured to oligodendrocytes, and produced myelin basic proteins (MBP. The F3.olig2 cells expressed growth and neurotrophic factors including brain-derived neurotrophic factor (BDNF, nerve growth factor (NGF, ciliary neurotrophic factor (CNTF, and leukemia inhibitory factor (LIF. In addition, the transplanted cells markedly attenuated inflammatory cell infiltration, reduced cytokine levels in the spinal cord and lymph nodes, and protected host myelins. The results indicate that F3.olig2 cells restore neurobehavioral symptoms of EAE mice by regulating autoimmune inflammatory responses as well as by stimulating remyelination and that F3.olig2 progenitors could be a candidate for the cell therapy of demyelinating diseases including MS.

  6. Dendritic cells tip the balance towards induction of regulatory T cells upon priming in experimental autoimmune encephalomyelitis.

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    Paterka, Magdalena; Voss, Jan Oliver; Werr, Johannes; Reuter, Eva; Franck, Sophia; Leuenberger, Tina; Herz, Josephine; Radbruch, Helena; Bopp, Tobias; Siffrin, Volker; Zipp, Frauke

    2017-01-01

    Counter-balancing regulatory mechanisms, such as the induction of regulatory T cells (Treg), limit the effects of autoimmune attack in neuroinflammation. However, the role of dendritic cells (DCs) as the most powerful antigen-presenting cells, which are intriguing therapeutic targets in this context, is not fully understood. Here, we demonstrate that conditional ablation of DCs during the priming phase of myelin-specific T cells in experimental autoimmune encephalomyelitis (EAE) selectively aborts inducible Treg (iTreg) induction, whereas generation of T helper (Th)1/17 cells is unaltered. DCs facilitate iTreg induction by creating a milieu with high levels of interleukin (IL)-2 due to a strong proliferative response. In the absence of DCs, B220 + B cells take over priming of Th17 cells in the place of antigen-presenting cells (APCs), but not the induction of iTreg, thus leading to unregulated, severe autoimmunity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. A herpes simplex virus-derived replicative vector expressing LIF limits experimental demyelinating disease and modulates autoimmunity.

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    Nygårdas, Michaela; Paavilainen, Henrik; Müther, Nadine; Nagel, Claus-Henning; Röyttä, Matias; Sodeik, Beate; Hukkanen, Veijo

    2013-01-01

    Herpes simplex virus type 1 (HSV-1) has properties that can be exploited for the development of gene therapy vectors. The neurotropism of HSV enables delivery of therapeutic genes to the nervous system. Using a bacterial artificial chromosome (BAC), we constructed an HSV-1(17(+))-based replicative vector deleted of the neurovirulence gene γ134.5, and expressing leukemia inhibitory factor (LIF) as a transgene for treatment of experimental autoimmune encephalomyelitis (EAE). EAE is an inducible T-cell mediated autoimmune disease of the central nervous system (CNS) and is used as an animal model for multiple sclerosis. Demyelination and inflammation are hallmarks of both diseases. LIF is a cytokine that has the potential to limit demyelination and oligodendrocyte loss in CNS autoimmune diseases and to affect the T-cell mediated autoimmune response. In this study SJL/J mice, induced for EAE, were treated with a HSV-LIF vector intracranially and the subsequent changes in disease parameters and immune responses during the acute disease were investigated. Replicating HSV-LIF and its DNA were detected in the CNS during the acute infection, and the vector spread to the spinal cord but was non-virulent. The HSV-LIF significantly ameliorated the EAE and contributed to a higher number of oligodendrocytes in the brains when compared to untreated mice. The HSV-LIF therapy also induced favorable changes in the expression of immunoregulatory cytokines and T-cell population markers in the CNS during the acute disease. These data suggest that BAC-derived HSV vectors are suitable for gene therapy of CNS disease and can be used to test the therapeutic potential of immunomodulatory factors for treatment of EAE.

  8. Distinctive Roles for α7*- and α9*-Nicotinic Acetylcholine Receptors in Inflammatory and Autoimmune Responses in the Murine Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis.

    Science.gov (United States)

    Liu, Qiang; Whiteaker, Paul; Morley, Barbara J; Shi, Fu-Dong; Lukas, Ronald J

    2017-01-01

    Previous studies have demonstrated immunosuppressive and anti-inflammatory effects of nicotine, including in the experimental autoimmune encephalomyelitis (EAE) model in mice of some forms of multiple sclerosis (MS). Other studies using knock-out (KO) mice have implicated nicotinic acetylcholine (ACh) receptors containing α7, α9, or β2 subunits (α7*-, α9*- or β2*-nAChR) in different, disease-exacerbating or disease-ameliorating processes. These outcomes are in harmony with gene expression analyses showing nAChR subunit mRNA in many classes of immune system cell types. Consistent with influences on disease status, predictable effects of nAChR subunit (and subtype) KO, or of nicotine exposure, are seen on immune cell numbers and distribution and on cytokine levels or other markers of immunity, inflammation, demyelination, and axonal degradation. Providing support for our hypotheses about distinctive roles for nAChR subtypes in EAE, here we have used direct and adoptive EAE induction and a nAChR subunit gene double knock-out (DKO) strategy. Immune cell expression of nAChR α9 subunits as protein is demonstrated by immunostaining of isolated CD4+, CD8+, CD11b+ and CD11c+ cells from wild-type (WT) mice, but not in cells from nAChR α9 subunit KO animals. Nicotine exposure is protective against directly-induced EAE in WT or α7/α9 DKO animals relative to effects seen in WT/vehicle-treated mice, but, remarkably, EAE is exacerbated in vehicle-treated α7/α9 DKO mice. Brain lesion volume and intra-cranial inflammatory activity similarly are higher in DKO/vehicle than in WT/vehicle-treated animals, although nicotine's protective effects are seen in each instance. By contrast, in adoptive transfer studies, disease severity is attenuated and disease onset is delayed in recipients of splenocytes from WT animals treated with nicotine rather than with vehicle. Moreover, protection as seen in nicotine-treated WT animals is the same in recipients of splenocytes from nAChR

  9. Distinctive Roles for α7*- and α9*-Nicotinic Acetylcholine Receptors in Inflammatory and Autoimmune Responses in the Murine Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Qiang Liu

    2017-09-01

    Full Text Available Previous studies have demonstrated immunosuppressive and anti-inflammatory effects of nicotine, including in the experimental autoimmune encephalomyelitis (EAE model in mice of some forms of multiple sclerosis (MS. Other studies using knock-out (KO mice have implicated nicotinic acetylcholine (ACh receptors containing α7, α9, or β2 subunits (α7*-, α9*- or β2*-nAChR in different, disease-exacerbating or disease-ameliorating processes. These outcomes are in harmony with gene expression analyses showing nAChR subunit mRNA in many classes of immune system cell types. Consistent with influences on disease status, predictable effects of nAChR subunit (and subtype KO, or of nicotine exposure, are seen on immune cell numbers and distribution and on cytokine levels or other markers of immunity, inflammation, demyelination, and axonal degradation. Providing support for our hypotheses about distinctive roles for nAChR subtypes in EAE, here we have used direct and adoptive EAE induction and a nAChR subunit gene double knock-out (DKO strategy. Immune cell expression of nAChR α9 subunits as protein is demonstrated by immunostaining of isolated CD4+, CD8+, CD11b+ and CD11c+ cells from wild-type (WT mice, but not in cells from nAChR α9 subunit KO animals. Nicotine exposure is protective against directly-induced EAE in WT or α7/α9 DKO animals relative to effects seen in WT/vehicle-treated mice, but, remarkably, EAE is exacerbated in vehicle-treated α7/α9 DKO mice. Brain lesion volume and intra-cranial inflammatory activity similarly are higher in DKO/vehicle than in WT/vehicle-treated animals, although nicotine’s protective effects are seen in each instance. By contrast, in adoptive transfer studies, disease severity is attenuated and disease onset is delayed in recipients of splenocytes from WT animals treated with nicotine rather than with vehicle. Moreover, protection as seen in nicotine-treated WT animals is the same in recipients of

  10. Raloxifene suppresses experimental autoimmune encephalomyelitis and NF-κB-dependent CCL20 expression in reactive astrocytes.

    Directory of Open Access Journals (Sweden)

    Rui Li

    Full Text Available Recent clinical data have led to the consideration of sexual steroids as new potential therapeutic tools for multiple sclerosis. Selective estrogen receptor modulators can exhibit neuroprotective effects like estrogen, with fewer systemic estrogen side effects than estrogen, offering a more promising therapeutic modality for multiple sclerosis. The important role of astrocytes in a proinflammatory effect mediated by CCL20 signaling on inflammatory cells has been documented. Their potential contribution to selective estrogen receptor modulator-mediated protection is still unknown. Using a mouse model of chronic neuroinflammation, we report that raloxifene, a selective estrogen receptor modulator, alleviated experimental autoimmune encephalomyelitis-an animal model of multiple sclerosis-and decreased astrocytic production of CCL20. Enzyme-linked immunosorbent assay, immunohistochemistry imaging and transwell migration assays revealed that reactive astrocytes express CCL20, which promotes Th17 cell migration. In cultured rodent astrocytes, raloxifene inhibited IL-1β-induced CCL20 expression and chemotaxis ability for Th17 migration, whereas the estrogen receptor antagonist ICI 182,780 blocked this effect. Western blotting further indicated that raloxifene suppresses IL-1β-induced NF-κB activation (phosphorylation of p65 and translocation but does not affect phosphorylation of IκB. In conclusion, these data demonstrate that raloxifene provides robust neuroprotection against experimental autoimmune encephalomyelitis, partially via an inhibitory action on CCL20 expression and NF-κB pathways in reactive astrocytes. Our results contribute to a better understanding of the critical roles of raloxifene in treating experimental autoimmune encephalomyelitis and uncover reactive astrocytes as a new target for the inhibitory action of estrogen receptors on chemokine CCL20 expression.

  11. Raloxifene Suppresses Experimental Autoimmune Encephalomyelitis and NF-κB-Dependent CCL20 Expression in Reactive Astrocytes

    Science.gov (United States)

    Qiu, Wei; Shu, Yaqing; Wu, Aimin; Dai, Yongqiang; Bao, Jian; Lu, Zhengqi; Hu, Xueqiang

    2014-01-01

    Recent clinical data have led to the consideration of sexual steroids as new potential therapeutic tools for multiple sclerosis. Selective estrogen receptor modulators can exhibit neuroprotective effects like estrogen, with fewer systemic estrogen side effects than estrogen, offering a more promising therapeutic modality for multiple sclerosis. The important role of astrocytes in a proinflammatory effect mediated by CCL20 signaling on inflammatory cells has been documented. Their potential contribution to selective estrogen receptor modulator-mediated protection is still unknown. Using a mouse model of chronic neuroinflammation, we report that raloxifene, a selective estrogen receptor modulator, alleviated experimental autoimmune encephalomyelitis–an animal model of multiple sclerosis–and decreased astrocytic production of CCL20. Enzyme-linked immunosorbent assay, immunohistochemistry imaging and transwell migration assays revealed that reactive astrocytes express CCL20, which promotes Th17 cell migration. In cultured rodent astrocytes, raloxifene inhibited IL-1β-induced CCL20 expression and chemotaxis ability for Th17 migration, whereas the estrogen receptor antagonist ICI 182,780 blocked this effect. Western blotting further indicated that raloxifene suppresses IL-1β-induced NF-κB activation (phosphorylation of p65) and translocation but does not affect phosphorylation of IκB. In conclusion, these data demonstrate that raloxifene provides robust neuroprotection against experimental autoimmune encephalomyelitis, partially via an inhibitory action on CCL20 expression and NF-κB pathways in reactive astrocytes. Our results contribute to a better understanding of the critical roles of raloxifene in treating experimental autoimmune encephalomyelitis and uncover reactive astrocytes as a new target for the inhibitory action of estrogen receptors on chemokine CCL20 expression. PMID:24722370

  12. Genetic analysis of inflammation, cytokine mRNA expression and disease course of relapsing experimental autoimmune encephalomyelitis in DA rats

    DEFF Research Database (Denmark)

    Lorentzen, J C; Andersson, M; Issazadeh-Navikas, Shohreh

    1997-01-01

    -MHC genes were decisive since a high incidence of SPR-EAE only occurred in rats with DA non-MHC genes. Analysis of cytokine mRNA expression and infiltrating cells in the spinal cords of congenic strains revealed that the av1 haplotype associated with a high CD4/CD8 ratio and expression of m......Genetic analysis of experimental autoimmune encephalomyelitis (EAE) can provide clues to the etiology of multiple sclerosis (MS). Identifying the susceptibility genes of DA rats may be particularly rewarding since they are prone to develop a remarkably MS-like chronic and demyelinating disease...

  13. Increased severity of experimental autoimmune encephalomyelitis, chronic macrophage/microglial reactivity, and demyelination in transgenic mice producing tumor necrosis factor-alpha in the central nervous system

    DEFF Research Database (Denmark)

    Taupin, V; Renno, T; Bourbonnière, L

    1997-01-01

    Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine implicated in a number of autoimmune diseases. Apoptotic cell death is induced by TNF-alpha in vitro, and has been suggested as one cause of autoimmune pathology, including autoimmune demyelinating diseases where oligodendrocytes...... and showed no spontaneous pathology, but they developed experimental autoimmune encephalomyelitis (EAE) with greater severity than nontransgenic controls when immunized with MBP in adjuvant. Unlike nontransgenic controls, EAE then progressed to a nonabating demyelinating disease. Macrophage....../microglial reactivity was evident in demyelinating lesions in spinal cord, but T cells were not detected during chronic disease. The participation of TNF-alpha in the demyelinating process is thus more probably due to the perpetuation of macrophage/microglial activation than to direct cytotoxicity of myelin...

  14. Functional interleukin-17 receptor A is expressed in central nervous system glia and upregulated in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Das Sarma, Jayasri; Ciric, Bogoljub; Marek, Ryan; Sadhukhan, Sanjoy; Caruso, Michael L; Shafagh, Jasmine; Fitzgerald, Denise C; Shindler, Kenneth S; Rostami, Am

    2009-04-28

    Interleukin-17A (IL-17A) is the founding member of a novel family of inflammatory cytokines that plays a critical role in the pathogenesis of many autoimmune diseases, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). IL-17A signals through its receptor, IL-17RA, which is expressed in many peripheral tissues; however, expression of IL-17RA in the central nervous system (CNS) and its role in CNS inflammation are not well understood. EAE was induced in C57Bl/6 mice by immunization with myelin oligodendroglial glycoprotein. IL-17RA expression in the CNS was compared between control and EAE mice using RT-PCR, in situ hybridization, and immunohistochemistry. Cell-type specific expression was examined in isolated astrocytic and microglial cell cultures. Cytokine and chemokine production was measured in IL-17A treated cultures to evaluate the functional status of IL-17RA. Here we report increased IL-17RA expression in the CNS of mice with EAE, and constitutive expression of functional IL-17RA in mouse CNS tissue. Specifically, astrocytes and microglia express IL-17RA in vitro, and IL-17A treatment induces biological responses in these cells, including significant upregulation of MCP-1, MCP-5, MIP-2 and KC chemokine secretion. Exogenous IL-17A does not significantly alter the expression of IL-17RA in glial cells, suggesting that upregulation of chemokines by glial cells is due to IL-17A signaling through constitutively expressed IL-17RA. IL-17RA expression is significantly increased in the CNS of mice with EAE compared to healthy mice, suggesting that IL-17RA signaling in glial cells can play an important role in autoimmune inflammation of the CNS and may be a potential pathway to target for therapeutic interventions.

  15. Functional interleukin-17 receptor A is expressed in central nervous system glia and upregulated in experimental autoimmune encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Shafagh Jasmine

    2009-04-01

    Full Text Available Abstract Background Interleukin-17A (IL-17A is the founding member of a novel family of inflammatory cytokines that plays a critical role in the pathogenesis of many autoimmune diseases, including multiple sclerosis (MS and its animal model, experimental autoimmune encephalomyelitis (EAE. IL-17A signals through its receptor, IL-17RA, which is expressed in many peripheral tissues; however, expression of IL-17RA in the central nervous system (CNS and its role in CNS inflammation are not well understood. Methods EAE was induced in C57Bl/6 mice by immunization with myelin oligodendroglial glycoprotein. IL-17RA expression in the CNS was compared between control and EAE mice using RT-PCR, in situ hybridization, and immunohistochemistry. Cell-type specific expression was examined in isolated astrocytic and microglial cell cultures. Cytokine and chemokine production was measured in IL-17A treated cultures to evaluate the functional status of IL-17RA. Results Here we report increased IL-17RA expression in the CNS of mice with EAE, and constitutive expression of functional IL-17RA in mouse CNS tissue. Specifically, astrocytes and microglia express IL-17RA in vitro, and IL-17A treatment induces biological responses in these cells, including significant upregulation of MCP-1, MCP-5, MIP-2 and KC chemokine secretion. Exogenous IL-17A does not significantly alter the expression of IL-17RA in glial cells, suggesting that upregulation of chemokines by glial cells is due to IL-17A signaling through constitutively expressed IL-17RA. Conclusion IL-17RA expression is significantly increased in the CNS of mice with EAE compared to healthy mice, suggesting that IL-17RA signaling in glial cells can play an important role in autoimmune inflammation of the CNS and may be a potential pathway to target for therapeutic interventions.

  16. Oriental Medicine Samhwangsasim-tang Alleviates Experimental Autoimmune Encephalomyelitis by Suppressing Th1 Cell Responses and Upregulating Treg Cell Responses.

    Science.gov (United States)

    Lee, Min J; Choi, Jong H; Lee, Sung J; Cho, Ik-Hyun

    2017-01-01

    Oriental medicine Samhwangsasim-tang (SHSST) has traditionally been used in East Asia to treat hypertension and its complications. However, little is known about its potential value regarding the treatment of chronic inflammatory diseases such as multiple sclerosis (MS). In this study, we investigated whether SHSST has a beneficial effect in treating myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE). Onset-treatment with SHSST was found to alleviate neurological symptoms as well as demyelination and glial activation in the spinal cords from the EAE mice. The SHSST also attenuated the mRNA or protein expression of pro-inflammatory cytokines (interleukin-1beta and tumor necrotic factor-alpha); chemokines (RANTES, monocyte chemotactic protein-1, and macrophage inflammatory protein-1alpha); inducible nitric oxide synthase; and cyclooxygenase-2 in correspondence with the down-regulation of the nuclear factor-kappa B and mitogen-activated protein kinases signal pathways in the spinal cords from EAE mice. Interestingly, the protective effect of the SHSST was related to a decreased number of Th1 cells and an increased number of Treg cells in spinal cords from EAE mice. Taken together, our finding firstly suggested that SHSST could delay or mitigate EAE with a wide therapeutic time-window by suppressing Th1 cell responses and upregulating Treg cell responses. Also, our findings are strong enough to warrant further investigation of SHSST as a treatment for chronic autoimmune diseases including MS.

  17. Hsp65-producing Lactococcus lactis prevents experimental autoimmune encephalomyelitis in mice by inducing CD4+LAP+ regulatory T cells.

    Science.gov (United States)

    Rezende, Rafael M; Oliveira, Rafael P; Medeiros, Samara R; Gomes-Santos, Ana C; Alves, Andrea C; Loli, Flávia G; Guimarães, Mauro A F; Amaral, Sylvia S; da Cunha, André P; Weiner, Howard L; Azevedo, Vasco; Miyoshi, Anderson; Faria, Ana M C

    2013-02-01

    Heat shock proteins (Hsps) participate in the cellular response to stress and they are hiperexpressed in inflammatory conditions. They are also known to play a major role in immune modulation, controlling, for instance, autoimmune responses. In this study, we showed that oral administration of a recombinant Lactococcus lactis strain that produces and releases LPS-free Hsp65 prevented the development of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. This was confirmed by the reduced inflammatory cell infiltrate and absence of injury signs in the spinal cord. The effect was associated with reduced IL-17 and increased IL-10 production in mesenteric lymph node and spleen cell cultures. Hsp65-producing-L. lactis-fed mice had a remarkable increase in the number of natural and inducible CD4+Foxp3+ regulatory T (Treg) cells and CD4+LAP+ (Latency-associated peptide) Tregs - which express the membrane-bound TGF-β - in spleen, inguinal and mesenteric lymph nodes as well as in spinal cord. Moreover, many Tregs co-expressed Foxp3 and LAP. In vivo depletion of LAP+ cells abrogated the effect of Hsp65-producing L. lactis in EAE prevention and worsened disease in medium-fed mice. Thus, Hsp65-L.lactis seems to boost this critical regulatory circuit involved in controlling EAE development in mice. Copyright © 2012 Elsevier Ltd. All rights reserved.

  18. IL2-caspase3 chimeric protein controls lymphocyte reactivity by targeted apoptosis, leading to amelioration of experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Irony-Tur-Sinai, Michal; Lichtenstein, Michal; Brenner, Talma; Lorberboum-Galski, Haya

    2009-09-01

    IL2-caspase3 chimeric protein was designed to target and kill cells expressing the high affinity IL-2 receptor. Its effects on lymphocyte reactivity and on experimental autoimmune encephalomyelitis (EAE), a T-cell mediated disease, were tested in this study. Our data show that IL2-caspase3 promoted cell specific apoptosis both in vitro and in vivo. Cell lines preferentially expressing the IL-2R alpha chain and encephalitogenic lymphocytes derived from EAE-induced mice were highly sensitive to the chimeras' activity. This was demonstrated by increased DNA fragmentation and annexin labeling together with reduced specific T-cell proliferation in response to IL2-casepase3 treatment. Furthermore, IL2-caspase3 treatment of EAE-induced mice caused a significant delay in disease onset together with a reduction in disease burden. The efficacy of IL2-caspase3 treatment was dependent on the time at which treatment begun, with the chimera ameliorating EAE only when administered at maximal activation of peripheral lymphocytes. According to our findings we suggest that the chimeric protein IL2-caspase3 may provide a novel approach for the treatment of a variety of autoimmune disorders, such as multiple sclerosis, as well as for other pathological conditions that involve uncontrolled expansion of activated T cells.

  19. Tissue-Resident Exhausted Effector Memory CD8+ T Cells Accumulate in the Retina during Chronic Experimental Autoimmune Uveoretinitis

    Science.gov (United States)

    Boldison, Joanne; Chu, Colin J.; Copland, David A.; Lait, Philippa J. P.; Khera, Tarnjit K.; Dick, Andrew D.

    2014-01-01

    Experimental autoimmune uveoretinitis is a model for noninfectious posterior segment intraocular inflammation in humans. Although this disease is CD4+ T cell dependent, in the persistent phase of disease CD8+ T cells accumulate. We show that these are effector memory CD8+ T cells that differ from their splenic counterparts with respect to surface expression of CD69, CD103, and Ly6C. These retinal effector memory CD8+ T cells have limited cytotoxic effector function, are impaired in their ability to proliferate in response to Ag-specific stimulation, and upregulate programmed death 1 receptor. Treatment with fingolimod (FTY720) during the late phase of disease revealed that retinal CD8+ T cells were tissue resident. Despite signs of exhaustion, these cells were functional, as their depletion resulted in an expansion of retinal CD4+ T cells and CD11b+ macrophages. These results demonstrate that, during chronic autoimmune inflammation, exhausted CD8+ T cells become established in the local tissue. They are phenotypically distinct from peripheral CD8+ T cells and provide local signals within the tissue by expression of inhibitory receptors such as programmed death 1 that limit persistent inflammation. PMID:24740509

  20. Treatment of Experimental Autoimmune Encephalomyelitis by Codelivery of Disease Associated Peptide and Dexamethasone in Acetalated Dextran Microparticles

    Science.gov (United States)

    2015-01-01

    Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system that can cause loss of motor function and is thought to result, in part, from chronic inflammation due to an antigen-specific T cell immune response. Current treatments suppress the immune system without antigen specificity, increasing the risks of cancer, chronic infection, and other long-term side effects. In this study, we show treatment of experimental autoimmune encephalomyelitis (EAE), a model of MS, by coencapsulating the immunodominant peptide of myelin oligodendrocyte glycoprotein (MOG) with dexamethasone (DXM) into acetalated dextran (Ac-DEX) microparticles (DXM/MOG/MPs) and administering the microparticles subcutaneously. The clinical score of the mice was reduced from 3.4 to 1.6 after 3 injections 3 days apart with the coencapsulated microparticulate formulation (MOG 17.6 μg and DXM 8 μg). This change in clinical score was significantly greater than observed with phosphate-buffered saline (PBS), empty MPs, free DXM and MOG, DXM/MPs, and MOG/MPs. Additionally, treatment with DXM/MOG/MPs significantly inhibited disease-associated cytokine (e.g., IL-17, GM-CSF) expression in splenocytes isolated in treated mice. Here we show a promising approach for the therapeutic treatment of MS using a polymer-based microparticle delivery platform. PMID:24433027

  1. Discordant effects of anti–VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis

    Science.gov (United States)

    Theien, Bradley E.; Vanderlugt, Carol L.; Eagar, Todd N.; Nickerson-Nutter, Cheryl; Nazareno, Remederios; Kuchroo, Vijay K.; Miller, Stephen D.

    2001-01-01

    Initial migration of encephalitogenic T cells to the central nervous system (CNS) in relapsing experimental autoimmune encephalomyelitis (R-EAE), an animal model of multiple sclerosis (MS), depends on the interaction of the α4 integrin (VLA-4) expressed on activated T cells with VCAM-1 expressed on activated cerebrovascular endothelial cells. Alternate homing mechanisms may be employed by infiltrating inflammatory cells after disease onset. We thus compared the ability of anti–VLA-4 to regulate proteolipid protein (PLP) 139-151–induced R-EAE when administered either before or after disease onset. Preclinical administration of anti–VLA-4 either to naive recipients of primed encephalitogenic T cells or to mice 1 week after peptide priming, i.e., before clinical disease onset, inhibited the onset and severity of clinical disease. In contrast, Ab treatment either at the peak of acute disease or during remission exacerbated disease relapses and increased the accumulation of CD4+ T cells in the CNS. Most significantly, anti–VLA-4 treatment either before or during ongoing R-EAE enhanced Th1 responses to both the priming peptide and endogenous myelin epitopes released secondary to acute tissue damage. Collectively, these results suggest that treatment with anti–VLA-4 Ab has multiple effects on the immune system and may be problematic in treating established autoimmune diseases such as MS. PMID:11306603

  2. A new small molecule for treating inflammation and chorioretinal neovascularization in relapsing-remitting and chronic experimental autoimmune uveitis.

    Science.gov (United States)

    Diedrichs-Möhring, Maria; Leban, Johann; Strobl, Stefan; Obermayr, Franz; Wildner, Gerhild

    2014-12-16

    We investigated the effect of PP-001, a new small molecule inhibitor of dihydro-orotate dehydrogenase in two experimental rat experimental autoimmune uveitis (EAU) models: a spontaneously relapsing-remitting model and a monophasic/chronic disease model that results in late chorioretinal neovascularization. Both of the diseases are induced by immunization with autoantigen peptides. Prevention was tested using daily oral applications of PP-001 after immunization with the retinal S-antigen peptide PDSAg (for induction of monophasic uveitis and neovascularization) or the interphotoreceptor retinoid-binding protein peptide R14 (for induction of spontaneously relapsing-remitting EAU). Treatment to inhibit relapses and neovascularization was tested using PP-001 daily after the first attack of R14-induced or after onset of PDSAg-induced EAU. Uveitis was graded clinically and histologically. The effect of PP-001 on cytokine secretion and proliferation was evaluated using rat T-cell lines. Preventive feeding of PP-001 abrogated both types of EAU. Starting treatment after the resolution of the first attack led to a significant reduction of the number and intensity of relapses in R14-induced EAU. PP-001-treatment initiated after onset or after peak of PDSAg-induced EAU significantly reduced neovascularization (as determined by histology). Proliferation of antigen-specific T-cell lines and secretion of IFN-γ, IL-17, IL-10, IP-10, and VEGF were efficiently suppressed by PP-001. We investigated a new dihydroorotate dehydrogenase inhibitor as treatment for primary and recurrent disease in relapsing-remitting and chronic rat models of experimental autoimmune uveitis. The small molecule compound PP-001 suppressed proliferation and cytokine secretion of autoreactive T cells (i.e., IFN-g, IL-17, and VEGF) and chorioretinal neovascularization in chronic EAU. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

  3. Contrasting Roles of Islet Resident Immunoregulatory Macrophages and Dendritic Cells in Experimental Autoimmune Type 1 Diabetes.

    Directory of Open Access Journals (Sweden)

    Thomas B Thornley

    Full Text Available The innate immune system critically shapes diabetogenic adaptive immunity during type 1 diabetes (T1D pathogenesis. While the role of tissue-infiltrating monocyte-derived macrophages in T1D is well established, the role of their tissue-resident counterparts remains undefined. We now demonstrate that islet resident macrophages (IRMs from non-autoimmune mice have an immunoregulatory phenotype and powerfully induce FoxP3+ Tregs in vitro. The immunoregulatory phenotype and function of IRMs is compromised by TLR4 activation in vitro. Moreover, as T1D approaches in NOD mice, the immunoregulatory phenotype of IRMs is diminished as is their relative abundance compared to immunostimulatory DCs. Our findings suggest that maintenance of IRM abundance and their immunoregulatory phenotype may constitute a novel therapeutic strategy to prevent and/or cure T1D.

  4. Reg-2, a downstream signaling protein in the ciliary neurotrophic factor survival pathway, alleviates experimental autoimmune encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Hong eJiang

    2016-05-01

    Full Text Available Ciliary neurotrophic factor (CNTF, originally described as a neurocytokine that could support the survival of neurons, has been recently found to alleviate demyelination, prevent axon loss, and improve functional recovery in a rat model of acute experimental autoimmune encephalomyelitis (EAE. However, poor penetration into the brain parenchyma and unfavorable side effects limit the utility of CNTF. Here, we evaluated the therapeutic potential of a protein downstream of CNTF, regeneration gene protein 2 (Reg-2. Using multiple morphological, molecular biology, and electrophysiological methods to assess neuroinflammation, axonal loss, demyelination, and functional impairment, we observed that Reg-2 and CNTF exert similar effects in the acute phase of EAE. Both treatments attenuated axonal loss and demyelination, improved neuronal survival, and produced functional improvement. With a smaller molecular weight and improved penetration into the brain parenchyma, Reg-2 may be a useful substitute for CNTF therapy in EAE and multiple sclerosis.

  5. Diazepam treatment reduces inflammatory cells and mediators in the central nervous system of rats with experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Fernández Hurst, Nicolás; Zanetti, Samanta R; Báez, Natalia S; Bibolini, Mario J; Bouzat, Cecilia; Roth, German A

    2017-12-15

    Benzodiazepines are psychoactive drugs and some of them also affect immune cells. We here characterized the inflammatory and infiltrating immune cells in the central nervous system (CNS) during the acute phase of experimental autoimmune encephalomyelitis (EAE) in animals treated with Diazepam. Also, we evaluated the expression of Translocator Protein (18kDa) (TSPO), which is a biomarker of neuroinflammatory diseases. The results indicate that Diazepam exerts protective effects on EAE development, decreasing the incidence of the disease and reducing the number of inflammatory cells in CNS, with a concomitant decrease of TSPO levels in brain tissue and CNS inflammatory CD11b + cells. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Suppression of murine experimental autoimmune encephalomyelitis development by 1,25-dihydroxyvitamin D3 with autophagy modulation.

    Science.gov (United States)

    Zhen, Chao; Feng, Xuedan; Li, Zhe; Wang, Yabo; Li, Bin; Li, Lin; Quan, Moyuan; Wang, Gaoning; Guo, Li

    2015-03-15

    Multiple sclerosis (MS) has been associated with a history of sub-optimal exposure to ultraviolet light, implicating vitamin D3 as a possible protective agent. We evaluated whether 1,25(OH)2D3 attenuates the progression of experimental autoimmune encephalomyelitis (EAE), and explored its potential mechanisms. EAE was induced in C57BL/6 mice via immunization with MOG35-55, and some mice received 1,25(OH)2D3. 1,25(OH)2D3 inhibited EAE progression. Additionally, 1,25(OH)2D3 reduced inflammation, demyelination, and neuron loss in the spinal cord. The protective effect of 1,25(OH)2D3 was associated with significantly elevated expression of Beclin1, increased Bcl-2/Bax ratio, and decreased LC3-II accumulation. Thus, 1,25(OH)2D3 may represent a promising new MS treatment. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Identification of protein networks involved in the disease course of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Annelies Vanheel

    Full Text Available A more detailed insight into disease mechanisms of multiple sclerosis (MS is crucial for the development of new and more effective therapies. MS is a chronic inflammatory autoimmune disease of the central nervous system. The aim of this study is to identify novel disease associated proteins involved in the development of inflammatory brain lesions, to help unravel underlying disease processes. Brainstem proteins were obtained from rats with MBP induced acute experimental autoimmune encephalomyelitis (EAE, a well characterized disease model of MS. Samples were collected at different time points: just before onset of symptoms, at the top of the disease and following recovery. To analyze changes in the brainstem proteome during the disease course, a quantitative proteomics study was performed using two-dimensional difference in-gel electrophoresis (2D-DIGE followed by mass spectrometry. We identified 75 unique proteins in 92 spots with a significant abundance difference between the experimental groups. To find disease-related networks, these regulated proteins were mapped to existing biological networks by Ingenuity Pathway Analysis (IPA. The analysis revealed that 70% of these proteins have been described to take part in neurological disease. Furthermore, some focus networks were created by IPA. These networks suggest an integrated regulation of the identified proteins with the addition of some putative regulators. Post-synaptic density protein 95 (DLG4, a key player in neuronal signalling and calcium-activated potassium channel alpha 1 (KCNMA1, involved in neurotransmitter release, are 2 putative regulators connecting 64% of the identified proteins. Functional blocking of the KCNMA1 in macrophages was able to alter myelin phagocytosis, a disease mechanism highly involved in EAE and MS pathology. Quantitative analysis of differentially expressed brainstem proteins in an animal model of MS is a first step to identify disease-associated proteins and

  8. The therapeutic effects of MSc1 nanocomplex, synthesized by nanochelating technology, on experimental autoimmune encephalomyelitic C57/BL6 mice

    Science.gov (United States)

    Fakharzadeh, Saideh; Sahraian, Mohammad Ali; Hafizi, Maryam; Kalanaky, Somayeh; Masoumi, Zahra; Mahdavi, Mehdi; Kamalian, Nasser; Minagar, Alireza; Nazaran, Mohammad Hassan

    2014-01-01

    Purpose Currently approved therapies for multiple sclerosis (MS) at best only slow down its progression. Therefore, it is necessary to utilize novel technologies in order to synthesize smart multifunctional structures. In the present study, for the first time we evaluated the therapeutic potential of MSc1 nanocomplex, which was designed based on novel nanochelating technology. Materials and methods MSc1 cell-protection capacity, with and without iron bond, was evaluated against hydrogen peroxide (H2O2)-induced oxidative stress in cultured rat pheochromocytoma-12 cells. The ability of MSc1 to maintain iron bond at pH ranges of 1–7 was evaluated. Nanocomplex toxicity was examined by estimating the intraperitoneal median lethal dose (LD50). Experimental autoimmune encephalomyelitic mice were injected with MSc1 14 days after disease induction, when the clinical symptoms appeared. The clinical score, body weight, and disease-induced mortality were monitored until day 54. In the end, after collecting blood samples for assessing hemoglobin and red blood cell count, the brains and livers of the mice were isolated for hematoxylin and eosin staining and analysis of iron content, respectively. Results The results showed that MSc1 prevented H2O2-induced cell death even after binding with iron, and it preserved its bond with iron constant at pH ranges 1–7. The nanocomplex intraperitoneal LD50 was 1,776.59 mg/kg. MSc1 prompted therapeutic behavior and improved the disabling features of experimental autoimmune encephalomyelitis, which was confirmed by decreased clinical scores versus increased body mass and 100% survival probability. It did not cause any adverse effects on hemoglobin or red blood cell count. Histopathological studies showed no neural loss or lymphocyte infiltration in MSc1-treated mice, while the hepatic iron content was also normal. Conclusion These results demonstrate that MSc1 could be a promising beneficial novel agent and has the capacity to be evaluated

  9. XY sex chromosome complement, compared with XX, in the CNS confers greater neurodegeneration during experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Du, Sienmi; Itoh, Noriko; Askarinam, Sahar; Hill, Haley; Arnold, Arthur P; Voskuhl, Rhonda R

    2014-02-18

    Women are more susceptible to multiple sclerosis (MS) and have more robust immune responses than men. However, men with MS tend to demonstrate a more progressive disease course than women, suggesting a disconnect between the severity of an immune attack and the CNS response to a given immune attack. We have previously shown in an MS model, experimental autoimmune encephalomyelitis, that autoantigen-sensitized XX lymph node cells, compared with XY, are more encephalitogenic. These studies demonstrated an effect of sex chromosomes in the induction of immune responses, but did not address a potential role of sex chromosomes in the CNS response to immune-mediated injury. Here, we examined this possibility using XX versus XY bone marrow chimeras reconstituted with a common immune system of one sex chromosomal type. We found that experimental autoimmune encephalomyelitis mice with an XY sex chromosome complement in the CNS, compared with XX, demonstrated greater clinical disease severity with more neuropathology in the spinal cord, cerebellum, and cerebral cortex. A candidate gene on the X chromosome, toll-like receptor 7, was then examined. Toll-like receptor 7 expression in cortical neurons was higher in mice with XY compared with mice with XX CNS, consistent with the known neurodegenerative role for toll-like receptor 7 in neurons. These results suggest that sex chromosome effects on neurodegeneration in the CNS run counter to effects on immune responses, and may bear relevance to the clinical enigma of greater MS susceptibility in women but faster disability progression in men. This is a demonstration of a direct effect of sex chromosome complement on neurodegeneration in a neurological disease.

  10. Elevated interferon gamma expression in the central nervous system of tumour necrosis factor receptor 1-deficient mice with experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Wheeler, Rachel D; Zehntner, Simone P; Kelly, Lisa M

    2006-01-01

    Inflammation in the central nervous system (CNS) can be studied in experimental autoimmune encephalomyelitis (EAE). The proinflammatory cytokines interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF) are implicated in EAE pathogenesis. Signals through the type 1 TNF receptor (TNFR1) are r...

  11. PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Vowinckel, E; Reutens, D; Becher, B

    1997-01-01

    Activated glial cells are implicated in regulating and effecting the immune response that occurs within the CNS as part of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). The peripheral benzodiazepine receptor (PBR) is expressed in glial cells. We...

  12. Induction of Experimental Autoimmune Encephalomyelitis With Recombinant Human Myelin Oligodendrocyte Glycoprotein in Incomplete Freund's Adjuvant in Three Non-human Primate Species

    NARCIS (Netherlands)

    Haanstra, Krista G.; Jagessar, S. Anwar; Bauchet, Anne-Laure; Doussau, Mireille; Fovet, Claire-Maelle; Heijmans, Nicole; Hofman, Sam O.; van Lubeek-Veth, Jennifer; Bajramovic, Jeffrey J.; Kap, Yolanda S.; Laman, Jon D.; Touin, Helene; Watroba, Laurent; Bauer, Jan; Lachapelle, Francois; Serguera, Che; 't Hart, Bert A.

    2013-01-01

    The experimental autoimmune encephalitis (EAE) model is used for preclinical research into the pathogenesis of multiple sclerosis (MS), mostly in inbred, specific pathogen free (SPF)-raised laboratory mice. However, the naive state of the laboratory mouse immune system is considered a major hurdle

  13. Immunomodulation of liver injury by Ascaris suum extract in an experimental model of autoimmune hepatitis.

    Science.gov (United States)

    Nascimento, Wheverton C; Silva, Roeckson P; Fernandes, Erica S; Silva, Maria C; Holanda, Gabriela C; Santos, Patrícia A; Albuquerque, Mônica P; Costa, Vlaudia A; Pontes-Filho, Nicodemos T; Souza, Valdênia O

    2014-09-01

    Adult worm extract from Ascaris suum (Asc) has immunosuppressive activity and elicits Th2/IL-4/IL-10 response. This study evaluated the prophylactic and therapeutic effect of Asc in a murine model of concanavalin A (ConA)-induced autoimmune hepatitis (AIH). BALB/c mice received ConA, iv, (20 mg/kg), and three groups of animals were formed: (1) AIH, received only ConA; (2) AIH + Asc prophylactic, treated with Asc (1 mg/ml), ip, 30 min before of the AIH; and (3) AIH + Asc therapeutic, treated with Asc 2 h after the AIH. Plasma transaminase and immunoglobulins (measured at 8 and 24 h and 7 days after treatment) and cytokine production (IL-4, IL-10, IL-13, and IFN-γ) by splenocytes upon ConA and Asc stimulus were compared. The livers were weighed and examined histologically. In the AIH group, there was an increase in liver weight, transaminase levels, and total immunoglobulins. These parameters were reduced by 8-24 h and 7 days in the prophylactic group, but in the therapeutic group, only on day 7. The survival rate of mice in the AIH group was 38.5%, compared to 67% in the therapeutic Asc group. The survival rate of the animals with AIH that were prophylactically treated with Asc was 100%. A decrease of cellular infiltration and high levels of IL-4, IL-10, and IL-13 were induced by Asc. An increase of liver fibrosis was also observed, but with less intensity with prophylactic treatment. Thus, the Ascaris components have an inhibitory effect on AIH, with an intense Th2 immune response.

  14. Zinc aspartate suppresses T cell activation in vitro and relapsing experimental autoimmune encephalomyelitis in SJL/J mice.

    Science.gov (United States)

    Stoye, Diana; Schubert, Claudia; Goihl, Alexander; Guttek, Karina; Reinhold, Annegret; Brocke, Stefan; Grüngreiff, Kurt; Reinhold, Dirk

    2012-06-01

    Zinc is an essential trace element with a critical role in normal growth and development and in immune homeostasis. Zinc deficiency impairs both the innate and the adaptive immune system and can be normalized by zinc supplementation. On the other end of the spectrum, high dosages of zinc diminish immune cell functions similar to zinc deficiency. Here, we investigated the influence of zinc aspartate on proliferation and cytokine production of stimulated human T cells and mouse splenocytes in vitro. Furthermore, the effect of zinc aspartate was examined in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of Multiple Sclerosis (MS) with a Th1/Th17 T cell-mediated immunopathogenesis. Zinc aspartate suppressed proliferation as well as IL-2, IL-10 and IL-17 production in stimulated human T cells and mouse splenocytes. Importantly, administration of a medium range dose of 30 μg/day zinc aspartate [1.5 mg/kg body weight (BW)] in a therapeutic manner led to a significant reduction of the clinical severity of the EAE during the first relapse of the disease. A lower zinc aspartate dose (6 μg/day, 0.3 mg/kg BW) had no significant therapeutic effect on the severity of the EAE, while administration of higher zinc aspartate amounts (120 μg/day, 6 mg/kg BW) led to more severe disease. Taken together, our data suggest that zinc aspartate can modulate activation, proliferation and cytokine production of effector T cells in vitro and in vivo and that activated autoreactive T cells may be potential therapeutic targets of tightly controlled zinc supplementation in autoimmune diseases like MS.

  15. Immunization with Recombinantly Expressed LRP4 Induces Experimental Autoimmune Myasthenia Gravis in C57BL/6 Mice.

    Science.gov (United States)

    Ulusoy, Canan; Çavuş, Filiz; Yılmaz, Vuslat; Tüzün, Erdem

    2017-07-01

    Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ), characterized with muscle weakness. While MG develops due to acetylcholine receptor (AChR) antibodies in most patients, antibodies to muscle-specific receptor tyrosine kinase (MuSK) or low-density lipoprotein receptor-related protein 4 (LRP4) may also be identified. Experimental autoimmune myasthenia gravis (EAMG) has been previously induced by both LRP4 immunization and passive transfer of LRP4 antibodies. Our aim was to confirm previous results and to test the pathogenic effects of LRP4 immunization in a commonly used mouse strain C57BL/6 (B6) using a recombinantly expressed human LRP4 protein. B6 mice were immunized with human LRP4 in CFA, Torpedo Californica AChR in CFA or only CFA. Clinical and pathogenic aspects of EAMG were compared among groups. LRP4- and AChR-immunized mice showed comparable EAMG clinical severity. LRP4-immunized mice displayed serum antibodies to LRP4 and NMJ IgG and complement factor C3 deposits. IgG2 was the dominant anti-LRP4 isotype. Cultured lymph node cells of LRP4- and AChR-immunized mice gave identical pro-inflammatory cytokine (IL-6, IFN-γ and IL-17) responses to LRP4 and AChR stimulation, respectively. Our results confirm the EAMG-inducing action of LRP4 immunization and identify B6 as a LRP4-EAMG-susceptible mouse strain. Demonstration of complement fixing anti-LRP4 antibodies in sera and complement/IgG deposits at the NMJ of LRP4-immunized mice indicates complement activation as a putative pathogenic mechanism. We have thus developed a practical LRP4-induced EAMG model using a non-conformational protein and a widely available mouse strain for future investigation of LRP4-related MG.

  16. Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬

    KAUST Repository

    Zeitelhofer, Manuel

    2017-02-15

    Vitamin D exerts multiple immunomodulatory functions and has been implicated in the etiology and treatment of several autoimmune diseases, including multiple sclerosis (MS). We have previously reported that in juvenile/adolescent rats, vitamin D supplementation protects from experimental autoimmune encephalomyelitis (EAE), a model of MS. Here we demonstrate that this protective effect associates with decreased proliferation of CD4+ T cells and lower frequency of pathogenic T helper (Th) 17 cells. Using transcriptome, methylome, and pathway analyses in CD4+ T cells, we show that vitamin D affects multiple signaling and metabolic pathways critical for T-cell activation and differentiation into Th1 and Th17 subsets in vivo. Namely, Jak/Stat, Erk/Mapk, and Pi3K/Akt/mTor signaling pathway genes were down-regulated upon vitamin D supplementation. The protective effect associated with epigenetic mechanisms, such as (i) changed levels of enzymes involved in establishment and maintenance of epigenetic marks, i.e., DNA methylation and histone modifications; (ii) genome-wide reduction of DNA methylation, and (iii) up-regulation of noncoding RNAs, including microRNAs, with concomitant down-regulation of their protein-coding target RNAs involved in T-cell activation and differentiation. We further demonstrate that treatment of myelin-specific T cells with vitamin D reduces frequency of Th1 and Th17 cells, down-regulates genes in key signaling pathways and epigenetic machinery, and impairs their ability to transfer EAE. Finally, orthologs of nearly 50% of candidate MS risk genes and 40% of signature genes of myelin-reactive T cells in MS changed their expression in vivo in EAE upon supplementation, supporting the hypothesis that vitamin D may modulate risk for developing MS.

  17. Regulatory T Cell Dysfunction Acquiesces to BTLA+ Regulatory B Cells Subsequent Oral Intervention of Experimental Autoimmune Encephalomyelitis

    Science.gov (United States)

    Huarte, Eduardo; Jun, SangMu; Rynda-Apple, Agnieszka; Golden, Sara; Jackiw, Larissa; Hoffman, Carol; Maddaloni, Massimo; Pascual, David W.

    2016-01-01

    Regulatory T cells (Tregs) induced during autoimmunity often become quiescent and unable to resolve disease, suggesting inadequate activation. Resolution of established experimental autoimmune encephalomyelitis (EAE) can be achieved with myelin oligodendrocyte glycoprotein (MOG) fused to reovirus protein σ1 (MOG-pσ1) which activates Tregs, restoring protection, but requiring other regulatory cells to revitalize them. B cells have a dichotomous role in both the pathogenesis and recovery from EAE. While inflammatory B cells contribute to EAE’s pathogenesis, treatment of EAE mice with MOG-pσ1, but not OVA-pσ1, resulted in an influx of IL-10-producing B220+CD5+ B regulatory cells (Bregs) enabling Tregs to recover their inhibitory activity, and in turn, leading to the rapid amelioration of EAE. These findings implicate direct interactions between Bregs and Tregs to facilitate this recovery. Adoptive transfer of B220+CD5− B cells from MOG-pσ1-treated EAE or Bregs from PBS-treated EAE mice did not resolve disease while the adoptive transfer of MOG-pσ1-induced B220+CD5+ Bregs greatly ameliorated EAE. MOG-pσ1-, but not OVA-pσ1-induced IL-10-producing Bregs, expressed elevated levels of BTLA relative to CD5− B cells, as opposed to Tregs or effector T (Teff) cells, whose BTLA expression was not affected. These induced Bregs restored EAE Treg function in a BTLA-dependent manner. BTLA−/− mice showed more pronounced EAE with fewer Tregs but, upon adoptive transfer of MOG-pσ1-induced BTLA+ Bregs, BTLA−/− mice were protected against EAE. Hence, this evidence shows the importance of BTLA in activating Tregs to facilitate recovery from EAE. PMID:27194787

  18. Bystander-mediated stimulation of proteolipid protein-specific regulatory T (Treg) cells confers protection against experimental autoimmune encephalomyelitis (EAE) via TGF-β

    Science.gov (United States)

    Jun, SangMu; Ochoa-Repáraz, Javier; Zlotkowska, Dagmara; Hoyt, Teri; Pascual, David W.

    2012-01-01

    To assess the potency of regulatory T (Treg) cells induced against an irrelevant Ag, mice were orally vaccinated with Salmonella expressing E. coli colonization factor antigen I fimbriae. Isolated CD25+ and CD25− CD4+ T cells were adoptively transferred to naive mice, and Treg cells effectively protected against experimental autoimmune encephalomyelitis (EAE), unlike Treg cells from Salmonella vector-immunized mice. This protection was abrogated upon in vivo neutralization of TGF-β, resulting in elevated IL-17 and loss of IL-4 and IL-10 production. Thus, Treg cells induced to irrelevant Ags offer a novel approach to treat autoimmune diseases independent of auto-Ag. PMID:22418032

  19. Inhibitory Effect of Matrine on Blood-Brain Barrier Disruption for the Treatment of Experimental Autoimmune Encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Su Zhang

    2013-01-01

    Full Text Available Dysfunction of the blood-brain barrier (BBB is a primary characteristic of experimental autoimmune encephalomyelitis (EAE, an experimental model of multiple sclerosis (MS. Matrine (MAT, a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been recently found to suppress clinical EAE and CNS inflammation. However, whether this effect of MAT is through protecting the integrity and function of the BBB is not known. In the present study, we show that MAT treatment had a therapeutic effect comparable to dexamethasone (DEX in EAE rats, with reduced Evans Blue extravasation, increased expression of collagen IV, the major component of the basement membrane, and the structure of tight junction (TJ adaptor protein Zonula occludens-1 (ZO-1. Furthermore, MAT treatment attenuated expression of matrix metalloproteinase-9 and -2 (MMP-9/-2, while it increased the expression of tissue inhibitors of metalloproteinase-1 and -2 (TIMP-1/-2. Our findings demonstrate that MAT reduces BBB leakage by strengthening basement membrane, inhibiting activities of MMP-2 and -9, and upregulating their inhibitors. Taken together, our results identify a novel mechanism underlying the effect of MAT, a natural compound that could be a novel therapy for MS.

  20. A Mushroom Extract Piwep from Phellinus igniarius Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibiting Immune Cell Infiltration in the Spinal Cord

    Directory of Open Access Journals (Sweden)

    Lan Li

    2014-01-01

    Full Text Available The present study aimed to evaluate the therapeutic potential of a mushroom extract from Phellinus igniarius in an animal model of multiple sclerosis. The medicinal mushroom, Phellinus igniarius, contains biologically active compounds that modulate the human immune system. Experimental autoimmune encephalomyelitis (EAE was induced by immunization with myelin oligodendrocyte glycoprotein (MOG 35–55 in C57BL/6 female mice. A water-ethanol extract of Phellinus igniarius (Piwep was delivered intraperitoneally every other day for the entire experimental course. Three weeks after the initial immunization, demyelination and immune cell infiltration in the spinal cord were examined. Piwep injection profoundly decreased the daily incidence rate and clinical score of EAE. The Piwep-mediated inhibition of the clinical course of EAE was accompanied by suppression of demyelination and infiltration of encephalitogenic immune cells including CD4+ T cells, CD8+ T cells, macrophages, and B cells in the spinal cord. Piwep reduced expression of vascular cell adhesion molecule-1 (VCAM-1 in the spinal cord and integrin-α4 in the lymph node of EAE mice. Piwep also inhibited proliferation of lymphocytes and secretion of interferon-γ in the lymph node of EAE mice. The results suggest that a mushroom extract, Piwep, may have a high therapeutic potential for ameliorating multiple sclerosis progression.

  1. Prophylactic Effect of Probiotics on the Development of Experimental Autoimmune Myasthenia Gravis

    OpenAIRE

    Chae, Chang-Suk; Kwon, Ho-Keun; Hwang, Ji-Sun; Kim, Jung-Eun; Im, Sin-Hyeog

    2012-01-01

    Probiotics are live bacteria that confer health benefits to the host physiology. Although protective role of probiotics have been reported in diverse diseases, no information is available whether probiotics can modulate neuromuscular immune disorders. We have recently demonstrated that IRT5 probiotics, a mixture of 5 probiotics, could suppress diverse experimental disorders in mice model. In this study we further investigated whether IRT5 probiotics could modulate the progression of experimen...

  2. "Warming yang and invigorating qi" acupuncture alters acetylcholine receptor expression in the neuromuscular junction of rats with experimental autoimmune myasthenia gravis

    Directory of Open Access Journals (Sweden)

    Hai-peng Huang

    2016-01-01

    Full Text Available Myasthenia gravis is an autoimmune disorder in which antibodies have been shown to form against the nicotinic acetylcholine nicotinic postsynaptic receptors located at the neuromuscular junction. "Warming yang and invigorating qi" acupuncture treatment has been shown to reduce serum inflammatory cytokine expression and increase transforming growth factor beta expression in rats with experimental autoimmune myasthenia gravis. However, few studies have addressed the effects of this type of acupuncture on the acetylcholine receptors at the neuromuscular junction. Here, we used confocal laser scanning microscopy to examine the area and density of immunoreactivity for an antibody to the nicotinic acetylcholine receptor at the neuromuscular junction in the phrenic nerve of rats with experimental autoimmune myasthenia gravis following "warming yang and invigorating qi" acupuncture therapy. Needles were inserted at acupressure points Shousanli (LI10, Zusanli (ST36, Pishu (BL20, and Shenshu (BL23 once daily for 7 consecutive days. The treatment was repeated after 1 day of rest. We found that area and the integrated optical density of the immunoreactivity for the acetylcholine receptor at the neuromuscular junction of the phrenic nerve was significantly increased following acupuncture treatment. This outcome of the acupuncture therapy was similar to that of the cholinesterase inhibitor pyridostigmine bromide. These findings suggest that "warming yang and invigorating qi" acupuncture treatment increases acetylcholine receptor expression at the neuromuscular junction in a rat model of autoimmune myasthenia gravis.

  3. Sex Difference in Oxidative Stress Parameters in Spinal Cord of Rats with Experimental Autoimmune Encephalomyelitis: Relation to Neurological Deficit.

    Science.gov (United States)

    Dimitrijević, Mirjana; Kotur-Stevuljević, Jelena; Stojić-Vukanić, Zorica; Vujnović, Ivana; Pilipović, Ivan; Nacka-Aleksić, Mirjana; Leposavić, Gordana

    2017-02-01

    The study examined (a) whether there is sex difference in spinal cord and plasma oxidative stress profiles in Dark Agouti rats immunised for experimental autoimmune encephalomyelitis (EAE), the principal experimental model of multiple sclerosis, and (b) whether there is correlation between the oxidative stress in spinal cord and neurological deficit. Regardless of rat sex, with the disease development xanthine oxidase (XO) activity and inducible nitric oxide synthase (iNOS) mRNA expression increased in spinal cord, whereas glutathione levels decreased. This was accompanied by the rise in spinal cord malondialdehyde level. On the other hand, with EAE development superoxide dismutase (SOD) activity decreased, while O2(-) concentration increased only in spinal cord of male rats. Consequently, SOD activity was lower, whereas O2(-) concentration was higher in spinal cord of male rats with clinically manifested EAE. XO activity and iNOS mRNA expression were also elevated in their spinal cord. Consistently, in the effector phase of EAE the concentration of advanced oxidation protein product (AOPP) was higher in spinal cord of male rats, which exhibit more severe neurological deficit than their female counterparts. In as much as data obtained in the experimental models could be translated to humans, the findings may be relevant for designing sex-specific antioxidant therapeutic strategies. Furthermore, the study indicated that the increased pro-oxidant-antioxidant balance in plasma may be an early indicator of EAE development. Moreover, it showed that plasma AOPP level may indicate not only actual activity of the disease, but also serve to predict severity of its course.

  4. Autoimmune Diseases

    Science.gov (United States)

    ... autoimmune diseases are rare, while others, such as Hashimoto's disease, affect many people. Who gets autoimmune diseases? ... often occur on both sides of the body. Hashimoto's (hah-shee-MOH-tohz) disease (underactive thyroid) A ...

  5. Metals and kidney autoimmunity.

    Science.gov (United States)

    Bigazzi, P E

    1999-10-01

    The causes of autoimmune responses leading to human kidney pathology remain unknown. However, environmental agents such as microorganisms and/or xenobiotics are good candidates for that role. Metals, either present in the environment or administered for therapeutic reasons, are prototypical xenobiotics that cause decreases or enhancements of immune responses. In particular, exposure to gold and mercury may result in autoimmune responses to various self-antigens as well as autoimmune disease of the kidney and other tissues. Gold compounds, currently used in the treatment of patients with progressive polyarticular rheumatoid arthritis, can cause a nephrotic syndrome. Similarly, an immune-mediated membranous nephropathy frequently occurred when drugs containing mercury were commonly used. Recent epidemiologic studies have shown that occupational exposure to mercury does not usually result in autoimmunity. However, mercury induces antinuclear antibodies, sclerodermalike disease, lichen planus, or membranous nephropathy in some individuals. Laboratory investigations have confirmed that the administration of gold or mercury to experimental animals leads to autoimmune disease quite similar to that observed in human subjects exposed to these metals. In addition, studies of inbred mice and rats have revealed that a few strains are susceptible to the autoimmune effects of gold and mercury, whereas the majority of inbred strains are resistant. These findings have emphasized the importance of genetic (immunogenetic and pharmacogenetic) factors in the induction of metal-associated autoimmunity. (italic)In vitro(/italic) and (italic)in vivo(/italic) research of autoimmune disease caused by mercury and gold has already yielded valuable information and answered a number of important questions. At the same time it has raised new issues about possible immunostimulatory or immunosuppressive mechanisms of xenobiotic activity. Thus it is evident that investigations of metal

  6. Teriflunomide reduces behavioral, electrophysiological, and histopathological deficits in the Dark Agouti rat model of experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Merrill, Jean E; Hanak, Susan; Pu, Su-Fen; Liang, Jinjun; Dang, Chelsea; Iglesias-Bregna, Deborah; Harvey, Brian; Zhu, Bin; McMonagle-Strucko, Kathleen

    2009-01-01

    Teriflunomide is an orally available anti-inflammatory drug that prevents T and B cell proliferation and function by inhibition of dihydroorotate dehydrogenase. It is currently being developed for the treatment of multiple sclerosis (MS). We report here for the first time the anti-inflammatory effects of teriflunomide in the Dark Agouti rat model of experimental autoimmune encephalomyelitis (EAE). Neurological evaluation demonstrated that prophylactic dosing of teriflunomide at 3 and 10 mg/kg delayed disease onset and reduced maximal and cumulative scores. Therapeutic administration of teriflunomide at doses of 3 or 10 mg/kg at disease onset significantly reduced maximal and cumulative disease scores as compared to vehicle treated rats. Dosing teriflunomide at disease remission, at 3 and 10 mg/kg, reduced the cumulative scores for the remaining course of the disease. Teriflunomide at 10 mg/kg significantly reduced inflammation, demyelination, and axonal loss when dosed prophylactically or therapeutically. In electrophysiological somatosensory evoked potential studies, therapeutic administration of teriflunomide, at the onset of disease, prevented both a decrease in waveform amplitude and an increase in the latency to waveform initiation in EAE animals compared to vehicle. Therapeutic dosing with teriflunomide at disease remission prevented a decrease in evoked potential amplitude, prevented an increase in latency, and enhanced recovery time within the CNS.

  7. S-Allylmercapto-N-acetylcysteine (ASSNAC) protects cultured nerve cells from oxidative stress and attenuates experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Savion, Naphtali; Izigov, Nira; Morein, Milana; Pri-Chen, Sarah; Kotev-Emeth, Shlomo

    2014-11-07

    Oxidative stress and/or low cellular glutathione are associated with development and progression of neurodegenerative diseases. We have shown that S-allylmercapto-N-acetylcysteine (ASSNAC) up-regulates the level of glutathione and phase II detoxifying enzymes in cultured vascular endothelial cells. The present study demonstrates that exposure of nerve cell lines to ASSNAC significantly increases the cellular level of glutathione probably via activation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and protects the cells from tBuOOH-induced cytotoxicity. Furthermore, ASSNAC increases the level of mice spinal cord and brain glutathione (by 54% and 47%, respectively) and attenuates the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in mice. In conclusion, these data implicate ASSNAC to protect nerve cells, both in vitro and in vivo, from oxidative stress and thereby to attenuate the clinical symptoms of EAE, suggesting its potential use for the treatment of neurodegenerative diseases. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  8. The leukotriene B{sub 4} receptor, BLT1, is required for the induction of experimental autoimmune encephalomyelitis

    Energy Technology Data Exchange (ETDEWEB)

    Kihara, Yasuyuki, E-mail: kihara-yasuyuki@umin.net [Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Yokomizo, Takehiko [Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582 (Japan); Core Research for Embryonic Science and Technology (CREST), Japan Science and Technology Agency (Japan); Kunita, Akiko; Morishita, Yasuyuki; Fukayama, Masashi [Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033 (Japan); Ishii, Satoshi; Shimizu, Takao [Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)

    2010-04-09

    Leukotriene B{sub 4} (LTB{sub 4}) is a potent chemoattractant and activator of neutrophils, macrophages and T cells. These cells are a key component of inflammation and all express BLT1, a high affinity G-protein-coupled receptor for LTB{sub 4}. However, little is known about the neuroimmune functions of BLT1. In this study, we describe a distinct role for BLT1 in the pathology of experimental autoimmune encephalomyelitis (EAE) and T{sub H}1/T{sub H}17 immune responses. BLT1 mRNA was highly upregulated in the spinal cord of EAE mice, especially during the induction phase. BLT1{sup -/-} mice had delayed onset and less severe symptoms of EAE than BLT1{sup +/+} mice. Additionally, inflammatory cells were recruited to the spinal cord of asymptomatic BLT1{sup +/+}, but not BLT1{sup -/-} mice before the onset of disease. Ex vivo studies showed that both the proliferation and the production of IFN-{gamma}, TNF-{alpha}, IL-17 and IL-6 were impaired in BLT1{sup -/-} cells, as compared with BLT1{sup +/+} cells. Thus, we suggest that BLT1 exacerbates EAE by regulating the migration of inflammatory cells and T{sub H}1/T{sub H}17 immune responses. Our findings provide a novel therapeutic option for the treatment of multiple sclerosis and other T{sub H}17-mediated diseases.

  9. Tolerogenic Dendritic Cells Generated with Tofacitinib Ameliorate Experimental Autoimmune Encephalomyelitis through Modulation of Th17/Treg Balance

    Directory of Open Access Journals (Sweden)

    Yan Zhou

    2016-01-01

    Full Text Available It is well known that dendritic cells (DCs play a pivotal role in triggering self-specific responses. Conversely, tolerogenic DCs (tolDCs, a specialized subset, induce tolerance and negatively regulate autoreactive responses. Tofacitinib, a Janus kinase inhibitor developed by Pfizer for treatment of rheumatoid arthritis, is probable to be a promising candidate for inducing tolDCs. The aims of this study were to evaluate the effectiveness of tolDCs induced by tofacitinib in a myelin oligodendrocyte glycoprotein- (MOG- specific experimental autoimmune encephalomyelitis (EAE model and to investigate their effects on Th17/Treg balance in the animal model of multiple sclerosis (MS. Our results revealed that tofacitinib-treated DCs maintained a steady semimature phenotype with a low level of proinflammatory cytokines and costimulatory molecules. DCs treated by tofacitinib also induced antigen-specific T cells hyporesponsiveness in a concentration-dependent manner. Upon intravenous injection into EAE mice, MOG pulsed tolDCs significantly dampened disease activity, and adoptive cell therapy (ACT disturbed Th17/Treg balance with a remarkable decrease of Th1/Th17 cells and an increase in regulatory T cells (Tregs. Overall, DCs modified by tofacitinib exhibited a typical tolerogenic phenotype, and the antigen-specific tolDCs may represent a new avenue of research for the development of future clinical treatments for MS.

  10. Periplocoside A prevents experimental autoimmune encephalomyelitis by suppressing IL-17 production and inhibits differentiation of Th17 cells.

    Science.gov (United States)

    Zhang, Jing; Ni, Jia; Chen, Zhen-hua; Li, Xin; Zhang, Ru-jun; Tang, Wei; Zhao, Wei-min; Yang, Yi-fu; Zuo, Jian-ping

    2009-08-01

    The aim of this study was to determine the therapeutic effect of Periplocoside A (PSA), a natural product isolated from the traditional Chinese herbal medicine Periploca sepium Bge, in MOG(35-55) (myelin oligodendrocyte glycoprotein 35-55)-induced experimental autoimmune encephalomyelitis (EAE). Female C57BL/6 mice immunized with MOG(35-55) were treated with (50 mg/kg or 25 mg/kg) or without PSA following immunization and continuously throughout the study. The degree of CNS inflammation was evaluated by H&E staining. Anti-MOG-specific recall responses were analyzed by [3H]-Thymidine incorporation, ELISA, and RT-PCR. The proportion of IL-17-producing T cells was measured by flow cytometry. Oral administration of PSA significantly reduced the incidence and severity of EAE, which closely paralleled the inhibition of MOG(35-55)-specific IL-17 production. Importantly, PSA inhibited the transcription of IL-17 mRNA and RORgammat. Further studies examining intracellular staining and adoptive transfer EAE validated the direct suppressive effect of PSA on Th17 cells. In vitro studies also showed that PSA significantly inhibited the differentiation of Th17 cells from murine purified CD4+ T cells in a dose-dependent manner. PSA ameliorated EAE by suppressing IL-17 production and inhibited the differentiation of Th17 cells in vitro. Our results provide new insight into the potential mechanisms underlying the immunosuppressive and anti-inflammatory effects of PSA.

  11. Paranodal myelin retraction in relapsing experimental autoimmune encephalomyelitis visualized by coherent anti-Stokes Raman scattering microscopy

    Science.gov (United States)

    Fu, Yan; Frederick, Terra J.; Huff, Terry B.; Goings, Gwendolyn E.; Miller, Stephen D.; Cheng, Ji-Xin

    2011-10-01

    How demyelination is initiated is a standing question for pathology of multiple sclerosis. By label-free coherent anti-Stokes Raman scattering (CARS) imaging of myelin lipids, we investigate myelin integrity in the lumbar spinal cord tissue isolated from naïve SJL mice, and from mice at the onset, peak acute, and remission stages of relapsing experimental autoimmune encephalomyelitis (EAE). Progressive demyelinating disease is initially characterized by the retraction of paranodal myelin both at the onset of disease and at the borders of acute demyelinating lesions. Myelin retraction is confirmed by elongated distribution of neurofascin proteins visualized by immunofluorescence. The disruption of paranodal myelin subsequently exposes Kv1.2 channels at the juxtaparanodes and lead to the displacement of Kv1.2 channels to the paranodal and nodal domains. Paranodal myelin is partially restored during disease remission, indicating spontaneous myelin regeneration. These findings suggest that paranodal domain injury precedes formation of internodal demyelinating lesions in relapsing EAE. Our results also demonstrate that CARS microscopy is an effective readout of myelin disease burden.

  12. Absence of PAF receptor alters cellular infiltrate but not rolling and adhesion of leukocytes in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Rodrigues, David Henrique; Lacerda-Queiroz, Norinne; de Miranda, Aline Silva; Fagundes, Caio Tavares; Campos, Roberta Dayrell de Lima; Arantes, Rosa Esteves; Vilela, Márcia de Carvalho; Rachid, Milene Alvarenga; Teixeira, Mauro Martins; Teixeira, Antônio Lúcio

    2011-04-18

    Experimental autoimmune encephalomyelitis (EAE) is a condition induced in some susceptible species to the study of multiple sclerosis (MS). The platelet activating factor (PAF) is an important mediator of immune responses and seems to be involved in MS. However, the participation of PAF in EAE and MS remains controversial. Thus, in this study, we aimed to evaluate the role of PAF receptor in the pathogenesis of EAE. EAE was induced using an emulsion containing MOG(35-55). EAE-induced PAF receptor knock out (PAFR(-/-)) mice presented milder disease when compared to C57BL/6 wild type (WT) animals. PAFR(-/-) animals had lower inflammatory infiltrates in central nervous system (CNS) tissue when compared to WT mice. However, intravital microscopy in cerebral microvasculature revealed similar levels of rolling and adhering leukocytes in both WT and PAFR(-/-) mice. Interleukine (IL)-17 and chemokines C-C motif legends (CCL)2 and CCL5 were significantly lower in PAFR(-/-) mice when compared to WT mice. Brain infiltrating cluster of differentiation (CD)4(+) leukocytes and IL-17(+) leukocytes was diminished in PAFR(-/-) when compared to WT mice. Taken together, our results suggest that PAF receptor is important in the induction and development of EAE, although it has no influence in rolling and adhesion steps of cell recruitment. The absence of PAF receptor results in milder disease by altering the type of inflammatory mediators and cells that are present in CNS tissue. Copyright © 2011 Elsevier B.V. All rights reserved.

  13. NG2 glia generate new oligodendrocytes but few astrocytes in a murine experimental autoimmune encephalomyelitis model of demyelinating disease.

    Science.gov (United States)

    Tripathi, Richa B; Rivers, Leanne E; Young, Kaylene M; Jamen, Francoise; Richardson, William D

    2010-12-01

    The adult mammalian brain and spinal cord contain glial precursors that express platelet-derived growth factor receptor α subunit (PDGFRA) and the NG2 proteoglycan. These "NG2 cells" descend from oligodendrocyte precursors in the perinatal CNS and continue to generate myelinating oligodendrocytes in the gray and white matter of the postnatal brain. It has been proposed that NG2 cells can also generate reactive astrocytes at sites of CNS injury or demyelination. To test this we examined the fates of PDGFRA/NG2 cells in the mouse spinal cord during experimental autoimmune encephalomyelitis (EAE)--a demyelinating condition that models some aspects of multiple sclerosis in humans. We administered tamoxifen to Pdgfra-CreER(T2):Rosa26R-YFP mice to induce yellow fluorescent protein (YFP) expression in PDGFRA/NG2 cells and their differentiated progeny. We subsequently induced EAE and observed a large (>4-fold) increase in the local density of YFP(+) cells, >90% of which were oligodendrocyte lineage cells. Many of these became CC1-positive, NG2-negative differentiated oligodendrocytes that expressed myelin markers CNP and Tmem10/Opalin. PDGFRA/NG2 cells generated very few GFAP(+)-reactive astrocytes (1-2% of all YFP(+) cells) or NeuN(+) neurons (demyelinated spinal cord.

  14. Mouse Models of Multiple Sclerosis: Experimental Autoimmune Encephalomyelitis and Theiler’s Virus-Induced Demyelinating Disease

    Science.gov (United States)

    McCarthy, Derrick P.; Richards, Maureen H.; Miller, Stephen D.

    2013-01-01

    Experimental autoimmune encephalomyelitis (EAE) and Theiler’s Murine Encephalitis Virus-Induced Demyelinating Disease (TMEV-IDD) are two clinically relevant murine models of multiple sclerosis (MS). Like MS, both are characterized by mononuclear cell infiltration into the CNS and demyelination. EAE is induced by either the administration of myelin protein or peptide in adjuvant or by the adoptive transfer of encephalitogenic T cell blasts into naïve recipients. The relative merits of each of these protocols are compared. Depending on the type of question being asked, different mouse strains and peptides are used. Different disease courses are observed with different strains and different peptides in active EAE. These variations are also addressed. Additionally, issues relevant to clinical grading of EAE in mice are discussed. In addition to EAE induction, useful references for other disease indicators such as DTH, in vitro proliferation, and immunohistochemistry are provided. TMEV-IDD is a useful model for understanding the possible viral etiology of MS. This section provides detailed information on the preparation of viral stocks and subsequent intracerebral infection of mice. Additionally, virus plaque assay and clinical disease assessment are discussed. Recently, recombinant TMEV strains have been created for the study of molecular mimicry which incorporate various 30 amino acid myelin epitopes within the leader region of TMEV. PMID:22933080

  15. Treatment with anti-interferon-gamma monoclonal antibodies modifies experimental autoimmune encephalomyelitis in interferon-gamma receptor knockout mice

    DEFF Research Database (Denmark)

    Espejo, C; Penkowa, M; Sáez-Torres, I

    2001-01-01

    antibodies (mAb) on day 8 postimmunization. Clinical scoring and both histological and immunohistochemical studies were undertaken for all groups. We hereby show that treatment with anti-IFN-gamma mAb worsened the disease course of 129Sv wild-type mice. However, it decreased the mean daily score in IFN......-gamma R(-/-) 129Sv and the incidence of the disease down to 50% in C57Bl/6x129Sv IFN-gamma R(-/-) mice. Moreover, after anti-IFN-gamma mAb treatment, oxidative stress levels, metallothionein I and II antioxidant protein expression, and apoptoticneuronal death were increased in wild-type mice while......The role of interferon-gamma (IFN-gamma) in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) is still controversial. We have studied the function of IFN-gamma and its receptor in the EAE model using two different IFN-gamma receptor knockout (IFN-gamma R...

  16. Prenatal Vitamin D Deficiency Induces an Early and More Severe Experimental Autoimmune Encephalomyelitis in the Second Generation

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    Francois Feron

    2012-08-01

    Full Text Available In a previous study, we demonstrated that mouse adult F1 offspring, exposed to a vitamin D deficiency during pregnancy, developed a less severe and delayed Experimental Autoimmune Encephalomyelitis (EAE, when compared with control offspring. We then wondered whether a similar response was observed in the subsequent generation. To answer this question, we assessed F2 females whose F1 parents (males or females were vitamin D-deprived when developing in the uterus of F0 females. Unexpectedly, we observed that the vitamin D deficiency affecting the F0 pregnant mice induced a precocious and more severe EAE in the F2 generation. This paradoxical finding led us to assess its implications for the epidemiology of Multiple Sclerosis (MS in humans. Using the REFGENSEP database for MS trios (the patient and his/her parents, we collected the parents’ dates of birth and assessed a potential season of birth effect that could potentially be indicative of the vitamin D status of the pregnant grandmothers. A trend for a reduced number of births in the Fall for the parents of MS patients was observed but statistical significance was not reached. Further well powered studies are warranted to validate the latter finding.

  17. PI3Kγ drives priming and survival of autoreactive CD4(+ T cells during experimental autoimmune encephalomyelitis.

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    Iain Comerford

    Full Text Available The class IB phosphoinositide 3-kinase gamma enzyme complex (PI3Kγ functions in multiple signaling pathways involved in leukocyte activation and migration, making it an attractive target in complex human inflammatory diseases including MS. Here, using pik3cg(-/- mice and a selective PI3Kγ inhibitor, we show that PI3Kγ promotes development of experimental autoimmune encephalomyelitis (EAE. In pik3cg(-/- mice, EAE is markedly suppressed and fewer leukocytes including CD4(+ and CD8(+ T cells, granulocytes and mononuclear phagocytes infiltrate the CNS. CD4(+ T cell priming in secondary lymphoid organs is reduced in pik3cg(-/- mice following immunisation. This is attributable to defects in DC migration concomitant with a failure of full T cell activation following TCR ligation in the absence of p110γ. Together, this results in suppressed autoreactive T cell responses in pik3cg(-/- mice, with more CD4(+ T cells undergoing apoptosis and fewer cytokine-producing Th1 and Th17 cells in lymphoid organs and the CNS. When administered from onset of EAE, the orally active PI3Kγ inhibitor AS605240 caused inhibition and reversal of clinical disease, and demyelination and cellular pathology in the CNS was reduced. These results strongly suggest that inhibitors of PI3Kγ may be useful therapeutics for MS.

  18. LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Mi, Sha; Hu, Bing; Hahm, Kyungmin; Luo, Yi; Kam Hui, Edward Sai; Yuan, Qiuju; Wong, Wai Man; Wang, Li; Su, Huanxing; Chu, Tak-Ho; Guo, Jiasong; Zhang, Wenming; So, Kwok-Fai; Pepinsky, Blake; Shao, Zhaohui; Graff, Christilyn; Garber, Ellen; Jung, Vincent; Wu, Ed Xuekui; Wu, Wutian

    2007-10-01

    Demyelinating diseases, such as multiple sclerosis, are characterized by the loss of the myelin sheath around neurons, owing to inflammation and gliosis in the central nervous system (CNS). Current treatments therefore target anti-inflammatory mechanisms to impede or slow disease progression. The identification of a means to enhance axon myelination would present new therapeutic approaches to inhibit and possibly reverse disease progression. Previously, LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) has been identified as an in vitro and in vivo negative regulator of oligodendrocyte differentiation and myelination. Here we show that loss of LINGO-1 function by Lingo1 gene knockout or by treatment with an antibody antagonist of LINGO-1 function leads to functional recovery from experimental autoimmune encephalomyelitis. This is reflected biologically by improved axonal integrity, as confirmed by magnetic resonance diffusion tensor imaging, and by newly formed myelin sheaths, as determined by electron microscopy. Antagonism of LINGO-1 or its pathway is therefore a promising approach for the treatment of demyelinating diseases of the CNS.

  19. Induction of endogenous Type I interferon within the central nervous system plays a protective role in experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Khorooshi, Reza; Mørch, Marlene Thorsen; Holm, Thomas Hellesøe

    2015-01-01

    The Type I interferons (IFN), beta (IFN-β) and the alpha family (IFN-α), act through a common receptor and have anti-inflammatory effects. IFN-β is used to treat multiple sclerosis (MS) and is effective against experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Mice with EAE......-endogenous Type I IFN influences EAE. Using IFN-β reporter mice, we showed that direct administration of polyinosinic-polycytidylic acid (poly I:C), a potent inducer of IFN-β, into the cerebrospinal fluid induced increased leukocyte numbers and transient upregulation of IFN-β in CD45/CD11b-positive cells located...... in the meninges and choroid plexus, as well as enhanced IFN-β expression by parenchymal microglial cells. Intrathecal injection of poly I:C to mice showing first symptoms of EAE substantially increased the normal disease-associated expression of IFN-α, IFN-β, interferon regulatory factor-7 and IL-10 in CNS...

  20. The nod-like receptor, Nlrp12, plays an anti-inflammatory role in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Gharagozloo, Marjan; Mahvelati, Tara M; Imbeault, Emilie; Gris, Pavel; Zerif, Echarki; Bobbala, Diwakar; Ilangumaran, Subburaj; Amrani, Abdelaziz; Gris, Denis

    2015-10-31

    Multiple sclerosis (MS) is an organ-specific autoimmune disease resulting in demyelinating plaques throughout the central nervous system. In MS, the exact role of microglia remains unknown. On one hand, they can present antigens, skew T cell responses, and upregulate the expression of pro-inflammatory molecules. On the other hand, microglia may express anti-inflammatory molecules and inhibit inflammation. Microglia express a wide variety of immune receptors such as nod-like receptors (NLRs). NLRs are intracellular receptors capable of regulating both innate and adaptive immune responses. Among NLRs, Nlrp12 is largely expressed in cells of myeloid origins. It plays a role in immune inflammatory responses by negatively regulating the nuclear factor-kappa B (NF-κB) pathway. Thus, we hypothesize that Nlrp12 suppresses inflammation and ameliorates the course of MS. We used experimental autoimmune encephalomyelitis (EAE), a well-characterized mouse model of MS. EAE was induced in wild-type (WT) and Nlrp12 (-/-) mice with myelin oligodendrocyte glycoprotein (MOG):complete Freud's adjuvant (CFA). The spinal cords of healthy and immunized mice were extracted for immunofluorescence and pro-inflammatory gene analysis. Primary murine cortical microglia cell cultures of WT and Nlrp12 (-/-) were prepared with cortices of 1-day-old pups. The cells were stimulated with lipopolysaccharide (LPS) and analyzed for the expression of pro-inflammatory genes as well as pro-inflammatory molecule secretions. Over the course of 9 weeks, the Nlrp12 (-/-) mice demonstrated increased severity in the disease state, where they developed the disease earlier and reached significantly higher clinical scores compared to the WT mice. The spinal cords of immunized WT mice relative to healthy WT mice revealed a significant increase in Nlrp12 messenger ribonucleic acid (mRNA) expression at 1, 3, and 5 weeks post injection. A significant increase in the expression of pro-inflammatory genes Ccr5, Cox2

  1. Attenuation of experimental autoimmune neuritis with locally administered lovastatin-encapsulating poly(lactic-co-glycolic) acid nanoparticles.

    Science.gov (United States)

    Langert, Kelly A; Goshu, Bruktawit; Stubbs, Evan B

    2017-01-01

    Acute inflammatory demyelinating polyneuropathy (AIDP) is an aggressive antibody- and T-cell-mediated variant of Guillain-Barré Syndrome (GBS), a prominent and debilitating autoimmune disorder of the peripheral nervous system. Despite advancements in clinical management, treatment of patients with AIDP/GBS and its chronic variant CIDP remains palliative and relies on the use of non-specific immunemodulating therapies. Our laboratory has previously reported that therapeutic administration of statins safely attenuates the clinical severity of experimental autoimmune neuritis (EAN), a well-characterized animal model of AIDP/GBS, by restricting the migration of autoreactive leukocytes across peripheral nerve microvascular endoneurial endothelial cells that form the blood-nerve barrier. Despite these advancements, the clinical application of systemically administered statins for the management of inflammatory disorders remains controversial as a result of disappointingly inconclusive phase trials. Here, poly(lactic-co-glycolic) acid (PLGA) nanoparticles were evaluated as an alternative strategy by which to locally administer statins for the management of EAN. When tested in vitro, lovastatin-encapsulating PLGA nanoparticles elicited a marked increase in RhoB mRNA content in peripheral nerve microvascular endoneurial endothelial cells, similar to cells treated with activated unencapsulated lovastatin. Unilateral peri-neural administration of lovastatin-encapsulating PLGA nanoparticles, but not empty nanoparticles, to naïve Lewis rats similarly enhanced RhoB mRNA content in adjacent nerve and muscle tissue. When administered in this manner, serum levels of lovastatin were below the level of detection. Bilateral peri-neural administration of lovastatin-encapsulating PLGA nanoparticles to EAN-induced Lewis rats significantly attenuated EAN clinical severity while protecting against EAN-induced peripheral nerve morphological and functional deficits. This study provides

  2. Galectin-3 in autoimmunity and autoimmune diseases.

    Science.gov (United States)

    de Oliveira, Felipe L; Gatto, Mariele; Bassi, Nicola; Luisetto, Roberto; Ghirardello, Anna; Punzi, Leonardo; Doria, Andrea

    2015-08-01

    Galectin-3 (gal-3) is a β-galactoside-binding lectin, which regulates cell-cell and extracellular interactions during self/non-self-antigen recognition and cellular activation, proliferation, differentiation, migration and apoptosis. It plays a significant role in cellular and tissue pathophysiology by organizing niches that drive inflammation and immune responses. Gal-3 has some therapeutic potential in several diseases, including chronic inflammatory disorders, cancer and autoimmune diseases. Gal-3 exerts a broad spectrum of functions which differs according to its intra- or extracellular localization. Recombinant gal-3 strategy has been used to identify potential mode of action of gal-3; however, exogenous gal-3 may not reproduce the functions of the endogenous gal-3. Notably, gal-3 induces monocyte-macrophage differentiation, interferes with dendritic cell fate decision, regulates apoptosis on T lymphocytes and inhibits B-lymphocyte differentiation into immunoglobulin secreting plasma cells. Considering the influence of these cell populations in the pathogenesis of several autoimmune diseases, gal-3 seems to play a role in development of autoimmunity. Gal-3 has been suggested as a potential therapeutic agent in patients affected with some autoimmune disorders. However, the precise role of gal-3 in driving the inflammatory process in autoimmune or immune-mediated disorders remains elusive. Here, we reviewed the involvement of gal-3 in cellular and tissue events during autoimmune and immune-mediated inflammatory diseases. © 2015 by the Society for Experimental Biology and Medicine.

  3. ANTI-ERGOTYPIC RESPONSE: ROLE IN NORMAL IMMUNE RESPONSE AND AUTOIMMUNE PATHOLOGY IN EXPERIMENTAL MODEL

    Directory of Open Access Journals (Sweden)

    N. A. Ilyina

    2011-01-01

    Full Text Available Abstract. Anti-ergotypic cells are a part of peripheral regulatory network, and they are thought to control autoreactive T cells by recognition of certain clonotypic and ergotypic determinants on the surface of activated T cells. The aim of our study was to investigate ability of anti-CD3 activated syngeneic splenocytes to induce anti-ergotypic  response  and  to  assess  immune  response  in  delayed-type hypersensitivity (DTH reaction.DTH response in experimental group was significantly greater than in control and intact groups. Upon crossadministration, DTH response was minimal and there were no significant differences between the groups. No changes in cellular and humoral immune response were observed under such conditions. These results suggest a development of immune response to activated antigen-nonspecific cells. In a model of chronic GvHD, donor immunization was shown to exert a protective effect, with regard of proteinuria dynamics in recipients, whereas immunization of recipients did not alter the GvHD dynamics. (Med. Immunol., 2011, vol. 13, N 1, pp 29-34

  4. Treatment with the Antipsychotic Agent, Risperidone, Reduces Disease Severity in Experimental Autoimmune Encephalomyelitis

    Science.gov (United States)

    Stone, Sarrabeth; Zareie, Pirooz; Kharkrang, Marie; Fong, Dahna; Connor, Bronwen; La Flamme, Anne Camille

    2014-01-01

    Recent studies have demonstrated that atypical antipsychotic agents, which are known to antagonize dopamine D2 and serotonin 5-HT2a receptors, have immunomodulatory properties. Given the potential of these drugs to modulate the immune system both peripherally and within the central nervous system, we investigated the ability of the atypical anti-psychotic agent, risperidone, to modify disease in the animal model of multiple sclerosis (MS)4, experimental autoimune encephalomyelitis (EAE). We found that chronic oral administration of risperidone dose-dependently reduced the severity of disease and decreased both the size and number of spinal cord lesions. Furthermore, risperidone treatment substantially reduced antigen-specific interleukin (IL)-17a, IL-2, and IL-4 but not interferon (IFN)-γ production by splenocytes at peak disease and using an in vitro model, we show that treatment of macrophages with risperidone alters their ability to bias naïve T cells. Another atypical antipsychotic agent, clozapine, showed a similar ability to modify macrophages in vitro and to reduce disease in the EAE model but this effect was not due to antagonism of the type 1 or type 2 dopamine receptors alone. Finally, we found that while risperidone treatment had little effect on the in vivo activation of splenic macrophages during EAE, it significantly reduced the activation of microglia and macrophages in the central nervous system. Together these studies indicate that atypical antipsychotic agents like risperidone are effective immunomodulatory agents with the potential to treat immune-mediated diseases such as MS. PMID:25116424

  5. Glucagon-Like Peptide-1 Analog, Liraglutide, Delays Onset of Experimental Autoimmune Encephalitis in Lewis Rats

    DEFF Research Database (Denmark)

    DellaValle, Brian; Brix, Gitte S; Brock, Birgitte

    2016-01-01

    Introduction: Recent findings indicate that metabolic disturbances are involved in multiple sclerosis (MS) pathology and influence the susceptibility to treatment, directing attention toward anti-diabetic drugs such as metformin and pioglitazone. Liraglutide, a drug of the glucagon-like peptide-1......, that liraglutide treatment delays onset of EAE in Lewis rats and is associated with improved protective capacity against oxidative stress. These data suggest GLP-1 receptor agonists should be investigated further as a potential therapy for MS.......Introduction: Recent findings indicate that metabolic disturbances are involved in multiple sclerosis (MS) pathology and influence the susceptibility to treatment, directing attention toward anti-diabetic drugs such as metformin and pioglitazone. Liraglutide, a drug of the glucagon-like peptide-1...... (GLP-1) family, is also anti-diabetic and weight-reducing and is, moreover, directly neuroprotective and anti-inflammatory in a broad spectrum of experimental models of brain disease. In this study we investigate the potential for this FDA-approved drug, liraglutide, as a treatment for MS by utilizing...

  6. Disruption of TGF-β signaling improves ocular surface epithelial disease in experimental autoimmune keratoconjunctivitis sicca.

    Directory of Open Access Journals (Sweden)

    Cintia S De Paiva

    Full Text Available TGF-β is a pleiotropic cytokine that can have pro- or anti-inflammatory effects depending on the context. Elevated levels of bioactive TGF-β1 in tears and elevated TGF-β1mRNA transcripts in conjunctiva and minor salivary glands of human Sjögren's Syndrome patients has also been reported. The purpose of this study was to evaluate the response to desiccating stress (DS, an experimental model of dry eye, in dominant-negative TGF-β type II receptor (CD4-DNTGFβRII mice. These mice have a truncated TGF-β receptor in CD4(+ T cells, rendering them unresponsive to TGF-β.DS was induced by subcutaneous injection of scopolamine and exposure to a drafty low humidity environment in CD4-DNTGFβRII and wild-type (WT mice, aged 14 weeks, for 5 days. Nonstressed (NS mice served as controls. Parameters of ocular surface disease included corneal smoothness, corneal barrier function and conjunctival goblet cell density. NS CD4-DNTGFβRII at 14 weeks of age mice exhibited a spontaneous dry eye phenotype; however, DS improved their corneal barrier function and corneal surface irregularity, increased their number of PAS+ GC, and lowered CD4(+ T cell infiltration in conjunctiva. In contrast to WT, CD4-DNTGFβRII mice did not generate a Th-17 and Th-1 response, and they failed to upregulate MMP-9, IL-23, IL-17A, RORγT, IFN-γ and T-bet mRNA transcripts in conjunctiva. RAG1KO recipients of adoptively transferred CD4+T cells isolated from DS5 CD4-DNTGFβRII showed milder dry eye phenotype and less conjunctival inflammation than recipients of WT control.Our results showed that disruption of TGF-β signaling in CD4(+ T cells causes paradoxical improvement of dry eye disease in mice subjected to desiccating stress.

  7. Systemic but no local effects of combined zoledronate and parathyroid hormone treatment in experimental autoimmune arthritis.

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    Kresten Krarup Keller

    Full Text Available INTRODUCTION: Local bone erosions and osteoporosis in rheumatoid arthritis (RA are the result of a more pronounced bone resorption than bone formation. Present treatment strategies for RA inhibit inflammation, but do not directly target bone erosions. The aim of the study was in experimental arthritis to investigate the juxtaarticular and systemic effects of simultaneous osteoclast inhibition with zoledronate (ZLN and osteoblast stimulation with parathyroid hormone (PTH. METHODS: Arthritis was induced in 36 SKG mice. The mice were randomized to three treatment groups and an untreated group: ZLN, PTH, PTH+ZLN, and untreated. Arthritis score and ankle width measurements were performed. Histological sections were cut from the right hind paw, and design-based stereological estimators were used to quantify histological variables of bone volume and bone formation and resorption. The femora were DXA- and μCT-scanned, and the bone strength was determined at the femoral neck and mid-diaphysis. RESULTS: Locally, we found no differences in arthritis score or ankle width throughout the study. Similarly, none of the treatments inhibited bone erosions or stimulated bone formation in the paw. Systemically, all treatments improved bone mineral density, strength of the femoral neck and mid-diaphysis, and μCT parameters of both cortical and trabecular bone. In addition, there was an additive effect of combination treatment compared with single treatments for most trabecular parameters including bone mineral density and bone volume fraction. CONCLUSIONS: No local effect on bone was found by the combined action of inhibiting bone resorption and stimulating bone formation. However, a clear systemic effect of the combination treatment was demonstrated.

  8. Bystander-mediated stimulation of proteolipid protein-specific regulatory T (Treg) cells confers protection against experimental autoimmune encephalomyelitis (EAE) via TGF-β

    OpenAIRE

    Jun, SangMu; Ochoa-Repáraz, Javier; Zlotkowska, Dagmara; Hoyt, Teri; Pascual, David W.

    2012-01-01

    To assess the potency of regulatory T (Treg) cells induced against an irrelevant Ag, mice were orally vaccinated with Salmonella expressing E. coli colonization factor antigen I fimbriae. Isolated CD25+ and CD25− CD4+ T cells were adoptively transferred to naive mice, and Treg cells effectively protected against experimental autoimmune encephalomyelitis (EAE), unlike Treg cells from Salmonella vector-immunized mice. This protection was abrogated upon in vivo neutralization of TGF-β, resulting...

  9. Glucagon-like peptide-1 analogue, liraglutide, delays onset and reduces severity of experimental autoimmune encephalitis in Lewis rats

    Directory of Open Access Journals (Sweden)

    Brian DellaValle

    2016-11-01

    Full Text Available AbstractIntroduction: Recent findings indicate that metabolic disturbances are involved in multiple sclerosis (MS pathology and influence the susceptibility to treatment, directing attention towards anti-diabetic drugs such as metformin and pioglitazone. Liraglutide, a drug of the glucagon-like peptide-1 (GLP-1 family, is also anti-diabetic and weight-reducing and is moreover, directly neuroprotective and anti-inflammatory in a broad spectrum of experimental models of brain disease. In this study we investigate the potential for this FDA-approved drug, liraglutide, as a treatment for MS by utilizing the experimental model, experimental autoimmune encephalitis (EAE.Methods: EAE was induced in 30 female Lewis rats that subsequently received twice-daily liraglutide (200 µg/kg s.c. or saline. Healthy controls were included (saline, n=6, liraglutide, n=7. Clinical score and weight were assessed daily by blinded observers. Animals were killed at peak disease severity (day 11 or if exceeding humane endpoint (clinical score ≥4. Protein levels of manganese superoxide dismutase (MnSOD, amyloid precursor protein (APP, and glial fibrillary acidic protein (GFAP were determined.Results: Liraglutide treatment delayed disease onset (group clinical score significantly >0 by two days and markedly reduced disease severity (median clinical score 2 vs. 5; p=0.0003. Fourteen of 15 (93% of vehicle-treated rats reached the humane endpoint (clinical score ≥4 by day 11 compared to 5 of 15 (33% of liraglutide-treated rats (p=0.0004. Liraglutide substantially increased the mitochondrial antioxidant MnSOD (p<0.01 and reduced the neurodegenerative marker APP (p=0.036 in the brain. GFAP levels were not significantly changed with drug treatment (p=0.09Conclusion: We demonstrate, for the first time, that liraglutide treatment delays onset of EAE in Lewis rats and is associated with improved protective capacity against oxidative stress. These data suggest GLP-1 receptor

  10. Synergistic and Superimposed Effect of Bone Marrow-Derived Mesenchymal Stem Cells Combined with Fasudil in Experimental Autoimmune Encephalomyelitis.

    Science.gov (United States)

    Yu, Jing-Wen; Li, Yan-Hua; Song, Guo-Bin; Yu, Jie-Zhong; Liu, Chun-Yun; Liu, Jian-Chun; Zhang, Hai-Fei; Yang, Wan-Fang; Wang, Qing; Yan, Ya-Ping; Xiao, Bao-Guo; Ma, Cun-Gen

    2016-12-01

    Bone marrow-derived mesenchymal stem cells (MSCs) are the ideal transplanted cells of cellular therapy for promoting neuroprotection and neurorestoration. However, the optimization of transplanted cells and the improvement of microenvironment around implanted cells are still two critical challenges for enhancing therapeutic effect. In the current study, we observed the therapeutic potential of MSCs combined with Fasudil in mouse model of experimental autoimmune encephalomyelitis (EAE) and explored possible mechanisms of action. The results clearly show that combined intervention of MSCs and Fasudil further reduced the severity of EAE compared with MSCs or Fasudil alone, indicating a synergistic and superimposed effect in treating EAE. The addition of Fasudil inhibited MSC-induced inflammatory signaling TLR-4/MyD88 and inflammatory molecule IFN-γ, IL-1β, and TNF-α but did not convert M1 microglia to M2 phenotype. The delivery of MSCs enhanced the expression of glial cell-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) compared with that of Fasudil. Importantly, combined intervention of MSCs and Fasudil further increased the expression of BDNF and GDNF compared with the delivery of MSCs alone, indicating that combined intervention of MSCs and Fasudil synergistically contributes to the expression of neurotrophic factors which should be related to the expression of increased galactocerebroside (GalC) compared with mice treated with Fasudil and MSCs alone. However, a lot of investigation is warranted to further elucidate the cross talk of MSCs and Fasudil in the therapeutic potential of EAE/multiple sclerosis.

  11. Melatonin exacerbates acute experimental autoimmune encephalomyelitis by enhancing the serum levels of lactate: A potential biomarker of multiple sclerosis progression.

    Science.gov (United States)

    Ghareghani, Majid; Dokoohaki, Shima; Ghanbari, Amir; Farhadi, Naser; Zibara, Kazem; Khodadoust, Saeid; Parishani, Mohammad; Ghavamizadeh, Mehdi; Sadeghi, Heibatollah

    2017-01-01

    Melatonin has a beneficial role in adult rat models of multiple sclerosis (MS). In this study, melatonin treatment (10 mg/kg/d) was investigated in young age (5-6 weeks old) Lewis rat model of acute experimental autoimmune encephalomyelitis (EAE) followed by assessing serum levels of lactate and melatonin. Results showed that clinical outcomes were exacerbated in melatonin- (neurological score = 6) vs PBS-treated EAE rats (score = 5). Melatonin caused a significant increase in serum IFN-γ, in comparison to PBS-treated EAE rats whereas no considerable change in IL-4 levels were found, although they were significantly lower than those of controls. The ratio of IFN-γ/IL-4, an indicator of Th-1/Th-2, was significantly higher in PBS- and melatonin- treated EAE rats, in comparison to controls. Moreover, results showed increased lymphocyte infiltration, activated astrocytes (GFAP+ cells) but also higher demyelinated plaques (MBP-deficient areas) in the lumbar spinal cord of melatonin-treated EAE rats. Finally, serum levels of lactate, but not melatonin, significantly increased in the melatonin group, compared to untreated EAE and normal rats. In conclusion, our results indicated a relationship between age and the development of EAE since a negative impact was found for melatonin on EAE recovery of young rats by enhancing IFN-γ, the ratio of Th1/Th2 cells, and astrocyte activation, which seems to delay the remyelination process. While melatonin levels decline in MS patients, lactate might be a potential diagnostic biomarker for prediction of disease progression. Early administration of melatonin in the acute phase of MS might be harmful and needs further investigations. © 2016 John Wiley & Sons Australia, Ltd.

  12. Experimental autoimmune encephalomyelitis (EAE): lesion visualization on a 3 tesla Clinical whole-body system after intraperitoneal contrast injection

    Energy Technology Data Exchange (ETDEWEB)

    Heckl, S.; Naegele, T.; Klose, U. [Dept. of Neuroradiology, Medical School, Univ. of Tuebingen (Germany); Herrmann, M.; Gaertner, S.; Weissert, R. [Dept. of Neurology, Medical School, Univ. of Tuebingen (Germany); Schick, F. [Dept. of Radiology, Medical School, Univ. of Tuebingen (Germany); Kueker, W. [Dept. of Neuroradiology, Medical School, Univ. of Tuebingen (Germany); Dept. of Neuroradiology, Radcliffe Infirmary, Oxford, England (United Kingdom)

    2004-11-01

    Purpose: To investigate the intravital visibility of CNS lesions in rats with experimental autoimmune encephalomyelitis (EAE), the animal correlate of multiple sclerosis, using a 3-Tesla (T) wholebody MR system. Materials and Methods: Three healthy Dark Agouti (DA) rats and 16 DA rats with clinical signs of EAE were examined on a 3T whole body-system using a normal wrist coil. In total, 25 examinations were preformed using T2- and T1-weighted images in transverse and sagittal orientation with a slice thickness of 2 mm or 1 mm (voxel size up to 0.2 x 0.2 x 1 mm). Sedation was achieved by intraperitoneal injection of ketamine and xylazine. In addition, T1-weighted images were obtained after the instillation of 1.0 ml of gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) (0.5 mmol/ml) into the peritoneal cavity. Results: T2- and T1-weighted images of the brain and spinal cord with high spatial and contrast resolution could be obtained in all animals. The anatomical details of the olfactory bulb glomeruli, cerebellum foliae, ventricles and corpus callosum were clearly visible. The EAE lesions presented as hyperintense area in T2-weighted images and could be demonstrated in all clinically affected animals by MRI and histologically verified. In total, the 16 affected rats had 28 cerebral and 2 spinal cord lesions (range 1 to 4, median 2). Contrast enhancement was noted in 12 animals and ranked as severe in ten and moderate in two cases. No adverse effects were noted due to sedation or intraperitoneal contrast injection. Conclusions: The intravital demonstration of cerebral and spinal cord EAE lesions in rats is possible on a 3T whole-body MR scanner using a normal wrist coil. Intraperitoneal injection of ketamine/xylazine and contrast agent is an easy, safe and effective procedure in rats. (orig.)

  13. Gene expression in the spinal cord in female lewis rats with experimental autoimmune encephalomyelitis induced with myelin basic protein.

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    Hayley R Inglis

    Full Text Available BACKGROUND: Experimental autoimmune encephalomyelitis (EAE, the best available model of multiple sclerosis, can be induced in different animal strains using immunization with central nervous system antigens. EAE is associated with inflammation and demyelination of the nervous system. Micro-array can be used to investigate gene expression and biological pathways that are altered during disease. There are few studies of the changes in gene expression in EAE, and these have mostly been done in a chronic mouse EAE model. EAE induced in the Lewis with myelin basic protein (MBP-EAE is well characterised, making it an ideal candidate for the analysis of gene expression in this disease model. METHODOLOGY/PRINCIPAL FINDINGS: MBP-EAE was induced in female Lewis rats by inoculation with MBP and adjuvants. Total RNA was extracted from the spinal cords and used for micro-array analysis using AffimetrixGeneChip Rat Exon 1.0 ST Arrays. Gene expression in the spinal cords was compared between healthy female rats and female rats with MBP-EAE. Gene expression in the spinal cord of rats with MBP-EAE differed from that in the spinal cord of normal rats, and there was regulation of pathways involved with immune function and nervous system function. For selected genes the change in expression was confirmed with real-time PCR. CONCLUSIONS/SIGNIFICANCE: EAE leads to modulation of gene expression in the spinal cord. We have identified the genes that are most significantly regulated in MBP-EAE in the Lewis rat and produced a profile of gene expression in the spinal cord at the peak of disease.

  14. The anti-inflammatory effect of donepezil on experimental autoimmune encephalomyelitis in C57 BL/6 mice.

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    Jiang, Ying; Zou, Yan; Chen, Shaoqiong; Zhu, Cansheng; Wu, Aimin; Liu, Yingying; Ma, Lili; Zhu, Dongliang; Ma, Xiaomeng; Liu, Mei; Kang, Zhuang; Pi, Rongbiao; Peng, Fuhua; Wang, Qing; Chen, Xiaohong

    2013-10-01

    Donepezil is a potent and selective acetylcholinesterase inhibitor. It has been reported to restore cognitive performance in multiple sclerosis (MS) patients and experimental autoimmune encephalomyelitis (EAE) mice, an established model of MS. However, there are no reports about the anti-inflammatory effects of donepezil on EAE. In this study, the donepezil treatments on EAE mice were initiated at day 7 post immunization (7 p.i., subclinical periods, early donepezil treatment) and day 13 p.i. (clinical periods, late donepezil treatment) with the dosage of 1, 2 and 4 mg/kg/d respectively and the treatments persisted throughout the experiments. Blood-brain barrier (BBB) permeability was detected by Evan's blue content, the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, Akt and phosphorylated Akt (p-Akt) as well as nerve growth factor (NGF) and its precursor form (proNGF) in the brains of EAE mice were detected by Western blot, and the levels of interferon-γ and interleukin-4 in the splenocytes culture supernatants and brains of EAE mice were evaluated by ELISA. The results showed that the 2 mg/kg/d late donepezil treatment was the optimal dosage and could ameliorate clinical and pathological parameters, improve magnetic resonance imaging outcomes, reduce the permeability of BBB, inhibit the production of MMP-2 and MMP-9, modulate the expression of NGF and proNGF, increase Th2 bias and the phosphorylation of Akt in the brains of EAE mice. Our data suggested that the anti-inflammatory effects of donepezil may be a novel mechanism on treating EAE and provided further insights to understand the donepezil's neuroprotective activities in MS. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. The extracellular domain of myelin oligodendrocyte glycoprotein elicits atypical experimental autoimmune encephalomyelitis in rat and Macaque species.

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    Alan D Curtis

    Full Text Available Atypical models of experimental autoimmune encephalomyelitis (EAE are advantageous in that the heterogeneity of clinical signs appears more reflective of those in multiple sclerosis (MS. Conversely, models of classical EAE feature stereotypic progression of an ascending flaccid paralysis that is not a characteristic of MS. The study of atypical EAE however has been limited due to the relative lack of suitable models that feature reliable disease incidence and severity, excepting mice deficient in gamma-interferon signaling pathways. In this study, atypical EAE was induced in Lewis rats, and a related approach was effective for induction of an unusual neurologic syndrome in a cynomolgus macaque. Lewis rats were immunized with the rat immunoglobulin variable (IgV-related extracellular domain of myelin oligodendrocyte glycoprotein (IgV-MOG in complete Freund's adjuvant (CFA followed by one or more injections of rat IgV-MOG in incomplete Freund's adjuvant (IFA. The resulting disease was marked by torticollis, unilateral rigid paralysis, forelimb weakness, and high titers of anti-MOG antibody against conformational epitopes of MOG, as well as other signs of atypical EAE. A similar strategy elicited a distinct atypical form of EAE in a cynomolgus macaque. By day 36 in the monkey, titers of IgG against conformational epitopes of extracellular MOG were evident, and on day 201, the macaque had an abrupt onset of an unusual form of EAE that included a pronounced arousal-dependent, transient myotonia. The disease persisted for 6-7 weeks and was marked by a gradual, consistent improvement and an eventual full recovery without recurrence. These data indicate that one or more boosters of IgV-MOG in IFA represent a key variable for induction of atypical or unusual forms of EAE in rat and Macaca species. These studies also reveal a close correlation between humoral immunity against conformational epitopes of MOG, extended confluent demyelinating plaques in

  16. The role of kinin receptors in preventing neuroinflammation and its clinical severity during experimental autoimmune encephalomyelitis in mice.

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    Rafael C Dutra

    Full Text Available BACKGROUND: Multiple sclerosis (MS is a demyelinating and neuroinflammatory disease of the human central nervous system (CNS. The expression of kinins is increased in MS patients, but the underlying mechanisms by which the kinin receptor regulates MS development have not been elucidated. METHODOLOGY/PRINCIPAL FINDINGS: Experimental autoimmune encephalomyelitis (EAE was induced in female C57BL/6 mice by immunization with MOG(35-55 peptide emulsified in complete Freund's adjuvant and injected with pertussis toxin on day 0 and day 2. Here, we report that blockade of the B(1R in the induction phase of EAE markedly suppressed its progression by interfering with the onset of the immune response. Furthermore, B(1R antagonist suppressed the production/expression of antigen-specific T(H1 and T(H17 cytokines and transcription factors, both in the periphery and in the CNS. In the chronic phase of EAE, the blockade of B(1R consistently impaired the clinical progression of EAE. Conversely, administration of the B(1R agonist in the acute phase of EAE suppressed disease progression and inhibited the increase in permeability of the blood-brain barrier (BBB and any further CNS inflammation. Of note, blockade of the B(2R only showed a moderate impact on all of the studied parameters of EAE progression. CONCLUSIONS/SIGNIFICANCE: Our results strongly suggest that kinin receptors, mainly the B(1R subtype, play a dual role in EAE progression depending on the phase of treatment through the lymphocytes and glial cell-dependent pathways.

  17. EphA4 receptor tyrosine kinase is a modulator of onset and disease severity of experimental autoimmune encephalomyelitis (EAE.

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    Kathryn M Munro

    Full Text Available The EphA4 receptor tyrosine kinase is a major regulator of axonal growth and astrocyte reactivity and is a possible inflammatory mediator. Given that multiple sclerosis (MS is primarily an inflammatory demyelinating disease and in mouse models of MS, such as experimental autoimmune encephalomyelitis (EAE, axonal degeneration and reactive gliosis are prominent clinical features, we hypothesised that endogenous EphA4 could play a role in modulating EAE. EAE was induced in EphA4 knockout and wildtype mice using MOG peptide immunisation and clinical severity and histological features of the disease were then compared in lumbar spinal cord sections. EphA4 knockout mice exhibited a markedly less severe clinical course than wildtype mice, with a lower maximum disease grade and a slightly later onset of clinical symptoms. Numbers of infiltrating T cells and macrophages, the number and size of the lesions, and the extent of astrocytic gliosis were similar in both genotypes; however, EphA4 knockout mice appeared to have decreased axonal pathology. Blocking of EphA4 in wildtype mice by administration of soluble EphA4 (EphA4-Fc as a decoy receptor following induction of EAE produced a delay in onset of clinical symptoms; however, most mice had clinical symptoms of similar severity by 22 days, indicating that EphA4 blocking treatment slowed early EAE disease evolution. Again there were no apparent differences in histopathology. To determine whether the role of EphA4 in modulating EAE was CNS mediated or due to an altered immune response, MOG primed T cells from wildtype and EphA4 knockout mice were passively transferred into naive recipient mice and both were shown to induce disease of equivalent severity. These results are consistent with a non-inflammatory, CNS specific, deleterious effect of EphA4 during neuroinflammation that results in axonal pathology.

  18. LINGO-1-Fc-Transduced Neural Stem Cells Are Effective Therapy for Chronic Stage Experimental Autoimmune Encephalomyelitis.

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    Li, Xing; Zhang, Yuan; Yan, Yaping; Ciric, Bogoljub; Ma, Cun-Gen; Chin, Jeannie; Curtis, Mark; Rostami, Abdolmohamad; Zhang, Guang-Xian

    2017-08-01

    The chronic stage multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), remains refractory to current treatments. This refractory nature may be due to the fact that current treatments are primarily immunomodulatory, which prevent further demyelination but lack the capacity to promote remyelination. Several approaches, including transplantation of neural stem cells (NSCs) or antagonists to LINGO-1, a key part of the receptor complex for neuroregeneration inhibitors, have been effective in suppressing the acute stage of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. However, their effect on the chronic stage EAE is not known. Here, we show that transplantation of NSCs had only a slight therapeutic effect when treatment started at the chronic stage of EAE (e.g., injected at day 40 postimmunization). However, NSCs engineered to produce LINGO-1-Fc, a soluble LINGO-1 antagonist, significantly promoted neurological recovery as demonstrated by amelioration of clinical signs, improvement in axonal integrity, and enhancement of oligodendrocyte maturation and neuron repopulation. Significantly enhanced NAD production and Sirt2 expression were also found in the CNS of mice treated with LINGO-1-Fc-producing NSC. Moreover, differentiation of LINGO-1-Fc-producing NSCs into oligodendrocytes in vitro was largely diminished by an NAMPT inhibitor, indicating that LINGO-1-Fc enhances the NAMPT/NAD/Sirt2 pathway. Together, our study establishes a CNS-targeted, novel LINGO-1-Fc delivery system using NSCs, which represents a novel and effective NSC-based gene therapy approach for the chronic stage of MS.

  19. The Extracellular Domain of Myelin Oligodendrocyte Glycoprotein Elicits Atypical Experimental Autoimmune Encephalomyelitis in Rat and Macaque Species

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    Curtis, Alan D.; Taslim, Najla; Reece, Shaun P.; Grebenciucova, Elena; Ray, Richard H.; Rosenbaum, Matthew D.; Wardle, Robert L.; Van Scott, Michael R.; Mannie, Mark D.

    2014-01-01

    Atypical models of experimental autoimmune encephalomyelitis (EAE) are advantageous in that the heterogeneity of clinical signs appears more reflective of those in multiple sclerosis (MS). Conversely, models of classical EAE feature stereotypic progression of an ascending flaccid paralysis that is not a characteristic of MS. The study of atypical EAE however has been limited due to the relative lack of suitable models that feature reliable disease incidence and severity, excepting mice deficient in gamma-interferon signaling pathways. In this study, atypical EAE was induced in Lewis rats, and a related approach was effective for induction of an unusual neurologic syndrome in a cynomolgus macaque. Lewis rats were immunized with the rat immunoglobulin variable (IgV)-related extracellular domain of myelin oligodendrocyte glycoprotein (IgV-MOG) in complete Freund’s adjuvant (CFA) followed by one or more injections of rat IgV-MOG in incomplete Freund’s adjuvant (IFA). The resulting disease was marked by torticollis, unilateral rigid paralysis, forelimb weakness, and high titers of anti-MOG antibody against conformational epitopes of MOG, as well as other signs of atypical EAE. A similar strategy elicited a distinct atypical form of EAE in a cynomolgus macaque. By day 36 in the monkey, titers of IgG against conformational epitopes of extracellular MOG were evident, and on day 201, the macaque had an abrupt onset of an unusual form of EAE that included a pronounced arousal-dependent, transient myotonia. The disease persisted for 6–7 weeks and was marked by a gradual, consistent improvement and an eventual full recovery without recurrence. These data indicate that one or more boosters of IgV-MOG in IFA represent a key variable for induction of atypical or unusual forms of EAE in rat and Macaca species. These studies also reveal a close correlation between humoral immunity against conformational epitopes of MOG, extended confluent demyelinating plaques in spinal cord

  20. Standardization of the experimental autoimmune myasthenia gravis (EAMG) model by immunization of rats with Torpedo californica acetylcholine receptors--Recommendations for methods and experimental designs.

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    Losen, Mario; Martinez-Martinez, Pilar; Molenaar, Peter C; Lazaridis, Konstantinos; Tzartos, Socrates; Brenner, Talma; Duan, Rui-Sheng; Luo, Jie; Lindstrom, Jon; Kusner, Linda

    2015-08-01

    Myasthenia gravis (MG) with antibodies against the acetylcholine receptor (AChR) is characterized by a chronic, fatigable weakness of voluntary muscles. The production of autoantibodies involves the dysregulation of T cells which provide the environment for the development of autoreactive B cells. The symptoms are caused by destruction of the postsynaptic membrane and degradation of the AChR by IgG autoantibodies, predominantly of the G1 and G3 subclasses. Active immunization of animals with AChR from mammalian muscles, AChR from Torpedo or Electrophorus electric organs, and recombinant or synthetic AChR fragments generates a chronic model of MG, termed experimental autoimmune myasthenia gravis (EAMG). This model covers cellular mechanisms involved in the immune response against the AChR, e.g. antigen presentation, T cell-help and regulation, B cell selection and differentiation into plasma cells. Our aim is to define standard operation procedures and recommendations for the rat EAMG model using purified AChR from the Torpedo californica electric organ, in order to facilitate more rapid translation of preclinical proof of concept or efficacy studies into clinical trials and, ultimately, clinical practice. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Resolvin D1 Programs Inflammation Resolution by Increasing TGF-β Expression Induced by Dying Cell Clearance in Experimental Autoimmune Neuritis.

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    Luo, Bangwei; Han, Fuyu; Xu, Kai; Wang, Jinsong; Liu, Zongwei; Shen, Zigang; Li, Jia; Liu, Yu; Jiang, Man; Zhang, Zhi-Yuan; Zhang, Zhiren

    2016-09-14

    Experimental autoimmune neuritis (EAN) is the animal model of human acute inflammatory demyelinating polyradiculoneuropathies (AIDP), an auto-immune inflammatory demyelination disease of the peripheral nervous system (PNS) and the world's leading cause of acute autoimmune neuromuscular paralysis. EAN and AIDP are characterized by self-limitation with spontaneous recovery; however, endogenous pathways that regulate inflammation resolution in EAN and AIDP remain elusive. A pathway of endogenous mediators, especially resolvins and clearance of apoptotic cells, may be involved. Here, we determined that resolvin D1 (RvD1), its synthetic enzyme, and its receptor were greatly increased in PNS during the recovery stage of EAN. Both endogenous and exogenous RvD1 increased regulatory T (Treg) cell and anti-inflammatory macrophage counts in PNS, enhanced inflammation resolution, and promoted disease recovery in EAN rats. Moreover, RvD1 upregulated the transforming growth factor-β (TGF-β) level and pharmacologic inhibition of TGF-β signaling suppressed RvD1-induced Treg cell counts, but not anti-inflammatory macrophage counts, and RvD1-improved inflammation resolution and disease recovery in EAN rats. Mechanistically, the RvD1-enhanced macrophage phagocytosis of apoptotic T cells leading to reduced apoptotic T-cell accumulation in PNS induced TGF-β production and caused Treg cells to promote inflammation resolution and disease recovery in EAN. Therefore, these data highlight the crucial role of RvD1 as an important pro-resolving molecule in EAN and suggest its potential as a therapeutic target in human neuropathies. Experimental autoimmune neuritis (EAN) is the animal model of human acute inflammatory demyelinating polyradiculoneuropathies, an auto-immune inflammatory demyelination disease of the peripheral nervous system (PNS) and the world's leading cause of acute autoimmune neuromuscular paralysis. Here, we demonstrated that resolvin D1 (RvD1) promoted macrophage

  2. A new formulation of cannabidiol in cream shows therapeutic effects in a mouse model of experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Giacoppo, Sabrina; Galuppo, Maria; Pollastro, Federica; Grassi, Gianpaolo; Bramanti, Placido; Mazzon, Emanuela

    2015-10-21

    The present study was designed to investigate the efficacy of a new formulation of alone, purified cannabidiol (CBD) (>98 %), the main non-psychotropic cannabinoid of Cannabis sativa, as a topical treatment in an experimental model of autoimmune encephalomyelitis (EAE), the most commonly used model for multiple sclerosis (MS). Particularly, we evaluated whether administration of a topical 1 % CBD-cream, given at the time of symptomatic disease onset, could affect the EAE progression and if this treatment could also recover paralysis of hind limbs, qualifying topical-CBD for the symptomatic treatment of MS. In order to have a preparation of 1 % of CBD-cream, pure CBD have been solubilized in propylene glycoland basic dense cream O/A. EAE was induced by immunization with myelin oligodendroglial glycoprotein peptide (MOG35-55) in C57BL/6 mice. After EAE onset, mice were allocated into several experimental groups (Naïve, EAE, EAE-1 % CBD-cream, EAE-vehicle cream, CTRL-1 % CBD-cream, CTRL-vehicle cream). Mice were observed daily for signs of EAE and weight loss. At the sacrifice of the animals, which occurred at the 28(th) day from EAE-induction, spinal cord and spleen tissues were collected in order to perform histological evaluation, immunohistochemistry and western blotting analysis. Achieved results surprisingly show that daily treatment with topical 1 % CBD-cream may exert neuroprotective effects against EAE, diminishing clinical disease score (mean of 5.0 in EAE mice vs 1.5 in EAE + CBD-cream), by recovering of paralysis of hind limbs and by ameliorating histological score typical of disease (lymphocytic infiltration and demyelination) in spinal cord tissues. Also, 1 % CBD-cream is able to counteract the EAE-induced damage reducing release of CD4 and CD8α T cells (spleen tissue localization was quantified about 10,69 % and 35,96 % of positive staining respectively in EAE mice) and expression of the main pro-inflammatory cytokines as well as several other

  3. ZSTK474, a novel PI3K inhibitor, modulates human CD14+ monocyte-derived dendritic cell functions and suppresses experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Xue, Zhenyi; Li, Wen; Wang, Huafeng; Huang, Biao; Ge, Zhenzhen; Gu, Chao; Liu, Ying; Zhang, Kai; Yang, Juhong; Han, Rong; Peng, Meiyu; Li, Yan; Zhang, Da; Da, Yurong; Yao, Zhi; Zhang, Rongxin

    2014-10-01

    ZSTK474 [2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine] is a novel phosphatidylinositol 3-kinase (PI3K) inhibitor that exhibits potent antitumor effects. Recent studies have shown that ZSTK474 is also with anti-inflammatory properties in collagen-induced arthritis. However, the effects of ZSTK474 on dendritic cells and inflammatory Th17 cell-mediated autoimmune central nervous system inflammation are not understood. In this study, we demonstrated that ZSTK474 suppressed human CD14(+) monocyte-derived dendritic cell differentiation, maturation, and endocytosis, and further inhibited the stimulatory function of mature dendritic cell on allogeneic T cell proliferation. In addition, ZSTK474 inhibited the expression of dendritic cell-derived Th1 and Th17 cells polarizing cytokines interferon-γ/interleukin (IL)-12 and IL-6/IL-23. Furthermore, our results indicated that the in vivo administration of ZSTK474, which targets the dendritic cell and inflammatory Th1 and Th17 cell, led to a reduction of clinical score, central nervous system inflammation, and demyelination of mouse experimental autoimmune encephalomyelitis. Therefore, ZSTK474 significantly suppressed the human CD14(+) monocyte-derived dendritic cell functions and ameliorated mouse experimental autoimmune encephalomyelitis. We further found that ZSTK474 inhibited the phosphorylation of PI3K downstream signaling Akt and glycogen synthase kinase 3 beta in the dendritic cell. These data suggested that ZSTK474 exerted potent anti-inflammatory and immunosuppressive properties via PI3K signaling and may serve as a potential therapeutic drug for multiple sclerosis and other autoimmune inflammatory diseases. Key messages: STK474 inhibits dendritic cell (DC) differentiation and maturation. ZSTK474 inhibits DC-derived Th1 and Th17-polarizing cytokines. ZSTK474 ameliorates EAE and suppresses DCs, Th1, and Th17 cells in EAE. ZSTK474 reduces CNS inflammation and demyelination of EAE mice. ZSTK474

  4. CCR2 gene deletion and pharmacologic blockade ameliorate a severe murine experimental autoimmune neuritis model of Guillain-Barre syndrome.

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    Furong Yuan

    Full Text Available The molecular determinants and signaling pathways responsible for hematogenous leukocyte trafficking during peripheral neuroinflammation are incompletely elucidated. Chemokine ligand/receptor pair CCL2/CCR2 has been pathogenically implicated in the acute inflammatory demyelinating polyradiculoneuropathy variant of Guillain-Barré syndrome (GBS. We evaluated the role of CCR2 in peripheral neuroinflammation utilizing a severe murine experimental autoimmune neuritis (sm-EAN model. Sm-EAN was induced in 8-12 week old female SJL CCR2 knockout (CCR2KO, heterozygote (CCR2HT and wild type (CCR2WT mice, and daily neuromuscular severity scores and weights recorded. In vitro and in vivo splenocyte proliferation and cytokine expression assays, and sciatic nerve Toll-like receptor (TLR 2, TLR4 and CCL2 expression assays were performed to evaluate systemic and local innate immune activation at disease onset. Motor nerve electrophysiology and sciatic nerve histology were also performed to characterize the inflammatory neuropathy at expected peak severity. To further determine the functional relevance of CCR2 in sm-EAN, 20 mg/kg CCR2 antagonist, RS 102895 was administered daily for 5 days to a cohort of CCR2WT mice following sm-EAN disease onset, with efficacy compared to 400 mg/kg human intravenous immunoglobulin (IVIg. CCR2KO mice were relatively resistant to sm-EAN compared to CCR2WT and CCR2HT mice, associated with attenuated peripheral nerve demyelinating neuritis. Partial CCR2 gene deletion did not confer any protection against sm-EAN. CCR2KO mice demonstrated similar splenocyte activation or proliferation profiles, as well as TLR2, TLR4 and CCL2 expression to CCR2WT or CCR2HT mice, implying a direct role for CCR2 in sm-EAN pathogenesis. CCR2 signaling blockade resulted in rapid, near complete recovery from sm-EAN following disease onset. RS 102895 was significantly more efficacious than IVIg. CCR2 mediates pathogenic hematogenous monocyte trafficking

  5. Eosinophils in Autoimmune Diseases

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    Daniela Čiháková

    2017-04-01

    Full Text Available Eosinophils are multifunctional granulocytes that contribute to initiation and modulation of inflammation. Their role in asthma and parasitic infections has long been recognized. Growing evidence now reveals a role for eosinophils in autoimmune diseases. In this review, we summarize the function of eosinophils in inflammatory bowel diseases, neuromyelitis optica, bullous pemphigoid, autoimmune myocarditis, primary biliary cirrhosis, eosinophilic granulomatosis with polyangiitis, and other autoimmune diseases. Clinical studies, eosinophil-targeted therapies, and experimental models have contributed to our understanding of the regulation and function of eosinophils in these diseases. By examining the role of eosinophils in autoimmune diseases of different organs, we can identify common pathogenic mechanisms. These include degranulation of cytotoxic granule proteins, induction of antibody-dependent cell-mediated cytotoxicity, release of proteases degrading extracellular matrix, immune modulation through cytokines, antigen presentation, and prothrombotic functions. The association of eosinophilic diseases with autoimmune diseases is also examined, showing a possible increase in autoimmune diseases in patients with eosinophilic esophagitis, hypereosinophilic syndrome, and non-allergic asthma. Finally, we summarize key future research needs.

  6. Eosinophils in Autoimmune Diseases.

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    Diny, Nicola L; Rose, Noel R; Čiháková, Daniela

    2017-01-01

    Eosinophils are multifunctional granulocytes that contribute to initiation and modulation of inflammation. Their role in asthma and parasitic infections has long been recognized. Growing evidence now reveals a role for eosinophils in autoimmune diseases. In this review, we summarize the function of eosinophils in inflammatory bowel diseases, neuromyelitis optica, bullous pemphigoid, autoimmune myocarditis, primary biliary cirrhosis, eosinophilic granulomatosis with polyangiitis, and other autoimmune diseases. Clinical studies, eosinophil-targeted therapies, and experimental models have contributed to our understanding of the regulation and function of eosinophils in these diseases. By examining the role of eosinophils in autoimmune diseases of different organs, we can identify common pathogenic mechanisms. These include degranulation of cytotoxic granule proteins, induction of antibody-dependent cell-mediated cytotoxicity, release of proteases degrading extracellular matrix, immune modulation through cytokines, antigen presentation, and prothrombotic functions. The association of eosinophilic diseases with autoimmune diseases is also examined, showing a possible increase in autoimmune diseases in patients with eosinophilic esophagitis, hypereosinophilic syndrome, and non-allergic asthma. Finally, we summarize key future research needs.

  7. Physical Exercise Attenuates Experimental Autoimmune Encephalomyelitis by Inhibiting Peripheral Immune Response and Blood-Brain Barrier Disruption.

    Science.gov (United States)

    Souza, Priscila S; Gonçalves, Elaine D; Pedroso, Giulia S; Farias, Hemelin R; Junqueira, Stella C; Marcon, Rodrigo; Tuon, Talita; Cola, Maíra; Silveira, Paulo C L; Santos, Adair R; Calixto, João B; Souza, Cláudio T; de Pinho, Ricardo A; Dutra, Rafael C

    2017-08-01

    Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) caused by demyelination, immune cell infiltration, and axonal damage. Herein, we sought to investigate the influence of physical exercise on mice experimental autoimmune encephalomyelitis (EAE), a reported MS model. Data show that both strength and endurance training protocols consistently prevented clinical signs of EAE and decreased oxidative stress, an effect which was likely due to improving genomic antioxidant defense-nuclear factor erythroid 2-related factor (Nrf2)/antioxidant response elements (ARE) pathway-in the CNS. In addition, physical exercise inhibited the production of pro-inflammatory cytokines interferon (IFN)-γ, interleukin (IL)-17, and IL-1β in the spinal cord of mice with EAE. Of note, spleen cells obtained from strength training group incubated with MOG 35-55 showed a significant upregulation of CD25 and IL-10 levels, with a decrease of IL-6, MCP-1, and tumor necrosis factor (TNF)-α production, mainly, during acute and chronic phase of EAE. Moreover, these immunomodulatory effects of exercise were associated with reduced expression of adhesion molecules, especially of platelet and endothelial cell adhesion molecule 1 (PECAM-1). Finally, physical exercise also restored the expression of tight junctions in spinal cord. Together, these results demonstrate that mild/moderate physical exercise, when performed regularly in mice, consistently attenuates the progression and pathological hallmarks of EAE, thereby representing an important non-pharmacological intervention for the improvement of immune-mediated diseases such as MS. Graphical Abstract Schematic diagram illustrating the beneficial effects of physical exercise during experimental model of MS. Physical exercise, especially strength (ST) and endurance (ET) training protocols, inhibits the development and progression of disease, measured by the mean maximal clinical score (1.5 and 1.0, respectively

  8. Vaccines, adjuvants and autoimmunity.

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    Guimarães, Luísa Eça; Baker, Britain; Perricone, Carlo; Shoenfeld, Yehuda

    2015-10-01

    Vaccines and autoimmunity are linked fields. Vaccine efficacy is based on whether host immune response against an antigen can elicit a memory T-cell response over time. Although the described side effects thus far have been mostly transient and acute, vaccines are able to elicit the immune system towards an autoimmune reaction. The diagnosis of a definite autoimmune disease and the occurrence of fatal outcome post-vaccination have been less frequently reported. Since vaccines are given to previously healthy hosts, who may have never developed the disease had they not been immunized, adverse events should be carefully accessed and evaluated even if they represent a limited number of occurrences. In this review of the literature, there is evidence of vaccine-induced autoimmunity and adjuvant-induced autoimmunity in both experimental models as well as human patients. Adjuvants and infectious agents may exert their immune-enhancing effects through various functional activities, encompassed by the adjuvant effect. These mechanisms are shared by different conditions triggered by adjuvants leading to the autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome). In conclusion, there are several case reports of autoimmune diseases following vaccines, however, due to the limited number of cases, the different classifications of symptoms and the long latency period of the diseases, every attempt for an epidemiological study has so far failed to deliver a connection. Despite this, efforts to unveil the connection between the triggering of the immune system by adjuvants and the development of autoimmune conditions should be undertaken. Vaccinomics is a field that may bring to light novel customized, personalized treatment approaches in the future. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Autoimmune gastritis.

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    Kulnigg-Dabsch, Stefanie

    2016-10-01

    Autoimmune gastritis is a chronic inflammatory disease with destruction of parietal cells of the corpus and fundus of the stomach. The known consequence is vitamin B12 deficiency and, consequently, pernicious anemia. However, loss of parietal cells reduces secretion of gastric acid which is also required for absorption of inorganic iron; thus, iron deficiency is commonly found in patients with autoimmune gastritis. This usually precedes vitamin B12 deficiency and is found mainly in young women. Patients with chronic iron deficiency, especially those refractory to oral iron therapy, should therefore be evaluated for the presence of autoimmune gastritis.

  10. Autoimmune disorders

    Science.gov (United States)

    ... at the same time. Common autoimmune disorders include: Addison disease Celiac disease - sprue (gluten-sensitive enteropathy) Dermatomyositis Graves ... In: McPherson RA, Pincus MR, eds. Henry's Clinical Diagnosis and Management by Laboratory Methods . 22nd ed. Philadelphia, ...

  11. Autoimmune Hepatitis

    Science.gov (United States)

    ... person usually needs blood tests for an exact diagnosis because a person with autoimmune hepatitis can have the same symptoms as those of other liver diseases or metabolic disorders. Blood tests. A blood test involves drawing ...

  12. Inosine, an Endogenous Purine Nucleoside, Suppresses Immune Responses and Protects Mice from Experimental Autoimmune Encephalomyelitis: a Role for A2A Adenosine Receptor.

    Science.gov (United States)

    Junqueira, Stella Célio; Dos Santos Coelho, Igor; Lieberknecht, Vicente; Cunha, Mauricio Peña; Calixto, João B; Rodrigues, Ana Lúcia S; Santos, Adair Roberto Soares; Dutra, Rafael Cypriano

    2017-07-01

    Multiple sclerosis (MS) is a T cell autoimmune, inflammatory, and demyelinating disease of the central nervous system (CNS). Currently available therapies have partially effective actions and numerous side reactions. Inosine, an endogenous purine nucleoside, has immunomodulatory, neuroprotective, and analgesic properties. Herein, we evaluated the effect of inosine on the development and progression of experimental autoimmune encephalomyelitis (EAE), an experimental model of MS. Inosine (1 or 10 mg/kg, i.p.) was administrated twice a day for 40 days. Immunological and inflammatory responses were evaluated by behavioral, histological, immunohistochemical, ELISA, RT-PCR, and Western blotting analysis. The administration of inosine exerted neuroprotective effects against EAE by diminishing clinical signs, including thermal and mechanical hyperalgesia, as well as weight loss typical of the disease. These beneficial effects of inosine seem to be associated with the blockade of inflammatory cell entry into the CNS, especially lymphocytes, thus delaying the demyelinating process and astrocytes activation. In particular, up-regulation of IL-17 levels in the secondary lymphoid tissues, a result of EAE, was prevented by inosine treatment in EAE mice. Additionally, inosine consistently prevented A2AR up-regulation in the spinal cord, likely, through an ERK1-independent pathway. Altogether, these results allow us to propose that this endogenous purine might be a putative novel and helpful tool for the prevention of autoimmune and neurodegenerative diseases, such as MS. Thus, inosine could have considerable implications for future therapies of MS, and this study may represent the starting point for further investigation into the role of inosine and adenosinergic receptors in neuroinflammation processes. Graphical Abstract Preventive treatment with inosine inhibits the development and progression of EAE in C57Bl/6 mice. Furthermore, neuroinflammation and demyelinating processes

  13. Autoimmune pancreatitis

    Directory of Open Access Journals (Sweden)

    Davorin Dajčman

    2007-05-01

    Full Text Available Background: Autoimmune pancreatitis is a recently described type of pancreatitis of presumed autoimmune etiology. Autoimmune pancreatitis is often misdiagnosed as pancreatic cancer difficult, since their clinical presentations are often similar. The concept of autoimmune pancreatitis was first published in 1961. Since then, autoimmune pancreatitis has often been treated not as an independent clinical entity but rather as a manifestation of systemic disease. The overall prevalence and incidence of the disease have yet to be determined, but three series have reported the prevalence as between 5 and 6 % of all patients with chronic pancreatitis. Patient vary widely in age, but most are older than 50 years. Patients with autoimmune pancreatitis usually complain of the painless jaundice, mild abdominal pain and weight loss. There is no laboratory hallmark of the disease, even if cholestatic profiles of liver dysfunction with only mild elevation of amylase and lipase levels have been reported.Conclusions: Proposed diagnostic criteria contains: (1 radiologic imaging, diffuse enlargement of the pancreas and diffusely irregular narrowing of the main pancreatic duct, (2 laboratory data, elevated levels of serum ã-globulin and/or IgG, specially IgG4, or the presence of autoantibodies and (3 histopathologic examination, fibrotic change with dense lymphoplasmacytic infiltration in the pancreas. For correct diagnosis of autoimmune pancreatitis, criterion 1 must be present with criterion 2 and/or 3. Autoimmune pancreatitis is frequently associated with rheumatoid arthritis, Sjogren’s syndrome, inflammatory bowel disease, tubulointersticial nephritis, primary sclerosing cholangitis and idiopathic retroperitoneal fibrosis. Pancreatic biopsy using an endoscopic ultrasound-guided fine needle aspiration biopsy is the most important diagnostic method today. Treatment with corticosteroids leads to the and resolution of pancreatic inflamation, obstruction and

  14. Treatment with tanshinone IIA suppresses disruption of the blood-brain barrier and reduces expression of adhesion molecules and chemokines in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Yang, Xue; Yan, Jun; Feng, Juan

    2016-01-15

    Tanshinone IIA (TSIIA), one of the major bioactive components of the traditional Chinese herb Salvia miltiorrhiza, has been reported to have both anti-inflammatory and immunoregulatory effects. The effect of treatment with TSIIA in multiple sclerosis, an autoimmune inflammatory neurodegenerative disease, however, remains poorly understood. In the present study, experimental autoimmune encephalomyelitis (EAE), a classical experimental model of MS, was used to investigate the therapeutic effect of TSIIA. TSIIA attenuated motor dysfunction and improved inflammation and demyelination associated with EAE in a dose-dependent manner. TSIIA also significantly reduced the levels of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule-1 (Iba-1), and protected the integrity of the blood-brain barrier (BBB) by increasing the expression of critical endothelial tight junction (TJ) proteins. TSIIA also inhibited the expression of some adhesion molecules and chemokines, which are considered to be critical for adhesion of immune cells and migration across the BBB. TSIIA was thus shown to be effective in the treatment of EAE through preventing the infiltration of immune cells into the CNS, strengthening the integrity of the BBB and decreasing the numbers of adhesion molecules and chemokines. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. A minimum number of autoimmune T cells to induce autoimmunity?

    Science.gov (United States)

    Bosch, Angela J T; Bolinger, Beatrice; Keck, Simone; Stepanek, Ondrej; Ozga, Aleksandra J; Galati-Fournier, Virginie; Stein, Jens V; Palmer, Ed

    2017-06-01

    While autoimmune T cells are present in most individuals, only a minority of the population suffers from an autoimmune disease. To better appreciate the limits of T cell tolerance, we carried out experiments to determine how many autoimmune T cells are required to initiate an experimental autoimmune disease. Variable numbers of autoimmune OT-I T cells were transferred into RIP-OVA mice, which were injected with antigen-loaded DCs in a single footpad; this restricted T cell priming to a few OT-I T cells that are present in the draining popliteal lymph node. Using selective plane illumination microscopy (SPIM) we counted the number of OT-I T cells present in the popliteal lymph node at the time of priming. Analysis of our data suggests that a single autoimmune T cell cannot induce an experimental autoimmune disease, but a "quorum" of 2-5 autoimmune T cells clearly has this capacity. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Constitutive Retinal CD200 Expression Regulates Resident Microglia and Activation State of Inflammatory Cells during Experimental Autoimmune Uveoretinitis

    OpenAIRE

    Broderick, Cathryn; Hoek, Robert M.; Forrester, John V.; Liversidge, Janet; Sedgwick, Jonathon D.; Dick, Andrew D

    2002-01-01

    Recent evidence supports the notion that tissue OX2 (CD200) constitutively provides down-regulatory signals to myeloid-lineage cells via CD200-receptor (CD200R). Thus, mice lacking CD200 (CD200−/−) show increased susceptibility to and accelerated onset of tissue-specific autoimmunity. In the retina there is extensive expression of CD200 on neurons and retinal vascular endothelium. We show here that retinal microglia in CD200−/− mice display normal morphology, but unlike microglia from wild-ty...

  17. Absence of Notch1 in murine myeloid cells attenuates the development of experimental autoimmune encephalomyelitis by affecting Th1 and Th17 priming.

    Science.gov (United States)

    Fernández, Miriam; Monsalve, Eva M; López-López, Susana; Ruiz-García, Almudena; Mellado, Susana; Caminos, Elena; García-Ramírez, José Javier; Laborda, Jorge; Tranque, Pedro; Díaz-Guerra, María José M

    2017-12-01

    Inhibition of Notch signalling in T cells attenuates the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Growing evidence indicates that myeloid cells are also key players in autoimmune processes. Thus, the present study evaluates the role of the Notch1 receptor in myeloid cells on the progression of myelin oligodendrocyte glycoprotein (MOG) 35-55 -induced EAE, using mice with a myeloid-specific deletion of the Notch1 gene (MyeNotch1KO). We found that EAE progression was less severe in the absence of Notch1 in myeloid cells. Thus, histopathological analysis revealed reduced pathology in the spinal cord of MyeNotch1KO mice, with decreased microglia/astrocyte activation, demyelination and infiltration of CD4 + T cells. Moreover, these mice showed lower Th1 and Th17 cell infiltration and expression of IFN-γ and IL-17 mRNA in the spinal cord. Accordingly, splenocytes from MyeNotch1KO mice reactivated in vitro presented reduced Th1 and Th17 activation, and lower expression of IL-12, IL-23, TNF-α, IL-6, and CD86. Moreover, reactivated wild-type splenocytes showed increased Notch1 expression, arguing for a specific involvement of this receptor in autoimmune T cell activation in secondary lymphoid tissues. In summary, our results reveal a key role of the Notch1 receptor in myeloid cells for the initiation and progression of EAE. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Autoimmune encephalopathies

    Science.gov (United States)

    Leypoldt, Frank; Armangue, Thaís; Dalmau, Josep

    2014-01-01

    Over the last 10 years the continual discovery of novel forms of encephalitis associated with antibodies to cell-surface or synaptic proteins has changed the paradigms for diagnosing and treating disorders that were previously unknown or mischaracterized. We review here the process of discovery, the symptoms, and the target antigens of twelve autoimmune encephatilic disorders, grouped by syndromes and approached from a clinical perspective. Anti-NMDAR encephalitis, several subtypes of limbic encephalitis, stiff-person spectrum disorders, and other autoimmune encephalitides that result in psychosis, seizures, or abnormal movements are described in detail. We include a novel encephalopathy with prominent sleep dysfunction that provides an intriguing link between chronic neurodegeneration and cell-surface autoimmunity (IgLON5). Some of the caveats of limited serum testing are outlined. In addition, we review the underlying cellular and synaptic mechanisms that for some disorders confirm the antibody pathogenicity. The multidisciplinary impact of autoimmune encephalitis has been expanded recently by the discovery that herpes simplex encephalitis is a robust trigger of synaptic autoimmunity, and that some patients may develop overlapping syndromes, including anti-NMDAR encephalitis and neuromyelitis optica or other demyelinating diseases. PMID:25315420

  19. Autoimmune sialadenitis

    NARCIS (Netherlands)

    Guntinas-Lichius, O.; Vissink, A.; Ihrler, S.

    Using the European-American classification criteria the diagnosis of autoimmune sialadenitis in Sjogren's syndrome can generally be easily established or excluded. In addition, sonography performed by the ENT physician is helpful in diagnosing and especially in follow-up screening for MALT

  20. Autoimmun hypophysitis

    DEFF Research Database (Denmark)

    Krarup, Therese; Hagen, Claus

    2010-01-01

    during pregnancy or postpartum, but also occurs in males and children. AH is often associated with other autoimmune diseases, most frequently with Hashimoto's thyroiditis. The symptoms are caused by enlargement of the pituitary gland and disturbances of the hormone function. Treatment is either...

  1. Vitamin D3 and Monomethyl Fumarate Enhance Natural Killer Cell Lysis of Dendritic Cells and Ameliorate the Clinical Score in Mice Suffering from Experimental Autoimmune Encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Zaidoon Al-Jaderi

    2015-11-01

    Full Text Available Experimental autoimmune encephalomyelitis (EAE is a CD4+ T cell mediated inflammatory demyelinating disease that is induced in mice by administration of peptides derived from myelin proteins. We developed EAE in SJL mice by administration of PLP139–151 peptide. The effect of treating these mice with 1α,25-Dihydroxyvitamin D3 (vitamin D3, or with monomethyl fumarate (MMF was then examined. We observed that both vitamin D3 and MMF inhibited and/or prevented EAE in these mice. These findings were corroborated with isolating natural killer (NK cells from vitamin D3-treated or MMF-treated EAE mice that lysed immature or mature dendritic cells. The results support and extend other findings indicating that an important mechanism of action for drugs used to treat multiple sclerosis (MS is to enhance NK cell lysis of dendritic cells.

  2. Induction of experimental autoimmune encephalomyelitis in C57BL/6 mice deficient in either the chemokine macrophage inflammatory protein-1alpha or its CCR5 receptor

    DEFF Research Database (Denmark)

    Tran, E H; Kuziel, W A; Owens, T

    2000-01-01

    Macrophage inflammatory protein (MIP)-1alpha is a chemokine that is associated with Th1 cytokine responses. Expression and antibody blocking studies have implicated MIP-1alpha in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE). We examined the role of MIP-1alpha...... and its CCR5 receptor in the induction of EAE by immunizing C57BL / 6 mice deficient in either MIP-1alpha or CCR5 with myelin oligodendrocyte glycoprotein (MOG). We found that MIP-1alpha-deficient mice were fully susceptible to MOG-induced EAE. These knockout animals were indistinguishable from wild-type...... mice in Th1 cytokine gene expression, the kinetics and severity of disease, and infiltration of the central nervous system by lymphocytes, macrophages and granulocytes. RNase protection assays showed comparable accumulation of mRNA for the chemokines interferon-inducible protein-10, RANTES, macrophage...

  3. Reversal of paralysis and reduced inflammation from peripheral administration of β-amyloid in TH1 and TH17 versions of experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Grant, Jacqueline L; Ghosn, Eliver Eid Bou; Axtell, Robert C; Herges, Katja; Kuipers, Hedwich F; Woodling, Nathan S; Andreasson, Katrin; Herzenberg, Leonard A; Herzenberg, Leonore A; Steinman, Lawrence

    2012-08-01

    β-Amyloid 42 (Aβ42) and β-amyloid 40 (Aβ40), major components of senile plaque deposits in Alzheimer's disease, are considered neurotoxic and proinflammatory. In multiple sclerosis, Aβ42 is up-regulated in brain lesions and damaged axons. We found, unexpectedly, that treatment with either Aβ42 or Aβ40 peptides reduced motor paralysis and brain inflammation in four different models of experimental autoimmune encephalomyelitis (EAE) with attenuation of motor paralysis, reduction of inflammatory lesions in the central nervous system (CNS), and suppression of lymphocyte activation. Aβ42 and Aβ40 treatments were effective in reducing ongoing paralysis induced with adoptive transfer of either autoreactive T helper 1 (T(H)1) or T(H)17 cells. High-dimensional 14-parameter flow cytometry of peripheral immune cell populations after in vivo Aβ42 and Aβ40 treatment revealed substantial modulations in the percentage of lymphoid and myeloid subsets during EAE. Major proinflammatory cytokines and chemokines were reduced in the blood after Aβ peptide treatment. Protection conferred by Aβ treatment did not require its delivery to the brain: Adoptive transfer with lymphocytes from donors treated with Aβ42 attenuated EAE in wild-type recipient mice, and Aβ deposition in the brain was not detected in treated EAE mice by immunohistochemical analysis. In contrast to the improvement in EAE with Aβ treatment, EAE was worse in mice with genetic deletion of the amyloid precursor protein. Therefore, in the absence of Aβ, there is exacerbated clinical EAE disease progression. Because Aβ42 and Aβ40 ameliorate experimental autoimmune inflammation targeting the CNS, we might now consider its potential anti-inflammatory role in other neuropathological conditions.

  4. 1,25-Dihydroxyvitamin D3 inhibits the differentiation and migration of T(H17 cells to protect against experimental autoimmune encephalomyelitis.

    Directory of Open Access Journals (Sweden)

    Jae-Hoon Chang

    Full Text Available BACKGROUND: Vitamin D(3, the most physiologically relevant form of vitamin D, is an essential organic compound that has been shown to have a crucial effect on the immune responses. Vitamin D(3 ameliorates the onset of the experimental autoimmune encephalomyelitis (EAE; however, the direct effect of vitamin D(3 on T cells is largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: In an in vitro system using cells from mice, the active form of vitamin D(3 (1,25-dihydroxyvitamin D(3 suppresses both interleukin (IL-17-producing T cells (T(H17 and regulatory T cells (Treg differentiation via a vitamin D receptor signal. The ability of 1,25-dihydroxyvitamin D(3 (1,25(OH(2D(3 to reduce the amount of IL-2 regulates the generation of Treg cells, but not T(H17 cells. Under T(H17-polarizing conditions, 1,25(OH(2D(3 helps to increase the numbers of IL-10-producing T cells, but 1,25(OH(2D(3's negative regulation of T(H17 development is still defined in the IL-10(-/- T cells. Although the STAT1 signal reciprocally affects the secretion of IL-10 and IL-17, 1,25(OH(2D(3 inhibits IL-17 production in STAT1(-/- T cells. Most interestingly, 1,25(OH(2D(3 negatively regulates CCR6 expression which might be essential for T(H17 cells to enter the central nervous system and initiate EAE. CONCLUSIONS/SIGNIFICANCE: Our present results in an experimental murine model suggest that 1,25(OH(2D(3 can directly regulate T cell differentiation and could be applied in preventive and therapeutic strategies for T(H17-mediated autoimmune diseases.

  5. Elevated serum [Met(5)]-enkephalin levels correlate with improved clinical and behavioral outcomes in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Ludwig, Michael D; Zagon, Ian S; McLaughlin, Patricia J

    2017-09-01

    Methionine enkephalin ([Met(5)]-enkephalin, Opioid growth factor (OGF)) is a small neuropeptide with growth-related as well as immunomodulatory properties. OGF is distributed widely throughout the body, is both autocrine and paracrine produced, and has a very short half-life in serum. In addition to its neurotransmitter functions, OGF inhibits cell replication of a wide variety of cells involved in the autoimmune process. In this preclinical study, mice were immunized with myelin oligodendrocytic glycoprotein (MOG35-55) to establish a chronic progressive form of autoimmune encephalomyelitis (EAE), and serum enkephalin levels were assessed throughout the disease as well as in response to OGF therapy in order to determine whether OGF may be a biological marker for EAE and multiple sclerosis. Immunized mice were randomly assigned to groups receiving daily 10mg/kg OGF (n=24) or saline (n=25) beginning at the time of established disease and clinical behavior. Open field activity, rearing, forced swimming, and novel object tests were monitored. Serum levels of peptide were measured prior to immunization, before clinical symptoms were observed, and at the onset and peak period of disease. Spinal cord neuropathology was evaluated 40days after immunization. EAE disease onset occurred on day 9 post immunization when the mean clinical score was 1.5. Peak disease scores for saline-injected EAE mice reached a mean of 5.7 on day 18, whereas mice receiving OGF had a peak clinical score of 2.5. Behavioral tests conducted 5days post-immunization (and before clinical signs of EAE) revealed that EAE mice had reduced serum enkephalin levels related to elevated clinical disease scores. Serum levels of enkephalin collected at peak disease and after 40days correlated with clinical scores. Disease status was associated with activity in the open field, rearing, time associating with a novel object, and pain sensitivity. Clinical signs of EAE correlated with levels of enkephalins such that

  6. Autoimmun pankreatitis

    DEFF Research Database (Denmark)

    Fjordside, Eva; Novovic, Srdan; Schmidt, Palle Nordblad

    2015-01-01

    Autoimmune pancreatitis (AIP) is a rare inflammatory disease. AIP has characteristic histology, serology and imaging findings. Two types of AIP exist, type 1, which is a part of the systemic immunoglobulin G4-related disease, and type 2, which is only localized to the pancreas. Patients with type 1...... are predominantly older men, have involvement of other organs and more often experience relapse than patients with type 2. Both types respond well to steroid treatment. The most important differential diagnose is pancreatic cancer....

  7. Dynamics of intraocular IFN-γ, IL-17 and IL-10-producing cell populations during relapsing and monophasic rat experimental autoimmune uveitis.

    Directory of Open Access Journals (Sweden)

    Ulrike Kaufmann

    Full Text Available A major limitation of most animal models of autoimmune diseases is that they do not reproduce the chronic or relapsing-remitting pattern characteristic of many human autoimmune diseases. This problem has been overcome in our rat models of experimentally induced monophasic or relapsing-remitting autoimmune uveitis (EAU, which depend on the inducing antigen peptides from retinal S-Antigen (monophasic EAU or interphotoreceptor retinoid-binding protein (relapsing EAU. These models enable us to compare autoreactive and regulatory T cell populations. Intraocular, but not peripheral T cells differ in their cytokine profiles (IFN-γ, IL-17 and IL-10 at distinct time points during monophasic or relapsing EAU. Only intraocular T cells concomitantly produced IFN-γ, IL-17 and/or IL-10. Monophasic EAU presented rising numbers of cells expressing IFN-γ and IL-17 (Th1/Th17 and cells expressing IL-10 or Foxp3. During relapsing uveitis an increase of intraocular IFN-γ+ cells and a concomitant decrease of IL-17+ cells was detected, while IL-10+ populations remained stable. Foxp3+ cells and cells expressing IL-10, even in combination with IFN-γ or IL-17, increased during the resolution of monophasic EAU, suggesting a regulatory role for these T cells. In general, cells producing multiple cytokines increased in monophasic and decreased in relapsing EAU. The distinct appearance of certain intraocular populations with characteristics of regulatory cells points to a differential influence of the ocular environment on T cells that induce acute and monophasic or relapsing disease. Here we provide evidence that different autoantigens can elicit distinct and differently regulated immune responses. IFN-γ, but not IL-17 seems to be the key player in relapsing-remitting uveitis, as shown by increased, synchronized relapses after intraocular application of IFN-γ. We demonstrated dynamic changes of the cytokine pattern during monophasic and relapsing-remitting disease

  8. CTLA4-Ig suppresses development of experimental autoimmune uveitis in the induction and effector phases: Comparison with blockade of interleukin-6.

    Science.gov (United States)

    Iwahashi, Chiharu; Fujimoto, Minoru; Nomura, Shintaro; Serada, Satoshi; Nakai, Kei; Ohguro, Nobuyuki; Nishida, Kohji; Naka, Tetsuji

    2015-11-01

    Recently, a number of biologics have been used in the treatment of autoimmune diseases. However, in the treatment of severe autoimmune uveitis, only TNF-alpha inhibitors are preferably used and the effect of other biologics such as interleukin-6 (IL-6) signaling blockade or cytotoxic T-lymphocyte antigen-4-immunoglobulin fusion protein (CTLA4-Ig) has not been well studied. Previously, we reported that IL-6 blockade effectively suppresses the development of experimental autoimmune uveitis (EAU), a mouse model for uveitis, by inhibiting Th17 cell development. In this study, we investigated the effect of CTLA4-Ig on EAU development and compared it with the effect of anti-IL-6 receptor monoclonal antibody (MR16-1). C57BL/6J mice were immunized with interphotoreceptor retinoid-binding protein (IRBP) and treated once with CTLA4-Ig or MR16-1. Both CTLA4-Ig and MR16-1 administered in the induction phase (the same day as immunization) significantly reduced the clinical and histopathological scores of EAU. Fluorescence-activated cell sorting studies using draining lymph node (LN) cells from EAU mice 10 days after immunization showed that CTLA4-Ig can suppress early T-helper cell activation. CTLA4-Ig administered in the effector phase of the disease (one week after immunization), when IRBP-reactive T cells have been primed, also significantly reduced the clinical and histopathological scores of EAU. In contrast, MR16-1 administered in the effector phase did not ameliorate EAU. To investigate the differences between these biologics in the effector phase, in vitro restimulation analysis of LN cells obtained from EAU mice one week after immunization was performed and revealed that CTLA4-Ig, but not MR16-1, added to culture media could inhibit the proliferation of IRBP-specific CD4(+) T cells which possessed capacities of producing IFN-gamma and/or IL-17. Collectively, CTLA4-Ig ameliorated EAU through preventing initial T-cell activation in the induction phase and suppressing

  9. Antineuroinflammatory and neurotrophic effects of CNTF and C16 peptide in an acute experimental autoimmune encephalomyelitis rat model

    Directory of Open Access Journals (Sweden)

    Marong eFang

    2013-12-01

    Full Text Available Experimentalallergic encephalomyelitis (EAE is an animal model for inflammatory demyelinating autoimmune disease, i.e., multiple sclerosis (MS. In the present study, we investigated the antineuroinflammatory/neuroprotective effects of C16, an ανβ3 integrin-binding peptide, and recombinant rat ciliary neurotrophic factor (CNTF, a cytokine that was originally identified as a survival factor for neurons, in an acute rodent EAE model. In this model, C16 peptide was injected intravenously every day for 2 weeks, and CNTF was delivered into the cerebral ventricles with Alzet miniosmotic pumps. Disease severity was assessed weekly using a scale ranging from 0 to 5. Multiple histological and molecular biological assays were employed to assess inflammation, axonal loss, neuronal apoptosis, white matter demyelination, and gliosis in the brain and spinal cord of different groups. Our results showed that the EAE induced rats revealed a significant increase in inflammatory cells infiltration, while C16 treatment could inhibit the infiltration of leukocytes and macrophages down to 2/3-1/3 of vehicle treated EAE control (P<0.05. The delayed onset of disease, reduced clinical score (P<0.01 in peak stage and more rapid recovery also were achieved in C16 treated group. Besides impairing inflammation, CNTF treatment also exerted direct neuroprotective effects, decreasing demyelination and axon loss score (P<0.05 Vs vehicle treated EAE control, and reducing the neuronal death from 40%-50% to 10%-20% (P<0.05. Both treatments suppressed the expression of cytokine tumor necrosis factor-α and interferon-when compared with the vehicle control (P<0.05. Combined treatment with C16 and CNTF produced more obvious functional recovery and neuroprotective effects than individually treatment (P<0.05. These results suggested that combination treatment with C16 and CNTF, which target different neuroprotection pathways, may be an effective therapeutic alternative to

  10. Treatment with a recombinant human IgM that recognizes PSA-NCAM preserves brain pathology in MOG-induced experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Lemus, Hernan Nicolas; Warrington, Arthur E; Denic, Aleksandar; Wootla, Bharath; Rodriguez, Moses

    2017-01-01

    A single peripheral dose of CNS-binding IgMs promote remyelination and preserve axons in a number of animal models of neurologic disease. A myelin-binding recombinant human IgM (rHIgM22) is presently in a safety trial in MS patients following an acute MS exacerbation. rHIgM22 (directed against oligodendrocytes) or rHIgM12 (directed against neurons) were administered to mice with MOG-induced experimental autoimmune encephalomyelitis (EAE) with study endpoints: clinical deficits and brain and spinal cord pathology. IgMs were administered at a therapeutic dose of 100 μ g intra peritoneal at the time of immunization (day -1, 0, +$1), disease onset (15 days) or peak of the disease (28 days). Disease course was not worsened by either human IgM regardless of the time of treatment. Of note, the human IgM that recognizes a carbohydrate epitope on gangliosides and NCAM, rHIgM12, reduced brain pathology when given at time of immunization or at onset of disease, but did not reduce clinical deficits or spinal cord disease burden. Hence, treatment with rHIgM12 resulted in marked reduction in meningeal inflammation. Data consistent with the hypothesis that in the EAE model this molecule has an immune-modulatory effect. Treatment with an anti-CD4 blocking IgG prevented both clinical course and CNS pathology. This pre-clinical study further supports the safety of therapeutic CNS-binding human IgMs in the presence of autoimmunity and clearly differentiates them from IgGs directed against MOG or aquaporin-4 that worsen neurologic disease.

  11. Dietary Omega-3 Fatty Acids Suppress Experimental Autoimmune Uveitis in Association with Inhibition of Th1 and Th17 Cell Function

    Science.gov (United States)

    Shoda, Hiromi; Yanai, Ryoji; Yoshimura, Takeru; Nagai, Tomohiko; Kimura, Kazuhiro; Sobrin, Lucia; Connor, Kip M.; Sakoda, Yukimi; Tamada, Koji; Ikeda, Tsunehiko; Sonoda, Koh-Hei

    2015-01-01

    Omega (ω)–3 long-chain polyunsaturated fatty acids (LCPUFAs) inhibit the production of inflammatory mediators and thereby contribute to the regulation of inflammation. Experimental autoimmune uveitis (EAU) is a well-established animal model of autoimmune retinal inflammation. To investigate the potential effects of dietary intake of ω-3 LCPUFAs on uveitis, we examined the anti-inflammatory properties of these molecules in comparison with ω-6 LCPUFAs in a mouse EAU model. C57BL/6 mice were fed a diet containing ω-3 LCPUFAs or ω-6 LCPUFAs for 2 weeks before as well as after the induction of EAU by subcutaneous injection of a fragment of human interphotoreceptor retinoid-binding protein emulsified with complete Freund’s adjuvant. Both clinical and histological scores for uveitis were smaller for mice fed ω-3 LCPUFAs than for those fed ω-6 LCPUFAs. The concentrations of the T helper 1 (Th1) cytokine interferon-γ and the Th17 cytokine interleukin-17 in intraocular fluid as well as the production of these cytokines by lymph node cells were reduced for mice fed ω-3 LCPUFAs. Furthermore, the amounts of mRNAs for the Th1- and Th17-related transcription factors T-bet and RORγt, respectively, were reduced both in the retina and in lymph node cells of mice fed ω-3 LCPUFAs. Our results thus show that a diet enriched in ω-3 LCPUFAs suppressed uveitis in mice in association with inhibition of Th1 and Th17 cell function. PMID:26393358

  12. CD1d(hi)CD5+ B cells expanded by GM-CSF in vivo suppress experimental autoimmune myasthenia gravis.

    Science.gov (United States)

    Sheng, Jian Rong; Quan, Songhua; Soliven, Betty

    2014-09-15

    IL-10-competent subset within CD1d(hi)CD5(+) B cells, also known as B10 cells, has been shown to regulate autoimmune diseases. Whether B10 cells can prevent or suppress the development of experimental autoimmune myasthenia gravis (EAMG) has not been studied. In this study, we investigated whether low-dose GM-CSF, which suppresses EAMG, can expand B10 cells in vivo, and whether adoptive transfer of CD1d(hi)CD5(+) B cells would prevent or suppress EAMG. We found that treatment of EAMG mice with low-dose GM-CSF increased the proportion of CD1d(hi)CD5(+) B cells and B10 cells. In vitro coculture studies revealed that CD1d(hi)CD5(+) B cells altered T cell cytokine profile but did not directly inhibit T cell proliferation. In contrast, CD1d(hi)CD5(+) B cells inhibited B cell proliferation and its autoantibody production in an IL-10-dependent manner. Adoptive transfer of CD1d(hi)CD5(+) B cells to mice could prevent disease, as well as suppress EAMG after disease onset. This was associated with downregulation of mature dendritic cell markers and expansion of regulatory T cells resulting in the suppression of acetylcholine receptor-specific T cell and B cell responses. Thus, our data have provided significant insight into the mechanisms underlying the tolerogenic effects of B10 cells in EAMG. These observations suggest that in vivo or in vitro expansion of CD1d(hi)CD5(+) B cells or B10 cells may represent an effective strategy in the treatment of human myasthenia gravis. Copyright © 2014 by The American Association of Immunologists, Inc.

  13. Simultaneous complement response via lectin pathway in retina and optic nerve in an experimental autoimmune glaucoma model

    Directory of Open Access Journals (Sweden)

    Sabrina eReinehr

    2016-06-01

    Full Text Available Glaucoma is a multifactorial disease and especially mechanisms occurring independently from an elevated intraocular pressure (IOP are still unknown. Likely, the immune system contributes to the glaucoma pathogenesis. Previously, IgG antibody depositions and retinal ganglion cell (RGC loss were found in an IOP-independent autoimmune glaucoma model. Therefore, we investigated the possible participation of the complement system in this model. Here, rats were immunized with bovine optic nerve homogenate antigen (ONA, while controls (Co received sodium chloride (n=5-6/group. After 14 days, RGC density was quantified on flatmounts. No changes in the number of RGCs could be observed at this point in time. Longitudinal optic nerve sections were stained against the myelin basic protein (MBP. We could note few signs of degeneration processes. In order to detect distinct complement components, retinas and optic nerves were labeled with complement markers at 3, 7, 14, and 28 days and analyzed. Significantly more C3 and MAC depositions were found in retinas and optic nerves of the ONA group. These were already present at day 7, before RGC loss and demyelination occurred. Additionally, an upregulation of C3 protein was noted via Western Blot at this time. After 14 days, quantitative real-time PCR revealed significant more C3 mRNA in the ONA retinas. An upregulation of the lectin pathway associated mannose-serine-protease-2 (MASP2 was observed in the retinas as well as in the optic nerves of the ONA group after 7 days. Significant more MASP2 in retinas could also be observed via Western Blot analyses at this point in time. No effect was noted in regard to C1q. Therefore, we assume that the immunization led to an activation of the complement system via the lectin pathway in retinas and optic nerves at an early stage in this glaucoma model. This activation seems to be an early response, which then triggers degeneration. These findings can help to develop novel

  14. AUTOIMMUNE HEPATITIS

    Directory of Open Access Journals (Sweden)

    Yusri Dianne Jurnalis

    2010-05-01

    Full Text Available AbstrakHepatitis autoimun merupakan penyakit inflamasi hati yang berat dengan penyebab pasti yang tidak diketahui yang mengakibatkan morbiditas dan mortalitas yang tinggi. Semua usia dan jenis kelamin dapat dikenai dengan insiden tertinggi pada anak perempuan usia prepubertas, meskipun dapat didiagnosis pada usia 6 bulan. Hepatitis autoimun dapat diklasifikasikan menjadi 2 bagian berdasarkan adanya antibodi spesifik: Smooth Muscle Antibody (SMA dengan anti-actin specificity dan/atau Anti Nuclear Antibody (ANA pada tipe 1 dan Liver-Kidney Microsome antibody (LKM1 dan/atau anti-liver cytosol pada tipe 2. Gambaran histologisnya berupa “interface hepatitis”, dengan infiltrasi sel mononuklear pada saluran portal, berbagai tingkat nekrosis, dan fibrosis yang progresf. Penyakit berjalan secara kronik tetapi keadaan yang berat biasanya menjadi sirosis dan gagal hati.Tipe onset yang paling sering sama dengan hepatitis virus akut dengan gagal hati akut pada beberapa pasien; sekitar sepertiga pasien dengan onset tersembunyi dengan kelemahan dan ikterik progresif ketika 10-15% asimptomatik dan mendadak ditemukan hepatomegali dan/atau peningkatan kadar aminotransferase serum. Adanya predominasi perempuan pada kedua tipe. Pasien LKM1 positif menunjukkan keadaan lebih akut, pada usia yang lebih muda, dan biasanya dengan defisiensi Immunoglobulin A (IgA, dengan durasi gejala sebelum diagnosis, tanda klinis, riwayat penyakit autoimun pada keluarga, adanya kaitan dengan gangguan autoimun, respon pengobatan dan prognosis jangka panjang sama pada kedua tipe.Kortikosteroid yang digunakan secara tunggal atau kombinasi azathioprine merupakan terapi pilihan yang dapat menimbulkan remisi pada lebih dari 90% kasus. Strategi terapi alternatif adalah cyclosporine. Penurunan imunosupresi dikaitkan dengan tingginya relap. Transplantasi hati dianjurkan pada penyakit hati dekom-pensata yang tidak respon dengan pengobatan medis lainnya.Kata kunci : hepatitis Autoimmune

  15. Autoimmune liver disease panel

    Science.gov (United States)

    Liver disease test panel - autoimmune ... Autoimmune disorders are a possible cause of liver disease. The most common of these diseases are autoimmune hepatitis and primary biliary cholangitis (formerly called primary biliary cirrhosis). This group of tests ...

  16. [Autoimmune pancreatitis].

    Science.gov (United States)

    Beyer, G; Menzel, J; Krüger, P-C; Ribback, S; Lerch, M M; Mayerle, J

    2013-11-01

    Autoimmune pancreatitis is a relatively rare form of chronic pancreatitis which is characterized by a lymphoplasmatic infiltrate with a storiform fibrosis and often goes along with painless jaundice and discrete discomfort of the upper abdomen. Clinically we distinguish between two subtypes, which differ in terms of their histology, clinical picture and prognosis. Type 1 autoimmune pancreatitis is the pancreatic manifestation of the IgG4-associated syndrome which also involves other organs. About one third of the patients can only be diagnosed after either histological prove or a successful steroid trail. Type 2 is IgG4-negative with the histological picture of an idiopathic duct centric pancreatitis and is to higher degree associated with inflammatory bowel disease. A definitive diagnosis can only be made using biopsy. Usually both forms show response to steroid treatment, but in type 1 up to 50 % of the patients might develop a relapse. The biggest challenge and most important differential diagnosis remains the discrimination of AIP from pancreatic cancer, because also AIP can cause mass of the pancreatic head, lymphadenopathy and ductal obstruction. This article summarizes recent advances on epidemiology, clinical presentation, diagnostic strategy, therapy and differential diagnosis in this relatively unknown disease. © Georg Thieme Verlag KG Stuttgart · New York.

  17. Selective enrichment of Th1 CD45RBlow CD4+ T cells in autoimmune infiltrates in experimental allergic encephalomyelitis

    DEFF Research Database (Denmark)

    Renno, T; Zeine, R; Girard, J M

    1994-01-01

    The cytokine effector status of CD4+ T cells from lymph nodes (LN) and the central nervous system (CNS) of SJL/J mice immunized with autoantigen in adjuvant for the induction of experimental allergic encephalomyelitis (EAE) was compared. CD4+ T cells were FACS sorted based on the levels of expres......The cytokine effector status of CD4+ T cells from lymph nodes (LN) and the central nervous system (CNS) of SJL/J mice immunized with autoantigen in adjuvant for the induction of experimental allergic encephalomyelitis (EAE) was compared. CD4+ T cells were FACS sorted based on the levels...... of expression of the activation marker CD45RB. Low levels of expression of this surface marker are induced by antigen recognition and are associated with 'effector' T cell function. Reverse transcriptase polymerase chain reaction (PCR) was used to analyze the expression of different T cell cytokine genes...

  18. Update in Endocrine Autoimmunity

    OpenAIRE

    Anderson, Mark S.

    2008-01-01

    Context: The endocrine system is a common target in pathogenic autoimmune responses, and there has been recent progress in our understanding, diagnosis, and treatment of autoimmune endocrine diseases.

  19. Effect of ethanol extract of saffron (Crocus sativus L.) on the inhibition of experimental autoimmune encephalomyelitis in C57bl/6 mice.

    Science.gov (United States)

    Ghazavi, A; Mosayebi, G; Salehi, H; Abtahi, H

    2009-05-01

    In this study, effect of ethanol extract of Saffron (Crocus sativus L.) in the treatment of Experimental Autoimmune Encephalomyelitis (EAE) in C57BL/6 mice was evaluated. EAE was induced by immunization of 8 week old mice with MOG(35-55) with complete Freunds adjuvant. Therapy with saffron was started on day the immunization. Total Antioxidant Capacity (TAC) was assessed by Ferric Reducing-Antioxidant Power (FRAP) method. Nitric oxide (NO) production was also estimated by Griess reaction. For histological analysis, mice brain was harvested and sections were stained with Hematoxylin-Eosin. After daily oral dosage the saffron significantly reduced the clinical symptoms in C57BL/6 mice with EAE. Also, treated mice displayed a delayed disease onset compared with control mice. TAC production was significantly elevated in saffron treated mice. Effect of saffron on serum NO production was not significant. Typical spinal cord leukocyte infiltration was observed in control mice compared with saffron treated mice. These results suggest for the first time that saffron is effective in the prevention of symptomatic EAE by inhibition of oxidative stress and leukocyte infiltration to CNS and may be potentially useful for the treatment of Multiple Sclerosis (MS).

  20. Effects of prophylactic and therapeutic teriflunomide in transcranial magnetic stimulation-induced motor-evoked potentials in the dark agouti rat model of experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Iglesias-Bregna, Deborah; Hanak, Susan; Ji, Zhongqi; Petty, Margaret; Liu, Li; Zhang, Donghui; McMonagle-Strucko, Kathleen

    2013-10-01

    Teriflunomide is a once-daily oral immunomodulatory agent recently approved in the United States for the treatment of relapsing multiple sclerosis (RMS). This study investigated neurophysiological deficits in descending spinal cord motor tracts during experimental autoimmune encephalomyelitis (EAE; a model of multiple sclerosis) and the functional effectiveness of prophylactic or therapeutic teriflunomide treatment in preventing the debilitating paralysis observed in this model. Relapsing-remitting EAE was induced in Dark Agouti rats using rat spinal cord homogenate. Animals were treated with oral teriflunomide (10 mg/kg daily) prophylactically, therapeutically, or with vehicle (control). Transcranial magnetic motor-evoked potentials were measured throughout the disease to provide quantitative assessment of the neurophysiological status of descending motor tracts. Axonal damage was quantified histologically by silver staining. Both prophylactic and therapeutic teriflunomide treatment significantly reduced maximum EAE disease scores (P teriflunomide treatment regimens prevented a delay in wave-form latency and a decrease in wave-form amplitude compared with that observed in vehicle-treated animals. A significant reduction in axonal loss was observed with both teriflunomide treatment regimens compared with vehicle (P teriflunomide can prevent the deficits observed in this animal model in descending spinal cord motor tracts. The mechanism behind reduced axonal loss and improved motor function may be primarily the reduced inflammation and consequent demyelination observed in these animals through the known effects of teriflunomide on impairing proliferation of stimulated T cells. These findings may have significant implications for patients with RMS.

  1. Progression of experimental autoimmune encephalomyelitis is associated with up-regulation of major sodium transporters in the mouse kidney cortex under a normal salt diet.

    Science.gov (United States)

    Zhou, Xiaoming; Packialakshmi, Balamurugan; Xiao, Yao; Nurmukhambetova, Saule; Lees, Jason R

    2017-07-01

    Recent demonstrations of exacerbation of experimental autoimmune encephalomyelitis (EAE) by high salt diets prompted us to study whether EAE stimulated Na absorption by the renal cortex, a primary regulatory site for Na balance, even under a normal NaCl diet. We found that as EAE progressed from mild to severe symptoms, there were parallel increases in the protein abundance of NHE3 and αENaC and the Na,K-ATPase activity with an affiliated elevation of its β1-subunit protein. These effects are associated with increases in the protein levels of the well-known regulators SGK1 and scaffold NHERF2, and phosphorylation of ERK1/2. These effects of EAE could not be explained by reduction in water or food intake. We conclude that EAE progression is associated with up-regulation of major Na transporters, which is most likely driven by increased expression of SGK1 and NHERF2 and activation of ERK1/2. These data suggest that EAE progression increases Na absorption by the renal cortex. Copyright © 2017. Published by Elsevier Inc.

  2. Ginger extracts influence the expression of IL-27 and IL-33 in the central nervous system in experimental autoimmune encephalomyelitis and ameliorates the clinical symptoms of disease.

    Science.gov (United States)

    Jafarzadeh, A; Mohammadi-Kordkhayli, M; Ahangar-Parvin, R; Azizi, V; Khoramdel-Azad, H; Shamsizadeh, A; Ayoobi, A; Nemati, M; Hassan, Z M; Moazeni, S M; Khaksari, M

    2014-11-15

    The immunomodulatory effects of the IL-27 and IL-33 and the anti-inflammatory effects of ginger have been reported in some studies. The aim was to evaluate the effects of the ginger extract on the expression of IL-27 and IL-33 in a model of experimental autoimmune encephalomyelitis (EAE). In PBS-treated EAE mice the expression of IL-27 P28 was significantly lower whereas the expression of IL-33 was significantly higher than unimmunized control mice. In 200 and 300 mg/kg ginger-treated EAE groups the expression of IL-27 P28 and IL-27 EBI3 was significantly higher whereas the expression of IL-33 was significantly lower than PBS-treated EAE mice. The EAE clinical symptoms and the pathological scores were significantly lower in ginger-treated EAE groups. These results showed that the ginger extract modulates the expression of the IL-27 and IL-33 in the spinal cord of EAE mice and ameliorates the clinical symptoms of disease. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Elevation of AQP4 and selective cytokines in experimental autoimmune encephalitis mice provides some potential biomarkers in optic neuritis and demyelinating diseases.

    Science.gov (United States)

    Sun, Li; Weng, Huan; Li, Zhenxin

    2015-01-01

    Idiopathic optic neuritis (ION) is an inflammation of the optic nerve that may result in a complete or partial loss of vision. ION is usually due to the immune attack of the myelin sheath covering the optic nerve. ION acts frequently as the first symptoms of multiple sclerosis (MS) and neuromyelitis optica (NMO), or other inflammatory demyelinating disorders. The pathogenic progression of ION remains unclear. Experimental autoimmune encephalitis (EAE) is a commonly used model of idiopathic inflammatory demyelinating disorders (IIDDs); the optic nerve is affected in EAE as well. The specific mediators of demyelination in optic neuritis are unknown. Recent studies have indicated what T-cell activation in peripheral blood is associated with optic neuritis pathogenesis. The object of the present study was to determine whether certain cytokines (IL-6, IL-17A, and IL-23) and AQP4 contribute to the demyelinating process using EAE model. We have found that IL-6R, AQP4 and IL-23R are significantly increased in mRNA and protein levels in optic nerves in EAE mice compared to control mice; serum AQP4, IL-6, IL-17A, IL-23 are increased whereas transforming growth factor beta (TGF-β) is decreased in EAE mice. These results suggest that AQP4 and selective cytokines in serum are associated with ION pathogenesis in the animal model, and these results shine light for future clinical diagnosis as potential biomarkers in ION patients.

  4. Deficits in Endogenous Adenosine Formation by Ecto-5′-Nucleotidase/CD73 Impair Neuromuscular Transmission and Immune Competence in Experimental Autoimmune Myasthenia Gravis

    Directory of Open Access Journals (Sweden)

    Laura Oliveira

    2015-01-01

    Full Text Available AMP dephosphorylation via ecto-5′-nucleotidase/CD73 is the rate limiting step to generate extracellular adenosine (ADO from released adenine nucleotides. ADO, via A2A receptors (A2ARs, is a potent modulator of neuromuscular and immunological responses. The pivotal role of ecto-5′-nucleotidase/CD73, in controlling extracellular ADO formation, prompted us to investigate its role in a rat model of experimental autoimmune myasthenia gravis (EAMG. Results show that CD4+CD25+FoxP3+ regulatory T cells express lower amounts of ecto-5′-nucleotidase/CD73 as compared to controls. Reduction of endogenous ADO formation might explain why proliferation of CD4+ T cells failed upon blocking A2A receptors activation with ZM241385 or adenosine deaminase in EAMG animals. Deficits in ADO also contribute to neuromuscular transmission failure in EAMG rats. Rehabilitation of A2AR-mediated immune suppression and facilitation of transmitter release were observed by incubating the cells with the nucleoside precursor, AMP. These findings, together with the characteristic increase in serum adenosine deaminase activity of MG patients, strengthen our hypothesis that the adenosinergic pathway may be dysfunctional in EAMG. Given that endogenous ADO formation is balanced by ecto-5′-nucleotidase/CD73 activity and that A2ARs exert a dual role to restore use-dependent neurocompetence and immune suppression in myasthenics, we hypothesize that stimulation of the two mechanisms may have therapeutic potential in MG.

  5. Development and Pre-Clinical Evaluation of Recombinant Human Myelin Basic Protein Nano Therapeutic Vaccine in Experimental Autoimmune Encephalomyelitis Mice Animal Model

    Science.gov (United States)

    Al-Ghobashy, Medhat A.; Elmeshad, Aliaa N.; Abdelsalam, Rania M.; Nooh, Mohammed M.; Al-Shorbagy, Muhammad; Laible, Götz

    2017-04-01

    Recombinant human myelin basic protein (rhMBP) was previously produced in the milk of transgenic cows. Differences in molecular recognition of either hMBP or rhMBP by surface-immobilized anti-hMBP antibodies were demonstrated. This indicated differences in immunological response between rhMBP and hMBP. Here, the activity of free and controlled release rhMBP poly(ε-caprolactone) nanoparticles (NPs), as a therapeutic vaccine against multiple sclerosis (MS) was demonstrated in experimental autoimmune encephalomyelitis (EAE) animal model. Following optimization of nanoformulation, discrete spherical, rough-surfaced rhMBP NPs with high entrapment efficiency and controlled release pattern were obtained. Results indicated that rhMBP was loaded into and electrostatically adsorbed onto the surface of NPs. Subcutaneous administration of free or rhMBP NPs before EAE-induction reduced the average behavioral score in EAE mice and showed only mild histological alterations and preservation of myelin sheath, with rhMBP NPs showing increased protection. Moreover, analysis of inflammatory cytokines (IFN-γ and IL-10) in mice brains revealed that pretreatment with free or rhMBP NPs significantly protected against induced inflammation. In conclusion: i) rhMBP ameliorated EAE symptoms in EAE animal model, ii) nanoformulation significantly enhanced efficacy of rhMBP as a therapeutic vaccine and iii) clinical investigations are required to demonstrate the activity of rhMBP NPs as a therapeutic vaccine for MS.

  6. A Novel Cervical Spinal Cord Window Preparation Allows for Two-Photon Imaging of T-Cell Interactions with the Cervical Spinal Cord Microvasculature during Experimental Autoimmune Encephalomyelitis

    Science.gov (United States)

    Haghayegh Jahromi, Neda; Tardent, Heidi; Enzmann, Gaby; Deutsch, Urban; Kawakami, Naoto; Bittner, Stefan; Vestweber, Dietmar; Zipp, Frauke; Stein, Jens V.; Engelhardt, Britta

    2017-01-01

    T-cell migration across the blood–brain barrier (BBB) is a crucial step in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Two-photon intravital microscopy (2P-IVM) has been established as a powerful tool to study cell–cell interactions in inflammatory EAE lesions in living animals. In EAE, central nervous system inflammation is strongly pronounced in the spinal cord, an organ in which 2P-IVM imaging is technically very challenging and has been limited to the lumbar spinal cord. Here, we describe a novel spinal cord window preparation allowing to use 2P-IVM to image immune cell interactions with the cervical spinal cord microvascular endothelium during EAE. We describe differences in the angioarchitecture of the cervical spinal cord versus the lumbar spinal cord, which will entail different hemodynamic parameters in these different vascular beds. Using T cells as an example, we demonstrate the suitability of this novel methodology in imaging the post-arrest multistep T-cell extravasation across the cervical spinal cord microvessels. The novel methodology includes an outlook to the analysis of the cellular pathway of T-cell diapedesis across the BBB by establishing visualization of endothelial junctions in this vascular bed. PMID:28443093

  7. Oral Administration of the Probiotic Strain Escherichia coli Nissle 1917 Reduces Susceptibility to Neuroinflammation and Repairs Experimental Autoimmune Encephalomyelitis-Induced Intestinal Barrier Dysfunction

    Directory of Open Access Journals (Sweden)

    Thomas Secher

    2017-09-01

    Full Text Available Multiple sclerosis (MS is a chronic inflammatory disease of the central nervous system (CNS with an increasing incidence in developed countries. Recent reports suggest that modulation of the gut microbiota might be one promising therapy for MS. Here, we investigated whether the probiotic Escherichia coli strain Nissle 1917 (ECN could modulate the outcome of experimental autoimmune encephalomyelitis (EAE, a murine model of MS. We evidenced that daily oral treatment with ECN, but not with the archetypal K12 E. coli strain MG1655, reduced the severity of EAE induced by immunization with the MOG35–55 peptide. This beneficial effect was associated with a decreased secretion of inflammatory cytokines and an increased production of the anti-inflammatory cytokine IL-10 by autoreactive CD4 T cells, both in peripheral lymph nodes and CNS. Interestingly, ECN-treated mice exhibited increased numbers of MOG-specific CD4+ T cells in the periphery contrasting with severely reduced numbers in the CNS, suggesting that ECN might affect T cell migration from the periphery to the CNS through a modulation of their activation and/or differentiation. In addition, we demonstrated that EAE is associated with a profound defect in the intestinal barrier function and that treatment with ECN, but not with MG1655, repaired intestinal permeability dysfunction. Collectively, our data reveal that EAE induces a disruption of the intestinal homeostasis and that ECN protects from disease and restores the intestinal barrier function.

  8. Rational design and synthesis of altered peptide ligands based on human myelin oligodendrocyte glycoprotein 35-55 epitope: inhibition of chronic experimental autoimmune encephalomyelitis in mice.

    Science.gov (United States)

    Tselios, Theodore; Aggelidakis, Mihalis; Tapeinou, Anthi; Tseveleki, Vivian; Kanistras, Ioannis; Gatos, Dimitrios; Matsoukas, John

    2014-11-04

    Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the central nervous system and is an animal model of multiple sclerosis (MS). Although the etiology of MS remains unclear, there is evidence T-cell recognition of immunodominant epitopes of myelin proteins, such as the 35-55 epitope of myelin oligodendrocyte glycoprotein (MOG), plays a pathogenic role in the induction of chronic EAE. Cyclization of peptides is of great interest since the limited stability of linear peptides restricts their potential use as therapeutic agents. Herein, we have designed and synthesized a number of linear and cyclic peptides by mutating crucial T cell receptor (TCR) contact residues of the human MOG35-55 epitope. In particular, we have designed and synthesized cyclic altered peptide ligands (APLs) by mutating Arg41 with Ala or Arg41 and Arg46 with Ala. The peptides were synthesized in solid phase on 2-chlorotrityl chloride resin (CLTR-Cl) using the Fmoc/t-Bu methodology. The purity of final products was verified by RP-HPLC and their identification was achieved by ESI-MS. It was found that the substitutions of Arg at positions 41 and 46 with Ala results in peptide analogues that reduce the severity of MOG-induced EAE clinical symptoms in C57BL/6 mice when co-administered with mouse MOG35-55 peptide at the time of immunization.

  9. GM-CSF Promotes Chronic Disability in Experimental Autoimmune Encephalomyelitis by Altering the Composition of Central Nervous System-Infiltrating Cells, but Is Dispensable for Disease Induction.

    Science.gov (United States)

    Duncker, Patrick C; Stoolman, Joshua S; Huber, Amanda K; Segal, Benjamin M

    2017-12-29

    GM-CSF has been portrayed as a critical cytokine in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and, ostensibly, in multiple sclerosis. C57BL/6 mice deficient in GM-CSF are resistant to EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG)35-55 The mechanism of action of GM-CSF in EAE is poorly understood. In this study, we show that GM-CSF augments the accumulation of MOG35-55-specific T cells in the skin draining lymph nodes of primed mice, but it is not required for the development of encephalitogenic T cells. Abrogation of GM-CSF receptor signaling in adoptive transfer recipients of MOG35-55-specific T cells did not alter the incidence of EAE or the trajectory of its initial clinical course, but it limited the extent of chronic CNS tissue damage and neurologic disability. The attenuated clinical course was associated with a relative dearth of MOG35-55-specific T cells, myeloid dendritic cells, and neutrophils, as well as an abundance of B cells, within CNS infiltrates. Our data indicate that GM-CSF drives chronic tissue damage and disability in EAE via pleiotropic pathways, but it is dispensable during early lesion formation and the onset of neurologic deficits. Copyright © 2017 by The American Association of Immunologists, Inc.

  10. Evaluation of the co-registration capabilities of a MRI/PET compatible bed in an Experimental autoimmune encephalomyelitis (EAE) model

    Energy Technology Data Exchange (ETDEWEB)

    Esposito, Giovanna, E-mail: giovanna.esposito@unito.it [Molecular and Preclinical Imaging Center, University of Torino (Italy); D' angeli, Luca; Bartoli, Antonietta [Molecular and Preclinical Imaging Center, University of Torino (Italy); Chaabane, Linda [INSPE-Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milano (Italy); Terreno, Enzo [Molecular and Preclinical Imaging Center, University of Torino (Italy)

    2013-02-21

    Positron Emission Tomography (PET) with {sup 18}F-FDG is a promising tool for the detection and evaluation of active inflammation in animal models of neuroinflammation. MRI is a complementary imaging technique with high resolution and contrast suitable to obtain the anatomical data required to analyze PET data. To combine PET and MRI modalities, we developed a support bed system compatible for both scanners that allowed to perform imaging exams without animal repositioning. With this approach, MRI and PET data were acquired in mice with Experimental autoimmune encephalomyelitis (EAE). In this model, it was possible to measure a variation of {sup 18}F-FDG uptake proportional to the degree of disease severity which is mainly related to Central Nervous System (CNS) inflammation. Against the low resolved PET images, the co-registered MRI/PET images allowed to distinguish the different brain structures and to obtain a more accurate tracer evaluation. This is essential in particular for brain regions whose size is of the order of the spatial resolution of PET.

  11. Experimental autoimmune encephalomyelitis: Association with mutual regulation of RelA (p65)/NF-{kappa}B and phospho-I{kappa}B in the CNS

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, Insun; Ha, Danbee [College of Veterinary Medicine and Applied Radiological Science Institute, Jeju National University, Jeju 690-756 (Korea, Republic of); Ahn, Ginnae [Department of Marine Life Science, Jeju National University, Jeju 690-756 (Korea, Republic of); Park, Eunjin; Joo, Haejin [College of Veterinary Medicine and Applied Radiological Science Institute, Jeju National University, Jeju 690-756 (Korea, Republic of); Jee, Youngheun, E-mail: yhjee@jejunu.ac.kr [College of Veterinary Medicine and Applied Radiological Science Institute, Jeju National University, Jeju 690-756 (Korea, Republic of)

    2011-07-29

    Highlights: {yields} The phosphorylation of RelA's inhibitory factor I{kappa}B and subsequent RelA activation are important to the disease process of EAE. {yields} The expression of RelA and phospho-I{kappa}B was markedly increased in the initiation and during the progression of EAE. {yields} TPCK-treated EAE mice showed lower incidence of EAE with less severe symptoms and quicker recovery than vehicle-treated EAE mice. {yields} TPCK significantly suppressed the MOG{sub 35-55}-specific T cell proliferation by reducing the production of IFN-{gamma} and IL-17 cytokines in EAE. {yields} The NF-{kappa}B cascade's activity increased gradually with the development of symptoms and brain pathology of EAE. -- Abstract: Recently emerging evidence that the NF-{kappa}B family plays an important role in autoimmune disease has produced very broad and sometimes paradoxical conclusions. In the present study, we elucidated that the activation of RelA (p65) of NF-{kappa}B and I{kappa}B dissociation assumes a distinct role in experimental autoimmune encephalomyelitis (EAE) progression by altering I{kappa}B phosphorylation and/or degradation. In the present study of factors that govern EAE, the presence and immunoreactivity of nuclear RelA and phospho-I{kappa}B were recorded at the initiation and peak stage, and degradation of I{kappa}B{alpha} progressed rapidly at an early stage then stabilized during recovery. The immunoreactivity to RelA and phospho-I{kappa}B occurred mainly in inflammatory cells and microglial cells but only slightly in astrocytes. Subsequently, the blockade of I{kappa}B dissociation from NF-{kappa}B reduced the severity of disease by decreasing antigen-specific T cell response and production of IL-17 in EAE. Thus, blocking the dissociation of I{kappa}B from NF-{kappa}B can be utilized as a strategy to inhibit the NF-{kappa}B signal pathway thereby to reduce the initiation, progression, and severity of EAE.

  12. 1,25-Dihydroxyvitamin D3 suppresses TLR8 expression and TLR8-mediated inflammatory responses in monocytes in vitro and experimental autoimmune encephalomyelitis in vivo.

    Directory of Open Access Journals (Sweden)

    Bo Li

    Full Text Available 1,25-Dihydroxyvitamin D3 (1,25(OH2D3 suppresses autoimmunity and inflammation; however, the mechanism of its action has not been fully understood. We sought in this study to determine whether the anti-immune/anti-inflammatory action of 1,25(OH2D3 is in part mediated through an interplay between 1,25(OH2D3 and toll-like receptor (TLR7/8 signaling. 1,25(OH2D3 treatment prior to and/or following experimental autoimmune encephalomyelitis (EAE induction effectively reduced inflammatory cytokine expression in the spinal cord and ameliorated EAE. These effects were accompanied with a reduction in expression of several TLRs with the most profound effect observed for TLR8. The expression of TLR8 adaptor protein MyD88 was also significantly reduced by 1,25(OH2D3. To determine the molecular mechanism by which 1,25(OH2D3 suppresses EAE induction of TLR8 and inflammatory cytokine expression, we evaluated whether 1,25(OH2D3 can directly inhibit TLR8 signaling and the resulting inflammatory responses in human THP-1 monocytes. 1,25(OH2D3 treatment not only significantly reduced TLR8 expression but also the expression or activity of MyD88, IRF-4, IRF-7 and NF-kB in monocytes challenged with TLR8 ligands. TLR8 promoter-luciferase reporter assays indicated that 1,25(OH2D3 decreases TLR8 mRNA level in part via inhibiting TLR8 gene transcription activity. As a result of inhibition on TLR8 signaling cascade at various stages, 1,25(OH2D3 significantly diminished the TLR8 target gene expression (TNF-α and IL-1β. In summary, our novel findings suggest that TLR8 is a new target of 1,25(OH2D3 and may mediate the anti-inflammatory action of 1,25(OH2D3. Our findings also point to a destructive role of TLR8 in EAE and shed lights on pathogenesis of multiple sclerosis.

  13. Exacerbation of experimental autoimmune encephalomyelitis in prion protein (PrPc-null mice: evidence for a critical role of the central nervous system

    Directory of Open Access Journals (Sweden)

    Gourdain Pauline

    2012-01-01

    Full Text Available Abstract Background The cellular prion protein (PrPc is a host-encoded glycoprotein whose transconformation into PrP scrapie (PrPSc initiates prion diseases. The role of PrPc in health is still obscure, but many candidate functions have been attributed to the protein, both in the immune and the nervous systems. Recent data show that experimental autoimmune encephalomyelitis (EAE is worsened in mice lacking PrPc. Disease exacerbation has been attributed to T cells that would differentiate into more aggressive effectors when deprived of PrPc. However, alternative interpretations such as reduced resistance of neurons to autoimmune insult and exacerbated gliosis leading to neuronal deficits were not considered. Method To better discriminate the contribution of immune cells versus neural cells, reciprocal bone marrow chimeras with differential expression of PrPc in the lymphoid or in the central nervous system (CNS were generated. Mice were subsequently challenged with MOG35-55 peptide and clinical disease as well as histopathology were compared in both groups. Furthermore, to test directly the T cell hypothesis, we compared the encephalitogenicity of adoptively transferred PrPc-deficient versus PrPc-sufficient, anti-MOG T cells. Results First, EAE exacerbation in PrPc-deficient mice was confirmed. Irradiation exacerbated EAE in all the chimeras and controls, but disease was more severe in mice with a PrPc-deleted CNS and a normal immune system than in the reciprocal construction. Moreover, there was no indication that anti-MOG responses were different in PrPc-sufficient and PrPc-deficient mice. Paradoxically, PrPc-deficient anti-MOG 2D2 T cells were less pathogenic than PrPc-expressing 2D2 T cells. Conclusions In view of the present data, it can be concluded that the origin of EAE exacerbation in PrPc-ablated mice resides in the absence of the prion protein in the CNS. Furthermore, the absence of PrPc on both neural and immune cells does not

  14. Active induction of experimental autoimmune encephalomyelitis by MOG35-55 peptide immunization is associated with differential responses in separate compartments of the choroid plexus

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    Murugesan Nivetha

    2012-08-01

    Full Text Available Abstract Background There is increasing awareness that, aside from producing cerebrospinal fluid, the choroid plexus (CP might be a key regulator of immune activity in the central nervous system (CNS during neuroinflammation. Specifically, the CP has recently been posited to control entry of sentinel T cells into the uninflamed CNS during the early stages of neuroinflammatory diseases, like multiple sclerosis (MS and its animal model experimental autoimmune encephalomyelitis (EAE. As the CP is compartmentalized into a stromal core containing fenestrated capillaries devoid of typical blood–brain barrier properties, surrounded by a tight junction-expressing choroidal epithelium, each of these compartments might mount unique responses that instigate the neuroinflammatory process. Methods To discern responses of the respective CP stromal capillary and choroidal epithelial tissues during evolving neuroinflammation, we investigated morphology and in situ expression of 93 immune-related genes during early stages of EAE induced by immunization with myelin oligodendrocyte glycoprotein peptide (MOG35-55. Specifically, 3-D immunofluorescent imaging was employed to gauge morphological changes, and laser capture microdissection was coupled to an Immune Panel TaqMan Low Density Array to detail alterations in gene expression patterns at these separate CP sites on days 9 and 15 post-immunization (p.i.. To resolve CP effects due to autoimmunity against MOG peptide, from those due to complete Freund’s adjuvant (CFA and pertussis toxin (PTX included in the immunization, analysis was performed on MOG-CFA/PTX-treated, CFA/PTX-treated, and naïve cohorts. Results The CP became swollen and displayed significant molecular changes in response to MOG-CFA/PTX immunization. Both stromal capillary and choroidal epithelial tissues mounted vigorous, yet different, changes in expression of numerous genes over the time course analyzed - including those encoding adhesion

  15. Genetic background can result in a marked or minimal effect of gene knockout (GPR55 and CB2 receptor in experimental autoimmune encephalomyelitis models of multiple sclerosis.

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    Sofia Sisay

    Full Text Available Endocannabinoids and some phytocannabinoids bind to CB1 and CB2 cannabinoid receptors, transient receptor potential vanilloid one (TRPV1 receptor and the orphan G protein receptor fifty-five (GPR55. Studies using C57BL/10 and C57BL/6 (Cnr2 (tm1Zim CB2 cannabinoid receptor knockout mice have demonstrated an immune-augmenting effect in experimental autoimmune encephalomyelitis (EAE models of multiple sclerosis. However, other EAE studies in Biozzi ABH mice often failed to show any treatment effect of either CB2 receptor agonism or antagonism on inhibition of T cell autoimmunity. The influence of genetic background on the induction of EAE in endocannabinoid system-related gene knockout mice was examined. It was found that C57BL/6.GPR55 knockout mice developed less severe disease, notably in female mice, following active induction with myelin oligodendrocyte glycoprotein 35-55 peptide. In contrast C57BL/6.CB2 (Cnr2 (Dgen receptor knockout mice developed augmented severity of disease consistent with the genetically and pharmacologically-distinct, Cnr2 (tm1Zim mice. However, when the knockout gene was bred into the ABH mouse background and EAE induced with spinal cord autoantigens the immune-enhancing effect of CB2 receptor deletion was lost. Likewise CB1 receptor and transient receptor potential vanilloid one knockout mice on the ABH background demonstrated no alteration in immune-susceptibility, in terms of disease incidence and severity of EAE, in contrast to that reported in some C57BL/6 mouse studies. Furthermore the immune-modulating influence of GPR55 was marginal on the ABH mouse background. Whilst sedative doses of tetrahydrocannabinol could induce immunosuppression, this was associated with a CB1 receptor rather than a CB2 receptor-mediated effect. These data support the fact that non-psychoactive doses of medicinal cannabis have a marginal influence on the immune response in MS. Importantly, it adds a note of caution for the translational

  16. Parent-of-origin effects implicate epigenetic regulation of experimental autoimmune encephalomyelitis and identify imprinted Dlk1 as a novel risk gene.

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    Pernilla Stridh

    2014-03-01

    Full Text Available Parent-of-origin effects comprise a range of genetic and epigenetic mechanisms of inheritance. Recently, detection of such effects implicated epigenetic mechanisms in the etiology of multiple sclerosis (MS, a chronic inflammatory disease of the central nervous system. We here sought to dissect the magnitude and the type of parent-of-origin effects in the pathogenesis of experimental neuroinflammation under controlled environmental conditions. We investigated inheritance of an MS-like disease in rat, experimental autoimmune encephalomyelitis (EAE, using a backcross strategy designed to identify the parental origin of disease-predisposing alleles. A striking 37-54% of all detected disease-predisposing loci depended on parental transmission. Additionally, the Y chromosome from the susceptible strain contributed to disease susceptibility. Accounting for parent-of-origin enabled more powerful and precise identification of novel risk factors and increased the disease variance explained by the identified factors by 2-4-fold. The majority of loci displayed an imprinting-like pattern whereby a gene expressed only from the maternal or paternal copy exerts an effect. In particular, a locus on chromosome 6 comprises a well-known cluster of imprinted genes including the paternally expressed Dlk1, an atypical Notch ligand. Disease-predisposing alleles at the locus conferred lower Dlk1 expression in rats and, together with data from transgenic overexpressing Dlk1 mice, demonstrate that reduced Dlk1 drives more severe disease and modulates adaptive immune reactions in EAE. Our findings suggest a significant epigenetic contribution to the etiology of EAE. Incorporating these effects enables more powerful and precise identification of novel risk factors with diagnostic and prognostic implications for complex disease.

  17. Parent-of-Origin Effects Implicate Epigenetic Regulation of Experimental Autoimmune Encephalomyelitis and Identify Imprinted Dlk1 as a Novel Risk Gene

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    Bergman, Petra; Thessén Hedreul, Mélanie; Flytzani, Sevasti; Beyeen, Amennai Daniel; Gillett, Alan; Krivosija, Nina; Öckinger, Johan; Ferguson-Smith, Anne C.; Jagodic, Maja

    2014-01-01

    Parent-of-origin effects comprise a range of genetic and epigenetic mechanisms of inheritance. Recently, detection of such effects implicated epigenetic mechanisms in the etiology of multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. We here sought to dissect the magnitude and the type of parent-of-origin effects in the pathogenesis of experimental neuroinflammation under controlled environmental conditions. We investigated inheritance of an MS-like disease in rat, experimental autoimmune encephalomyelitis (EAE), using a backcross strategy designed to identify the parental origin of disease-predisposing alleles. A striking 37–54% of all detected disease-predisposing loci depended on parental transmission. Additionally, the Y chromosome from the susceptible strain contributed to disease susceptibility. Accounting for parent-of-origin enabled more powerful and precise identification of novel risk factors and increased the disease variance explained by the identified factors by 2-4-fold. The majority of loci displayed an imprinting–like pattern whereby a gene expressed only from the maternal or paternal copy exerts an effect. In particular, a locus on chromosome 6 comprises a well-known cluster of imprinted genes including the paternally expressed Dlk1, an atypical Notch ligand. Disease-predisposing alleles at the locus conferred lower Dlk1 expression in rats and, together with data from transgenic overexpressing Dlk1 mice, demonstrate that reduced Dlk1 drives more severe disease and modulates adaptive immune reactions in EAE. Our findings suggest a significant epigenetic contribution to the etiology of EAE. Incorporating these effects enables more powerful and precise identification of novel risk factors with diagnostic and prognostic implications for complex disease. PMID:24676147

  18. Seronegative autoimmune diseases.

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    Alessandri, Cristiano; Conti, Fabrizio; Conigliaro, Paola; Mancini, Riccardo; Massaro, Laura; Valesini, Guido

    2009-09-01

    A close relationship exists between autoimmunity and autoantibodies; despite this, some patients are persistently negative for disease-specific autoantibodies. These conditions have been defined as seronegative autoimmune diseases. Although the prevalence of seronegative autoimmune diseases is low, they may represent a practical problem because they are often difficult cases. There are also situations in which autoantibodies are positive in healthy subjects. In particular, three different conditions can be described: latent autoimmunity, preclinical autoimmunity, and postclinical autoimmunity. Here, we analyze briefly the meaning of autoantibody negativity in the seronegative autoimmune diseases, focusing in particular on the specificities associated with systemic lupus erythematosus, antiphospholipid syndrome, and rheumatoid arthritis.

  19. Autoimmune Pancreatitis.

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    Majumder, Shounak; Takahashi, Naoki; Chari, Suresh T

    2017-07-01

    Autoimmune pancreatitis (AIP) is a chronic fibroinflammatory disease of the pancreas that belongs to the spectrum of immunoglobulin G-subclass4-related diseases (IgG4-RD) and typically presents with obstructive jaundice. Idiopathic duct-centric pancreatitis (IDCP) is a closely related but distinct disease that mimics AIP radiologically but manifests clinically most commonly as recurrent acute pancreatitis in young individuals with concurrent inflammatory bowel disease. IgG4 levels are often elevated in AIP and normal in IDCP. Histologically, lymphoplasmacytic acinar inflammation and storiform fibrosis are seen in both. In addition, the histologic hallmark of IDCP is the granulocyte epithelial lesion: intraluminal and intraepithelial neutrophils in medium-sized and small ducts with or without granulocytic acinar inflammation often associated with destruction of ductal architecture. Initial treatment of both AIP and IDCP is with oral corticosteroids for duration of 4 weeks followed by a gradual taper. Relapses are common in AIP and relatively uncommon in IDCP, a relatively rare disease for which the natural history is not well understood. For patients with relapsing AIP, treatment with immunomodulators and more recently rituximab has been recommended. Although rare instances of pancreaticobiliary malignancy has been reported in patients with AIP, overall the lifetime risk of developing pancreatic cancer does not appear to be elevated.

  20. Autoimmune pancreatitis.

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    Pannala, Rahul; Chari, Suresh T

    2008-09-01

    Autoimmune pancreatitis (AIP) is an increasingly recognized clinical condition. Our objective is to provide a concise review of the advances in the past year in our understanding of AIP. In a hospital survey from Japan, the prevalence of AIP was estimated at 0.82 per 100,000 individuals. The pathogenesis of AIP remains unclear but a recent report noted that T helper type 2 and T regulatory cells predominantly mediate the immune reaction in AIP. Genetic associations that may predispose to relapse of AIP were reported. Multiple case series further described the clinical profile of AIP and its extrapancreatic manifestations. A large series on immunoglobulin G4 (IgG4)-associated cholangitis noted that patients with IgG4-associated cholangitis presented with obstructive jaundice and had increased serum IgG4 levels and IgG4-positive cells in bile duct biopsy specimens. Tissue IgG4 staining is likely to be a useful adjunct to serological diagnosis. AIP is steroid-responsive but maintaining remission continues to remain challenging. Presently low-dose steroids or immunomodulators are being used but efficacy of these medications remains to be determined. There has been significant progress in understanding the clinical profile of AIP but knowledge of pathogenesis remains limited. Treatment practices vary widely and management of refractory disease continues to be challenging.

  1. A GPBAR1 (TGR5 small molecule agonist shows specific inhibitory effects on myeloid cell activation in vitro and reduces experimental autoimmune encephalitis (EAE in vivo.

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    Nuruddeen D Lewis

    Full Text Available GPBAR1 is a G protein-coupled receptor that is activated by certain bile acids and plays an important role in the regulation of bile acid synthesis, lipid metabolism, and energy homeostasis. Recent evidence suggests that GPBAR1 may also have important effects in reducing the inflammatory response through its expression on monocytes and macrophages. To further understand the role of GPBAR1 in inflammation, we generated a novel, selective, proprietary GPBAR1 agonist and tested its effectiveness at reducing monocyte and macrophage activation in vitro and in vivo. We have used this agonist, together with previously described agonists to study agonism of GPBAR1, and shown that they can all induce cAMP and reduce TLR activation-induced cytokine production in human monocytes and monocyte-derived macrophages in vitro. Additionally, through the usage of RNA sequencing (RNA-Seq, we identified a select set of genes that are regulated by GPBAR1 agonism during LPS activation. To further define the in vivo role of GPBAR1 in inflammation, we assessed GPBAR1 expression and found high levels on circulating mouse monocytes. Agonism of GPBAR1 reduced LPS-induced cytokine production in mouse monocytes ex vivo and serum cytokine levels in vivo. Agonism of GPBAR1 also had profound effects in the experimental autoimmune encephalomyelitis (EAE mouse model of multiple sclerosis, where monocytes play an important role. Mice treated with the GPBAR1 agonist exhibited a significant reduction in the EAE clinical score which correlated with reduced monocyte and microglial activation and reduced trafficking of monocytes and T cells into the CNS. These data confirm the importance of GPBAR1 in controlling monocyte and macrophage activation in vivo and support the rationale for selective agonists of GPBAR1 in the treatment of inflammatory diseases.

  2. A GPBAR1 (TGR5) Small Molecule Agonist Shows Specific Inhibitory Effects on Myeloid Cell Activation In Vitro and Reduces Experimental Autoimmune Encephalitis (EAE) In Vivo

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    Lewis, Nuruddeen D.; Patnaude, Lori A.; Pelletier, Josephine; Souza, Donald J.; Lukas, Susan M.; King, F. James; Hill, Jonathan D.; Stefanopoulos, Dimitria E.; Ryan, Kelli; Desai, Sudha; Skow, Donna; Kauschke, Stefan G.; Broermann, Andre; Kuzmich, Daniel; Harcken, Christian; Hickey, Eugene R.; Modis, Louise K.

    2014-01-01

    GPBAR1 is a G protein-coupled receptor that is activated by certain bile acids and plays an important role in the regulation of bile acid synthesis, lipid metabolism, and energy homeostasis. Recent evidence suggests that GPBAR1 may also have important effects in reducing the inflammatory response through its expression on monocytes and macrophages. To further understand the role of GPBAR1 in inflammation, we generated a novel, selective, proprietary GPBAR1 agonist and tested its effectiveness at reducing monocyte and macrophage activation in vitro and in vivo. We have used this agonist, together with previously described agonists to study agonism of GPBAR1, and shown that they can all induce cAMP and reduce TLR activation-induced cytokine production in human monocytes and monocyte-derived macrophages in vitro. Additionally, through the usage of RNA sequencing (RNA-Seq), we identified a select set of genes that are regulated by GPBAR1 agonism during LPS activation. To further define the in vivo role of GPBAR1 in inflammation, we assessed GPBAR1 expression and found high levels on circulating mouse monocytes. Agonism of GPBAR1 reduced LPS-induced cytokine production in mouse monocytes ex vivo and serum cytokine levels in vivo. Agonism of GPBAR1 also had profound effects in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis, where monocytes play an important role. Mice treated with the GPBAR1 agonist exhibited a significant reduction in the EAE clinical score which correlated with reduced monocyte and microglial activation and reduced trafficking of monocytes and T cells into the CNS. These data confirm the importance of GPBAR1 in controlling monocyte and macrophage activation in vivo and support the rationale for selective agonists of GPBAR1 in the treatment of inflammatory diseases. PMID:24967665

  3. Transient decomplementation of mice delays onset of experimental autoimmune encephalomyelitis and impairs MOG-specific T cell response and autoantibody production.

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    Terényi, Nóra; Nagy, Nándor; Papp, Krisztián; Prechl, József; Oláh, Imre; Erdei, Anna

    2009-11-01

    Multiple sclerosis (MS) is the most common inflammatory and demyelinating disease of the central nervous system. In both MS and its animal model experimental autoimmune encephalomyelitis (EAE), it is thought that infiltrating CD4(+) T cells initiate an inflammatory process and collect other immune effectors to mediate tissue damage. The pathophysiology of the disease however remains unclear. Here we focus on the role of the complement system in the pathomechanism of EAE, employing mice with transiently depleted complement activity achieved by a single injection of cobra venom factor (CVF) 2 days before the induction of the disease. Our results show that in decomplemented C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55, the onset of the disease is significantly delayed. In SJL/J mice which develop a relapsing-remitting form of EAE after injection with proteolipid protein (PLP) peptide 139-151, the attenuation of both phases could be observed in CVF-treated animals. In C57BL/6 mice the level of MOG specific autoantibodies and their complement activating capacity evaluated on day 21 were found significantly reduced in animals transiently decomplemented before induction of the disease. The in vitro response of T cells isolated from the lymph nodes of MOG-immunized animals at the onset of EAE was also investigated. We found that the proliferative capacity of MOG-specific T lymphocytes derived from CVF treated animals is significantly reduced, in agreement with the histology of the spinal cords showing a decreased infiltration of CD4(+) T cells in these mice. Our data suggest, that lack of systemic complement at the time of induction of EAE delays the onset and attenuates the course of the disease most probably via diminishing the response of MOG-specific T cells and production of autoantibodies.

  4. Murine experimental autoimmune encephalomyelitis is diminished by treatment with the angiogenesis inhibitors B20-4.1.1 and angiostatin (K1-3.

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    Carolyn J MacMillan

    Full Text Available Angiogenesis is the formation of new blood vessels form pre-existing vasculature whose contribution to inflammatory conditions of the Central Nervous System is being studied in order to generate novel therapeutic targets. This study is the first to investigate the impact of two particular angiogenesis inhibitors on murine Experimental Autoimmune Encephalomyelitis (EAE, an inflammatory disease that mimics aspects of the human disease Multiple Sclerosis. The inhibitors were chosen to reduce angiogenesis by complimentary means. Extrinsic factors were targeted with B20-4.1.1 through its ability to bind to murine Vascular Endothelial Growth Factor (VEGF. Vascular processes connected to angiogenesis were targeted directly with K(1-3, the first three kringle domains of angiostatin. Mice treated with B20-4.1.1 and K(1-3 from onset of signs had reduced clinical scores 18-21 days after EAE induction. Both agents suppressed spinal cord angiogenesis without effect on local VEGF expression. B20-4.1.1 reduced spinal cord vascular permeability while K(1-3 had no effect. T cell infiltration into the spinal cord at day 21 was unaffected by either treatment. B20-4.1.1 reduced peripheral T cell proliferation while K(1-3 had no effect. Lymphoid cells from treated mice produced reduced levels of the T helper-17 (Th-17 cell cytokine interleukin (IL-17 with no effect on the Th-1 cytokine interferon (IFN-γ or Th-2 cytokine IL-4. However, when both drugs were added in vitro to naive T cells or to antigen stimulated T cells from mice with untreated EAE they had no effect on proliferation or levels of IL-17 or IFN-γ. We conclude that these angiogenesis inhibitors mitigate EAE by both suppressing spinal cord angiogenesis and reducing peripheral T cell activation.

  5. Intestinal barrier dysfunction develops at the onset of experimental autoimmune encephalomyelitis, and can be induced by adoptive transfer of auto-reactive T cells.

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    Mehrnaz Nouri

    Full Text Available Multiple sclerosis (MS is a chronic inflammatory demyelinating disease of the central nervous system with a pathogenesis involving a dysfunctional blood-brain barrier and myelin-specific, autoreactive T cells. Although the commensal microbiota seems to affect its pathogenesis, regulation of the interactions between luminal antigens and mucosal immune elements remains unclear. Herein, we investigated whether the intestinal mucosal barrier is also targeted in this disease. Experimental autoimmune encephalomyelitis (EAE, the prototypic animal model of MS, was induced either by active immunization or by adoptive transfer of autoreactive T cells isolated from these mice. We show increased intestinal permeability, overexpression of the tight junction protein zonulin and alterations in intestinal morphology (increased crypt depth and thickness of the submucosa and muscularis layers. These intestinal manifestations were seen at 7 days (i.e., preceding the onset of neurological symptoms and at 14 days (i.e., at the stage of paralysis after immunization. We also demonstrate an increased infiltration of proinflammatory Th1/Th17 cells and a reduced regulatory T cell number in the gut lamina propria, Peyer's patches and mesenteric lymph nodes. Adoptive transfer to healthy mice of encephalitogenic T cells, isolated from EAE-diseased animals, led to intestinal changes similar to those resulting from the immunization procedure. Our findings show that disruption of intestinal homeostasis is an early and immune-mediated event in EAE. We propose that this intestinal dysfunction may act to support disease progression, and thus represent a potential therapeutic target in MS. In particular, an increased understanding of the regulation of tight junctions at the blood-brain barrier and in the intestinal wall may be crucial for design of future innovative therapies.

  6. Loss of the receptor tyrosine kinase Axl leads to enhanced inflammation in the CNS and delayed removal of myelin debris during Experimental Autoimmune Encephalomyelitis

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    Prieto Anne L

    2011-05-01

    Full Text Available Abstract Background Axl, together with Tyro3 and Mer, constitute the TAM family of receptor tyrosine kinases. In the nervous system, Axl and its ligand Growth-arrest-specific protein 6 (Gas6 are expressed on multiple cell types. Axl functions in dampening the immune response, regulating cytokine secretion, clearing apoptotic cells and debris, and maintaining cell survival. Axl is upregulated in various disease states, such as in the cuprizone toxicity-induced model of demyelination and in multiple sclerosis (MS lesions, suggesting that it plays a role in disease pathogenesis. To test for this, we studied the susceptibility of Axl-/- mice to experimental autoimmune encephalomyelitis (EAE, an animal model for multiple sclerosis. Methods WT and Axl-/- mice were immunized with myelin oligodendrocyte glycoprotein (MOG35-55 peptide emulsified in complete Freund's adjuvant and injected with pertussis toxin on day 0 and day 2. Mice were monitored daily for clinical signs of disease and analyzed for pathology during the acute phase of disease. Immunological responses were monitored by flow cytometry, cytokine analysis and proliferation assays. Results Axl-/- mice had a significantly more severe acute phase of EAE than WT mice. Axl-/- mice had more spinal cord lesions with larger inflammatory cuffs, more demyelination, and more axonal damage than WT mice during EAE. Strikingly, lesions in Axl-/- mice had more intense Oil-Red-O staining indicative of inefficient clearance of myelin debris. Fewer activated microglia/macrophages (Iba1+ were found in and/or surrounding lesions in Axl-/- mice relative to WT mice. In contrast, no significant differences were noted in immune cell responses between naïve and sensitized animals. Conclusions These data show that Axl alleviates EAE disease progression and suggests that in EAE Axl functions in the recruitment of microglia/macrophages and in the clearance of debris following demyelination. In addition, these data

  7. The anti-IRBP IgG1 and IgG2a response does not correlate with susceptibility to experimental autoimmune uveitis

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    L. Vieira de Moraes

    2006-06-01

    Full Text Available Susceptibility to experimental autoimmune uveitis (EAU in inbred mice has been associated with a dominant Th1 response. Elevated anti-inter-photoreceptor retinoid-binding protein (anti-IRBP IgG2a/IgG1 antibody ratios have been implicated as candidate markers to predict disease severity. In the present study, both the anti-IRBP antibody isotype and severity of EAU phenotypes were examined in 4 non-isogenic genetically selected mouse lines to determine if they can be used as general markers of disease. Mice between 8 and 12 weeks old selected for high (H III or low (L III antibody response and for maximum (AIR MAX or minimum (AIR MIN acute inflammatory reaction (AIR were immunized with IRBP. Each experiment was performed with at least 5 mice per group. EAU was evaluated by histopathology 21 days after immunization and the minimal criterion was inflammatory cell infiltration of the ciliary body, choroid and retina. Serum IgG1- and IgG2a-specific antibodies were determined by ELISA. EAU was graded by histological examination of the enucleated eyes. The incidence of EAU was lower in AIR MIN mice whereas in the other strains approximately 40% of the animals developed the disease. Low responder animals did not produce anti-IRBP IgG2a antibodies or interferon-gamma. No correlation was observed between susceptibility to EAU and anti-IRBP isotype profiles. Susceptibility to EAU is related to the intrinsic capacity to mount higher inflammatory reactions and increased production of anti-IRBP IgG2a isotype is not necessarily a marker of this immunologic profile.

  8. A Cyclic Altered Peptide Analogue Based on Myelin Basic Protein 87–99 Provides Lasting Prophylactic and Therapeutic Protection Against Acute Experimental Autoimmune Encephalomyelitis

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    Mary Emmanouil

    2018-01-01

    Full Text Available In this report, amide-linked cyclic peptide analogues of the 87–99 myelin basic protein (MBP epitope, a candidate autoantigen in multiple sclerosis (MS, are tested for therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE. Cyclic altered peptide analogues of MBP87–99 with substitutions at positions 91 and/or 96 were tested for protective effects when administered using prophylactic or early therapeutic protocols in MBP72–85-induced EAE in Lewis rats. The Lys91 and Pro96 of MBP87–99 are crucial T-cell receptor (TCR anchors and participate in the formation of trimolecular complex between the TCR-antigen (peptide-MHC (major histocompability complex for the stimulation of encephalitogenic T cells that are necessary for EAE induction and are implicated in MS. The cyclic peptides were synthesized using Solid Phase Peptide Synthesis (SPPS applied on the 9-fluorenylmethyloxycarboxyl/tert-butyl Fmoc/tBu methodology and combined with the 2-chlorotrityl chloride resin (CLTR-Cl. Cyclo(91–99[Ala96]MBP87–99, cyclo(87–99[Ala91,96]MBP87–99 and cyclo(87–99[Arg91, Ala96]MBP87–99, but not wild-type linear MBP87–99, strongly inhibited MBP72–85-induced EAE in Lewis rats when administered using prophylactic and early therapeutic vaccination protocols. In particular, cyclo(87–99[Arg91, Ala96]MBP87–99 was highly effective in preventing the onset and development of clinical symptoms and spinal cord pathology and providing lasting protection against EAE induction.

  9. Modulation of Neurological Deficits and Expression of Glutamate Receptors during Experimental Autoimmune Encephalomyelitis after Treatment with Selected Antagonists of Glutamate Receptors

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    Grzegorz Sulkowski

    2013-01-01

    Full Text Available The aim of our investigation was to characterize the role of group I mGluRs and NMDA receptors in pathomechanisms of experimental autoimmune encephalomyelitis (EAE, the rodent model of MS. We tested the effects of LY 367385 (S-2-methyl-4-carboxyphenylglycine, a competitive antagonist of mGluR1, MPEP (2-methyl-6-(phenylethynyl-pyridine, an antagonist of mGluR5, and the uncompetitive NMDA receptor antagonists amantadine and memantine on modulation of neurological deficits observed in rats with EAE. The neurological symptoms of EAE started at 10-11 days post-injection (d.p.i. and peaked after 12-13 d.p.i. The protein levels of mGluRs and NMDA did not increase in early phases of EAE (4 d.p.i., but starting from 8 d.p.i. to 25 d.p.i., we observed a significant elevation of mGluR1 and mGluR5 protein expression by about 20% and NMDA protein expression by about 10% over the control at 25 d.p.i. The changes in protein levels were accompanied by changes in mRNA expression of group I mGluRs and NMDARs. During the late disease phase (20–25 d.p.i., the mRNA expression levels reached 300% of control values. In contrast, treatment with individual receptor antagonists resulted in a reduction of mRNA levels relative to untreated animals.

  10. ASP4058, a novel agonist for sphingosine 1-phosphate receptors 1 and 5, ameliorates rodent experimental autoimmune encephalomyelitis with a favorable safety profile.

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    Rie Yamamoto

    Full Text Available Sphingosine-1-phosphate (S1P is a biologically active sphingolipid that acts through the members of a family of five G protein-coupled receptors (S1P1-S1P5. S1P1 is a major regulator of lymphocyte trafficking, and fingolimod, whose active metabolite fingolimod phosphate acts as a nonselective S1P receptor agonist, exerts its immunomodulatory effect, at least in part, by regulating the lymphocyte trafficking by inducing down regulation of lymphocyte S1P1. Here, we detail the pharmacological profile of 5-{5-[3-(trifluoromethyl-4-{[(2S-1,1,1-trifluoropropan-2-yl]oxy}phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole (ASP4058, a novel next-generation S1P receptor agonist selective for S1P1 and S1P5. ASP4058 preferentially activates S1P1 and S1P5 compared with S1P2, 3, 4 in GTPγS binding assays in vitro. Oral administration of ASP4058 reduced the number of peripheral lymphocytes and inhibited the development of experimental autoimmune encephalomyelitis (EAE in Lewis rats. Further, ASP4058 prevented relapse of disease in a mouse model of relapsing-remitting EAE. Although these immunomodulatory effects were comparable to those of fingolimod, ASP4058 showed a wider safety margin than fingolimod for bradycardia and bronchoconstriction in rodents. These observations suggest that ASP4058 represents a new therapeutic option for treating multiple sclerosis that is safer than nonselective S1P receptor agonists such as fingolimod.

  11. Astrocyte matricellular proteins that control excitatory synaptogenesis are regulated by inflammatory cytokines and correlate with paralysis severity during experimental autoimmune encephalomyelitis

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    Pennelope K. Blakely

    2015-10-01

    Full Text Available The matricellular proteins, secreted protein acidic and rich in cysteine (SPARC and SPARC-like 1 (SPARCL1, are produced by astrocytes and control excitatory synaptogenesis in the central nervous system. While SPARCL1 directly promotes excitatory synapse formation in vitro and in the developing nervous system in vivo, SPARC specifically antagonizes the synaptogenic actions of SPARCL1. We hypothesized these proteins also help maintain existing excitatory synapses in adult hosts, and that local inflammation in the spinal cord alters their production in a way that dynamically modulates motor synapses and impacts the severity of paralysis during experimental autoimmune encephalomyelitis (EAE in mice. Using a spontaneously remitting EAE model, paralysis severity correlated inversely with both expression of synaptic proteins and the number of synapses in direct contact with the perikarya of motor neurons in spinal grey matter. In both remitting and non-remitting EAE models, paralysis severity also correlated inversely with sparcl1:sparc transcript and SPARCL1:SPARC protein ratios directly in lumbar spinal cord tissue. In vitro, astrocyte production of both SPARCL1 and SPARC was regulated by T cell-derived cytokines, causing dynamic modulation of the SPARCL1:SPARC expression ratio. Taken together, these data support a model whereby proinflammatory cytokines inhibit SPARCL1 and/or augment SPARC expression by astrocytes in spinal grey matter that, in turn, cause either transient or sustained synaptic retraction from lumbar spinal motor neurons thereby regulating hind limb paralysis during EAE. Ongoing studies seek ways to alter this SPARCL1:SPARC expression ratio in favor of synapse reformation/maintenance and thus help to modulate neurologic deficits during times of inflammation. This could identify new astrocyte-targeted therapies for diseases such as multiple sclerosis.

  12. The disease-ameliorating function of autoregulatory CD8 T cells is mediated by targeting of encephalitogenic CD4 T cells in experimental autoimmune encephalomyelitis.

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    Ortega, Sterling B; Kashi, Venkatesh P; Tyler, Andrew F; Cunnusamy, Khrishen; Mendoza, Jason P; Karandikar, Nitin J

    2013-07-01

    Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS, and CD8 T cells are the predominant T cell population in MS lesions. Given that transfer of CNS-specific CD8 T cells results in an attenuated clinical demyelinating disease in C57BL/6 mice with immunization-induced experimental autoimmune encephalomyelitis (EAE), we investigated the cellular targets and mechanisms of autoreactive regulatory CD8 T cells. In this study we report that myelin oligodendrocyte glycoprotein peptide (MOG35-55)-induced CD8 T cells could also attenuate adoptively transferred, CD4 T cell-mediated EAE. Whereas CD8(-/-) mice exhibited more severe EAE associated with increased autoreactivity and inflammatory cytokine production by myelin-specific CD4 T cells, this was reversed by adoptive transfer of MOG-specific CD8 T cells. These autoregulatory CD8 T cells required in vivo MHC class Ia (K(b)D(b)) presentation. Interestingly, MOG-specific CD8 T cells could also suppress adoptively induced disease using wild-type MOG35-55-specific CD4 T cells transferred into K(b)D(b-/-) recipient mice, suggesting direct targeting of encephalitogenic CD4 T cells. In vivo trafficking analysis revealed that autoregulatory CD8 T cells are dependent on neuroinflammation for CNS infiltration, and their suppression/cytotoxicity of MOG-specific CD4 T cells is observed both in the periphery and in the CNS. These studies provide important insights into the mechanism of disease suppression mediated by autoreactive CD8 T cells in EAE.

  13. In Vivo Quantification of Inflammation in Experimental Autoimmune Encephalomyelitis Rats Using Fluorine-19 Magnetic Resonance Imaging Reveals Immune Cell Recruitment outside the Nervous System.

    Directory of Open Access Journals (Sweden)

    Jia Zhong

    Full Text Available Progress in identifying new therapies for multiple sclerosis (MS can be accelerated by using imaging biomarkers of disease progression or abatement in model systems. In this study, we evaluate the ability to noninvasively image and quantitate disease pathology using emerging "hot-spot" 19F MRI methods in an experimental autoimmune encephalomyelitis (EAE rat, a model of MS. Rats with clinical symptoms of EAE were compared to control rats without EAE, as well as to EAE rats that received daily prophylactic treatments with cyclophosphamide. Perfluorocarbon (PFC nanoemulsion was injected intravenously, which labels predominately monocytes and macrophages in situ. Analysis of the spin-density weighted 19F MRI data enabled quantification of the apparent macrophage burden in the central nervous system and other tissues. The in vivo MRI results were confirmed by extremely high-resolution 19F/1H magnetic resonance microscopy in excised tissue samples and histopathologic analyses. Additionally, 19F nuclear magnetic resonance spectroscopy of intact tissue samples was used to assay the PFC biodistribution in EAE and control rats. In vivo hot-spot 19F signals were detected predominantly in the EAE spinal cord, consistent with the presence of inflammatory infiltrates. Surprising, prominent 19F hot-spots were observed in bone-marrow cavities adjacent to spinal cord lesions; these were not observed in control animals. Quantitative evaluation of cohorts receiving cyclophosphamide treatment displayed significant reduction in 19F signal within the spinal cord and bone marrow of EAE rats. Overall, 19F MRI can be used to quantitatively monitored EAE disease burden, discover unexpected sites of inflammatory activity, and may serve as a sensitive biomarker for the discovery and preclinical assessment of novel MS therapeutic interventions.

  14. The suppressive effect of IL-27 on encephalitogenic Th17 cells induced by multiwalled carbon nanotubes reduces the severity of experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Moraes, Adriel S; Paula, Rosemeire F O; Pradella, Fernando; Santos, Mariana P A; Oliveira, Elaine C; von Glehn, Felipe; Camilo, Daniela S; Ceragioli, Helder; Peterlevitz, Alfredo; Baranauskas, Vitor; Volpini, Walkyria; Farias, Alessandro S; Santos, Leonilda M B

    2013-09-01

    Both Th1 and Th17 cells specific for neuroantigen are described as encephalitogenic in the experimental autoimmune encephalomyelitis (EAE) model. The proposal of this study was to investigate how carbon nanotubes internalized by antigen-presenting cells (APCs) affect the development of encephalitogenic CD4(+) T cells. Therefore, we stimulated encephalitogenic T cells in the presence or not of multiwalled carbon nanotube (MWCNT). After the incubation, we analyzed the expression profile of the encephalitogenic T cells and their capacity to induce EAE. Encephalitogenic CD4(+) T cells cultured with APCs that were previously incubated with MWCNTs do not express IL-17. The adoptive transfer of these cells causes less severe EAE than the transfer of both Th1 and Th17 cells that are not incubated with MWCNTs. These results suggest that the increased IL-27 level produced by the APCs incubated with the carbon nanotubes inhibits the development of Th17 cells. This observation is confirmed by the concomitant reduction in the level of RORγt, which is a transcription factor essential for the development of Th17 cells. Moreover, the incubation of encephalitogenic T cells devoid of Th17 cells with neutralizing anti-IL-27 antibodies restored the production of IL-17. This finding confirms the suppressive effect of IL-27 on encephalitogenic Th17 cells. The results presented suggest that the stimulation of APCs with carbon nanoparticles prior to neuroantigen presentation affects the development of the Th17 subset of encephalitogenic CD4(+) T lymphocytes and results in less severe EAE. © 2013 John Wiley & Sons Ltd.

  15. The epigenetic drug Trichostatin A ameliorates experimental autoimmune encephalomyelitis via T cell tolerance induction and impaired influx of T cells into the spinal cord.

    Science.gov (United States)

    Jayaraman, Arathi; Soni, Advait; Prabhakar, Bellur S; Holterman, Mark; Jayaraman, Sundararajan

    2017-12-01

    Multiple sclerosis is a T cell mediated chronic demyelinating disease of the central nervous system. Although currently available therapies reduce relapses, they do not facilitate tolerization of myelin antigen-specific T lymphocytes to ensure prolonged protection against multiple sclerosis. Here, we show that treatment of NOD mice with the histone deacetylase inhibitor, Trichostatin A affords robust protection against myelin peptide induced experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Protection was accompanied by histone hyperacetylation, and reduced inflammation and axonal damage in the spinal cord. Drug treatment diminished the generation of CD4+ memory T cells and induced tolerance in CD4+ T cells recognizing the immunizing myelin peptide. During the early immunization period, CD4+ T cells producing GM-CSF+IFN-γ, GM-CSF+IL-17A, as well as those expressing both IL-17A+IFN-γ (double-producers) were detected in the secondary lymphoid organs followed by the appearance of cells producing IFN-γ and GM-CSF. On the other hand, IFN-γ producing Th1 cells appear first in the spinal cord followed by cells producing IL-17A and GM-CSF. Treatment with Trichostatin A substantially reduced the frequencies of all T cells secreting various lymphokines both in the periphery and in the spinal cord. These data indicate that epigenetic modifications induced by histone hyperacetylation facilitates T cell tolerance induction in the periphery leading to reduced migration of T cells to the spinal cord and mitigation of neuronal damage and improved clinical outcome. These results suggest that epigenetic modulation of the genome may similarly offer benefits to multiple sclerosis patients via abrogating the function of encephalitogenic T lymphocytes without exerting severe side effects associated with currently used disease-modifying therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Ctla-4 modulates the differentiation of inducible Foxp3+ Treg cells but IL-10 mediates their function in experimental autoimmune encephalomyelitis.

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    Johan Verhagen

    Full Text Available In vitro induced Foxp3+ T regulatory (iTreg cells form a novel and promising target for therapeutic tolerance induction. However, the potential of these cells as a target for the treatment of various immune diseases, as well as the factors involved in their development and function, remain debated. Here, we demonstrate in a myelin basic protein (MBP-specific murine model of CNS autoimmune disease that adoptive transfer of antigen-specific iTreg cells ameliorates disease progression. Moreover, we show that the co-stimulatory molecule CTLA-4 mediates in vitro differentiation of iTreg cells. Finally, we demonstrate that the secreted, immunosuppressive cytokine IL-10 controls the ability of antigen-specific iTreg cells to suppress autoimmune disease. Overall, we conclude that antigen-specific iTreg cells, which depend on various immune regulatory molecules for their differentiation and function, represent a major target for effective immunotherapy of autoimmune disease.

  17. Autoimmunity and Gastric Cancer

    Directory of Open Access Journals (Sweden)

    Nicola Bizzaro

    2018-01-01

    Full Text Available Alterations in the immune response of patients with autoimmune diseases may predispose to malignancies, and a link between chronic autoimmune gastritis and gastric cancer has been reported in many studies. Intestinal metaplasia with dysplasia of the gastric corpus-fundus mucosa and hyperplasia of chromaffin cells, which are typical features of late-stage autoimmune gastritis, are considered precursor lesions. Autoimmune gastritis has been associated with the development of two types of gastric neoplasms: intestinal type and type I gastric carcinoid. Here, we review the association of autoimmune gastritis with gastric cancer and other autoimmune features present in gastric neoplasms.

  18. American Autoimmune Related Diseases Association

    Science.gov (United States)

    ... Help Patients ARNet Research Survey AD Knowledge Base Autoimmune Disease List Common Thread Women & Autoimmunity Diagnosis Tips Coping ... Caregiver Relationship The Male Caregiver AD Knowledge Base Autoimmune Disease List Common Thread Women & Autoimmunity Diagnosis Tips Published ...

  19. IFN-gamma signaling in the central nervous system controls the course of experimental autoimmune encephalomyelitis independently of the localization and composition of inflammatory foci

    Directory of Open Access Journals (Sweden)

    Lee Eunyoung

    2012-01-01

    Full Text Available Abstract Background Murine experimental autoimmune encephalomyelitis (EAE, a model for multiple sclerosis, presents typically as ascending paralysis. However, in mice in which interferon-gamma (IFNγ signaling is disrupted by genetic deletion, limb paralysis is accompanied by atypical deficits, including head tilt, postural imbalance, and circling, consistent with cerebellar/vestibular dysfunction. This was previously attributed to intense cerebellar and brainstem infiltration by peripheral immune cells and formation of neutrophil-rich foci within the CNS. However, the exact mechanism by which IFNγ signaling prohibits the development of vestibular deficits, and whether the distribution and composition of inflammatory foci within the CNS affects the course of atypical EAE remains elusive. Methods We induced EAE in IFNγ-/- mice and bone marrow chimeric mice in which IFNγR is not expressed in the CNS but is intact in the periphery (IFNγRCNSKO and vice versa (IFNγRperiKO. Blood-brain barrier permeability was determined by Evans blue intravenous administration at disease onset. Populations of immune cell subsets in the periphery and the CNS were quantified by flow cytometry. CNS tissues isolated at various time points after EAE induction, were analyzed by immunohistochemistry for composition of inflammatory foci and patterns of axonal degeneration. Results Incidence and severity of atypical EAE were more pronounced in IFNγRCNSKO as compared to IFNγRperiKO mice. Contrary to what we anticipated, cerebella/brainstems of IFNγRCNSKO mice were only minimally infiltrated, while the same areas of IFNγRperiKO mice were extensively populated by peripheral immune cells. Furthermore, the CNS of IFNγRperiKO mice was characterized by persistent neutrophil-rich foci as compared to IFNγRCNSKO. Immunohistochemical analysis of the CNS of IFNγ-/- and IFNγR chimeric mice revealed that IFNγ protective actions are exerted through microglial STAT1

  20. The effect of omeprazole on the development of experimental autoimmune encephalomyelitis in C57BL/6J and SJL/J mice.

    Science.gov (United States)

    Sands, Scott A; Tsau, Sheila; Yankee, Thomas M; Parker, Brooks L; Ericsson, Aaron C; LeVine, Steven M

    2014-09-04

    Gastric disturbances such as dyspepsia are routinely encountered by multiple sclerosis (MS) patients, and these conditions are often treated with gastric acid suppressors such as proton pump inhibitors, histamine H2 receptor antagonists, or antacids. The proton pump inhibitor omeprazole can alter the gut flora and immune responses, both of which can influence the course of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The objective of the current study was to examine the effect of omeprazole treatment on the development of EAE. Bacterial microbiome analysis of mouse fecal pellets was determined in C57BL/6J EAE mice chronically treated with omeprazole, and spleen immune cell content, clinical scores, weight, rotarod latency, and histopathology were used as outcome measures in C57BL/6J and SJL/J mice with EAE. Omeprazole treatment resulted in decreases in Akkermansia muciniphila and Coprococcus sp. and an increase in unidentified bacteria in the family S24-7 (order Bacteroidales) in C57BL/6J mice with EAE. Omeprazole did not alter spleen immune cell content compared to vehicle in EAE mice, but differences independent of treatment were observed in subsets of T cells between early and advanced disease in C57BL/6J mice as well as between the two strains of mice at an advanced disease stage. Omeprazole caused no difference in clinical scores in either strain, but significantly lowered weight gain compared to vehicle in the C57BL/6J mice with EAE. Omeprazole also did not alter rotarod behavior or hindbrain inflammatory cell infiltration compared to vehicle in both strains of mice with EAE. Rotarod latency did reveal a negative correlation with clinical scores during active disease in both mouse strains, but not during clinical remission in SJL/J mice, suggesting that rotarod can detect disability not reflected in the clinical scores. Despite alterations in the gut microbiota and weight gain in the C57BL/6J EAE model, omeprazole had no effect on

  1. Mesenchymal stem cells (MSC) derived from mice with experimental autoimmune encephalomyelitis (EAE) suppress EAE and have similar biological properties with MSC from healthy donors.

    Science.gov (United States)

    Kassis, Ibrahim; Petrou, Panayiota; Halimi, Michelle; Karussis, Dimitrios

    2013-01-01

    Several animal studies and few pilot clinical trials have tested the therapeutic potential of mesenchymal stem cells (MSC) in experimental autoimmune encephalomyelitis (EAE) and in multiple sclerosis (MS). In almost all of the preclinical studies, healthy animals (or humans) served as donors of the MSCs. This setting does not accurately simulate the clinical situation of autologous transplantation in patients with MS. In the current research we used MSC isolated from mice with EAE in order to mimic human autologous transplantation and to test if the inflammatory process affects the functional properties of MSC. MSC(EAE) were found to retain their mesodermal features (as evidenced by the expression of surface cell markers and their ability to differentiate toward cells of the mesodermal lineage). Moreover, MSC(EAE) were able to support neurite outgrowth in the N2A cell line and to suppress the proliferation of lymphocytes induced by the mitogen phytohaemagglutinin (PHA). Intravenous administration of MSC(EAE) suppressed the clinical course of EAE (0% mortality, disease score 1.09±0.22 vs. 40% mortality and 2.95±0.31 EAE score in saline-treated controls), paralleled by a strong reduction of CNS inflammation and demyelination (9.7±2.79 perivascular cuffs in the treated mice, as compared to 25.8±7.4 in the controls; demyelination area: 1.73±0.3 in MSC(EAE)-treated animals vs. 3.8±0.26 in the controls) and by a significant protection of the axons (axonal density: 1.26±0.24 in the MSC(EAE)-treated animals vs. 3.06±0.38 in the control group). All these beneficial effects were indistinguishable from the effects induced by MSC obtained from healthy syngeneic donors. These data demonstrate that the inflammatory process in EAE does not exert any deleterious effect on the functional/biological properties of the MSC and provide additional support for the use of autologous MSC that are obtained from MS-patients, in future clinical applications. Copyright © 2013 Elsevier

  2. Evaluation of a radiolabelled peripheral benzodiazepine receptor ligand in the central nervous system inflammation of experimental autoimmune encephalomyelitis: a possible probe for imaging multiple sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Mattner, F.; Katsifis, A.; Ballantyne, P. [ANSTO, Radiopharmaceuticals Division, Lucas Heights (Australia); Staykova, M.; Willenborg, D.O. [Australian National University Medical School, The Canberra Hospital, Neurosciences Research Unit, Woden, Canberra (Australia)

    2005-04-01

    Peripheral benzodiazepine receptors (PBRs) are upregulated on macrophages and activated microglia, and radioligands for the PBRs can be used to detect in vivo neuroinflammatory changes in a variety of neurological insults, including multiple sclerosis. Substituted 2-phenyl imidazopyridine-3-acetamides with high affinity and selectivity for PBRs have been prepared that are suitable for radiolabelling with a number of positron emission tomography and single-photon emission computed tomography (SPECT) isotopes. In this investigation, the newly developed high-affinity PBR ligand 6-chloro-2-(4'-iodophenyl)-3-(N,N-diethyl)imidazo[1,2-a]pyridine-3-acetamide, or CLINDE, was radiolabelled with{sup 123}I and its biodistribution in the central nervous system (CNS) of rats with experimental autoimmune encephalomyelitis (EAE) evaluated. EAE was induced in male Lewis rats by injection of an emulsion of myelin basic protein and incomplete Freund's adjuvant containing Mycobacterium butyricum. Biodistribution studies with{sup 123}I-CLINDE were undertaken on EAE rats exhibiting different clinical disease severity and compared with results in controls. Disease severity was confirmed by histopathology in the spinal cord of rats. The relationship between inflammatory lesions and PBR ligand binding was investigated using ex vivo autoradiography and immunohistochemistry on rats with various clinical scores. {sup 123}I-CLINDE uptake was enhanced in the CNS of all rats exhibiting EAE when compared to controls. Binding reflected the ascending nature of EAE inflammation, with lumbar/sacral cord > thoracic cord > cervical cord > medulla. The amount of ligand binding also reflected the clinical severity of disease. Ex vivo autoradiography and immunohistochemistry revealed a good spatial correspondence between radioligand signal and foci of inflammation and in particular ED-1{sup +} cells representing macrophages and microglia. These results demonstrate the ability of {sup 123}I

  3. Autoimmunity and Gastric Cancer

    OpenAIRE

    Nicola Bizzaro; Antonio Antico; Danilo Villalta

    2018-01-01

    Alterations in the immune response of patients with autoimmune diseases may predispose to malignancies, and a link between chronic autoimmune gastritis and gastric cancer has been reported in many studies. Intestinal metaplasia with dysplasia of the gastric corpus-fundus mucosa and hyperplasia of chromaffin cells, which are typical features of late-stage autoimmune gastritis, are considered precursor lesions. Autoimmune gastritis has been associated with the development of two types of gastri...

  4. Autoimmune Thyroid Disorders

    OpenAIRE

    B. N. Macharia; Iddah, M. A.

    2013-01-01

    Purpose of Review. Studies have been published in the field of autoimmune thyroid diseases since January 2005. The review is organized into areas of etiology, autoimmune features, autoantibodies, mechanism of thyroid cell injury, B-cell responses, and T-cell responses. Also it reviews the diagnosis and the relationship between autoimmune thyroid disease, neoplasm, and kidney disorders. Recent Findings. Autoimmune thyroid diseases have been reported in people living in different parts of the w...

  5. Vitiligo and Autoimmune Thyroid Disorders

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    Enke Baldini

    2017-10-01

    Full Text Available Vitiligo represents the most common cause of acquired skin, hair, and oral depigmentation, affecting 0.5–1% of the population worldwide. It is clinically characterized by the appearance of disfiguring circumscribed skin macules following melanocyte destruction by autoreactive cytotoxic T lymphocytes. Patients affected by vitiligo usually show a poorer quality of life and are more likely to suffer from depressive symptoms, particularly evident in dark-skinned individuals. Although vitiligo is a non-fatal disease, exposure of affected skin to UV light increases the chance of skin irritation and predisposes to skin cancer. In addition, vitiligo has been associated with other rare systemic disorders due to the presence of melanocytes in other body districts, such as in eyes, auditory, nervous, and cardiac tissues, where melanocytes are thought to have roles different from that played in the skin. Several pathogenetic models have been proposed to explain vitiligo onset and progression, but clinical and experimental findings point mainly to the autoimmune hypothesis as the most qualified one. In this context, it is of relevance the strong association of vitiligo with other autoimmune diseases, in particular with autoimmune thyroid disorders, such as Hashimoto thyroiditis and Graves’ disease. In this review, after a brief overview of vitiligo and its pathogenesis, we will describe the clinical association between vitiligo and autoimmune thyroid disorders and discuss the possible underlying molecular mechanism(s.

  6. Polyglandular autoimmune syndromes.

    Science.gov (United States)

    Kahaly, G J; Frommer, L

    2018-01-01

    In recent years, scientific knowledge pertaining to the rare ORPHAN polyglandular autoimmune syndrome (registered code ORPHA 282196) has accumulated. To offer current demographic, clinical, serological and immunogenic data on PAS. Review of the pertinent and current literature. Polyglandular autoimmune syndromes (PAS) are multifactorial diseases with at least two coexisting autoimmune-mediated endocrinopathies. PAS show a great heterogeneity of syndromes and manifest sequentially with a large time interval between the occurrence of the first and second glandular autoimmune disease. PAS cluster with several non-endocrine autoimmune diseases. In most endocrinopathies of PAS, the autoimmune process causes an irreversible loss of function, while chronic autoimmune aggressions can simultaneously modify physiological processes in the affected tissue and lead to altered organ function. The rare juvenile PAS type I is inherited in a monogenetic manner, whereas several susceptibility gene polymorphisms have been reported for the more prevalent adult types. Relevant for a timely diagnosis at an early stage is the screening for polyglandular autoimmunity in patients with monoglandular autoimmune disease and/or first degree relatives of patients with PAS. The most prevalent adult PAS type is the combination of type 1 diabetes with autoimmune thyroid disease. Early detection of specific autoantibodies and latent organ-specific dysfunction is advocated to alert physicians to take appropriate action in order to prevent full-blown PAS disease.

  7. Sirolimus for Autoimmune Disease of Blood Cells

    Science.gov (United States)

    2017-03-16

    Autoimmune Pancytopenia; Autoimmune Lymphoproliferative Syndrome (ALPS); Evans Syndrome; Idiopathic Thrombocytopenic Purpura; Anemia, Hemolytic, Autoimmune; Autoimmune Neutropenia; Lupus Erythematosus, Systemic; Inflammatory Bowel Disease; Rheumatoid Arthritis

  8. Longitudinal Intravital Imaging of the Retina Reveals Long-term Dynamics of Immune Infiltration and Its Effects on the Glial Network in Experimental Autoimmune Uveoretinitis, without Evident Signs of Neuronal Dysfunction in the Ganglion Cell Layer

    Science.gov (United States)

    Bremer, Daniel; Pache, Florence; Günther, Robert; Hornow, Jürgen; Andresen, Volker; Leben, Ruth; Mothes, Ronja; Zimmermann, Hanna; Brandt, Alexander U.; Paul, Friedemann; Hauser, Anja E.; Radbruch, Helena; Niesner, Raluca

    2016-01-01

    A hallmark of autoimmune retinal inflammation is the infiltration of the retina with cells of the innate and adaptive immune system, leading to detachment of the retinal layers and even to complete loss of the retinal photoreceptor layer. As the only optical system in the organism, the eye enables non-invasive longitudinal imaging studies of these local autoimmune processes and of their effects on the target tissue. Moreover, as a window to the central nervous system (CNS), the eye also reflects general neuroinflammatory processes taking place at various sites within the CNS. Histological studies in murine neuroinflammatory models, such as experimental autoimmune uveoretinitis (EAU) and experimental autoimmune encephalomyelitis, indicate that immune infiltration is initialized by effector CD4+ T cells, with the innate compartment (neutrophils, macrophages, and monocytes) contributing crucially to tissue degeneration that occurs at later phases of the disease. However, how the immune attack is orchestrated by various immune cell subsets in the retina and how the latter interact with the target tissue under in vivo conditions is still poorly understood. Our study addresses this gap with a novel approach for intravital two-photon microscopy, which enabled us to repeatedly track CD4+ T cells and LysM phagocytes during the entire course of EAU and to identify a specific radial infiltration pattern of these cells within the inflamed retina, starting from the optic nerve head. In contrast, highly motile CX3CR1+ cells display an opposite radial motility pattern, toward the optic nerve head. These inflammatory processes induce modifications of the microglial network toward an activated morphology, especially around the optic nerve head and main retinal blood vessels, but do not affect the neurons within the ganglion cell layer. Thanks to the new technology, non-invasive correlation of clinical scores of CNS-related pathologies with immune infiltrate behavior and subsequent

  9. Metals and kidney autoimmunity.

    OpenAIRE

    Bigazzi, P. E.

    1999-01-01

    The causes of autoimmune responses leading to human kidney pathology remain unknown. However, environmental agents such as microorganisms and/or xenobiotics are good candidates for that role. Metals, either present in the environment or administered for therapeutic reasons, are prototypical xenobiotics that cause decreases or enhancements of immune responses. In particular, exposure to gold and mercury may result in autoimmune responses to various self-antigens as well as autoimmune disease o...

  10. Autoimmune liver diseases

    OpenAIRE

    Invernizzi, Pietro; Mackay, Ian R

    2008-01-01

    The liver was one of the earliest recognized sites among autoimmune diseases yet autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and their overlap forms, are still problematic in diagnosis and causation. The contributions herein comprise 'pairs of articles' on clinical characteristics, and concepts of etiopathogenesis, for each of the above diseases, together with childhood autoimmune liver disease, overlaps, interpretations of diagnostic serology, and liver t...

  11. Autoimmune pancreatitis: a review.

    Science.gov (United States)

    Zandieh, Iman; Byrne, Michael-F

    2007-12-21

    Autoimmune pancreatitis has emerged over the last 40 years from a proposed concept to a well established and recognized entity. As an efficient mimicker of pancreatic carcinoma, its early and appropriate recognition are crucial. With mounting understanding of its pathogenesis and natural history, significant advances have been made in the diagnosis of autoimmune pancreatitis. The characteristic laboratory features and imaging seen in autoimmune pancreatitis are reviewed along with some of the proposed diagnostic criteria and treatment algorithms.

  12. Autoimmune pancreatitis: A review

    OpenAIRE

    Zandieh, Iman; Michael F Byrne

    2007-01-01

    Autoimmune pancreatitis has emerged over the last 40 years from a proposed concept to a well established and recognized entity. As an efficient mimicker of pancreatic carcinoma, its early and appropriate recognition are crucial. With mounting understanding of its pathogenesis and natural history, significant advances have been made in the diagnosis of autoimmune pancreatitis. The characteristic laboratory features and imaging seen in autoimmune pancreatitis are reviewed along with some of the...

  13. [Thymoma and autoimmune diseases].

    Science.gov (United States)

    Jamilloux, Y; Frih, H; Bernard, C; Broussolle, C; Petiot, P; Girard, N; Sève, P

    2017-03-29

    The association between thymoma and autoimmunity is well known. Besides myasthenia gravis, which is found in 15 to 20% of patients with thymoma, other autoimmune diseases have been reported: erythroblastopenia, systemic lupus erythematosus, inflammatory myopathies, thyroid disorders, Isaac's syndrome or Good's syndrome. More anecdotally, Morvan's syndrome, limbic encephalitis, other autoimmune cytopenias, autoimmune hepatitis, and bullous skin diseases (pemphigus, lichen) have been reported. Autoimmune diseases occur most often before thymectomy, but they can be discovered at the time of surgery or later. Two situations require the systematic investigation of a thymoma: the occurrence of myasthenia gravis or autoimmune erythroblastopenia. Nevertheless, the late onset of systemic lupus erythematosus or the association of several autoimmune manifestations should lead to look for a thymoma. Neither the characteristics of the patients nor the pathological data can predict the occurrence of an autoimmune disease after thymectomy. Thus, thymectomy usefulness in the course of the autoimmune disease, except myasthenia gravis, has not been demonstrated. This seems to indicate the preponderant role of self-reactive T lymphocytes distributed in the peripheral immune system prior to surgery. Given the high infectious morbidity in patients with thymoma, immunoglobulin replacement therapy should be considered in patients with hypogammaglobulinemia who receive immunosuppressive therapy, even in the absence of prior infection. Copyright © 2017 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  14. Helicobacter pylori and autoimmune disease: Cause or bystander

    Science.gov (United States)

    Smyk, Daniel S; Koutsoumpas, Andreas L; Mytilinaiou, Maria G; Rigopoulou, Eirini I; Sakkas, Lazaros I; Bogdanos, Dimitrios P

    2014-01-01

    Helicobacter pylori (H. pylori) is the main cause of chronic gastritis and a major risk factor for gastric cancer. This pathogen has also been considered a potential trigger of gastric autoimmunity, and in particular of autoimmune gastritis. However, a considerable number of reports have attempted to link H. pylori infection with the development of extra-gastrointestinal autoimmune disorders, affecting organs not immediately relevant to the stomach. This review discusses the current evidence in support or against the role of H. pylori as a potential trigger of autoimmune rheumatic and skin diseases, as well as organ specific autoimmune diseases. We discuss epidemiological, serological, immunological and experimental evidence associating this pathogen with autoimmune diseases. Although over one hundred autoimmune diseases have been investigated in relation to H. pylori, we discuss a select number of papers with a larger literature base, and include Sjögrens syndrome, rheumatoid arthritis, systemic lupus erythematosus, vasculitides, autoimmune skin conditions, idiopathic thrombocytopenic purpura, autoimmune thyroid disease, multiple sclerosis, neuromyelitis optica and autoimmune liver diseases. Specific mention is given to those studies reporting an association of anti-H. pylori antibodies with the presence of autoimmune disease-specific clinical parameters, as well as those failing to find such associations. We also provide helpful hints for future research. PMID:24574735

  15. Autoimmune liver disease, autoimmunity and liver transplantation.

    Science.gov (United States)

    Carbone, Marco; Neuberger, James M

    2014-01-01

    Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) represent the three major autoimmune liver diseases (AILD). PBC, PSC, and AIH are all complex disorders in that they result from the effects of multiple genes in combination with as yet unidentified environmental factors. Recent genome-wide association studies have identified numerous risk loci for PBC and PSC that host genes involved in innate or acquired immune responses. These loci may provide a clue as to the immune-based pathogenesis of AILD. Moreover, many significant risk loci for PBC and PSC are also risk loci for other autoimmune disorders, such type I diabetes, multiple sclerosis and rheumatoid arthritis, suggesting a shared genetic basis and possibly similar molecular pathways for diverse autoimmune conditions. There is no curative treatment for all three disorders, and a significant number of patients eventually progress to end-stage liver disease requiring liver transplantation (LT). LT in this context has a favourable overall outcome with current patient and graft survival exceeding 80% at 5years. Indications are as for other chronic liver disease although recent data suggest that while lethargy improves after transplantation, the effect is modest and variable so lethargy alone is not an indication. In contrast, pruritus rapidly responds. Cholangiocarcinoma, except under rigorous selection criteria, excludes LT because of the high risk of recurrence. All three conditions may recur after transplantation and are associated with a greater risk of both acute cellular and chronic ductopenic rejection. It is possible that a crosstalk between alloimmune and autoimmune response perpetuate each other. An immunological response toward self- or allo-antigens is well recognised after LT in patients transplanted for non-autoimmune indications and sometimes termed "de novo autoimmune hepatitis". Whether this is part of the spectrum of rejection or an autoimmune

  16. A Functional and Neuropathological Testing Paradigm Reveals New Disability-Based Parameters and Histological Features for P0180-190-Induced Experimental Autoimmune Neuritis in C57BL/6 Mice.

    Science.gov (United States)

    Gonsalvez, David G; De Silva, Mithraka; Wood, Rhiannon J; Giuffrida, Lauren; Kilpatrick, Trevor J; Murray, Simon S; Xiao, Junhua

    2017-02-01

    We assessed novel disability-based parameters and neuropathological features of the P0180-190 peptide-induced model of experimental autoimmune neuritis (EAN) in C57BL/6 mice. We show that functional assessments such as running capacity provide a more sensitive method for detecting alterations in disease severity than a classical clinical scoring paradigm. We performed detailed ultrastructural analysis and show for the first time that tomaculous neuropathy is a neuropathological feature of this disease model. In addition, we demonstrate that ultrastructural assessments of myelin pathology are sufficiently sensitive to detect significant differences in both mean G-ratio and mean axon diameter between mice with EAN induced with different doses of pertussis toxin. In summary, we have established a comprehensive assessment paradigm for discriminating variations in disease severity and the extent of myelin pathology in this model. Our findings indicate that this model is a powerful tool to study the pathogenesis of human peripheral demyelinating neuropathies and that this assessment paradigm could be used to determine the efficacy of potential therapies that aim to promote myelin repair and protect against nerve damage in autoimmune neuritides. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

  17. THE AUTOIMMUNE ECOLOGY.

    Directory of Open Access Journals (Sweden)

    Juan-Manuel eAnaya

    2016-04-01

    Full Text Available Autoimmune diseases (ADs represent a heterogeneous group of disorders that affect specific target organs or multiple organ systems. These conditions share common immunopathogenic mechanisms (i.e., the autoimmune tautology, which explain the clinical similarities they have among them as well as their familial clustering (i.e., coaggregation. As part of the autoimmune tautology, the influence of environmental exposure on the risk of developing ADs is paramount (i.e., the autoimmune ecology. In fact, environment, more than genetics, shapes immune system. Autoimmune ecology is akin to exposome, that is all the exposures - internal and external - across the lifespan, interacting with hereditary factors (both genetics and epigenetics to favor or protect against autoimmunity and its outcomes. Herein we provide an overview of the autoimmune ecology, focusing on the immune response to environmental agents in general, and microbiota, cigarette smoking, alcohol and coffee consumption, socioeconomic status, gender and sex hormones, vitamin D, organic solvents and vaccines in particular. Inclusion of the autoimmune ecology in disease etiology and health will improve the way personalized medicine is currently conceived and applied.

  18. Bistability in autoimmune diseases

    DEFF Research Database (Denmark)

    Rapin, Nicolas; Mosekilde, Erik; Lund, Ole

    2011-01-01

    Autoimmune diseases damage host tissue, which, in turn, may trigger a stronger immune response. Systems characterized by such positive feedback loops can display co-existing stable steady states. In a mathematical model of autoimmune disease, one steady state may correspond to the healthy state...

  19. Cancer and autoimmune diseases.

    Science.gov (United States)

    Giat, Eitan; Ehrenfeld, Michael; Shoenfeld, Yehuda

    2017-10-01

    The association between autoimmunity and cancer is well established. Cancer has been implicated in some autoimmune disorders (AID), such as scleroderma and myositis. On the other hand, many autoimmune disorders and immunosuppressive therapy, have been linked to an increased risk for cancer. We reviewed the accumulating data on the association between autoimmunity and cancer during the past three years, with an emphasis on large cohorts, as well as concept changing discoveries in the association of cancer and auto-immunity. Recent published data from large registries and databases have changed our perspective on the association of AID and cancer, as well as the presumed association between anti-tumor necrosis factor (anti -TNF) therapy and certain malignancies, suggesting a small to no increase in almost all types of cancers. Similarly, the increased risk of malignancies in some AID, such as Sjogren's syndrome (SS) and lupus, may be different from previous estimations. New associations with malignancies were discovered, such as IgG4 related disease, Behcet's and sarcoidosis, which were not clearly associated with cancer in the past. These newly described associations may have clinical implications and contribute to our understanding of both autoimmunity and cancer. Similarly, we reviewed studies of autoimmunity secondary to malignancy, and the concomitant appearance of cancer with autoimmune disease, such as the discovery of a specific mutation in scleroderma (SS) patients that developed cancer, which establishes the association between these disorders and sheds light on the pathology behind this association. Copyright © 2017. Published by Elsevier B.V.

  20. Direct angiotensin AT2-receptor stimulation attenuates T-cell and microglia activation and prevents demyelination in experimental autoimmune encephalomyelitis in mice

    DEFF Research Database (Denmark)

    Valero-Esquitino, Verónica; Lucht, Kristin; Namsolleck, Pawel

    2015-01-01

    , accelerated re-myelination and reduced the number of microglia. Cytokine synthesis and NO production by microglia in vitro were significantly reduced after C21 treatment. These results suggest that AT2R-stimulation protects the myelin sheaths in autoimmune CNS inflammation by inhibiting the T-cell response...... immunised with myelin-oligodendrocyte-peptide (MOG) and treated for 4 weeks with C21 (0.3mg/kg/day i.p.). Potential effects on myelination, microglia and T-cell composition were estimated by immunostaining and FACS analyses of lumbar spinal cords. The in vivo study was complemented by experiments...... in aggregating brain cell cultures and microglia in vitro. In the EAE model, treatment with C21 ameliorated microglia activation and decreased the number of total T-cells and CD4+ T-cells in the spinal cord. Fluorescent myelin staining of spinal cords further revealed a significant reduction of EAE...

  1. Cytokine production in the central nervous system of Lewis rats with experimental autoimmune encephalomyelitis: dynamics of mRNA expression for interleukin-10, interleukin-12, cytolysin, tumor necrosis factor alpha and tumor necrosis factor beta

    DEFF Research Database (Denmark)

    Issazadeh-Navikas, Shohreh; Ljungdahl, A; Höjeberg, B

    1995-01-01

    The kinetics of mRNA expression in the central nervous system (CNS) for a series of putatively disease-promoting and disease-limiting cytokines during the course of experimental autoimmune encephalomyelitis (EAE) in Lewis rats were studied. Cytokine mRNA-expressing cells were detected...... proliferation and activation of T helper 1 (Th1) type cells producing IFN-gamma. The TNF-beta mRNA expression prior to onset of clinical signs favours a role for this cytokine in disease initiation. A pathogenic effector role of TNF-alpha was suggested from these observations that TNF-alpha mRNA expression...... of putative disease-promoting and -limiting cytokines in the CNS during acute monophasic EAE....

  2. The role of neutrophils in autoimmune diseases.

    Science.gov (United States)

    Németh, Tamás; Mócsai, Attila

    2012-03-30

    Though chronic autoimmune disorders such as rheumatoid arthritis or systemic lupus erythematosus affect a significant percentage of the human population and strongly diminish the quality of life and life expectancy in Western societies, the molecular pathomechanisms of those diseases are still poorly understood, hindering the development of novel treatment strategies. Autoimmune diseases are thought to be caused by disturbed recognition of foreign and self antigens, leading to the emergence of autoreactive T-cells (so-called immunization phase). Those autoreactive T-cells then trigger the second (so-called effector) phase of the disease which is characterized by immune-mediated damage to host tissues. For a long time, neutrophils have mainly been neglected as potential players of the development of autoimmune diseases. However, a significant amount of new experimental data now indicates that neutrophils likely play an important role in both the immunization and the effector phase of autoimmune diseases. Here we review the current literature on the role of neutrophils in autoimmune diseases with special emphasis on rheumatoid arthritis, systemic lupus erythematosus, autoimmune vasculitides and blistering skin diseases. We also discuss the role of neutrophil cell surface receptors (e.g. integrins, Fc-receptors or chemokine receptors) and intracellular signal transduction pathways (e.g. Syk and other tyrosine kinases) in the pathogenesis of autoimmune inflammation. Though many of the results discussed in this review were obtained using animal models, additional data indicate that those mechanisms likely also contribute to human pathology. Taken together, neutrophils should be considered as one of the important cell types in autoimmune disease pathogenesis and they may also prove to be suitable targets of the pharmacological control of those diseases in the future. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. Leptin and autoimmune disease.

    Science.gov (United States)

    Fujita, Yoshimasa

    2017-01-01

    Leptin is secreted from adipocytes and acts mainly on the hypothalamus causing weight loss due to suppression of appetite and increased energy expenditure. On the other hand, the leptin receptor is also expressed in hematopoietic cells and its action on the immune system has become known, and the significance of leptin in autoimmune diseases has gradually become clear. It has been shown that leptin acts as an exacerbating factor in many autoimmune diseases and it is suggested that inhibition of leptin signal may be a novel therapeutic method for autoimmune diseases. In this article, we will outline the significance of leptin in the immune system based on the current reports.

  4. Allogeneic Adipose-Derived Mesenchymal Stromal Cells Ameliorate Experimental Autoimmune Encephalomyelitis by Regulating Self-Reactive T Cell Responses and Dendritic Cell Function

    Directory of Open Access Journals (Sweden)

    Per Anderson

    2017-01-01

    Full Text Available Multipotent mesenchymal stromal cells (MSCs have emerged as a promising therapy for autoimmune diseases, including multiple sclerosis (MS. Administration of MSCs to MS patients has proven safe with signs of immunomodulation but their therapeutic efficacy remains low. The aim of the current study has been to further characterize the immunomodulatory mechanisms of adipose tissue-derived MSCs (ASCs in vitro and in vivo using the EAE model of chronic brain inflammation in mice. We found that murine ASCs (mASCs suppress T cell proliferation in vitro via inducible nitric oxide synthase (iNOS and cyclooxygenase- (COX- 1/2 activities. mASCs also prevented the lipopolysaccharide- (LPS- induced maturation of dendritic cells (DCs in vitro. The addition of the COX-1/2 inhibitor indomethacin, but not the iNOS inhibitor L-NAME, reversed the block in DC maturation implicating prostaglandin (PG E2 in this process. In vivo, early administration of murine and human ASCs (hASCs ameliorated myelin oligodendrocyte protein- (MOG35-55- induced EAE in C57Bl/6 mice. Mechanistic studies showed that mASCs suppressed the function of autoantigen-specific T cells and also decreased the frequency of activated (CD11c+CD40high and CD11c+TNF-α+ DCs in draining lymph nodes (DLNs. In summary, these data suggest that mASCs reduce EAE severity, in part, through the impairment of DC and T cell function.

  5. Autoimmune rheumatic disease and sleep: a review.

    Science.gov (United States)

    Sangle, Shirish R; Tench, Colin M; D'Cruz, David P

    2015-11-01

    Sleep has an important role to play in the human immune system and it is critical in the restoration and maintenance of homeostasis. Sleep deprivation and disorders may have a profound impact on health, well being and the ability to resist infection. Autoimmune rheumatic diseases are multisystem disorders that involve complicated hormonal and immunological pathophysiology. Previous studies have suggested that sleep deprivation may lead to immunological disturbance in experimental mouse models. Sleep disorders may trigger immune system abnormalities inducing autoantibody production, possibly leading to the development of autoimmune disease such as systemic lupus erythematosus, scleroderma or rheumatoid arthritis. Indeed, in experimental models, it has been suggested that sleep deprivation may induce the onset of autoimmune disease. Chronic deprivation of sleep is common in modern society and has been seen in various autoimmune inflammatory rheumatic diseases. We have reviewed various aspects of sleep deprivation and sleep apnoea syndrome, and their effects on the immune system and their relevance to autoimmune diseases. We hope that these data will encourage greater awareness of the role that improved sleep hygiene may play in the management of these rheumatic diseases.

  6. Silica, Silicosis and Autoimmunity.

    Directory of Open Access Journals (Sweden)

    Kenneth Michael Pollard

    2016-03-01

    Full Text Available Inhalation of dust containing crystalline silica is associated with a number of acute and chronic diseases including systemic autoimmune diseases. Evidence for the link with autoimmune disease comes from epidemiological studies linking occupational exposure to crystalline silica dust with the systemic autoimmune diseases SLE, SSc and RA. Although little is known regarding the mechanism by which silica exposure leads to systemic autoimmune disease, there is a voluminous literature on silica exposure and silicosis that may help identify immune processes that precede development of autoimmunity. The pathophysiology of silicosis consists of deposition of silica particles in the alveoli of the lung. Ingestion of these particles by macrophages initiates an inflammatory response which stimulates fibroblasts to proliferate and produce collagen. Silica particles are encased by collagen leading to fibrosis and the nodular lesions characteristic of the disease. The steps in the development of silicosis, including acute and chronic inflammation and fibrosis, have different molecular and cellular requirements suggesting that silica-induced inflammation and fibrosis may be mechanistically separate. Significantly, it is unclear whether silica-induced inflammation and fibrosis contribute similarly to the development of autoimmunity. Nonetheless, the findings from human and animal model studies are consistent with an autoimmune pathogenesis that begins with activation of the innate immune system leading to proinflammatory cytokine production, pulmonary inflammation leading to activation of adaptive immunity, breaking of tolerance, autoantibodies and tissue damage. The variable frequency of these immunological features following silica exposure suggests substantial genetic involvement and gene/environment interaction in silica-induced autoimmunity. However numerous questions remain unanswered.

  7. Interleukin-17 (IL-17)-induced MicroRNA 873 (miR-873) Contributes to the Pathogenesis of Experimental Autoimmune Encephalomyelitis by Targeting A20 Ubiquitin-editing Enzyme*

    Science.gov (United States)

    Liu, Xiaomei; He, Fengxia; Pang, Rongrong; Zhao, Dan; Qiu, Wen; Shan, Kai; Zhang, Jing; Lu, Yanlai; Li, Yan; Wang, Yingwei

    2014-01-01

    Interleukin 17 (IL-17), produced mainly by T helper 17 (Th17) cells, is increasingly recognized as a key regulator in various autoimmune diseases, including human multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Although several microRNAs (miRNAs) with aberrant expression have been shown to contribute to the pathogenesis of MS and EAE, the mechanisms underlying the regulation of abnormal miRNA expression in astrocytes upon IL-17 stimulation remain unclear. In the present study, we detected the changes of miRNA expression profiles both in the brain tissue of EAE mice and in cultured mouse primary astrocytes stimulated with IL-17 and identified miR-873 as one of the co-up-regulated miRNAs in vivo and in vitro. The overexpression of miR-873, demonstrated by targeting A20 (TNFα-induced protein 3, TNFAIP3), remarkably reduced the A20 level and promoted NF-κB activation in vivo and in vitro as well as increasing the production of inflammatory cytokines and chemokines (i.e. IL-6, TNF-α, MIP-2, and MCP-1/5). More importantly, silencing the endogenous miR-873 or A20 gene with lentiviral vector of miR-873 sponge (LV-miR-873 sponge) or short hairpin RNA (shRNA) of A20 (LV-A20 shRNA) in vivo significantly lessened or aggravated inflammation and demyelination in the central nervous system (CNS) of EAE mice, respectively. Taken together, these findings indicate that miR-873 induced by IL-17 stimulation promotes the production of inflammatory cytokines and aggravates the pathological process of EAE mice through the A20/NF-κB pathway, which provides a new insight into the mechanism of inflammatory damage in MS. PMID:25183005

  8. Interleukin-17 (IL-17)-induced microRNA 873 (miR-873) contributes to the pathogenesis of experimental autoimmune encephalomyelitis by targeting A20 ubiquitin-editing enzyme.

    Science.gov (United States)

    Liu, Xiaomei; He, Fengxia; Pang, Rongrong; Zhao, Dan; Qiu, Wen; Shan, Kai; Zhang, Jing; Lu, Yanlai; Li, Yan; Wang, Yingwei

    2014-10-17

    Interleukin 17 (IL-17), produced mainly by T helper 17 (Th17) cells, is increasingly recognized as a key regulator in various autoimmune diseases, including human multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Although several microRNAs (miRNAs) with aberrant expression have been shown to contribute to the pathogenesis of MS and EAE, the mechanisms underlying the regulation of abnormal miRNA expression in astrocytes upon IL-17 stimulation remain unclear. In the present study, we detected the changes of miRNA expression profiles both in the brain tissue of EAE mice and in cultured mouse primary astrocytes stimulated with IL-17 and identified miR-873 as one of the co-up-regulated miRNAs in vivo and in vitro. The overexpression of miR-873, demonstrated by targeting A20 (TNFα-induced protein 3, TNFAIP3), remarkably reduced the A20 level and promoted NF-κB activation in vivo and in vitro as well as increasing the production of inflammatory cytokines and chemokines (i.e. IL-6, TNF-α, MIP-2, and MCP-1/5). More importantly, silencing the endogenous miR-873 or A20 gene with lentiviral vector of miR-873 sponge (LV-miR-873 sponge) or short hairpin RNA (shRNA) of A20 (LV-A20 shRNA) in vivo significantly lessened or aggravated inflammation and demyelination in the central nervous system (CNS) of EAE mice, respectively. Taken together, these findings indicate that miR-873 induced by IL-17 stimulation promotes the production of inflammatory cytokines and aggravates the pathological process of EAE mice through the A20/NF-κB pathway, which provides a new insight into the mechanism of inflammatory damage in MS. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Mechanism of action and efficacy of RX-111, a thieno[2,3-c]pyridine derivative and small molecule inhibitor of protein interaction with glycosaminoglycans (SMIGs), in delayed-type hypersensitivity, TNBS-induced colitis and experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Harris, Nicholas; Koppel, Juraj; Zsila, Ferenc; Juhas, Stefan; Il'kova, Gabriela; Kogan, Faina Yurgenzon; Lahmy, Orly; Wildbaum, Gizi; Karin, Nathan; Zhuk, Regina; Gregor, Paul

    2016-04-01

    Elucidate the mechanism of action of the small molecule inhibitor of protein binding to glycosaminoglycans, RX-111 and assay its anti-inflammatory activity in animal models of inflammatory disease. The glycosaminoglycan, heparin, was used in the mechanism of action study of RX-111. Human T lymphocytes and umbilical vein endothelial cells were used to assay the in vitro activity of RX-111. Mouse and rat models of disease were used to assay the anti-inflammatory activity of RX-111 in vivo. Circular dichroism and UV/Vis absorption spectroscopy were used to study the binding of RX-111 to the glycosaminoglycan, heparin. T lymphocyte rolling on endothelial cells under shear flow was used to assay RX-111 activity in vitro. Delayed-type hypersensitivity (DTH) and tri-nitrobenzene sulfonic acid (TNBS)-induced colitis in mice and experimental autoimmune encephalomyelitis (EAE) in rats were used to assay anti-inflammatory activity of RX-111 in vivo. RX-111 was shown to bind directly to heparin. It inhibited leukocyte rolling on endothelial cells under shear flow and reduced inflammation in the mouse model of DTH. RX-111 was efficacious in the mouse model of inflammatory bowel disease, TNBS-induced colitis and the rat model of multiple sclerosis, EAE. RX-111 exercises its broad spectrum anti-inflammatory activity by a singular mechanism of action, inhibition of protein binding to the cell surface GAG, heparan sulfate. RX-111 and related thieno[2,3-c]pyridine derivatives are potential therapeutics for the treatment of inflammatory and autoimmune diseases.

  10. Autoimmune gastritis: Pathologist's viewpoint.

    Science.gov (United States)

    Coati, Irene; Fassan, Matteo; Farinati, Fabio; Graham, David Y; Genta, Robert M; Rugge, Massimo

    2015-11-14

    Western countries are seeing a constant decline in the incidence of Helicobacter pylori-associated gastritis, coupled with a rising epidemiological and clinical impact of autoimmune gastritis. This latter gastropathy is due to autoimmune aggression targeting parietal cells through a complex interaction of auto-antibodies against the parietal cell proton pump and intrinsic factor, and sensitized T cells. Given the specific target of this aggression, autoimmune gastritis is typically restricted to the gastric corpus-fundus mucosa. In advanced cases, the oxyntic epithelia are replaced by atrophic (and metaplastic) mucosa, creating the phenotypic background in which both gastric neuroendocrine tumors and (intestinal-type) adenocarcinomas may develop. Despite improvements in our understanding of the phenotypic changes or cascades occurring in this autoimmune setting, no reliable biomarkers are available for identifying patients at higher risk of developing a gastric neoplasm. The standardization of autoimmune gastritis histology reports and classifications in diagnostic practice is a prerequisite for implementing definitive secondary prevention strategies based on multidisciplinary diagnostic approaches integrating endoscopy, serology, histology and molecular profiling.

  11. Autoimmunity and Asbestos Exposure

    Directory of Open Access Journals (Sweden)

    Jean C. Pfau

    2014-01-01

    Full Text Available Despite a body of evidence supporting an association between asbestos exposure and autoantibodies indicative of systemic autoimmunity, such as antinuclear antibodies (ANA, a strong epidemiological link has never been made to specific autoimmune diseases. This is in contrast with another silicate dust, crystalline silica, for which there is considerable evidence linking exposure to diseases such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Instead, the asbestos literature is heavily focused on cancer, including mesothelioma and pulmonary carcinoma. Possible contributing factors to the absence of a stronger epidemiological association between asbestos and autoimmune disease include (a a lack of statistical power due to relatively small or diffuse exposure cohorts, (b exposure misclassification, (c latency of clinical disease, (d mild or subclinical entities that remain undetected or masked by other pathologies, or (e effects that are specific to certain fiber types, so that analyses on mixed exposures do not reach statistical significance. This review summarizes epidemiological, animal model, and in vitro data related to asbestos exposures and autoimmunity. These combined data help build toward a better understanding of the fiber-associated factors contributing to immune dysfunction that may raise the risk of autoimmunity and the possible contribution to asbestos-related pulmonary disease.

  12. Epigenetics and Autoimmune Diseases

    Science.gov (United States)

    Quintero-Ronderos, Paula; Montoya-Ortiz, Gladis

    2012-01-01

    Epigenetics is defined as the study of all inheritable and potentially reversible changes in genome function that do not alter the nucleotide sequence within the DNA. Epigenetic mechanisms such as DNA methylation, histone modification, nucleosome positioning, and microRNAs (miRNAs) are essential to carry out key functions in the regulation of gene expression. Therefore, the epigenetic mechanisms are a window to understanding the possible mechanisms involved in the pathogenesis of complex diseases such as autoimmune diseases. It is noteworthy that autoimmune diseases do not have the same epidemiology, pathology, or symptoms but do have a common origin that can be explained by the sharing of immunogenetic mechanisms. Currently, epigenetic research is looking for disruption in one or more epigenetic mechanisms to provide new insights into autoimmune diseases. The identification of cell-specific targets of epigenetic deregulation will serve us as clinical markers for diagnosis, disease progression, and therapy approaches. PMID:22536485

  13. [Autoimmune thyroid disease and other non-endocrine autoimmune diseases].

    Science.gov (United States)

    Dilas, Ljiljana Todorović; Icin, Tijana; Paro, Jovanka Novaković; Bajkin, Ivana

    2011-01-01

    Autoimmune diseases are chronic conditions initiated by the loss of immunological tolerance to self-antigens. They constitute heterogeneous group of disorders, in which multiple alterations in the immune system result in a spectrum of syndromes that either target specific organs or affect the body systematically. Recent epidemiological studies have shown a possible shift of one autoimmune disease to another or the fact that more than one autoimmune disease may coexist in a single patient or in the same family. Numerous autoimmune diseases have been shown to coexist frequently with thyroid autoimmune diseases. AUTOIMMNUNE THYROID DISEASE AND OTHER ORGAN SPECIFIC NON-ENDOCRINE AUTOIMMUNE DISEASES: This part of the study reviews the prevalence of autoimmune thyroid disease coexisting with: pernicious anaemia, vitiligo, celiac disease, autoimmune liver disease, miastenia gravis, alopecia areata and sclerosis multiplex, and several recommendations for screening have been given. AUTOIMMUNE THYROID DISEASE AND OTHER ORGAN NON-SPECIFIC NON-ENDOCRINE AUTOIMMUNE DISEASES: Special attention is given to the correlation between autoimmune thyroid disease and rheumatoid arthritis, systemic lupus erythematosus, syndrome Sjögren, systemic sclerosis and mixed connective tissue disease. Screening for autoimmune thyroid diseases should be recommended in everyday clinical practice, in patients with primary organ-specific or organ non-specific autoimmune disease. Otherwise, in patients with primary thyroid autoimmune disease, there is no good reason of seeking for all other autoimmune diseases, although these patients have a greater risk of developing other autoimmune disease. Economic aspects of medicine require further analyzing of these data, from cost/benefit point of view to justified either mandatory screening or medical practitioner judgment.

  14. Epigenomics of autoimmune diseases.

    Science.gov (United States)

    Gupta, Bhawna; Hawkins, R David

    2015-03-01

    Autoimmune diseases are complex disorders of largely unknown etiology. Genetic studies have identified a limited number of causal genes from a marginal number of individuals, and demonstrated a high degree of discordance in monozygotic twins. Studies have begun to reveal epigenetic contributions to these diseases, primarily through the study of DNA methylation, but chromatin and non-coding RNA changes are also emerging. Moving forward an integrative analysis of genomic, transcriptomic and epigenomic data, with the latter two coming from specific cell types, will provide an understanding that has been missed from genetics alone. We provide an overview of the current state of the field and vision for deriving the epigenomics of autoimmunity.

  15. Autoimmune basis of glaucoma.

    Science.gov (United States)

    Shazly, Tarek A; Aljajeh, Mouhab; Latina, Mark A

    2011-01-01

    Glaucoma is one of the leading causes of blindness worldwide. The current view of glaucoma is that it is a multifactorial disease. Elevated IOP is a recognized etiologic factor which can trigger initial damage through biomechanical and ischemic injury to the retinal ganglion cells. However, elevated intraocular pressure cannot be entirely responsible for the development of glaucoma. Accumulating evidence suggests that abnormal immunity may be contributing to the glaucomatous optic neuropathy. Autoimmunity may be responsible for initiating or exacerbating glaucoma. This review provides an evaluation of the potential role of autoimmunity in some patients with glaucoma.

  16. Methylthioadenosine reverses brain autoimmune disease.

    Science.gov (United States)

    Moreno, Beatriz; Hevia, Henar; Santamaria, Monica; Sepulcre, Jorge; Muñoz, Javier; García-Trevijano, Elena R; Berasain, Carmen; Corrales, Fernando J; Avila, Matias A; Villoslada, Pablo

    2006-09-01

    To assess the immunomodulatory activity of methylthioadenosine (MTA) in rodent experimental autoimmune encephalomyelitis (EAE) and in patients with multiple sclerosis. We studied the effect of intraperitoneal MTA in the acute and chronic EAE model by quantifying clinical and histological scores and by performing immunohistochemistry stains of the brain. We studied the immunomodulatory effect of MTA in lymphocytes from EAE animals and in peripheral blood mononuclear cells from healthy control subjects and multiple sclerosis patients by assessing cell proliferation and cytokine gene expression, by real-time polymerase chain reaction, and by nuclear factor-kappaB modulation by Western blot. We found that MTA prevents acute EAE and, more importantly, reverses chronic-relapsing EAE. MTA treatment markedly inhibited brain inflammation and reduced brain damage. Administration of MTA suppressed T-cell activation in vivo and in vitro, likely through a blockade in T-cell signaling resulting in the prevention of inhibitor of kappa B (IkappaB-alpha) degradation and in the impaired activation transcription factor nuclear factor-kappaB. Indeed, MTA suppressed the production of proinflammatory genes and cytokines (interferon-gamma, tumor necrosis factor-alpha, and inducible nitric oxide synthase) and increased the production of antiinflammatory cytokines (interleukin-10). MTA has a remarkable immunomodulatory activity and may be beneficial for multiple sclerosis and other autoimmune diseases.

  17. Autoimmunity and Turner's syndrome.

    Science.gov (United States)

    Lleo, Ana; Moroni, Luca; Caliari, Lisa; Invernizzi, Pietro

    2012-05-01

    Turner Syndrome (TS) is a common genetic disorder, affecting female individuals, resulting from the partial or complete absence of one sex chromosome, and occurring in approximately 50 per 100,000 liveborn girls. TS is associated with reduced adult height and with gonadal dysgenesis, leading to insufficient circulating levels of female sex steroids and to infertility. Morbidity and mortality are increased in TS but average intellectual performance is within the normal range. TS is closely associated to the presence of autoantibodies and autoimmune diseases (AID), especially autoimmune thyroiditis and inflammatory bowel disease. Despite the fact that the strong association between TS and AID is well known and has been widely studied, the underlying immunopathogenic mechanism remains partially unexplained. Recent studies have displayed how TS patients do not show an excess of immunogenic risk markers. This is evocative for a higher responsibility of X-chromosome abnormalities in the development of AID, and particularly of X-genes involved in immune response. For instance, the long arm of the X chromosome hosts a MHC-locus, so the loss of that region may lead to a deficiency in immune regulation. Currently no firm guidelines for diagnosis exist. In conclusion, TS is a condition associated with a number of autoimmune manifestations. Individuals with TS need life-long medical attention. As a consequence of these findings, early diagnosis and regular screening for potential associated autoimmune conditions are essential in the medical follow-up of TS patients. Copyright © 2011 Elsevier B.V. All rights reserved.

  18. Selenium and thyroid autoimmunity

    Directory of Open Access Journals (Sweden)

    Roberto Negro

    2008-06-01

    Full Text Available Roberto NegroDepartment of Endocrinology, “V. Fazzi” Hospital, Lecce, ItalyAbstract: The trace element selenium (Se occurs in the form of the amino acid selenocysteine in selenoproteins. Selenoproteins exerts multiple physiological effects in human health, many of which are related with regulation of reduction-oxidation processes. In fact, the selenoenzyme families of glutathione peroxidase (GPx and thioredoxin reductase (TRx display the ability to act as antioxidants, protecting cells from oxidative damage. Furthermore, another class of selenoproteins are the iodothyronine deiodinase enzymes (DIO, which catalyze the conversion of thyroxine (T4 in triiodothyronine (T3, then exerting a fine tuned control on thyroid hormones metabolism. Several studies have investigated the potential positive effects of Se supplementation in thyroid diseases, characterized by increased levels of hydrogen peroxide and free radicals, like autoimmune chronic thyroiditis. These studies have supplied evidences indicating that Se supplementation, maximizing the antioxidant enzymes activity, may reduce the thyroid inflammatory status. Then, it may be postulated that Se could play a therapeutical role in thyroid autoimmune diseases. Despite the fact that recent studies seem to be concordant about Se beneficial effects in decreasing thyroid peroxidase antibodies (TPOAb titers and ameliorating the ultrasound echogenicity pattern, several doubts have to be still clarified, before advising Se supplementation in chronic autoimmune thyroiditis.Keywords: selenium, thyroid, autoimmunity

  19. Safety of vaccine adjuvants: focus on autoimmunity.

    Science.gov (United States)

    van der Laan, Jan Willem; Gould, Sarah; Tanir, Jennifer Y

    2015-03-24

    Questions have been recently raised regarding the safety of vaccine adjuvants, particularly in relation to autoimmunity or autoimmune disease(s)/disorder(s) (AID). The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) formed a scientific committee and convened a 2-day workshop, consisting of technical experts from around the world representing academia, government regulatory agencies, and industry, to investigate and openly discuss the issues around adjuvant safety in vaccines. The types of adjuvants considered included oil-in-water emulsions and toll-like receptor (TLR) agonists. The state of science around the use of animal models and biomarkers for the evaluation and prediction of AID were also discussed. Following extensive literature reviews by the HESI committee, and presentations by experts at the workshop, several key points were identified, including the value of animal models used to study autoimmunity and AID toward studying novel vaccine adjuvants; whether there is scientific evidence indicating an intrinsic risk of autoimmunity and AID with adjuvants, or a higher risk resulting from the mechanism of action; and if there is compelling clinical data linking adjuvants and AID. The tripartite group of experts concluded that there is no compelling evidence supporting the association of vaccine adjuvants with autoimmunity signals. Additionally, it is recommended that future research on the potential effects of vaccine adjuvants on AID should consider carefully the experimental design in animal models particularly if they are to be used in any risk assessment, as an improper design and model could result in misleading information. Finally, studies on the mechanistic aspects and potential biomarkers related to adjuvants and autoimmunity phenomena could be developed. Copyright © 2015. Published by Elsevier Ltd.. All rights reserved.

  20. Psychosis: an autoimmune disease?

    Science.gov (United States)

    Al-Diwani, Adam A J; Pollak, Thomas A; Irani, Sarosh R; Lennox, Belinda R

    2017-11-01

    Psychotic disorders are common and disabling. Overlaps in clinical course in addition to epidemiological and genetic associations raise the possibility that autoimmune mechanisms may underlie some psychoses, potentially offering novel therapeutic approaches. Several immune loci including the major histocompatibility complex and B-cell markers CD19 and CD20 achieve genome-wide significance in schizophrenia. Emerging evidence suggests a potential role via neurodevelopment in addition to classical immune pathways. Additionally, lymphocyte biology is increasingly investigated. Some reports note raised peripheral CD19(+) and reduced CD3(+) lymphocyte counts, with altered CD4 : CD8 ratios in acute psychosis. Also, post-mortem studies have found CD3(+) and CD20(+) lymphocyte infiltration in brain regions that are of functional relevance to psychosis. More specifically, the recent paradigm of neuronal surface antibody-mediated (NSAb) central nervous system disease provides an antigen-specific model linking adaptive autoimmunity to psychopathology. NSAbs bind extracellular epitopes of signalling molecules that are classically implicated in psychosis such as NMDA and GABA receptors. This interaction may cause circuit dysfunction leading to psychosis among other neurological features in patients with autoimmune encephalitis. The detection of these cases is crucial as autoimmune encephalitis is ameliorated by commonly available immunotherapies. Meanwhile, the prevalence and relevance of these antibodies in people with isolated psychotic disorders is an area of emerging scientific and clinical interest. Collaborative efforts to achieve larger sample sizes, comparison of assay platforms, and placebo-controlled randomized clinical trials are now needed to establish an autoimmune contribution to psychosis. © 2017 John Wiley & Sons Ltd.

  1. Is Lipotoxicity presents in the early stages of an experimental model of autoimmune diabetes? Further studies in the multiple low dose of streptozotocin model.

    Science.gov (United States)

    Karabatas, Liliana; Oliva, Maria Eugenia; Dascal, Eduardo; Hein, Gustavo J; Pastorale, Claudia; Chicco, Adriana; Lombardo, Yolanda B; Basabe, Juan C

    2010-01-01

    An increased availability of plasma free fatty acids (FFA) seems to play a role in the early stages of experimental type 1 diabetes mellitus induced in C57BL/6J mice by multiple low doses of streptozotoxin (mld-STZ). We analyzed the temporal changes of: (1) plasma and skeletal muscle lipids and their relationship with glucose metabolism; (2) triglyceride (Tg) concentration in isolated islets; (3) intraperitoneal glucose tolerance test; and (4) insulin secretion patterns when the three mutually interactive glucose signaling pathways were activated. Animals were killed by cervical dislocation at days 4, 6, 7, 8, 9 and 12 post first injection of mld-STZ. Compared with control mice, we observed: (1) at day 6, a significant increase of plasma FFA and both muscle and islet Tg content and a significant decrease of muscle pyruvate dehydrogenase activity. These parameters further deteriorated with time. (2) plasma Tg, glucose and insulin levels and glucose tolerance test were significantly different only after day 8. (3) an increase in both phases of the glucose plus palmitate-stimulated insulin secretion was observed at day 4. This effect progressively decreased since day 7 up to day 9. Moreover, an inhibitory action of cerulenin over glucose plus palmitate-stimulated insulin secretion was observed between days 6 and 9. Taken together these results suggest that early alteration in carbohydrate and lipid metabolism could represent a "metabolic window" which would develop between days 6 and 8. Afterwards, subsequent immunological alterations, apoptosis and necrosis induced the destruction of β cells and would mask the results mentioned above.

  2. Sarcoidosis and Thyroid Autoimmunity

    Directory of Open Access Journals (Sweden)

    Piera Fazzi

    2017-08-01

    Full Text Available Most of the studies have shown a higher risk for subclinical and clinical hypothyroidism, antithyroid autoantibodies [overall antithyroid peroxidase antibodies (TPOAb], and in general, thyroid autoimmunity, overall in the female gender in patients with sarcoidosis (S. A significantly higher prevalence of clinical hypothyroidism and Graves’ disease was also described in female S patients with respect to controls. Gallium-67 (Ga-67 scyntigraphy in S patients, in the case of thyroid uptake, suggests the presence of aggressive autoimmune thyroiditis and hypothyroidism. For this reason, ultrasonography and thyroid function should be done in the case of Ga-67 thyroid uptake. In conclusion, thyroid function, TPOAb measurement, and ultrasonography should be done to assess the clinical profile in female S patients, and the ones at high risk (female individuals, with TPOAb positivity, and hypoechoic and small thyroid should have periodically thyroid function evaluations and suitable treatments.

  3. Autophagy and Autoimmunity CrossTalks

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    Abhisek eBhattacharya

    2013-04-01

    Full Text Available Autophagy, initially viewed as a conserved bulk-degradation mechanism, has emerged as a central player in a multitude of immune functions. Autophagy is important in host defense against intracellular and extracellular pathogens, metabolic syndromes, immune cell homeostasis, antigen processing and presentation and maintenance of tolerance. The observation that the above processes are implicated in triggering or exacerbating autoimmunity raises the possibility that the autophagy pathway is involved in mediating autoimmune processes, either directly or as a consequence of innate or adaptive functions mediated by the pathway. Genome-wide association studies have shown association between single nucleotide polymorphisms (SNPs in autophagy related gene 5 (Atg5, and Atg16l1 with susceptibility to systemic lupus erythematous (SLE and Crohn’s disease, respectively. Enhanced expression of Atg5 was also reported in blood of mice with experimental autoimmune encephalomyelitis (EAE, a mouse model of multiple sclerosis (MS, and in T cells isolated from blood or brain tissues from patients with active relapse of MS. This review explores the roles of autophagy pathway in the innate and adaptive immune systems on regulating or mediating the onset, progression or exacerbation of autoimmune processes.

  4. IL-35 and Autoimmunity: a Comprehensive Perspective.

    Science.gov (United States)

    Choi, Jinjung; Leung, Patrick S C; Bowlus, Christopher; Gershwin, M Eric

    2015-12-01

    Interleukin 35 (IL-35) is the most recently identified member of the IL-12 family of cytokines and offers the potential to be a target for new therapies for autoimmune, inflammatory, and infectious diseases. Similar to other members of the IL-12 family including IL-12, IL-23, and IL-27, IL-35 is composed of a heterodimer of α and β chains, which in the case of IL-35 are the p35 and Epstein-Barr virus-induced gene 3 (EBI3) proteins. However, unlike its proinflammatory relatives, IL-35 has immunosuppressive effects that are mediated through regulatory T and B cells. Although there are limited data available regarding the role of IL-35 in human autoimmunity, several murine models of autoimmunity suggest that IL-35 may have potent effects in regulating immunoreactivity via IL-10-dependent mechanisms. We suggest that similar effects are operational in human disease and IL-35-directed therapies hold significant promise. In particular, we emphasize that IL-35 has immunosuppressive ability that are mediated via regulatory T and B cells that are IL-10 dependent. Further, although deletion of IL-35 does not result in spontaneous breach of tolerance, recombinant IL-35 can improve autoimmune responses in several experimental models.

  5. Thymoma and autoimmunity

    OpenAIRE

    Shelly, Shahar; Agmon-Levin, Nancy; Altman, Arie; Shoenfeld, Yehuda

    2011-01-01

    The thymus is a central lymphatic organ that is responsible for many immunological functions, including the production of mature, functional T cells and the induction of self-tolerance. Benign or malignant tumors may originate from the thymus gland, with thymoma being the most common and accounting for 50% of anterior mediastinal tumors. Malignancies linked to thymoma include the loss of self-tolerance and the presence of autoimmunity. In this review, we compiled the current scientific eviden...

  6. Depression in autoimmune diseases

    OpenAIRE

    Pryce, Christopher R.; Fontana, Adriano

    2016-01-01

    Up to 50% of patients with autoimmune diseases show an impairment of health-related quality of life and exhibit depression-like symptoms. The immune system not only leads to inflammation in affected organs, but also mediates behavior abnormalities including fatigue and depression-like symptoms. This review focuses on the different pathways involved in the communication of the immune system with the neuronal network and the body's timing system. The latter is built up by a hierarchically organ...

  7. Autoimmunity in 2016.

    Science.gov (United States)

    Selmi, Carlo

    2017-08-01

    The number of peer-reviewed articles published during the 2016 solar year and retrieved using the "autoimmunity" key word remained stable while gaining a minimal edge among the immunology articles. Nonetheless, the quality of the publications has been rising significantly and, importantly, acquisitions have become available through scientific journals dedicated to immunology or autoimmunity. Major discoveries have been made in the fields of systemic lupus erythematosus, rheumatoid arthritis, autoimmunity of the central nervous system, vasculitis, and seronegative spondyloarthrithritides. Selected examples include the role of IL17-related genes and long noncoding RNAs in systemic lupus erythematosus or the effects of anti-pentraxin 3 (PTX3) in the treatment of this paradigmatic autoimmune condition. In the case of rheumatoid arthritis, there have been reports of the role of induced regulatory T cells (iTregs) or fibrocytes and T cell interactions with exciting implications. The large number of studies dealing with neuroimmunology pointed to Th17 cells, CD56(bright) NK cells, and low-level TLR2 ligands as involved in multiple sclerosis, along with a high salt intake or the micriobiome-derived Lipid 654. Lastly, we focused on the rare vasculitides to which numerous studies were devoted and suggested that unsuspected cell populations, including monocytes, mucosal-associated invariant T cells, and innate lymphoid cells, may be crucial to ANCA-associated manifestations. This brief and arbitrary discussion of the findings published in 2016 is representative of a promising background for developments that will enormously impact the work of laboratory scientists and physicians at an exponential rate.

  8. Prolactin and autoimmunity.

    Science.gov (United States)

    De Bellis, Annamaria; Bizzarro, Antonio; Pivonello, Rosario; Lombardi, Gaetano; Bellastella, Antonio

    2005-01-01

    The interrelationship between prolactin (PRL) and the immune system have been elucitaded in the last decade, opening new important horizons in the field of the immunoendocrinology. PRL is secreted not only by anterior pituitary gland but also by many extrapituitary sites including the immune cells. The endocrine/paracrine PRL has been shown to stimulate the immune cells by binding to PRL receptors. Increased PRL levels, frequently described in autoimmune diseases, could depend on the enhancement of coordinated bi-directional communications between PRL and the immune system observed in these diseases. Hyperprolactinemia has been described in the active phase of some non organ-specific autoimmune diseases, as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and organ-specific autoimmune diseases, as celiac disease, type 1 diabetes mellitus, Addison's disease, autoimmune thyroid diseases. In these diseases PRL increases the syntesis of IFNgamma and IL-2 by Th1 lymphocytes. Moreover, PRL activates Th2 lymphocytes with autoantibody production. Of particular interest is the association between hyperprolactinemia and levels of anti DNA antibodies, islet cell antibodies (ICA), thyreoglobulin antibodies (TgAb), thyroperoxidase antibodies (TPOAb), adrenocortical antibodies (ACA), transglutaminase antibodies (tTGAb) in SLE, in type 1 diabetes mellitus, in Hashimoto's thyroiditis, in Addison's disease and in celiac disease, respectively. High levels of PRL have been also frequently detected in patients with lymphocytic hypophysitis (LYH). Several mechanisms have been invoked to explain the hyperprolactinemia in LYH. The PRL increase could be secondary to the inflammatory process of the pituitary gland but, on the other hand, this increase could have a role in enhancing the activity of the immune process in LYH. Moreover, the detection of antipituitary antibodies targeting PRL-secreting cells in some patients with idiopathic hyperprolactinemia suggests the

  9. AUTOIMMUNE EPIDERMAL BLISTERING DISEASES

    OpenAIRE

    Ana Maria Abreu Velez; Juliana Calle; Howard, Michael S.

    2013-01-01

    Autoimmune bullous skin diseases (ABDs) are uncommon, potentially fatal diseases of skin and mucous membranes which are associated with deposits of autoantibodies and complement against distinct molecules of the epidermis and dermal/epidermal basement membrane zone (BMZ). These autoantibodies lead to a loss in skin molecular integrity, which manifests clinically as formation of blisters or erosions. In pemphigus vulgaris, loss of adhesion occurs within the epidermis. The pioneering work of Er...

  10. Autoantibodies in Autoimmune Pancreatitis

    Directory of Open Access Journals (Sweden)

    Daniel S. Smyk

    2012-01-01

    Full Text Available Autoimmune pancreatitis (AIP was first used to describe cases of pancreatitis with narrowing of the pancreatic duct, enlargement of the pancreas, hyper-γ-globulinaemia, and antinuclear antibody (ANA positivity serologically. The main differential diagnosis, is pancreatic cancer, which can be ruled out through radiological, serological, and histological investigations. The targets of ANA in patients with autoimmune pancreatitis do not appear to be similar to those found in other rheumatological diseases, as dsDNA, SS-A, and SS-B are not frequently recognized by AIP-related ANA. Other disease-specific autoantibodies, such as, antimitochondrial, antineutrophil cytoplasmic antibodies or diabetes-specific autoantibodies are virtually absent. Further studies have focused on the identification of pancreas-specific autoantigens and reported significant reactivity to lactoferrin, carbonic anhydrase, pancreas secretory trypsin inhibitor, amylase-alpha, heat-shock protein, and plasminogen-binding protein. This paper discusses the findings of these investigations and their relevance to the diagnosis, management, and pathogenesis of autoimmune pancreatitis.

  11. [Autoimmune blistering diseases].

    Science.gov (United States)

    Duvert-Lehembre, S; Joly, P

    2014-03-01

    Autoimmune blistering diseases are characterized by the production of pathogenic autoantibodies that are responsible for the formation of epidermal blisters. Major advances in the understanding of the pathogenesis of these disorders have allowed the development of new therapeutic agents. Recent epidemiologic data showed that bullous pemphigoid mainly affects elderly patients. Bullous pemphigoid is often associated with degenerative neurologic disorders. A major increase in the incidence of bullous pemphigoid has been observed in France. Treatment of bullous pemphigoid is mainly based on superpotent topical corticosteroids. The role of desmosomal proteins has been demonstrated in the initiation, propagation and persistence of the autoimmune response in pemphigus. Several studies have shown a correlation between anti-desmoglein antibody titers and disease activity. Pemphigus susceptibility genes have been identified. Oral corticosteroids remain the mainstay of pemphigus treatment. Dramatic and long-lasting improvement has been recently obtained with rituximab in recalcitrant types of pemphigus. Other autoimmune junctional blistering diseases are rare entities, whose prognosis can be severe. Their diagnosis has been improved by the use of new immunological assays and immunoelectronic microscopy. Immunosupressants are widely used in severe types in order to prevent mucosal sequelae. Copyright © 2013 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  12. Paediatric Autoimmune Liver Disease.

    Science.gov (United States)

    Liberal, Rodrigo; Vergani, Diego; Mieli-Vergani, Giorgina

    2015-01-01

    In paediatrics, there are 2 liver disorders in which liver damage most likely stems from an autoimmune attack: 'classical' autoimmune hepatitis (AIH) and the AIH/sclerosing cholangitis overlap syndrome (also known as autoimmune sclerosing cholangitis, ASC). The presentation of childhood autoimmune liver disease (AILD) is non-specific and can mimic most other liver disorders. AIH is exquisitely responsive to immunosuppressive treatment, which should be instituted promptly to prevent rapid deterioration and promote remission and long-term survival. Difficult-to-treat or non-responsive patients should be treated with mycophenolate mofetil; if this fails then calcineurin inhibitors can be tried. Persistent failure to respond or lack of adherence to treatment result in end-stage liver disease. These patients, and those with fulminant liver failure at diagnosis, will require liver transplantation. ASC responds to the same immunosuppressive treatment used for AIH when treatment is initiated early. Abnormal liver function tests often resolve within a few months of treatment, although medium- to long-term prognosis is worse than that of AIH because bile duct disease continues to progress despite treatment in approximately 50% of patients. Ursodeoxycholic acid is usually added to conventional treatment regimen in ASC, but whether this actually helps arrest the progression of bile duct disease remains to be established. The pathogenesis of paediatric-onset AILD is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4pos T-cells. While Th1 effector cells are associated with hepatocyte damage in both AIH and ASC, Th17 immune responses predominate in the latter where they correlate with biochemical indices of cholestasis, indicating that IL-17 is involved in the

  13. The effect of 1, 25(OH)2 D3 (calcitriol) alone and in combination with all-trans retinoic acid on ROR-γt, IL-17, TGF-β, and FOXP3 gene expression in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Parastouei, Karim; Mirshafiey, Abbas; Eshraghian, Mohammad Reza; Shiri-Shahsavar, Mohammad Reza; Solaymani-Mohammadi, Farid; Chahardoli, Reza; Alvandi, Ehsan; Saboor-Yaraghi, Ali Akbar

    2016-12-20

    It has been shown that calcitriol and all-trans retinoic acid (ATRA) have modulatory effects on the immune system. The present study investigates the synergistic effects of combination treatment of calcitriol and ATRA in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). The mice were allocated to four preventive groups, each consisting of eight animals, ATRA (250 μg/mouse), calcitriol (100 ng/mouse), combination of ATRA and calcitriol (125  μg/mouse and 50 ng/mouse) and vehicle groups. EAE was induced by MOG35-55 peptide in female C57BL/6 mice. Treatments were initiated at day 1 before immunization and continued every other day throughout the study until the day 21 post-immunization. Splenocytes were isolated from EAE-induced mice and the expression of retinoic acid receptor-related orphan receptor gamma t (ROR-γt), Interleukin-17 (IL-17), transforming growth factor beta (TGF-β), and forkhead box P3 (FOXP3) genes was measured using real-time polymerase chain reaction. The expression of FOXP3 and TGF-β genes in the splenocytes of combination-treated and calcitriol alone-treated mice was significantly increased compared to vehicle group (P ROR-γt and IL-17 genes in the splenocytes of ATRA, calcitriol and combination- treated mice was significantly reduced compared to those of vehicle- treated mice (P ROR-γt was significantly (P < 0.05) lower in the combination group than in the mice treated by ATRA or calcitriol alone. This study demonstrated that treatment with combination of calcitriol and ATRA can be considered as a new strategy for MS prevention and treatment.

  14. Imaging of autoimmune biliary disease.

    Science.gov (United States)

    Yeh, Melinda J; Kim, So Yeon; Jhaveri, Kartik S; Behr, Spencer C; Seo, Nieun; Yeh, Benjamin M

    2017-01-01

    Autoimmune biliary diseases are poorly understood but important to recognize. Initially, autoimmune biliary diseases are asymptomatic but may lead to progressive cholestasis with associated ductopenia, portal hypertension, cirrhosis, and eventually liver failure. The three main forms of autoimmune biliary disease are primary biliary cirrhosis, primary sclerosing cholangitis, and IgG4-associated cholangitis. Although some overlap may occur between the three main autoimmune diseases of the bile ducts, each disease typically affects a distinct demographic group and requires a disease-specific diagnostic workup. For all the autoimmune biliary diseases, imaging provides a means to monitor disease progression, assess for complications, and screen for the development of hepatobiliary malignancies that are known to affect patients with these diseases. Imaging is also useful to suggest or corroborate the diagnosis of primary sclerosing cholangitis and IgG4-associated cholangitis. We review the current literature and emphasize radiological findings and considerations for these autoimmune diseases of the bile ducts.

  15. B Cells in Autoimmune Diseases

    OpenAIRE

    Hampe, Christiane S.

    2012-01-01

    The role of B cells in autoimmune diseases involves different cellular functions, including the well-established secretion of autoantibodies, autoantigen presentation and ensuing reciprocal interactions with T cells, secretion of inflammatory cytokines, and the generation of ectopic germinal centers. Through these mechanisms B cells are involved both in autoimmune diseases that are traditionally viewed as antibody mediated and also in autoimmune diseases that are commonly classified as T cell...

  16. Autoantibodies in autoimmune liver diseases.

    Science.gov (United States)

    Sener, Asli Gamze

    2015-11-01

    Autoimmune hepatitis is a chronic hepatitis of unknown etiology characterized by clinical, histological, and immunological features, generally including circulating autoantibodies and a high total serum and/or gamma globulin. Liver-related autoantibodies are very significant for the correct diagnosis and classification of autoimmune liver diseases (AILD), namely autoimmune hepatitis types 1 and 2 (AIH-1 and 2), primary biliary cirrhosis (PBC), and the sclerosing cholangitis types in adults and children. This article intends to review recent studies that investigate autoantibodies in autoimmune liver diseases from a microbiological perspective. © 2015 APMIS. Published by John Wiley & Sons Ltd.

  17. [Autoimmune hemolytic anemia in children].

    Science.gov (United States)

    Becheur, M; Bouslama, B; Slama, H; Toumi, N E H

    2015-01-01

    Autoimmune hemolytic anemia is a rare condition in children which differs from the adult form. It is defined by immune-mediated destruction of red blood cells caused by autoantibodies. Characteristics of the autoantibodies are responsible for the various clinical entities. Classifications of autoimmune hemolytic anemia include warm autoimmune hemolytic anemia, cold autoimmune hemolytic anemia, and paroxysmal cold hemoglobinuria. For each classification, this review discusses the epidemiology, etiology, clinical presentation, laboratory evaluation, and treatment options. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  18. Lymph node-derived donor encephalitogenic CD4+ T cells in C57BL/6 mice adoptive transfer experimental autoimmune encephalomyelitis highly express GM-CSF and T-bet

    Directory of Open Access Journals (Sweden)

    Lambracht-Washington Doris

    2011-06-01

    Full Text Available Abstract Experimental autoimmune encephalomyelitis (EAE is a relevant animal model for the human demyelinating inflammatory disorder of the central nervous system (CNS, multiple sclerosis (MS. Induction of EAE by adoptive transfer allows studying the role of the donor T lymphocyte in disease pathogenesis. It has been challenging to reliably induce adoptive transfer EAE in C57BL/6 (H-2b mice. The goal of this study was to develop a reproducible and high yield protocol for adoptive transfer EAE in C57BL/6 mice. A step-wise experimental approach permitted us to develop a protocol that resulted in a consistent relatively high disease incidence of ~70% in recipient mice. Donor mice were immunized with myelin oligodendrocyte glycoprotein (MOGp35-55 in complete Freund's adjuvant (CFA followed by pertussis toxin (PT. Only lymph node cells (LNC isolated at day 12 post immunization, and restimulated in vitro for 72 hours with 10 μg/mL of MOGp35-55 and 0.5 ng/mL of interleukin-12 (IL-12 were able to transfer disease. The ability of LNC to transfer disease was associated with the presence of inflammatory infiltrates in the CNS at day 12. Interferon gamma (IFNγ was produced at comparable levels in cell cultures prepared from mice at both day 6 and day 12 post immunization. By contrast, there was a trend towards a negative association between IL-17 and disease susceptibility in our EAE model. The amount of GM-CSF secreted was significantly increased in the culture supernatants from cells collected at day 12 post immunization versus those collected at day 6 post-immunization. Activated CD4+ T cells present in the day 12 LNC cultures maintained expression of the transcription factor T-bet, which has been shown to regulate the expression of the IL-23 receptor. Also, there was an increased prevalence of MOGp35-55-specific CD4+ T cells in day 12 LNC after in vitro re-stimulation. In summary, encephalitogenic LNC that adoptively transfer EAE in C57BL/6 mice were

  19. Lymph node-derived donor encephalitogenic CD4+ T cells in C57BL/6 mice adoptive transfer experimental autoimmune encephalomyelitis highly express GM-CSF and T-bet.

    Science.gov (United States)

    Cravens, Petra D; Hussain, Rehana Z; Zacharias, Tresa E; Ben, Li-Hong; Herndon, Emily; Vinnakota, Ramya; Lambracht-Washington, Doris; Nessler, Stefan; Zamvil, Scott S; Eagar, Todd N; Stüve, Olaf

    2011-06-24

    Experimental autoimmune encephalomyelitis (EAE) is a relevant animal model for the human demyelinating inflammatory disorder of the central nervous system (CNS), multiple sclerosis (MS). Induction of EAE by adoptive transfer allows studying the role of the donor T lymphocyte in disease pathogenesis. It has been challenging to reliably induce adoptive transfer EAE in C57BL/6 (H-2b) mice. The goal of this study was to develop a reproducible and high yield protocol for adoptive transfer EAE in C57BL/6 mice. A step-wise experimental approach permitted us to develop a protocol that resulted in a consistent relatively high disease incidence of ~70% in recipient mice. Donor mice were immunized with myelin oligodendrocyte glycoprotein (MOG)p35-55 in complete Freund's adjuvant (CFA) followed by pertussis toxin (PT). Only lymph node cells (LNC) isolated at day 12 post immunization, and restimulated in vitro for 72 hours with 10 μg/mL of MOGp35-55 and 0.5 ng/mL of interleukin-12 (IL-12) were able to transfer disease. The ability of LNC to transfer disease was associated with the presence of inflammatory infiltrates in the CNS at day 12. Interferon gamma (IFNγ) was produced at comparable levels in cell cultures prepared from mice at both day 6 and day 12 post immunization. By contrast, there was a trend towards a negative association between IL-17 and disease susceptibility in our EAE model. The amount of GM-CSF secreted was significantly increased in the culture supernatants from cells collected at day 12 post immunization versus those collected at day 6 post-immunization. Activated CD4+ T cells present in the day 12 LNC cultures maintained expression of the transcription factor T-bet, which has been shown to regulate the expression of the IL-23 receptor. Also, there was an increased prevalence of MOGp35-55-specific CD4+ T cells in day 12 LNC after in vitro re-stimulation. In summary, encephalitogenic LNC that adoptively transfer EAE in C57BL/6 mice were not characterized

  20. [Keratitis - Infectious or Autoimmune?].

    Science.gov (United States)

    Messmer, E M

    2016-07-01

    Histopathological evaluation of ocular tissues is important in differentiating between infectious and autoimmune disease. Inflammation, necrosis and keratolysis are common to most forms of keratitis. Histopathology can be of great help in identifying the causative organism, establishing a final diagnosis and/or managing the patient with herpes simplex virus keratitis, mycotic keratitis, acanthamoeba keratitis or microsporidia keratoconjunctivitis. Important pathogenetic knowledge with therapeutic relevance has been gained from histopathological studies in nummular keratitis after epidemic keratoconjunctivitis and atopic keratoconjunctivitis. Georg Thieme Verlag KG Stuttgart · New York.

  1. Vaccination and autoimmunity-'vaccinosis': a dangerous liaison?

    Science.gov (United States)

    Shoenfeld, Y; Aron-Maor, A

    2000-02-01

    The question of a connection between vaccination and autoimmune illness (or phenomena) is surrounded by controversy. A heated debate is going on regarding the causality between vaccines, such as measles and anti-hepatitis B virus (HBV), and multiple sclerosis (MS). Brain antibodies as well as clinical symptoms have been found in patients vaccinated against those diseases. Other autoimmune illnesses have been associated with vaccinations. Tetanus toxoid, influenza vaccines, polio vaccine, and others, have been related to phenomena ranging from autoantibodies production to full-blown illness (such as rheumatoid arthritis (RA)). Conflicting data exists regarding also the connection between autism and vaccination with measles vaccine. So far only one controlled study of an experimental animal model has been published, in which the possible causal relation between vaccines and autoimmune findings has been examined: in healthy puppies immunized with a variety of commonly given vaccines, a variety of autoantibodies have been documented but no frank autoimmune illness was recorded. The findings could also represent a polyclonal activation (adjuvant reaction). The mechanism (or mechanisms) of autoimmune reactions following immunization has not yet been elucidated. One of the possibilities is molecular mimicry; when a structural similarity exists between some viral antigen (or other component of the vaccine) and a self-antigen. This similarity may be the trigger to the autoimmune reaction. Other possible mechanisms are discussed. Even though the data regarding the relation between vaccination and autoimmune disease is conflicting, it seems that some autoimmune phenomena are clearly related to immunization (e.g. Guillain-Barre syndrome). The issue of the risk of vaccination remains a philosophical one, since to date the advantages of this policy have not been refuted, while the risk for autoimmune disease has not been irrevocably proved. We discuss the pros and cons of this

  2. An introduction to biomaterial-based strategies for curbing autoimmunity.

    Science.gov (United States)

    Lewis, Jamal S; Allen, Riley P

    2016-05-01

    Recently, scientists have made significant progress in the development of immunotherapeutics that correct aberrant, autoimmune responses. Yet, concerns about the safety, efficacy, and wide scale applicability continue to hinder use of contemporary, immunology-based strategies. There is a clear need for therapies that finely control molecular and cellular elements of the immune system. Biomaterial engineers have taken up this challenge to develop therapeutics with selective spatial and temporal control of immune cells. In this review, we introduce the immunology of autoimmune disorders, survey the current therapeutic strategies for autoimmune diseases, and highlight the ongoing research efforts to engineer the immune system using biomaterials, for positive therapeutic outcomes in treatment of autoimmune disorders. © 2016 by the Society for Experimental Biology and Medicine.

  3. Autoimmune diseases and myelodysplastic syndromes.

    Science.gov (United States)

    Komrokji, Rami S; Kulasekararaj, Austin; Al Ali, Najla H; Kordasti, Shahram; Bart-Smith, Emily; Craig, Benjamin M; Padron, Eric; Zhang, Ling; Lancet, Jeffrey E; Pinilla-Ibarz, Javier; List, Alan F; Mufti, Ghulam J; Epling-Burnette, Pearlie K

    2016-05-01

    Immune dysregulation and altered T-cell hemostasis play important roles in the pathogenesis of myelodysplastic syndromes (MDS). Recent studies suggest an increased risk of MDS among patients with autoimmune diseases. Here, we investigated the prevalence of autoimmune diseases among MDS patients, comparing characteristics and outcomes in those with and without autoimmune diseases. From our study group of 1408 MDS patients, 391 (28%) had autoimmune disease, with hypothyroidism being the most common type, accounting for 44% (n = 171) of patients (12% among all MDS patients analyzed). Other autoimmune diseases with ≥5% prevalence included idiopathic thrombocytopenic purpura in 12% (n = 46), rheumatoid arthritis in 10% (n = 41), and psoriasis in 7% (n = 28) of patients. Autoimmune diseases were more common in female MDS patients, those with RA or RCMD WHO subtype, and those who were less dependent on red blood cell transfusion. Median overall survival (OS) was 60 months (95% CI, 50-70) for patients with autoimmune diseases versus 45 months (95% CI, 40-49) for those without (log-rank test, P = 0.006). By multivariate analysis adjusting for revised IPSS and age >60 years, autoimmune diseases were a statistically significant independent factor for OS (HR 0.78; 95% CI, 0.66-0.92; P = 0.004). The rate of acute myeloid leukemia (AML) transformation was 23% (n = 89) in MDS patients with autoimmune disease versus 30% (n = 301) in those without (P = 0.011). Patient groups did not differ in response to azacitidine or lenalidomide treatment. Autoimmune diseases are prevalent among MDS patients. MDS patients with autoimmune diseases have better OS and less AML transformation. © 2016 Wiley Periodicals, Inc.

  4. Autoimmune liver disease and concomitant extrahepatic autoimmune disease.

    Science.gov (United States)

    Muratori, Paolo; Fabbri, Angela; Lalanne, Claudine; Lenzi, Marco; Muratori, Luigi

    2015-10-01

    To assess the frequency and clinical impact of associated extrahepatic autoimmune diseases (EAD) on autoimmune liver diseases (ALD). We investigated 608 patients with ALD (327 autoimmune hepatitis - AIH and 281 primary biliary cirrhosis - PBC) for concomitant EAD. In both AIH and PBC, we observed a high prevalence of EAD (29.9 and 42.3%, respectively); both diseases showed a significant association with autoimmune thyroid disease, followed by autoimmune skin disease, celiac disease, and vasculitis in AIH patients and sicca syndrome, CREST syndrome, and celiac disease in PBC patients. At diagnosis, AIH patients with concurrent EAD were more often asymptomatic than patients with isolated AIH (Pautoimmune thyroid disease. In the light of our results, all patients with an EAD should be assessed for the concomitant presence of an asymptomatic ALD.

  5. Autoimmunity in the pathogenesis of hypertension.

    Science.gov (United States)

    Rodríguez-Iturbe, Bernardo; Pons, Héctor; Quiroz, Yasmir; Lanaspa, Miguel A; Johnson, Richard J

    2014-01-01

    Hypertension affects more than one-third of the adult population of the world. However, the cause of high blood pressure is unknown in the vast majority of patients, classified as patients with essential hypertension. Evidence accumulated over the past decade supports the participation of inflammation in the development of experimental hypertension. Investigations have also demonstrated that immune reactivity to overexpressed heat shock protein 70 (HSP70) is involved in the pathogenesis of salt-induced hypertension. This article reviews, first, the role of T cell-induced inflammation in the arteries, kidney and central nervous system in hypertension and the amelioration of hypertension induced by regulatory T cells. Second, experiments showing that autoimmunity directed to HSP70 in the kidney impairs the pressure natriuresis relationship and has a pivotal role in the pathogenesis of salt sensitive hypertension. Finally, we highlight the clinical evidence that supports the participation of autoimmunity in essential hypertension.

  6. Th17 cells in autoimmune demyelinating disease.

    Science.gov (United States)

    Segal, Benjamin Matthew

    2010-03-01

    Recently published studies in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) have demonstrated an association between the development of demyelinating plaques and the accumulation of Th17 cells in the central nervous system and periphery. However, a causal relationship has been difficult to establish. In fact, in reports published thus far, interleukin (IL)-17A deficiency or neutralization in vivo attenuates, but does not completely abrogate, EAE. There is growing evidence that clinically similar forms of autoimmune demyelinating disease can be driven by myelin-specific T cells of distinct lineages with different degrees of dependence on IL-17A production to achieve their pathological effects. While such observations cast doubts about the potential therapeutic efficacy of Th17 blocking agents in MS, the collective data suggest that IL-17A expression in peripheral blood mononuclear cells could serve as a surrogate biomarker of neuroinflammation and plaque formation and be a useful outcome measure for future clinical trials.

  7. NMR and molecular dynamics studies of an autoimmune myelin basic protein peptide and its antagonist : structural implications for the MHC II (I-Au)–peptide complex from docking calculations

    NARCIS (Netherlands)

    Tzakos, A.G.; Fuchs, P.; van Nuland, N.A.J.; Troganis, A.; Tselios, T.; Deraos, S.; Gerothanassis, I.P.; Bonvin, A.M.J.J.

    2004-01-01

    Experimental autoimmune encephalomyelitis can be induced in susceptible animals by immunodominant determinants of myelin basic protein (MBP). To characterize the molecular features of antigenic sites important for designing experimental autoimmune encephalomyelitis suppressing molecules, we report

  8. [Hydroxychloroquine for autoimmune diseases].

    Science.gov (United States)

    Danza, Álvaro; Graña, Diego; Goñi, Mabel; Vargas, Andrea; Ruiz-Irastorza, Guillermo

    2016-02-01

    Hydroxychloroquine (HCQ) is by far the most frequently used antimalarial for the management of Systemic Autoimmune Diseases. It has immunomodulatory, hypolipidemic, hypoglycemic and antithrombotic properties and it diminishes the risk of malignancies. The most important mechanisms to explain the immunomodulatory actions are its ability to reduce inflammatory pathways and Toll-like receptors activation. The safety profile is favorable. In spite of its low frequency, retinal toxicity is potentially severe. In systemic lupus erythematous HCQ therapy reduces activity, the accrual of organ damage, risk of infections and thrombosis and improves the cardiometabolic profile. It contributes to induce lupus nephritis remission, spares steroid use and increases survival rates. In rheumatoid arthritis, it improves cardiometabolic risk and has a favorable effect in joint inflammation. In Sjögren's syndrome, an increased lacrimal quality as well as an improvement in objective and subjective inflammatory markers has been demonstrated with HCQ. In Antiphospholipid Syndrome, HCQ is effective in primary and secondary thrombosis prevention. The effectiveness of the drug in other systemic autoimmune diseases is less established. HCQ therapy may improve dermatological manifestations in Dermatomyositis and may have a positive effects in the treatment of Sarcoidosis and Still disease.

  9. Autoimmune hypophysitis: a study of natural course

    OpenAIRE

    Vijaya Sarathi; Anish Kolly

    2016-01-01

    Background: Autoimmune hypophysitis is a rare autoimmune endocrinopathy. Literature on natural history of autoimmune hypophysitis is scarce. Methods: We prospectively studied patients with autoimmune hypophysitis between January 2013 to June 2015 and all subjects were followed for at least 6 months. Autoimmune hypophysitis was diagnosed based on clinicoradiologic findings. All patients diagnosed with autoimmune hypophysitis were followed every three monthly with evaluation for pituitary fu...

  10. Is Tolerance Broken in Autoimmunity?

    Directory of Open Access Journals (Sweden)

    Dama Laxminarayana

    2017-11-01

    Full Text Available Autoimmune diseases are classified into about 80 different types based on their specificity related to system, organ and/or tissue. About 5% of the western population is affected by this anomaly, but its worldwide incidence is unknown. Autoimmune diseases are heterogeneous in nature and clinical manifestations range from benign disorders to life-threatening conditions. Autoimmunity strikes at any stage of life, but age and/or gender also play role in onset of some of these anomalies. The autoimmune pathogenesis is initiated by the origination of autoantigens, which leads to the development of autoantibodies followed by auto-immunogenicity and the ultimate onset of autoimmunity. There is a lack of suitable therapies to treat autoimmune diseases, because mechanisms involved in the onset of these anomalies were poorly understood. Present therapies are limited to symptomatic treatment and come with severe side effects. Here, I described the molecular mechanisms and cellular events involved in the initiation of autoimmunity and proposed better strategies to modulate such molecular and cellular anomalies, which will help in preventing and/or controlling autoimmune pathogenesis and ultimately aid in enhancing the quality of life.

  11. [Autoimmune hepatitis and CREST syndrome].

    Science.gov (United States)

    Ngo Mandag, N; Van Gossum, M; Rickaert, F; Golstein, M

    2007-01-01

    We report the case of an autoimmune hepatitis in a 59-year old woman who was referred for a progressive jaundice. The patient had an history of CREST syndrome. The particularity of this case report is the rare association between these two autoimmune diseases.

  12. Interferon gamma, interleukin 4 and transforming growth factor beta in experimental autoimmune encephalomyelitis in Lewis rats: dynamics of cellular mRNA expression in the central nervous system and lymphoid cells

    DEFF Research Database (Denmark)

    Issazadeh-Navikas, Shohreh; Mustafa, M; Ljungdahl, A

    1995-01-01

    The potential role of certain important immunoregulatory and effector cytokines in autoimmune neuroinflammation have been studied. We have examined the expression of mRNA, with in situ hybridization, of interferon gamma (IFN-gamma), interleukin 4 (IL-4) and transforming growth factor beta (TGF...

  13. Mechanism of action and efficacy of RX-111, a thieno[2,3-c]pyridine derivative and small molecule inhibitor of protein interaction with glycosaminoglycans (SMIGs), in delayed-type hypersensitivity, TNBS-induced colitis and experimental autoimmune encephalomyelitis

    Czech Academy of Sciences Publication Activity Database

    Harris, N.; Koppel, J.; Zsila, F.; Juhás, Štefan; Ilková, G.; Kogan, F. Y.; Lahmy, O.; Wildbaum, G.; Karin, N.; Zhuk, R.; Gregor, P.

    2016-01-01

    Roč. 65, č. 4 (2016), s. 285-294 ISSN 1023-3830 Institutional support: RVO:67985904 Keywords : small molecule drug * glycosaminoglycan * heparin binding protein * heparan sulfate * inflammation * autoimmune disease Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.659, year: 2016

  14. Spontaneous germinal centers and autoimmunity.

    Science.gov (United States)

    Domeier, Phillip P; Schell, Stephanie L; Rahman, Ziaur S M

    2017-02-01

    Germinal centers (GCs) are dynamic microenvironments that form in the secondary lymphoid organs and generate somatically mutated high-affinity antibodies necessary to establish an effective humoral immune response. Tight regulation of GC responses is critical for maintaining self-tolerance. GCs can arise in the absence of purposeful immunization or overt infection (called spontaneous GCs, Spt-GCs). In autoimmune-prone mice and patients with autoimmune disease, aberrant regulation of Spt-GCs is thought to promote the development of somatically mutated pathogenic autoantibodies and the subsequent development of autoimmunity. The mechanisms that control the formation of Spt-GCs and promote systemic autoimmune diseases remain an open question and the focus of ongoing studies. Here, we discuss the most current studies on the role of Spt-GCs in autoimmunity.

  15. A modular theory of autoimmunity.

    Science.gov (United States)

    Irie, Junichiro; Ridgway, William M

    2005-09-01

    The traditional overarching concept of disease pathogenesis entails the natural history of disease, i.e. the concept that any disease is a unified entity from beginning to termination. The concept of the natural history of disease encourages researchers and clinicians alike to conceptualize all clinical signs and symptoms in a patient as manifestations of a single disease process. Our experiences in dissecting the genetic control of autoimmune diseases and autoimmune phenotypes suggest that for many autoimmune processes, an alternative conceptual framework may be more useful. We term this approach a "modular" theory of autoimmunity. "Modules" are distinct, genetically controlled clinical or pathological phenotypes which can interact to construct a disease process. Modules may interact additively, synergistically, or antagonistically in any given individual. Multiple modules can coexist and produce unique disease phenotypes. We illustrate this concept with examples from the murine autoimmune model of type one diabetes, the nonobese diabetic (NOD) mouse.

  16. Psychoneuroimmunology - psyche and autoimmunity.

    Science.gov (United States)

    Ziemssen, Tjalf

    2012-01-01

    Psychoneuroimmunology is a relatively young field of research that investigates interactions between central nervous and immune system. The brain modulates the immune system by the endocrine and autonomic nervous system. Vice versa, the immune system modulates brain activity including sleep and body temperature. Based on a close functional and anatomical link, the immune and nervous systems act in a highly reciprocal manner. From fever to stress, the influence of one system on the other has evolved in an intricate manner to help sense danger and to mount an appropriate adaptive response. Over recent decades, reasonable evidence has emerged that these brain-to-immune interactions are highly modulated by psychological factors which influence immunity and autoimmune disease. For several diseases, the relevance of psychoneuroimmunological findings has already been demonstrated.

  17. Autoimmune premature ovarian failure

    Directory of Open Access Journals (Sweden)

    Beata Komorowska

    2017-02-01

    Full Text Available Premature ovarian failure (POF, also termed as primary ovarian insufficiency (POI, is a highly heterogenous condition affecting 0.5-3.0% of women in childbearing age. These young women comprise quite a formidable group with unique physical and psychological needs that require special attention. Premature ovarian senescence (POS in all of its forms evolves insidiously as a basically asymptomatic process, leading to complete loss of ovarian function, and POI/POF diagnoses are currently made at relatively late stages. Well-known and well-documented risk factors exist, and the presence or suspicion of autoimmune disorder should be regarded as an important one. Premature ovarian failure is to some degree predictable in its occurrence and should be considered while encountering young women with loss of menstrual regularity, especially when there is a concomitant dysfunction in the immune system.

  18. Autoimmune disease: A role for new anti-viral therapies?

    Science.gov (United States)

    Dreyfus, David H

    2011-12-01

    Many chronic human diseases may have an underlying autoimmune mechanism. In this review, the author presents a case of autoimmune CIU (chronic idiopathic urticaria) in stable remission after therapy with a retroviral integrase inhibitor, raltegravir (Isentress). Previous reports located using the search terms "autoimmunity" and "anti-viral" and related topics in the pubmed data-base are reviewed suggesting that novel anti-viral agents such as retroviral integrase inhibitors, gene silencing therapies and eventually vaccines may provide new options for anti-viral therapy of autoimmune diseases. Cited epidemiologic and experimental evidence suggests that increased replication of epigenomic viral pathogens such as Epstein-Barr Virus (EBV) in chronic human autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus Erythematosus (SLE), and multiple sclerosis (MS) may activate endogenous human retroviruses (HERV) as a pathologic mechanism. Memory B cells are the reservoir of infection of EBV and also express endogenous retroviruses, thus depletion of memory b-lymphocytes by monoclonal antibodies (Rituximab) may have therapeutic anti-viral effects in addition to effects on B-lymphocyte presentation of both EBV and HERV superantigens. Other novel anti-viral therapies of chronic autoimmune diseases, such as retroviral integrase inhibitors, could be effective, although not without risk. Copyright © 2011 Elsevier B.V. All rights reserved.

  19. Selfie: Autoimmunity, boon or bane.

    Science.gov (United States)

    Ahsan, Haseeb

    2017-01-01

    The immune system provides protection to tissues damaged by infectious microrganisms or physical damage. In autoimmune diseases, the immune system recognizes and attacks its own tissues, i.e., self-destruction. Various agents such as genetic factors and environmental triggers are thought to play a major role in the development of autoimmune diseases. A common feature of all autoimmune diseases is the presence of autoantibodies and inflammation, including mononuclear phagocytes, autoreactive T lymphocytes, and autoantibody producing B cells (plasma cells). It has long been known that B cells produce autoantibodies and, thereby, contribute to the pathogenesis of many autoimmune diseases. Autoimmune diseases can be classified as organ-specific or non-organ specific depending on whether the autoimmune response is directed against a particular tissue or against widespread antigens as in chronic inflammatory autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Both SLE and RA are characterized by the presence of autoantibodies which play a major role in their etiopathogenesis. SLE is characterized by circulating antibodies and immune complex deposition that can trigger an inflammatory damage in organs. RA is a progressive inflammatory disease in which T cells, B cells, and pro-inflammatory cytokines play a key role in its pathophysiology.

  20. Recent advances in understanding autoimmune thyroid disease

    DEFF Research Database (Denmark)

    Bliddal, Sofie; Nielsen, Claus Henrik; Feldt-Rasmussen, Ulla

    2017-01-01

    Autoimmune thyroid disease (AITD) is often observed together with other autoimmune diseases. The coexistence of two or more autoimmune diseases in the same patient is referred to as polyautoimmunity, and AITD is the autoimmune disease most frequently involved. The occurrence of polyautoimmunity has...

  1. [Stress and auto-immunity].

    Science.gov (United States)

    Delévaux, I; Chamoux, A; Aumaître, O

    2013-08-01

    The etiology of auto-immune disorders is multifactorial. Stress is probably a participating factor. Indeed, a high proportion of patients with auto-immune diseases report uncommon stress before disease onset or disease flare. The biological consequences of stress are increasingly well understood. Glucocorticoids and catecholamines released by hypothalamic-pituitary-adrenal axis during stress will alter the balance Th1/Th2 and the balance Th17/Treg. Stress impairs cellular immunity, decreases immune tolerance and stimulates humoral immunity exposing individuals to autoimmune disease among others. The treatment for autoimmune disease should include stress management. Copyright © 2012 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  2. Epigenetic alterations underlying autoimmune diseases.

    Science.gov (United States)

    Aslani, Saeed; Mahmoudi, Mahdi; Karami, Jafar; Jamshidi, Ahmad Reza; Malekshahi, Zahra; Nicknam, Mohammad Hossein

    2016-01-01

    Recent breakthroughs in genetic explorations have extended our understanding through discovery of genetic patterns subjected to autoimmune diseases (AID). Genetics, on the contrary, has not answered all the conundrums to describe a comprehensive explanation of causal mechanisms of disease etiopathology with regard to the function of environment, sex, or aging. The other side of the coin, epigenetics which is defined by gene manifestation modification without DNA sequence alteration, reportedly has come in to provide new insights towards disease apprehension through bridging the genetics and environmental factors. New investigations in genetic and environmental contributing factors for autoimmunity provide new explanation whereby the interactions between genetic elements and epigenetic modifications signed by environmental agents may be responsible for autoimmune disease initiation and perpetuation. It is aimed through this article to review recent progress attempting to reveal how epigenetics associates with the pathogenesis of autoimmune diseases.

  3. CARDIOVASCULAR MANIFESTATIONS IN AUTOIMMUNE DISEASES

    Directory of Open Access Journals (Sweden)

    Alina-Costina LUCA

    2016-06-01

    Full Text Available Involving systemic autoimmune diseases, they primarily affect the joints, muscles and connective tissues. Cardiovascular impairment is often common in these disease manifestations ranging from asymptomatic to life-situations in danger. Otherwise impaired cardiovascular reason may be the first presentation. This may require aggressive therapy immunosuppressed, therefore the diagnosis is very important for a good choice of therapy. This article discusses the cardiovascular manifestations of systemic autoimmune diseases, mainly rheumatic diseases, focusing on diagnosis and manangement cardiovascular implications.

  4. [Smoking and chronic autoimmune thyroiditis].

    Science.gov (United States)

    Buzoianu, Ioana Cristina; Arghir, Oana Cristina; Circo, E

    2010-01-01

    The chronic autoimmune thyroiditis are heterogeneous entities by the functional, lesional and evolutive point of view. Ethiopathogenic factors involved in chronic autoimmune thyroiditis are genetical factors, combines with environmental factors, hormonal factors, infectious factors etc. The exact role of smoking on the autoimmune mechanism is unclear, but smoking is known to have an antithyroid effect. Our study tries to estimate the influence of smoking on serum levels of antithyroid peroxidase antibodies and antithyroglobulin antibodies, in a group of patients with various clinical forms of chronic autoimmune thyroiditis. We studied a group consists of 310 patients with chronic autoimmune thyroiditis, hospitalised in the Endocrinology Department of Constanta County Hospital, between January 2006 - December 2009. We detected serum values of antithyroidperoxidase antibodies and antithyroglobulin antibodies of our patients. We also followed the age, sex and presence of smoking in our study group. For statistical processing of the data we use Student's t-test. In our study group 24.28% of patients were smokers. Serum levels of antithyroid peroxidase antibodies were significantly increased (p < 0.001) in the smokers patients, compared with the nonsmokers patients. Serum levels of antithyroglobulin antibodies were significantly increased (p < 0.01) in smokers patients, compared with those who were nonsmokers. Smoking increased the serum levels of antithyroid antibodies in patients with chronic autoimmune thyroiditis.

  5. Autoimmune Thyroiditis and Glomerulopathies

    Directory of Open Access Journals (Sweden)

    Domenico Santoro

    2017-06-01

    Full Text Available Autoimmune thyroiditis (AIT is generally associated with hypothyroidism. It affects ~2% of the female population and 0.2% of the male population. The evidence of thyroid function- and thyroid autoantibody-unrelated microproteinuria in almost half of patients with AIT and sometimes heavy proteinuria as in the nephrotic syndrome point to a link of AIT with renal disease. The most common renal diseases observed in AIT are membranous nephropathy, membranoproliferative glomerulonephritis, minimal change disease, IgA nephropathy, focal segmental glomerulosclerosis, antineutrophil cytoplasmic autoantibody (ANCA vasculitis, and amyloidosis. Different hypotheses have been put forward regarding the relationship between AIT and glomerulopathies, and several potential mechanisms for this association have been considered. Glomerular deposition of immunocomplexes of thyroglobulin and autoantibodies as well as the impaired immune tolerance for megalin (a thyrotropin-regulated glycoprotein expressed on thyroid cells are the most probable mechanisms. Cross-reactivity between antigens in the setting of genetic predisposition has been considered as a potential mechanism that links the described association between ANCA vasculitis and AIT.

  6. Autoimmune kidney diseases.

    Science.gov (United States)

    Segelmark, Mårten; Hellmark, Thomas

    2010-03-01

    The second most common cause of chronic renal failure is glomerulonephritis, which is a collective term used for numerous diseases with the common denominator of histological renal inflammation emanating from the glomerular tuft. Whether all forms of glomerulonephritis should be considered as autoimmune disease is debatable, but immune mechanisms are important in all of them. This review focuses on four relatively well delineated forms of primary glomerulonephritis: Goodpastures or anti-GBM disease, IgA nephritis, membranous nephropathy and membranoproliferative glomerulonephritis. The autoantibodies are directed either to molecules within the glomeruli, such as the glomerular basement membrane in anti-GBM disease and to the podocytes in membranous glomerulonephritis, or to components of the immune system such as C3 convertase in membranoproliferative glomerulonephritis and IgA in IgA nephritis. Differences in diagnostic practices and classification controversies obscure comparative epidemiological studies, but there seem to be huge differences between incidence rates between countries and over time, both genetic factors and infections seem to matter but strong indications for a role of other environmental factors are still lacking. 2009 Elsevier B.V. All rights reserved.

  7. Antiviral TRIMs: friend or foe in autoimmune and autoinflammatory disease?

    Science.gov (United States)

    Jefferies, Caroline; Wynne, Claire; Higgs, Rowan

    2011-08-25

    The concept that viral sensing systems, via their ability to drive pro-inflammatory cytokine and interferon production, contribute to the development of autoimmune and autoinflammatory disease is supported by a wide range of clinical and experimental observations. Recently, the tripartite motif-containing proteins (TRIMs) have emerged as having key roles in antiviral immunity - either as viral restriction factors or as regulators of pathways downstream of viral RNA and DNA sensors, and the inflammasome. Given their involvement in these pathways, we propose that TRIM proteins contribute to the development and pathology of autoimmune and autoinflammatory conditions, thus making them potential novel targets for therapeutic manipulation.

  8. AUTOIMMUNE EPIDERMAL BLISTERING DISEASES

    Directory of Open Access Journals (Sweden)

    Ana Maria Abreu Velez

    2013-11-01

    Full Text Available Autoimmune bullous skin diseases (ABDs are uncommon, potentially fatal diseases of skin and mucous membranes which are associated with deposits of autoantibodies and complement against distinct molecules of the epidermis and dermal/epidermal basement membrane zone (BMZ. These autoantibodies lead to a loss in skin molecular integrity, which manifests clinically as formation of blisters or erosions. In pemphigus vulgaris, loss of adhesion occurs within the epidermis. The pioneering work of Ernst H. Beutner, Ph.D. and Robert E. Jordon, M.D. confirmed the autoimmune nature of these diseases. Walter F. Lever, M.D. contributed significantly to our understanding of the histopathologic features of these diseases. Walter Lever, M.D. and Ken Hashimoto, M.D. contributed electron microscopic studies of these diseases, especially in pemphigus vulgaris and bullous pemphigoid. In bullous pemphigoid (BP, linear IgA bullous dermatosis, epidermolysis bullosa acquisita (EBA and dermatitis herpetiformis (DH, loss of adhesion takes place within or underneath the BMZ. Classic EBA demonstrates extensive skin fragility; DH is commonly associated with gluten-sensitive enteropathy, and manifests clinically with pruritic papulovesicles on the extensor surfaces of the extremities and the lumbosacral area. The clinical spectrum of bullous pemphigoid includes tense blisters, urticarial plaques, and prurigo-like eczematous lesions. Pemphigoid gestationis mostly occurs during the last trimester of pregnancy, and mucous membrane pemphigoid primarily involves the oral mucosa and conjunctivae and leads to scarring. Linear IgA bullous dermatosis manifests with tense blisters in a „cluster of jewels”-like pattern in childhood (chronic bullous disease of childhood and is more clinically heterogeneous in adulthood. Many of the autoantigens in these disorders are known and have been well characterized. ABDs may be influenced by both genetic and exogenous factors. The diagnoses of

  9. Autoimmune hepatitis in association with lymphocytic colitis.

    LENUS (Irish Health Repository)

    Cronin, Edmond M

    2012-02-03

    Autoimmune hepatitis is a rare, chronic inflammatory disorder which has been associated with a number of other auto-immune conditions. However, there are no reports in the medical literature of an association with microscopic (lymphocytic) colitis. We report the case of a 53-year-old woman with several autoimmune conditions, including lymphocytic colitis, who presented with an acute hepatitis. On the basis of the clinical features, serology, and histopathology, we diagnosed autoimmune hepatitis. To our knowledge, this is the first report of autoimmune hepatitis in association with lymphocytic colitis, and lends support to the theory of an autoimmune etiology for lymphocytic colitis.

  10. Type 1 autoimmune pancreatitis

    Directory of Open Access Journals (Sweden)

    Zen Yoh

    2011-12-01

    Full Text Available Abstract Before the concept of autoimmune pancreatitis (AIP was established, this form of pancreatitis had been recognized as lymphoplasmacytic sclerosing pancreatitis or non-alcoholic duct destructive chronic pancreatitis based on unique histological features. With the discovery in 2001 that serum IgG4 concentrations are specifically elevated in AIP patients, this emerging entity has been more widely accepted. Classical cases of AIP are now called type 1 as another distinct subtype (type 2 AIP has been identified. Type 1 AIP, which accounts for 2% of chronic pancreatitis cases, predominantly affects adult males. Patients usually present with obstructive jaundice due to enlargement of the pancreatic head or thickening of the lower bile duct wall. Pancreatic cancer is the leading differential diagnosis for which serological, imaging, and histological examinations need to be considered. Serologically, an elevated level of IgG4 is the most sensitive and specific finding. Imaging features include irregular narrowing of the pancreatic duct, diffuse or focal enlargement of the pancreas, a peri-pancreatic capsule-like rim, and enhancement at the late phase of contrast-enhanced images. Biopsy or surgical specimens show diffuse lymphoplasmacytic infiltration containing many IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis. A dramatic response to steroid therapy is another characteristic, and serological or radiological effects are normally identified within the first 2 or 3 weeks. Type 1 AIP is estimated as a pancreatic manifestation of systemic IgG4-related disease based on the fact that synchronous or metachronous lesions can develop in multiple organs (e.g. bile duct, salivary/lacrimal glands, retroperitoneum, artery, lung, and kidney and those lesions are histologically identical irrespective of the organ of origin. Several potential autoantigens have been identified so far. A Th2-dominant immune reaction and the activation of

  11. Kidney transplantation during autoimmune diseases.

    Science.gov (United States)

    Ounissi, M; Abderrahim, E; Hedri, H; Sfaxi, M; Fayala, H; Turki, S; Ben Maïz, H; Ben Abdallah, T; Chebil, M; Kheder, A

    2009-09-01

    Herein, we report the results of kidney transplantation in 9 of 376 patients who underwent kidney transplantation at our center between 1986 and 2007 because of chronic renal failure associated with autoimmune disease. Four of the 9 patients had systemic lupus erythematosus, 3 had Wegener granulomatosis, and 2 had Goodpasture syndrome. Six patients received organs from living donors, and 3 received cadaver organs. Infections were frequent and included cytomegalovirus and urinary tract infection in most cases. There was no difference in occurrence of metabolic and cardiovascular complications in our study patients compared with other transplant recipients. Incidence of allograft loss (n = 1) was similar to that in our entire transplantation population, with an overall rate of 2.9%. We conclude that kidney transplantation is a reasonable therapeutic option in patients with autoimmune disease with end-stage renal disease because of good graft and patient survival compared with kidney recipients without autoimmune diseases.

  12. A minimum number of autoimmune T cells to induce autoimmunity?

    Czech Academy of Sciences Publication Activity Database

    Bosch, A.J.T.; Bolinger, B.; Keck, S.; Štěpánek, Ondřej; Ozga, A.J.; Galati-Fournier, V.; Stein, J.V.; Palmer, E.

    2017-01-01

    Roč. 316, jaro (2017), s. 21-31 ISSN 0008-8749 R&D Projects: GA ČR GJ16-09208Y Institutional support: RVO:68378050 Keywords : T cell * Tolerance * Autoimmunity Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.172, year: 2016

  13. Genetics Home Reference: autoimmune Addison disease

    Science.gov (United States)

    ... features of other genetic conditions, including X-linked adrenoleukodystrophy and autoimmune polyglandular syndrome, type 1, which are ... disease Patient Support and Advocacy Resources (3 links) Adrenoleukodystrophy Foundation American Autoimmune Related Diseases Association National Adrenal ...

  14. Shaking Out Clues to Autoimmune Disease

    Science.gov (United States)

    ... of Autoimmunity-Causing T Cells Landmark Analysis Probes Nature vs. Nurture in Multiple Sclerosis Understanding Autoimmune Diseases Immune Cells References: Nature. 2013 Mar 6. doi: 10.1038/nature11981. [Epub ...

  15. Multiple autoimmune syndrome with celiac disease.

    Science.gov (United States)

    Harpreet, Singh; Deepak, Jain; Kiran, B

    2016-01-01

    Multiple autoimmune syndrome (MAS) is a condition characterised by three or more autoimmune disorders in a same individual. Familial, immunologic and infectious factors are implicated in the development of MAS. Here we report a case of a 32-year-old woman with co-existence of four auto-immune diseases, namely autoimmune hypothyroidism, Sjögren's syndrome, systemic lupus erythematosus (SLE) and celiac disease which leads to the final diagnosis of multiple autoimmune syndrome type 3 with celiac disease. Patients with single autoimmune disorder are at 25% risk of developing other autoimmune disorders. The present case emphasises to clinicians that there is a need for continued surveillance for the development of new autoimmune disease in predisposed patients.

  16. Perception of self : Distinguishing autoimmunity from autoinflammation

    NARCIS (Netherlands)

    Van Kempen, Tessa S.; Wenink, Mark H.; Leijten, Emmerik F A; Radstake, Timothy R D J; Boes, Marianne

    2015-01-01

    Rheumatic diseases can be divided in two groups, autoinflammatory and autoimmune disorders. The clinical presentation of both types of diseases overlap, but the pathological pathways underlying rheumatic autoinflammation and autoimmunity are distinct and are the subject of ongoing research. There

  17. An autosomal locus causing autoimmune disease: Autoimmune polyglandular disease type I assigned to chromosome 21

    NARCIS (Netherlands)

    J. Aaltonen (Johanna); P. Björses (Petra); L.A. Sandkuijl (Lodewijk); J. Perheentupa (Jaakko); L. Peltonen (Leena Johanna)

    1994-01-01

    textabstractAutoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease characterized by a variable combination of the failure of the endocrine glands. The pathogenesis of this unique autoimmune disease is unknown; unlike many other autoimmune diseases, APECED does

  18. Multiplex autoantibody detection for autoimmune liver diseases and autoimmune gastritis.

    Science.gov (United States)

    Vanderlocht, Joris; van der Cruys, Mart; Stals, Frans; Bakker-Jonges, Liesbeth; Damoiseaux, Jan

    2017-09-01

    Autoantibody detection for autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and autoimmune gastritis (AIG) is traditionally performed by IIF on a combination of tissues. Multiplex line/dot blots (LIA/DIA) offer multiple advantages, i.e. automation, objective reading, no interfering reactivities, no coincidental findings. In the current study we evaluated automated DIA (D-Tek) for detecting autoantibodies related to autoimmune diseases of the gastrointestinal tract. We tested samples of the Dutch EQC program and compared the results with the consensus of the participating labs. For the autoimmune liver diseases and AIG, respectively, 64 and 36 samples were tested. For anti-mitochondrial and anti-smooth muscle antibodies a concordance rate of 97% and 88% was observed, respectively. The concordance rate for anti-parietal cell antibodies was 92% when samples without EQC consensus (n=15) were excluded. For antibodies against intrinsic factor a concordance of 96% was observed. For all these antibodies discrepancies were identified that relate to the different test characteristics and the preponderance of IIF utilizing labs in the EQC program. In conclusion, we observed good agreement of the tested DIA blots with the consensus results of the Dutch EQC program. Taken together with the logistic advantages these blots are a good alternative for autoantibody detection in the respective diseases. A large prospective multicenter study is warranted to position these novel tests further in the whole spectrum of assays for the detection of these antibodies in a routine autoimmune laboratory. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Cacao polyphenols ameliorate autoimmune myocarditis in mice.

    Science.gov (United States)

    Zempo, Hirofumi; Suzuki, Jun-ichi; Watanabe, Ryo; Wakayama, Kouji; Kumagai, Hidetoshi; Ikeda, Yuichi; Akazawa, Hiroshi; Komuro, Issei; Isobe, Mitsuaki

    2016-04-01

    Myocarditis is a clinically severe disease; however, no effective treatment has been established. The aim of this study was to determine whether cacao bean (Theobroma cacao) polyphenols ameliorate autoimmune myocarditis. We used an experimental autoimmune myocarditis (EAM) model in Balb/c mice. Mice with induced EAM were treated with a cacao polyphenol extract (CPE, n=12) or vehicle (n=12). On day 21, hearts were harvested and analyzed. Elevated heart weight to body weight and fibrotic area ratios as well as high cardiac cell infiltration were observed in the vehicle-treated EAM mice. However, these increases were significantly suppressed in the CPE-treated mice. Reverse transcriptase-PCR revealed that mRNA expressions of interleukin (Il)-1β, Il-6, E-selectin, vascular cell adhesion molecule-1 and collagen type 1 were lower in the CPE group compared with the vehicle group. The mRNA expressions of nicotinamide adenine dinucleotide phosphate-oxidase (Nox)2 and Nox4 were increased in the vehicle-treated EAM hearts, although CPE treatment did not significantly suppress the transcription levels. However, compared with vehicle treatment of EAM hearts, CPE treatment significantly suppressed hydrogen peroxide concentrations. Cardiac myeloperoxidase activity, the intensity of dihydroethidium staining and the phosphorylation of nuclear factor-κB p65 were also lower in the CPE group compared with the vehicle group. Our data suggest that CPE ameliorates EAM in mice. CPE is a promising dietary supplement to suppress cardiovascular inflammation and oxidative stress.

  20. Autoimmune hemolytic anemia: transfusion challenges and solutions

    Directory of Open Access Journals (Sweden)

    Barros MM

    2017-03-01

    Full Text Available Melca M O Barros, Dante M Langhi Jr, José O Bordin Department of Clinical and Experimental Oncology, Universidade Federal de São Paulo, São Paulo, Brazil Abstract: Autoimmune hemolytic anemia (AIHA is defined as the increased destruction of red blood cells (RBCs in the presence of anti-RBC autoantibodies and/or complement. Classification of AIHA is based on the optimal auto-RBC antibody reactivity temperatures and includes warm, cold-reactive, mixed AIHA, and drug-induced AIHA subtypes. AIHA is a rare disease, and recommendations for transfusion are based mainly on results from retrospective data and relatively small cohort studies, including heterogeneous patient samples or single case reports. In this article, we will review the challenges and solutions to safely transfuse AIHA patients. We will reflect on the indication for transfusion in AIHA and the difficulty in the accomplishment of immunohematological procedures for the selection of the safest and most compatible RBC units. Keywords: hemolytic anemia, RBC autoantibodies, autoimmunity, hemolysis, direct ­antiglobulin test

  1. [Seronegative systemic lupus erythematosus and autoimmune thyroiditis].

    Science.gov (United States)

    González-Gay, M A; Cereijo, M J; Agüero, J J; Alonso, M D; Fernández Sueiro, J L; Vidal, J I

    1993-08-01

    The association of systemic lupus erythematosus (SLE) and autoimmune thyroiditis has been previously described. We report a woman with negative antinuclear antibodies (ANA) and criteria for the diagnosis of SLE. The patient was also diagnosed with autoimmune thyroiditis. We review the clinical characteristics and the association of both entities. We also remark in this case the association of autoimmune thyroiditis with seronegative SLE.

  2. Aldosterone promotes autoimmune damage by enhancing Th17-mediated immunity.

    Science.gov (United States)

    Herrada, Andrés A; Contreras, Francisco J; Marini, Natacha P; Amador, Cristian A; González, Pablo A; Cortés, Claudia M; Riedel, Claudia A; Carvajal, Cristián A; Figueroa, Fernando; Michea, Luis F; Fardella, Carlos E; Kalergis, Alexis M

    2010-01-01

    Excessive production of aldosterone leads to the development of hypertension and cardiovascular disease by generating an inflammatory state that can be promoted by T cell immunity. Because nature and intensity of T cell responses is controlled by dendritic cells (DCs), it is important to evaluate whether the function of these cells can be modulated by aldosterone. In this study we show that aldosterone augmented the activation of CD8(+) T cells in a DC-dependent fashion. Consistently, the mineralocorticoid receptor was expressed by DCs, which showed activation of MAPK pathway and secreted IL-6 and TGF-beta in response to aldosterone. In addition, DCs stimulated with aldosterone impose a Th17 phenotype to CD4(+) T cells, which have recently been associated with the promotion of inflammatory and autoimmune diseases. Accordingly, we observed that aldosterone enhances the progression of experimental autoimmune encephalomyelitis, an autoimmune disease promoted by Th17 cells. In addition, blockade of the mineralocorticoid receptor prevented all aldosterone effects on DCs and attenuated experimental autoimmune encephalomyelitis development in aldosterone-treated mice. Our data suggest that modulation of DC function by aldosterone enhances CD8(+) T cell activation and promotes Th17-polarized immune responses, which might contribute to the inflammatory damage leading to hypertension and cardiovascular disease.

  3. Levamisole toxicity mimicking autoimmune disease.

    Science.gov (United States)

    Strazzula, Lauren; Brown, Katherine K; Brieva, Joaquin C; Camp, Brendan J; Frankel, Hillary C; Kissin, Eugene; Mahlberg, Matthew J; Mina, Mary Alice; Pomeranz, Miriam K; Brownell, Isaac; Kroshinsky, Daniela

    2013-12-01

    Levamisole is present as a contaminant or additive in most cocaine sold in the United States. Cases of agranulocytosis attributed to levamisole-tainted cocaine have been widely described. A vasculopathic reaction to levamisole has also been reported; however, diagnostic features such as antineutrophil cytoplasmic antibody (ANCA) and additional autoimmune marker positivity are not well recognized. As such, many patients are given a misdiagnosis, prompting aggressive and often unnecessary treatment. We hope to educate practitioners about the clinical and laboratory features of levamisole-induced vasculopathy to ensure accurate diagnosis and management. This was a case series. Six patients were admitted with purpuric lesions and vasculitic changes on biopsy specimen; 5 of them were given the diagnosis of and treated for autoimmune conditions before their true diagnosis was revealed. All patients had ANCA positivity, and 4 had additional abnormalities in autoimmune markers. All patients reported recent cocaine abuse, and were ultimately given the diagnosis of levamisole-induced vasculopathy. This observational study is limited by sample size. Patients presenting with purpuric lesions with ANCA positivity should be assessed for cocaine exposure. It is important to recognize that levamisole may not only induce ANCA positivity but also other autoimmune marker abnormalities. Patients can often be treated with less aggressive therapeutic strategies than what is used for primary ANCA-associated vasculitides. Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  4. Vernal keratoconjunctivitis: atopy and autoimmunity.

    Science.gov (United States)

    Zicari, A M; Nebbioso, M; Lollobrigida, V; Bardanzellu, F; Celani, C; Occasi, F; Cesoni Marcelli, A; Duse, M

    2013-05-01

    Vernal Keratoconjunctivitis (VKC) is a rare chronic ocular inflammatory disease and it mainly affects boys in the first decade of life. Although it is a self-limiting disease, patients may present many phases characterized by an exacerbation of inflammatory symptoms with a consequent decline of the quality of life. define the clinical and immunological profile of patients affected by VKC and investigate their familiar history of autoimmune disorders and their autoimmunity pattern. 28 children were enrolled (20 males, 71%) aged between 4 and 14 years of life affected by VKC. Family history of allergic and immunological diseases was collected for each patient. In particular, it was asked whether some components of their families were affected by Hashimoto's thyroiditis, type I diabetes, psoriasis or rheumatoid arthritis and Systemic Lupus Erythematosus (SLE). All VKC children underwent a serological evaluation of anti-nuclear antibodies (ANA). A family history of immunological disorders was found in 46% of patients, 28% of Hashimoto's thyroiditis, 14% of type I diabetes, 14% of psoriasis, and 1 of Systemic Lupus Erythematosus. Furthermore, 35% of patients was ANA positive and they corresponded to patients with a higher ocular score and with the most important clinical symptoms. the detection of ANA positivity and of a familiar history of autoimmune disorders in a high percentage of children with VKC may help us to better understand the association of this ocular inflammatory disease with systemic autoimmune disorders and atopic condition.

  5. Polyautoimmunity and familial autoimmunity in systemic sclerosis.

    Science.gov (United States)

    Hudson, Marie; Rojas-Villarraga, Adriana; Coral-Alvarado, Paola; López-Guzmán, Silvia; Mantilla, Ruben D; Chalem, Philippe; Baron, Murray; Anaya, Juan-Manuel

    2008-09-01

    Characterization of the extent to which particular combinations of autoimmune diseases occur in excess of that expected by chance may offer new insights into possible common pathophysiological mechanisms. The goal of this study was to investigate the spectrum of polyautoimmunity (i.e. autoimmune diseases co-occurring within patients) and familial autoimmunity (i.e. diverse autoimmune diseases co-occurring within families) in patients with systemic sclerosis (SSc). A cross-sectional study of two convenience samples of patients with SSc, one in Canada and the other in Colombia, was performed. History of other autoimmune diseases in the SSc patients as well as a family history of autoimmunity was obtained. Of 719 patients, 273 (38%) had at least one other autoimmune disease. A total of 366 autoimmune diseases were reported, of which the most frequent were autoimmune thyroid disease (AITD, 38%), rheumatoid arthritis (RA, 21%), Sjögren's syndrome (18%), and primary biliary cirrhosis (4%). There were 260 (36%) patients with first-degree relatives with at least one autoimmune disease, of which the most frequent were RA (18%) and AITD (9%). Having at least one first-degree relative with autoimmune disease was a significant predictor of polyautoimmunity in SSc patients. No significant differences in polyautoimmunity or familial autoimmunity were noted between diffuse and limited subsets of disease. Our results indicate that polyautoimmunity is frequent in patients with SSc and autoimmune diseases cluster within families of these patients. Clinically different autoimmune phenotypes might share common susceptibility variants, which acting in epistatic pleiotropy may represent risk factors for autoimmunity.

  6. Rheumatic Manifestations in Autoimmune Liver Disease.

    Science.gov (United States)

    Selmi, Carlo; Generali, Elena; Gershwin, Merrill Eric

    2018-02-01

    Autoimmune liver diseases coexist with rheumatic disorders in approximately 30% of cases and may also share pathogenic mechanisms. Autoimmune liver diseases result from an immune-mediated injury of different tissues, with autoimmune hepatitis (AIH) targeting hepatocytes, and primary biliary cholangitis (PBC) and primary sclerosing cholangitis targeting cholangiocytes. Sjogren syndrome is diagnosed in 7% of AIH cases and serologic autoimmunity profiles are a common laboratory abnormality, particularly in the case of serum antimitochondrial (PBC) or anti-liver kidney microsomal antibodies (AIH). Therapeutic strategies may overlap between rheumatic and autoimmune liver diseases and practitioners should be vigilant in managing bone loss. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. AIRE-mutations and autoimmune disease.

    Science.gov (United States)

    Bruserud, Øyvind; Oftedal, Bergithe E; Wolff, Anette B; Husebye, Eystein S

    2016-12-01

    The gene causing the severe organ-specific autoimmune disease autoimmune polyendocrine syndrome type-1 (APS-1) was identified in 1997 and named autoimmune regulator (AIRE). AIRE plays a key role in shaping central immunological tolerance by facilitating negative selection of T cells in the thymus, building the thymic microarchitecture, and inducing a specific subset of regulatory T cells. So far, about 100 mutations have been identified. Recent advances suggest that certain mutations located in the SAND and PHD1 domains exert a dominant negative effect on wild type AIRE resulting in milder seemingly common forms of autoimmune diseases, including pernicious anemia, vitiligo and autoimmune thyroid disease. These findings indicate that AIRE also contribute to autoimmunity in more common organ-specific autoimmune disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. The role of the autoimmunity laboratory in autoimmune diseases

    Directory of Open Access Journals (Sweden)

    SS Hasson

    2012-04-01

    Full Text Available Laboratory testing is of great value when evaluating a patient with a suspected autoimmune disease. The results can confirm a diagnosis, estimate disease severity, aid in assessing prognosis and are useful to follow disease activity. Components of the laboratory exam include complete blood count with differential, comprehensive metabolic panel, inflammatory markers, autoantibodies, and flow cytometry. Currently, autoimmunity laboratories are very vibrant owing to the constant and increasing availability of new tests, mainly due to the detection of new autoantibodies. The main characteristic that differentiates the autoimmunity laboratory from other laboratories is the use of immunoassays such as enzyme-linked immunosorbent assay (ELISA, as basic techniques which determines antibodies (autoantibodies and not antigens. For this reason, immunoassay techniques must employ antigens as reagents. However, over the last few years, a significant trend at autoimmunity laboratories has been the gradual replacement of immunofluorescence microscopy by immunoassay. Nowadays the revolution of new technology has taken place significantly, for examples; recombinant DNA technology has allowed the production of large quantities of antigens for autoantibody analysis. Flow cytometry for the analysis of microsphere-based immunoassays allows the simultaneous measurement of several autoantibodies. In the same way, autoantigen microarrays provide a practical means to analyse biological fluids in the search for a high number of autoantibodies. We are now at the beginning of an era of multiplexed analysis, with a high capacity of autoantibody specificities. The future tendency in this field will include immunoassays with greater analytical sensitivity, specificity, simultaneous multiplexed capability, the use of protein microarrays, and the use of other technologies such as microfluidics.

  9. Definition of human autoimmunity--autoantibodies versus autoimmune disease.

    Science.gov (United States)

    Lleo, Ana; Invernizzi, Pietro; Gao, Bin; Podda, Mauro; Gershwin, M Eric

    2010-03-01

    The critical function of the immune system is to discriminate self from non-self. Tolerance against self-antigens is a highly regulated process and, in order to maintain it, the immune system must be able to distinguish self-reactive lymphocytes as they develop. The presence of autoantibodies is the consequence of breakdown of tolerance and, although they are an important serological feature of autoimmune diseases, their presence is not exclusive of these conditions. Antibodies against self-antigens are also found in cancer, during massive tissue damage and even in healthy subjects. Natural autoantibodies provide immediate protection against infection and also prevent inflammation by facilitating the clearance of oxidized lipids, oxidized proteins, and apoptotic cells; their role in development of autoimmunity is still unclear. Detection of serum autoantibodies in clinical practice has become more available to clinicians worldwide while providing a powerful diagnostic tool. This review discusses the clinical significance of autoantibodies, their pathogenic mechanisms in autoimmune diseases and, finally, illustrates the technology available for appropriate autoantibody detection. 2009 Elsevier B.V. All rights reserved.

  10. The Fos-Related Antigen 1–JUNB/Activator Protein 1 Transcription Complex, a Downstream Target of Signal Transducer and Activator of Transcription 3, Induces T Helper 17 Differentiation and Promotes Experimental Autoimmune Arthritis

    Directory of Open Access Journals (Sweden)

    Young-Mee Moon

    2017-12-01

    Full Text Available Dysfunction of T helper 17 (Th17 cells leads to chronic inflammatory disorders. Signal transducer and activator of transcription 3 (STAT3 orchestrates the expression of proinflammatory cytokines and pathogenic cell differentiation from interleukin (IL-17-producing Th17 cells. However, the pathways mediated by STAT3 signaling are not fully understood. Here, we observed that Fos-related antigen 1 (FRA1 and JUNB are directly involved in STAT3 binding to sites in the promoters of Fosl1 and Junb. Promoter binding increased expression of IL-17 and the development of Th17 cells. Overexpression of Fra1 and Junb in mice resulted in susceptibility to collagen-induced arthritis and an increase in Th17 cell numbers and inflammatory cytokine production. In patients with rheumatoid arthritis, FRA1 and JUNB were colocalized with STAT3 in the inflamed synovium. These observations suggest that FRA1 and JUNB are associated closely with STAT3 activation, and that this activation leads to Th17 cell differentiation in autoimmune diseases and inflammation.

  11. Autoimmune regulator expression in thymomas with or without autoimmune disease.

    Science.gov (United States)

    Liu, Yimei; Zhang, Hui; Zhang, Peng; Meng, Fanjie; Chen, Yuan; Wang, Yuanguo; Yao, Yuanyuan; Qi, Bin

    2014-09-01

    The autoimmune regulator (AIRE) regulates autoimmunity and self-antigen expression, such as acetylcholine receptor (AchR), in the thymus. Regulatory T cells (Tregs) can down-regulate autoimmunity, but also promote tumor growth. The objective of this study was to examine the levels of AIRE, AchR, and Foxp3 expression in thymomas. The relative levels of AIRE, AchR, and Foxp3 mRNA transcripts and the frequency of AIRE+, AchR+, and Foxp3+ cells were determined by quantitative RT-PCR and immunohistochemistry in 79 thymoma tissue samples from 21 patients with simple thymoma (the Tm group), 39 patients with myasthenia gravis (the MG group) and 19 patients with myasthenia gravis and one other autoimmune disease (the AD group). The numbers of peripheral blood CD4+CD25+Foxp3+ Tregs were determined by flow cytometry analysis. The relative levels of AIRE and AchR mRNA transcripts in the MG group were significantly lower than that in the Tm group (p=0.04, p=0.03), but higher than that in the AD group (p=0.03, p=0.04). The relative levels of Foxp3 mRNA transcripts in the Tm group were significantly higher than that in the MG and AD groups (p=0.03 for both). A similar pattern of the percentages of AIRE+, AchR+, and Foxp3+ cells in the thymoma tissues and the numbers of peripheral blood Tregs were detected in these patients. The levels of AIRE mRNA transcripts were correlated positively with that of the AchR and Foxp3 in this population. The levels of AIRE and AchR mRNA transcripts in the A/AB/B1 types of thymomas were significantly higher than that in the B2/B3/C types of thymomas in this population. Significantly lower levels of AIRE, AchR, and Foxp3 expression are associated with the development of thymoma-related autoimmune diseases. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. Proteomics and autoimmune kidney disease.

    Science.gov (United States)

    Rovin, Brad H; Klein, Jon B

    2015-11-01

    Proteomics has long been considered an ideal platform, and urine an ideal source for biomarker discovery in human autoimmune kidney diseases. A number of studies have examined the urine proteome to identify biomarkers of disease activity, kidney pathology, and response to therapy. Increasingly, proteomic studies of kidney disease have expanded to include blood, circulating cells and kidney tissue. Recently the clinical potential of renal proteomics has been realized through a handful of investigations whose results appear to be applicable to patient care. In this review, approaches to the proteomic evaluation of autoimmune kidney diseases will be considered in the context of developing clinically useful disease biomarkers. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Autoimmune encephalitis and sleep disorders

    Directory of Open Access Journals (Sweden)

    Yan HUANG

    2017-10-01

    Full Text Available Research shows that autoimmune encephalitis is associated with sleep disorders. Paraneoplastic neurological syndrome (PNS with Ma2 antibodies can cause sleep disorders, particularly narcolepsy and rapid eye movement sleep behavior disorder (RBD. Limbic encephalitis (LE and Morvan syndrome, associated with voltage - gated potassium channel (VGKC-complex antibodies, which include leucine-rich glioma-inactivated 1 (LGI1 antibody and contactin-associated protein 2 (Caspr2, can result in profound insomnia and other sleep disorders. Central neurogenic hypoventilation are found in patients with anti-N-methyl-D-aspartate (NMDA receptor encephalitis, whereas obstructive sleep apnea (OSA, stridor and parasomnia are prominent features of encephalopathy associated with IgLON5 antibodies. Sleep disorders are cardinal manifestations in patients with autoimmune encephalitis. Immunotherapy possiblely can improve clinical symptoms and prognosis in a positive way. DOI: 10.3969/j.issn.1672-6731.2017.10.004

  14. CARDIOVASCULAR MANIFESTATIONS IN AUTOIMMUNE DISEASES

    OpenAIRE

    Alina-Costina LUCA; Constantin IORDACHE; Mariana PĂGUȚE

    2016-01-01

    Involving systemic autoimmune diseases, they primarily affect the joints, muscles and connective tissues. Cardiovascular impairment is often common in these disease manifestations ranging from asymptomatic to life-situations in danger. Otherwise impaired cardiovascular reason may be the first presentation. This may require aggressive therapy immunosuppressed, therefore the diagnosis is very important for a good choice of therapy. This article discusses the cardiovascular manifestations of sys...

  15. Helminth Immunomodulation in Autoimmune Disease

    OpenAIRE

    John J. Miles; John J. Miles; John J. Miles; John J. Miles; Taylor B. Smallwood; Paul R. Giacomin; Alex Loukas; Jason P. Mulvenna; Jason P. Mulvenna; Jason P. Mulvenna; Richard J. Clark

    2017-01-01

    Helminths have evolved to become experts at subverting immune surveillance. Through potent and persistent immune tempering, helminths can remain undetected in human tissues for decades. Redirecting the immunomodulating “talents” of helminths to treat inflammatory human diseases is receiving intensive interest. Here, we review therapies using live parasitic worms, worm secretions, and worm-derived synthetic molecules to treat autoimmune disease. We review helminth therapy in both mouse models ...

  16. Migraine in Systemic Autoimmune Diseases.

    Science.gov (United States)

    Cinzia, Cavestro; Marcella, Ferrero

    2017-11-24

    Migraine and systemic autoimmune diseases are 2-3-fold more common in women and various studies have reported an association between the two pathologies. This review takes into account epidemiological studies involving migraine and systemic lupus erythematosus, antiphospholipid syndrome, Sjogren's syndrome, and other diffuse connective tissue diseases. This scientific literature analysis consists of the main articles found in Medline with a search up to April 2017. Many epidemiological studies were carried out on patients suffering from systemic lupus erythematosus. Results showed that headache and migraine are more prevalent in systemic lupus erythematosus patients compared to controls, especially migraine with aura. Patients with Lupus and migraine show a higher lupus activity and association with Raynaud and/or antiphospholipids in these populations are contradictory. There are not enough data to establish an association between antiphospholipid syndrome and migraine. However, data are more consistent between antiphospholipid carrier condition and migraine. Systemic sclerosis is a rare disease, for this reason the amount of available data on this disorder are scanty. However, some studies reported an association between headache, migraine and systemic sclerosis, especially where gliotic brain lesions and Raynaud are coexisting. Finally, large propensity cohort population based studies suggested that systemic autoimmune diseases are more frequent in patients suffering from migraine. An attempt at explaining the possible link between these disorders and migraine is discussed at the end of the review. Several autoimmune alterations are shared by most autoimmune diseases and headache types. Endothelial dysfunction is the only alteration that is common among all these disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Proteomics and Autoimmune Kidney Disease

    OpenAIRE

    Rovin, Brad H; Klein, Jon B.

    2015-01-01

    Proteomics has long been considered an ideal platform, and urine an ideal source for biomarker discovery in human autoimmune kidney diseases. A number of studies have examined the urine proteome to identify biomarkers of disease activity, kidney pathology, and response to therapy. Increasingly, proteomic studies of kidney disease have expanded to include blood, circulating cells and kidney tissue. Recently the clinical potential of renal proteomics has been realized through a handful of inves...

  18. Amplification of Anti-Tumor Immunity Without Autoimmune Complications

    Science.gov (United States)

    2007-05-01

    neu, and an unrelated self-antigen, thyroglobulin. BALB/c mice were inoculated with TUBO cells expressing an activated rat neu and treated with anti...nonspecific (12, 13) manner through a contact-dependent mechanism. In this study, rat neu is used as the model tumor-associated antigen. Overexpression...experimental autoimmune thyroiditis (24), the murine model of Hashimoto’s thyroiditis. Hashimoto’s thyroid- itis, the leading cause of hypothyroidism , is

  19. Harnessing Apoptotic Cell Clearance to Treat Autoimmune Arthritis

    OpenAIRE

    Philippe Saas; Francis Bonnefoy; Eric Toussirot; Sylvain Perruche

    2017-01-01

    Early-stage apoptotic cells possess immunomodulatory properties. Proper apoptotic cell clearance during homeostasis has been shown to limit subsequent immune responses. Based on these observations, early-stage apoptotic cell infusion has been used to prevent unwanted inflammatory responses in different experimental models of autoimmune diseases or transplantation. Moreover, this approach has been shown to be feasible without any toxicity in patients undergoing allogeneic hematopoietic cell tr...

  20. Autoimmune Thyroiditis and Myasthenia Gravis

    Directory of Open Access Journals (Sweden)

    Angela Lopomo

    2017-07-01

    Full Text Available Autoimmune diseases (AIDs are the result of specific immune responses directed against structures of the self. In normal conditions, the molecules recognized as “self” are tolerated by immune system, but when the self-tolerance is lost, the immune system could react against molecules from the body, causing the loss of self-tolerance, and subsequently the onset of AID that differs for organ target and etiology. Autoimmune thyroid disease (ATD is caused by the development of autoimmunity against thyroid antigens and comprises Hashimoto’s thyroiditis and Graves disease. They are frequently associated with other organ or non-organ specific AIDs, such as myasthenia gravis (MG. In fact, ATD seems to be the most associated pathology to MG. The etiology of both diseases is multifactorial and it is due to genetic and environmental factors, and each of them has specific characteristics. The two pathologies show many commonalities, such as the organ-specificity with a clear pathogenic effect of antibodies, the pathological mechanisms, such as deregulation of the immune system and the implication of the genetic predisposition. They also show some differences, such as the mode of action of the antibodies and therapies. In this review that focuses on ATD and MG, the common features and the differences between the two diseases are discussed.

  1. Vitamin D and autoimmune diseases

    Directory of Open Access Journals (Sweden)

    E. A. Potrokhova

    2017-01-01

    Full Text Available The review discusses the effect of vitamin D on the tolerogenic modulation of an immune response, its relationship to cells of the monocyte-macrophage series, including dendritic cells, monocytes, and macrophages, in the context of the impact of the expression of anti-inflammatory proinflammatory cytokines in some autoimmune diseases (rheumatoid arthritis, systemic scleroderma, multiple sclerosis, type 1 diabetes mellitus, systemic lupus erythematosus, and Crohn`s disease. It discusses the role of vitamin D in the development of innate and adaptive immunity. Despite some conflicting evidence, the immune regulatory function of vitamin D is generally directed toward inhibition of the components of innate and acquired immunity, which are responsible for the induction of autoimmune reactions; in this connection there are a growing number of publications devoted to the issues of vitamin D supplementation in patients with autoimmune diseases, the preventive effect of vitamin D intake on the risk of an abnormality and that of therapeutic doses of the vitamin on its course. The maintenance of the threshold value for serum 25(OHD3 at least 30 ng/ml, which is achieved by the intake of about 2000 IU of vitamin D, is shown to be required for its immune regulatory function. The data given raise the question as to whether it is necessity to revise the Russian recommended daily dietary allowances for vitamin D through its infant food fortification.

  2. Human Cytomegalovirus and Autoimmune Disease

    Science.gov (United States)

    2014-01-01

    Human cytomegalovirus (HCMV) represents a prototypic pathogenic member of the β-subgroup of the herpesvirus family. A range of HCMV features like its lytic replication in multiple tissues, the lifelong persistence through periods of latency and intermitting reactivation, the extraordinary large proteome, and extensive manipulation of adaptive and innate immunity make HCMV a high profile candidate for involvement in autoimmune disorders. We surveyed the available literature for reports on HCMV association with onset or exacerbation of autoimmune disease. A causative linkage between HCMV and systemic lupus erythematosus (SLE), systemic sclerosis (SSc), diabetes mellitus type 1, and rheumatoid arthritis (RA) is suggested by the literature. However, a clear association of HCMV seroprevalence and disease could not be established, leaving the question open whether HCMV could play a coresponsible role for onset of disease. For convincing conclusions population-based prospective studies must be performed in the future. Specific immunopathogenic mechanisms by which HCMV could contribute to the course of autoimmune disease have been suggested, for example, molecular mimicry by UL94 in SSc and UL83/pp65 in SLE patients, as well as aggravation of joint inflammation by induction and expansion of CD4+/CD28− T-cells in RA patients. Further studies are needed to validate these findings and to lay the grounds for targeted therapeutic intervention. PMID:24967373

  3. Human Cytomegalovirus and Autoimmune Disease

    Directory of Open Access Journals (Sweden)

    Anne Halenius

    2014-01-01

    Full Text Available Human cytomegalovirus (HCMV represents a prototypic pathogenic member of the β-subgroup of the herpesvirus family. A range of HCMV features like its lytic replication in multiple tissues, the lifelong persistence through periods of latency and intermitting reactivation, the extraordinary large proteome, and extensive manipulation of adaptive and innate immunity make HCMV a high profile candidate for involvement in autoimmune disorders. We surveyed the available literature for reports on HCMV association with onset or exacerbation of autoimmune disease. A causative linkage between HCMV and systemic lupus erythematosus (SLE, systemic sclerosis (SSc, diabetes mellitus type 1, and rheumatoid arthritis (RA is suggested by the literature. However, a clear association of HCMV seroprevalence and disease could not be established, leaving the question open whether HCMV could play a coresponsible role for onset of disease. For convincing conclusions population-based prospective studies must be performed in the future. Specific immunopathogenic mechanisms by which HCMV could contribute to the course of autoimmune disease have been suggested, for example, molecular mimicry by UL94 in SSc and UL83/pp65 in SLE patients, as well as aggravation of joint inflammation by induction and expansion of CD4+/CD28− T-cells in RA patients. Further studies are needed to validate these findings and to lay the grounds for targeted therapeutic intervention.

  4. Vitamin D in autoimmune liver disease.

    Science.gov (United States)

    Smyk, Daniel S; Orfanidou, Timoklia; Invernizzi, Pietro; Bogdanos, Dimitrios P; Lenzi, Marco

    2013-11-01

    The development of autoimmune disease is based on the interaction of genetic susceptibility and environmental causes. Environmental factors include infectious and non-infectious agents, with some of these factors being implicated in several autoimmune diseases. Vitamin D is now believed to play a role in the development (or prevention) of several autoimmune diseases, based on its immunomodulatory properties. As well, the increasing incidence of autoimmune disease as one moves away from the equator, may be due to the lack of sunlight, which is crucial for the maintenance of normal vitamin D levels. A deficiency in vitamin D levels or vitamin D receptors is commonly indicated in autoimmune diseases, with multiple sclerosis (MS) being one of the best-studied and well-known examples. However, the role of vitamin D in other autoimmune diseases is not well defined, including autoimmune liver diseases such as primary biliary cirrhosis, autoimmune hepatitis, and primary sclerosing cholangitis. This review will examine the role of vitamin D as an immunomodulator, followed by a comparison of vitamin D in MS versus autoimmune liver disease. From this comparison, it will become clear that vitamin D likely plays a role in the development of autoimmune liver disease, but this area requires further investigation. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  5. [Pulmonary arterial hypertension: a flavor of autoimmunity].

    Science.gov (United States)

    Perros, Frédéric; Humbert, Marc; Cohen-Kaminsky, Sylvia

    2013-01-01

    It is admitted that autoimmunity results from a combination of risks such as genetic background, environmental triggers, and stochastic events. Pulmonary arterial hypertension (PAH) shares with the so-called prototypic autoimmune diseases, genetic risk factors, female predominance and sex hormone influence, association with other chronic inflammatory and autoimmune diseases, defects in regulatory T cells function, and presence of autoantibodies. Case reports have been published indicating the beneficial effect of some immunosuppressive and anti-inflammatory therapies in PAH, supporting the potential role of immune mechanisms in the pathophysiology of the disease. In this review, we discuss the current knowledge on autoimmune mechanisms operating in PAH, especially mounting a local autoimmune response inside the pulmonary tissue, namely pulmonary lymphoid neogenesis. A better understanding of the role of autoimmunity in pulmonary vascular remodelling may help develop targeted immunomodulatory strategies in PAH. © 2013 médecine/sciences – Inserm.

  6. Sex-based differences in autoimmune diseases.

    Science.gov (United States)

    Ortona, Elena; Pierdominici, Marina; Maselli, Angela; Veroni, Caterina; Aloisi, Francesca; Shoenfeld, Yehuda

    2016-01-01

    Autoimmune diseases are characterized by an exaggerated immune response leading to damage and dysfunction of specific or multiple organs and tissues. Most autoimmune diseases are more prevalent in women than in men. Symptom severity, disease course, response to therapy and overall survival may also differ between males and females with autoimmune diseases. Sex hormones have a crucial role in this sex bias, with estrogens being potent stimulators of autoimmunity and androgens playing a protective role. Accumulating evidence indicates that genetic, epigenetic and environmental factors may also contribute to sex-related differences in risk and clinical course of autoimmune diseases. In this review, we discuss possible mechanisms for sex specific differences in autoimmunity with a special focus on three paradigmatic diseases: systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis.

  7. CD24: from a Hematopoietic Differentiation Antigen to a Genetic Risk Factor for Multiple Autoimmune Diseases.

    Science.gov (United States)

    Tan, Yixin; Zhao, Ming; Xiang, Bo; Chang, Christopher; Lu, Qianjin

    2016-02-01

    The autoantibody is an essential characteristic of inflammatory disorders, including autoimmune diseases. Although the exact pathogenic mechanisms of these diseases remain elusive, accumulated evidence has implicated that genetic factors play important roles in autoimmune inflammation. Among these factors, CD24 was first identified as a heat-stable antigen in 1978 and first successfully cloned in 1990. Thereafter, its functional roles have been intensively investigated in various human diseases, especially autoimmune diseases and cancers. It is currently known that CD24 serves as a costimulatory factor of T cells that regulate their homeostasis and proliferation, while in B cells, CD24 is functionally involved in cell activation and differentiation. CD24 can enhance autoimmune diseases in terms of its protective role in the clonal deletion of autoreactive thymocytes. Furthermore, CD24 deficiency has been linked to mouse experimental autoimmune encephalomyelitis. Finally, CD24 genetic variants, including single-nucleotide polymorphisms and deletions, are etiologically relevant to autoimmune diseases, such as multiple sclerosis and systemic lupus erythematosus. Therefore, CD24 is a promising biomarker and novel therapeutic target for autoimmune diseases.

  8. Vitiligo associated with other autoimmune diseases: polyglandular autoimmune syndrome types 3B+C and 4.

    Science.gov (United States)

    Amerio, P; Tracanna, M; De Remigis, P; Betterle, C; Vianale, L; Marra, M E; Di Rollo, D; Capizzi, R; Feliciani, C; Tulli, A

    2006-09-01

    Vitiligo is a common skin disease characterized by depigmented maculae resulting from a reduction of the number and function of melanocytes. Many studies suggest that vitiligo might be an autoimmune disease. Vitiligo has been frequently described in association with other autoimmune diseases. Among the diseases described in association with vitiligo are the so-called autoimmune polyglandular syndromes (APS). Vitiligo can be present in all types of APS but the most frequent association appears to be in APS-3. APS-3 was defined as the association between autoimmune thyroiditis and another autoimmune disease. Here we report one patient with thyroiditis, vitiligo and autoimmune gastritis (APS-3B+C), one patient with chronic autoimmune thyroiditis, vitiligo and alopecia (APS-3C), and one case of a young patient with type 1 diabetes mellitus and vitiligo (APS-4), according to the newest classification. We stress the importance of a thorough assessment for autoimmune diseases in selected patients with vitiligo.

  9. Epidemiology and treatment of autoimmune hepatitis

    Directory of Open Access Journals (Sweden)

    Francque S

    2012-03-01

    Full Text Available Sven Francque1,2, Luisa Vonghia1,3, Albert Ramon1,4, Peter Michielsen1,21Antwerp University Hospital, Department of Gastroenterology Hepatology, Antwerp, Belgium; 2Antwerp University, Faculty of Medicine and Health Sciences, Laboratory of Experimental Medicine and Paediatrics, Antwerp, Belgium; 3Department of Internal Medicine, Immunology and Infectious Diseases, University of Bari, Italy; 4Institute and Laboratory for Genetic Diseases and Molecular Biology, Cologne, GermanyAbstract: Autoimmune hepatitis (AIH is a chronic inflammatory disease of the liver that occurs worldwide with a low and probably underestimated prevalence. Although it typically affects young and middle-aged women, it can occur in both sexes and across all age groups. AIH runs a fluctuating course, but can present as severe and even fulminant hepatic failure or at a stage of advanced fibrosis or cirrhosis. Prognosis of severe AIH is poor if untreated. The pathogenesis is complex, combining environmental factors (external chemical or infectious triggers and host genetic susceptibility. The diagnosis is based, after exclusion of other etiologies of chronic liver disease, on a combination of different elements, including the presence of elevated transaminases, elevated immunoglobulin G (IgG levels, the presence and pattern of typical autoantibodies, and a liver biopsy showing interface hepatitis and other characteristic features. No single test can be used to make the diagnosis. Response to treatment can also help to establish the diagnosis. Simplified criteria can be used to make a bedside diagnosis with relatively high accuracy. Treatment consists of corticosteroids or other immunosuppressive regimens according to the severity of the disease, the response to the treatment, and the tolerance to therapy, with liver transplantation as an ultimate remedy in treatment-resistant cases with liver decompensation.Keywords: autoimmune hepatitis, antibodies, pathophysiology, treatment

  10. Microbiota and Autoimmunity: exploring new avenues

    OpenAIRE

    Yurkovetskiy, Leonid; Pickard, Joseph M.; Chervonsky, Alexander V.

    2015-01-01

    Given the recognized role of the commensal microbiota in regulating host immunity to pathogens, it is not surprising that microbiota are also capable of regulating autoimmune responses. The underlying mechanisms of autoimmune regulation by the microbiota are just beginning to emerge. Here, we discuss possible pressure points towards the development of autoimmune diseases that can be influenced by the microbiota. Besides acting on the adaptive and innate arms of the immune response, the microb...

  11. Recurrent Oral Inflammation in Autoimmune Lymphoproliferative Syndrome

    OpenAIRE

    Pac, Malgorzata; Olczak-Kowalczyk, Dorota; Wolska-Kuśnierz, Beata; Piątosa, Barbara; Górska, Renata; Bernatowska, Ewa

    2014-01-01

    Abstract   Background and aim: Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by dysregulation of the Fas apoptotic pathway. In ALPS defective lymphocyte apoptosis manifests as a chronic, nonmalignant lymphadenopathy and/or splenomegaly/hepatosplenomegaly, expansion of double negative T cell (DNTC) – CD4-CD8-TCRαβ+ T cells, autoimmune cytopenias and other autoimmune diseases.  Patients demonstrate oral lesions which have not yet been repo...

  12. Role of Complement in Autoimmune Hemolytic Anemia

    OpenAIRE

    Berentsen, Sigbj?rn

    2015-01-01

    Summary The classification of autoimmune hemolytic anemias and the complement system are reviewed. In autoimmune hemolytic anemia of the warm antibody type, complement-mediated cell lysis is clinically relevant in a proportion of the patients but is hardly essential for hemolysis in most patients. Cold antibody-mediated autoimmune hemolytic anemias (primary cold agglutinin disease, secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria) are entirely complement-mediated disorder...

  13. Castleman disease and associated autoimmune disease.

    Science.gov (United States)

    Muskardin, Theresa W; Peterson, Bruce A; Molitor, Jerry A

    2012-01-01

    Castleman disease can occur in association with autoimmune connective tissue disease and confound the clinical picture, resulting in delayed diagnosis and suboptimal treatment. This review focuses on the intersection of Castleman disease and autoimmunity with an emphasis on shared pathology and mutually beneficial treatments. Targeting CD-20, interleukin-6, and the nuclear factor-κB pathway has shown promise in achieving long-term remission in patients with Castleman disease and associated autoimmune features. Advances in understanding of pathogenic cell types and cytokines in Castleman disease have allowed the development of targeted therapies successful in the treatment of both Castleman disease and associated autoimmune disease.

  14. Autoimmune hepatitis/primary biliary cirrhosis overlap syndrome and associated extrahepatic autoimmune diseases.

    Science.gov (United States)

    Efe, Cumali; Wahlin, Staffan; Ozaslan, Ersan; Berlot, Alexandra Heurgue; Purnak, Tugrul; Muratori, Luigi; Quarneti, Chiara; Yüksel, Osman; Thiéfin, Gérard; Muratori, Paolo

    2012-05-01

    To assess the prevalence of concurrent extrahepatic autoimmune diseases in patients with autoimmune hepatitis (AIH)/primary biliary cirrhosis (PBC) overlap syndrome and applicability of the 'mosaic of autoimmunity' in these patients. The medical data of 71 AIH/PBC overlap patients were evaluated for associated autoimmune diseases. In the study population, 31 (43.6%) patients had extrahepatic autoimmune diseases, including autoimmune thyroid diseases (13 patients, 18.3%), Sjögren syndrome (six patients, 8.4%), celiac disease (three patients, 4.2%), psoriasis (three patients, 4.2%), rheumatoid arthritis (three patients, 4.2%), vitiligo (two patients, 2.8%), and systemic lupus erythematosus (two patients, 2.8%). Autoimmune hemolytic anemia, antiphospholipid syndrome, multiple sclerosis, membranous glomerulonephritis, sarcoidosis, systemic sclerosis, and temporal arteritis were identified in one patient each (1.4%). A total of 181 autoimmune disease diagnoses were found in our patients. Among them, 40 patients (56.4%) had two, 23 (32.3%) had three, and eight (11.3%) had four diagnosed autoimmune diseases. A large number of autoimmune diseases were associated with AIH/PBC overlap patients. Therefore, extended screening for existing autoimmune diseases during the routine assessment of these patients is recommended. Our study suggests that the concept of 'mosaic of autoimmunity' is a valid clinical entity that is applicable to patients with AIH/PBC overlap syndrome.

  15. Association between autoimmune pancreatitis and systemic autoimmune diseases.

    Science.gov (United States)

    Terzin, Viktória; Földesi, Imre; Kovács, László; Pokorny, Gyula; Wittmann, Tibor; Czakó, László

    2012-06-07

    To investigate the association between autoimmune pancreatitis (AIP) and systemic autoimmune diseases (SAIDs) by measurement of serum immunoglobulin G4 (IgG4). The serum level of IgG4 was measured in 61 patients with SAIDs of different types who had not yet participated in glucocorticosteroid treatment. Patients with an elevated IgG4 level were examined by abdominal ultrasonography (US) and, in some cases, by computer tomography (CT). Elevated serum IgG4 levels (919 ± 996 mg/L) were detected in 17 (28%) of the 61 SAID patients. 10 patients had Sjögren's syndrome (SS) (IgG4: 590 ± 232 mg/L), 2 of them in association with Hashimoto's thyroiditis, and 7 patients (IgG4: 1388 ± 985.5 mg/L) had systemic lupus erythematosus (SLE). The IgG4 level in the SLE patients and that in patients with SS were not significantly different from that in AIP patients (783 ± 522 mg/L). Abdominal US and CT did not reveal any characteristic features of AIP among the SAID patients with an elevated IgG4 level. The serum IgG4 level may be elevated in SAIDs without the presence of AIP. The determination of serum IgG4 does not seem to be suitable for the differentiation between IgG4-related diseases and SAIDs.

  16. Autoimmune pancreatitis--recent advances.

    Science.gov (United States)

    Novotný, I; Díte, P; Lata, J; Nechutová, H; Kianicka, B

    2010-01-01

    Autoimmune pancreatitis (AIP) is recognized as a distinct clinical entity, identified as a chronic inflammatory process of the pancreas in which the autoimmune mechanism is involved. Clinically and histologically, AIP has two subsets: type 1--lymphoplasmatic sclerosing pancreatitis with abundant infiltration of the pancreas and other affected organs with immunoglobulin G4-positive plasma cells, and type 2--duct centric fibrosis, characterized by granulocyte epithelial lesions in the pancreas without systemic involvement. In the diagnosis of AIP, two diagnostic criterions are used--the HISORt criteria and Asian Diagnostic Criteria. In the differential diagnosis, the pancreatic cancer must be excluded by endosonographically guided pancreatic biopsy. Typical signs of AIP are concomitant disorders in other organs (kidney, liver, biliary tract, salivary glands, colon, retroperitoneum, prostate). Novel clinicopathological entity was proposed as an 'IgG4-related sclerosing disease' (IgG4-RSC). Extensive IgG4-positive plasma cells and T lymphocyte infiltration is a common characteristics of this disease. Recently, IgG4-RSC syndrome was extended to a new entity, characterized by IgG4 hypergammaglobulinemia and IgG4-positive plasma cell infiltration, this being considered an expression of a lymphoproliferative disease, 'IgG4-positive multiorgan lymphoproliferative syndrome'. This syndrome includes Mikulicz's disease, mediastinal fibrosis, autoimmune hypophysitis, and inflammatory pseudotumor--lung, liver, breast. In the therapy of AIP, steroids constitute first-choice treatment. High response to the corticosteroid therapy is an important diagnostic criterion. In the literature, there are no case-control studies that determine if AIP predisposes to pancreatic cancer. Undoubtedly, AIP is currently a hot topic in pancreatology. Copyright (c) 2010 S. Karger AG, Basel.

  17. Autoimmune atrophic gastritis: current perspectives

    Directory of Open Access Journals (Sweden)

    Minalyan A

    2017-02-01

    Full Text Available Artem Minalyan,1 Jihane N Benhammou,1 Aida Artashesyan,1 Michael S Lewis,2 Joseph R Pisegna1 1Division of Gastroenterology, Hepatology and Parenteral Nutrition, 2Department of Pathology and Laboratory Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA Abstract: At present there is no universally accepted classification for gastritis. The first successful classification (The Sydney System that is still commonly used by medical professionals was first introduced by Misiewicz et al in Sydney in 1990. In fact, it was the first detailed classification after the discovery of Helicobacter pylori by Warren and Marshall in 1982. In 1994, the Updated Sydney System was proposed during the International Workshop on the Histopathology of Gastritis followed by the publication in The American Journal of Surgical Pathology by Dixon et al. Using the new classification, distinction between atrophic and nonatrophic gastritis was revised, and the visual scale grading was incorporated. According to the Updated Sydney System Classification, atrophic gastritis is categorized into multifocal (H. pylori, environmental factors, specific diet and corpus-predominant (autoimmune. Since metaplasia is a key histological characteristic in patients with atrophic gastritis, it has been recommended to use the word “metaplastic” in both variants of atrophic gastritis: autoimmune metaplastic atrophic gastritis (AMAG and environmental metaplastic atrophic gastritis. Although there are many overlaps in the course of the disease and distinction between those two entities may be challenging, the aim of this review article was to describe the etiology, epidemiology, pathogenesis, diagnosis, clinical manifestations and treatment in patients with AMAG. However, it is important to mention that H. pylori is the most common etiologic factor for the development of gastritis in the world. Keywords: autoimmune gastritis, pernicious anemia, gastric carcinoid

  18. Helminth Immunomodulation in Autoimmune Disease.

    Science.gov (United States)

    Smallwood, Taylor B; Giacomin, Paul R; Loukas, Alex; Mulvenna, Jason P; Clark, Richard J; Miles, John J

    2017-01-01

    Helminths have evolved to become experts at subverting immune surveillance. Through potent and persistent immune tempering, helminths can remain undetected in human tissues for decades. Redirecting the immunomodulating "talents" of helminths to treat inflammatory human diseases is receiving intensive interest. Here, we review therapies using live parasitic worms, worm secretions, and worm-derived synthetic molecules to treat autoimmune disease. We review helminth therapy in both mouse models and clinical trials and discuss what is known on mechanisms of action. We also highlight current progress in characterizing promising new immunomodulatory molecules found in excretory/secretory products of helminths and their potential use as immunotherapies for acute and chronic inflammatory diseases.

  19. [Narcolepsy as an autoimmune disease].

    Science.gov (United States)

    Sarkanen, Tomi; Vaarala, Outi; Julkunen, Ilkka; Partinen, Markku

    2015-01-01

    Narcolepsy is a sleep disorder of central origin. Hypocretin deficiency is the essential feature of type 1 narcolepsy. The biological background of type 2 narcolepsy (without cataplexy) is less clear. Infections or other external factors are thought to function as triggers of narcolepsy. After the H1N1 vaccination campaign, the incidence of narcolepsy increased clearly in countries where a vaccine boosted with the AS03 adjuvant was used. According to the current view, the increase of narcolepsy in connection with the pandemic vaccine especially in children and adolescents was associated with the virus component of the vaccine, but the adjuvant may also have boosted the development of autoimmune response.

  20. Bioluminescence in vivo imaging of autoimmune encephalomyelitis predicts disease

    Directory of Open Access Journals (Sweden)

    Steinman Lawrence

    2008-02-01

    Full Text Available Abstract Background Experimental autoimmune encephalomyelitis is a widely used animal model to understand not only multiple sclerosis but also basic principles of immunity. The disease is scored typically by observing signs of paralysis, which do not always correspond with pathological changes. Methods Experimental autoimmune encephalomyelitis was induced in transgenic mice expressing an injury responsive luciferase reporter in astrocytes (GFAP-luc. Bioluminescence in the brain and spinal cord was measured non-invasively in living mice. Mice were sacrificed at different time points to evaluate clinical and pathological changes. The correlation between bioluminescence and clinical and pathological EAE was statistically analyzed by Pearson correlation analysis. Results Bioluminescence from the brain and spinal cord correlates strongly with severity of clinical disease and a number of pathological changes in the brain in EAE. Bioluminescence at early time points also predicts severity of disease. Conclusion These results highlight the potential use of bioluminescence imaging to monitor neuroinflammation for rapid drug screening and immunological studies in EAE and suggest that similar approaches could be applied to other animal models of autoimmune and inflammatory disorders.

  1. MMP-mediated cleavage of beta-dystroglycan in myelin sheath is involved in autoimmune neuritis.

    Science.gov (United States)

    Zhao, Xiu Li; Li, Guo Zhong; Sun, Bo; Zhang, Zhong Ling; Yin, Yan Hong; Tian, Yu Shuang; Li, He; Li, Hu Lun; Wang, De Sheng; Zhong, Di

    2010-02-19

    Alpha-/beta-dystroglycans (DG) located at the outmost layer of myelin sheath play a critical role in its formation and stability in the peripheral nerve system. The demyelination of nerve fibers is present in autoimmune neuritis, however, it is not known about the molecular mechanisms underlying this pathological process. In an animal model of experimental autoimmune neuritis, we observed that beta-DG cleavage was associated with the demyelination of peripheral nerves. The neuritis and beta-DG cleavage were accompanied by matrix metalloproteinase (MMP)-2/-9 over-expressions and attenuated by captopril, a MMP inhibitor. The blockade of MMPs also improves clinical signs. Our results reveal a crucial role of MMP-mediated beta-DG cleavage in autoimmune neuritis, such as Guillain-Barre' syndrome, and bring insights into therapeutic strategies for autoimmune diseases. Copyright (c) 2010 Elsevier Inc. All rights reserved.

  2. Therapeutic manipulation of natural killer (NK) T cells in autoimmunity: are we close to reality?

    Science.gov (United States)

    Simoni, Y; Diana, J; Ghazarian, L; Beaudoin, L; Lehuen, A

    2013-01-01

    T cells reactive to lipids and restricted by major histocompatibility complex (MHC) class I-like molecules represent more than 15% of all lymphocytes in human blood. This heterogeneous population of innate cells includes the invariant natural killer T cells (iNK T), type II NK T cells, CD1a,b,c-restricted T cells and mucosal-associated invariant T (MAIT) cells. These populations are implicated in cancer, infection and autoimmunity. In this review, we focus on the role of these cells in autoimmunity. We summarize data obtained in humans and preclinical models of autoimmune diseases such as primary biliary cirrhosis, type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, psoriasis and atherosclerosis. We also discuss the promise of NK T cell manipulations: restoration of function, specific activation, depletion and the relevance of these treatments to human autoimmune diseases. © 2012 The Authors. Clinical and Experimental Immunology © 2012 British Society for Immunology.

  3. Autoimmune Cytopenias In Common Variable Immunodeficiency (CVID

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    Roshini Sarah Abraham

    2012-07-01

    Full Text Available Common variable immunodeficiency (CVID is a humoral immunodeficiency whose primary diagnostic features include hypogammaglobulinemia involving two or more immunoglobulin isotypes and impaired functional antibody responses in the majority of patients. While increased susceptibility to respiratory and other infections is a common thread that binds a large cross-section of CVID patients, the presence of autoimmune complications in this immunologically and clinically heterogeneous disorder is recognized in up to two-thirds of patients. Among the autoimmune manifestations reported in CVID (20-50%(Chapel et al., 2008;Cunningham-Rundles, 2008, autoimmune cytopenias are by far the most common occurring variably in 4-20% (Michel et al., 2004;Chapel et al., 2008 of these patients who have some form of autoimmunity. Association of autoimmune cytopenias with granulomatous disease and splenomegaly has been reported. The spectrum of autoimmune cytopenias includes thrombocytopenia, anemia and neutropenia. While it may seem paradoxical prima facie that autoimmunity is present in patients with primary immune deficiencies, in reality, it could be considered two sides of the same coin, each reflecting a different but inter-connected facet of immune dysregulation. The expansion of CD21low B cells in CVID patients with autoimmune cytopenias and other autoimmune features has also been previously reported. It has been demonstrated that this unique subset of B cells is enriched for autoreactive germline antibodies. Further, a correlation has been observed between various B cell subsets, such as class-switched memory B cells and plasmablasts, and autoimmunity in CVID. This review attempts to explore the most recent concepts and highlights, along with treatment of autoimmune hematological manifestations of CVID.

  4. Molecular mimicry and horror autotoxicus: do chlamydial infections elicit autoimmunity?

    Science.gov (United States)

    Swanborg, Robert H; Boros, Dov L; Whittum-Hudson, Judith A; Hudson, Alan P

    2006-11-30

    All species of the order Chlamydiales are obligate intracellular eubacterial pathogens of their various hosts. Two chlamydial species, Chlamydia trachomatis and Chlamydia pneumoniae, are primarily human pathogens, and each is known to cause important diseases. Some strains of C. trachomatis are sexually transmitted and frequently cause severe reproductive problems, primarily in women. Other strains of the organism serve as the aetiological agents for blinding trachoma, still the leading cause of preventable blindness in underdeveloped nations. C. pneumoniae is a respiratory pathogen known to cause community-acquired pneumonia. Importantly, both organisms engender an immunopathogenic response in the human host, and both have been associated with widely diverse, relatively common and currently idiopathic chronic diseases, most of which include an important autoimmune component. In this article, we explore the available experimental data regarding the possible elicitation of autoimmunity in various contexts by chlamydial infection, and we suggest several avenues for research to explore this potentially important issue further.

  5. An Animal Model Using Metallic Ions to Produce Autoimmune Nephritis

    Directory of Open Access Journals (Sweden)

    Roxana Ramírez-Sandoval

    2015-01-01

    Full Text Available Autoimmune nephritis triggered by metallic ions was assessed in a Long-Evans rat model. The parameters evaluated included antinuclear autoantibody production, kidney damage mediated by immune complexes detected by immunofluorescence, and renal function tested by retention of nitrogen waste products and proteinuria. To accomplish our goal, the animals were treated with the following ionic metals: HgCl2, CuSO4, AgNO3, and Pb(NO32. A group without ionic metals was used as the control. The results of the present investigation demonstrated that metallic ions triggered antinuclear antibody production in 60% of animals, some of them with anti-DNA specificity. Furthermore, all animals treated with heavy metals developed toxic glomerulonephritis with immune complex deposition along the mesangium and membranes. These phenomena were accompanied by proteinuria and increased concentrations of urea. Based on these results, we conclude that metallic ions may induce experimental autoimmune nephritis.

  6. Inositol(s) in thyroid function, growth and autoimmunity.

    Science.gov (United States)

    Benvenga, Salvatore; Antonelli, Alessandro

    2016-12-01

    Myo-inositol and phosphatidylinositol(s) play a pivotal function in many metabolic pathways that, if impaired, impact unfavorably on human health. This review analyzes several experimental and clinical investigations regarding the involvement of this class of molecules in physiological and pathological situations, with a major focus on thyroid. Central issues are the relationship between phosphatidylinositol and thyrotropin (TSH) signaling on one hand, and phosphatydylinositol and autoimmunity on the other hand. Other issues are the consequences of malfunction of some receptors, such as those ones for TSH (TSHR), insulin (IR) and insulin-like growth factor-1 (IGF-1R), or the connection between serum TSH concentrations and insulin resistance. Also covered are insulin resistance, metabolic syndrome and their allied disorders (diabetes, polycystic ovary syndrome [PCOS]), autoimmunity and certain malignancies, with their reciprocal links. Myoinositol has promising therapeutic potential. Appreciation of the inositol pathways involved in certain disorders, as mentioned in this review, may stimulate researchers to envisage additional therapeutic applications.

  7. Susceptibility Genes in Thyroid Autoimmunity

    Directory of Open Access Journals (Sweden)

    Yoshiyuki Ban

    2005-01-01

    Full Text Available The autoimmune thyroid diseases (AITD are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions that are linked with AITD, and in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD and Hashimoto's thyroiditis (HT and some are common to both the diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4 and thyroid specific genes (e.g. TSHR, Tg. Most likely, these loci interact and their interactions may influence disease phenotype and severity.

  8. Epigenetic histone code and autoimmunity.

    Science.gov (United States)

    Dieker, Jürgen; Muller, Sylviane

    2010-08-01

    The multiple inter-dependent post-translational modifications of histones represent fine regulators of chromatin dynamics. These covalent modifications, including phosphorylation, acetylation, ubiquitination, deimination, and methylation, affect therefore the numerous processes involving chromatin, such as replication, repair, transcription, genome stability, and cell death. Specific enzymes introducing modified residues in histones are precisely regulated, and a single amino acid residue can be subjected to a single or several, independent modifications. Disruption of histone post-translational modifications perturbs the pattern of gene expression, which may result in disease manifestations. It has become evident in recent years that apoptosis-modified histones exert a central role in the induction of autoimmunity, for example in systemic lupus erythematosus and rheumatoid arthritis. Certain histone post-translational modifications are linked to cell death (apoptotic and non-apoptotic cell death) and might be involved in lupus in the activation of normally tolerant lymphocyte subpopulations. In this review, we discuss how these modifications can affect the antigenicity and immunogenicity of histones with potential consequences in the pathogenesis of autoimmune diseases.

  9. Warm antibody autoimmune hemolytic anemia.

    Science.gov (United States)

    Kalfa, Theodosia A

    2016-12-02

    Autoimmune hemolytic anemia (AIHA) is a rare and heterogeneous disease that affects 1 to 3/100 000 patients per year. AIHA caused by warm autoantibodies (w-AIHA), ie, antibodies that react with their antigens on the red blood cell optimally at 37°C, is the most common type, comprising ∼70% to 80% of all adult cases and ∼50% of pediatric cases. About half of the w-AIHA cases are called primary because no specific etiology can be found, whereas the rest are secondary to other recognizable underlying disorders. This review will focus on the postulated immunopathogenetic mechanisms in idiopathic and secondary w-AIHA and report on the rare cases of direct antiglobulin test-negative AIHA, which are even more likely to be fatal because of inherent characteristics of the causative antibodies, as well as because of delays in diagnosis and initiation of appropriate treatment. Then, the characteristics of w-AIHA associated with genetically defined immune dysregulation disorders and special considerations on its management will be discussed. Finally, the standard treatment options and newer therapeutic approaches for this chronic autoimmune blood disorder will be reviewed. © 2016 by The American Society of Hematology. All rights reserved.

  10. Cardiovascular Involvement in Autoimmune Diseases

    Science.gov (United States)

    Amaya-Amaya, Jenny

    2014-01-01

    Autoimmune diseases (AD) represent a broad spectrum of chronic conditions that may afflict specific target organs or multiple systems with a significant burden on quality of life. These conditions have common mechanisms including genetic and epigenetics factors, gender disparity, environmental triggers, pathophysiological abnormalities, and certain subphenotypes. Atherosclerosis (AT) was once considered to be a degenerative disease that was an inevitable consequence of aging. However, research in the last three decades has shown that AT is not degenerative or inevitable. It is an autoimmune-inflammatory disease associated with infectious and inflammatory factors characterized by lipoprotein metabolism alteration that leads to immune system activation with the consequent proliferation of smooth muscle cells, narrowing arteries, and atheroma formation. Both humoral and cellular immune mechanisms have been proposed to participate in the onset and progression of AT. Several risk factors, known as classic risk factors, have been described. Interestingly, the excessive cardiovascular events observed in patients with ADs are not fully explained by these factors. Several novel risk factors contribute to the development of premature vascular damage. In this review, we discuss our current understanding of how traditional and nontraditional risk factors contribute to pathogenesis of CVD in AD. PMID:25177690

  11. Autoimmune hepatitis and juvenile systemic lupus erythematosus

    NARCIS (Netherlands)

    Deen, M. E. J.; Porta, G.; Fiorot, F. J.; Campos, L. M. A.; Sallum, A. M. E.; Silva, C. A. A.

    Juvenile systemic lupus erythematosus (JSLE) and autoimmune hepatitis (AIH) are both autoimmune disorders that are rare in children and have a widespread clinical manifestation. A few case reports have shown a JSLE-AIH associated disorder. To our knowledge, this is the first study that

  12. Chronic autoimmune urticaria : Where we stand ?

    Directory of Open Access Journals (Sweden)

    Goh C

    2009-01-01

    Full Text Available It is well-recognized that 30-40% of chronic idiopathic urticaria is autoimmune in nature. Chronic autoimmune urticaria is caused by anti-FcåRI and less frequently, by anti-IgE autoantibodies that lead to mast cell and basophil activation, thereby giving rise to the release of histamine and other proinflammatory mediators. Activation of the classical complement pathway and formation of C5a are important in dermal mast cell activation. C5a is also a neutrophil and eosinophil chemoattractant. Chronic autoimmune urticaria has been found to be associated with autoimmune thyroid disease. The autologous serum skin test is used as a screening test for chronic autoimmune urticaria and has a sensitivity and specificity of about 70 and 80%, respectively. The current gold standard diagnostic test is the basophil histamine release assay. The treatment of chronic autoimmune urticaria, as in chronic idiopathic urticaria, is with H1 antihistamines. Oral corticosteroids may be used during acute flares. Refractory cases have been shown to respond to cyclosporine and other immunomodulators. The prevalence of chronic autoimmune urticaria in Singapore is similar to that reported in Western countries at about 42%. The presence of thyroid autoimmunity appears to be higher than reported, with 22.5% of patients with chronic idiopathic urticaria here, exhibiting presence of thyroid autoantibodies.

  13. Autoimmune disease and subsequent urological cancer.

    Science.gov (United States)

    Liu, Xiangdong; Ji, Jianguang; Forsti, Asta; Sundquist, Kristina; Sundquist, Jan; Hemminki, Kari

    2013-06-01

    We examined the subsequent risk and prognosis of urological cancer in individuals diagnosed with autoimmune disease. We systematically analyzed the risk and prognosis of prostate, kidney and bladder cancers in individuals diagnosed with any of 33 autoimmune diseases based on a national Swedish database for 1964 through 2008. The SIR and HR were calculated for subsequent urological cancers between 1964 and 2008 in individuals hospitalized for autoimmune disease. An increased SIR for urological cancer was recorded after 26 autoimmune diseases. An increased HR for cancer specific survival was noted after 4 autoimmune diseases and for overall survival after 18. The highest SIRs were seen for kidney cancer after polyarteritis nodosa (2.85) and polymyositis/dermatomyositis (2.68), and for bladder cancer after polymyositis/dermatomyositis (2.45). The highest risk of prostate cancer (1.70) was observed after polyarteritis nodosa. SIRs were lower during followup from 1990 to 2008 compared to the previous period. Individuals diagnosed with prostate and kidney cancers showed an improved cancer specific prognosis, in contrast to the poorer overall prognosis for all 3 urological cancers. The risk of urological cancer was increased after all autoimmune diseases. The most significant changes after individual autoimmune diseases were toward higher risk. Survival data were reassuring since autoimmune disease only marginally influences the prognosis of cancer specific mortality. However, overall survival was decreased for the 3 types of cancer. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  14. Autoimmune diseases in adults with atopic dermatitis

    DEFF Research Database (Denmark)

    Andersen, Yuki M F; Egeberg, Alexander; Gislason, Gunnar H.

    2017-01-01

    Background: An increased susceptibility to autoimmune disease has been shown in patients with atopic dermatitis (AD), but data remain scarce and inconsistent. Objective: We examined the co-occurrence of selected autoimmune diseases in adult patients with AD. Methods: Nationwide health registers w...

  15. Autoimmune diseases in adults with atopic dermatitis.

    Science.gov (United States)

    Andersen, Yuki M F; Egeberg, Alexander; Gislason, Gunnar H; Skov, Lone; Thyssen, Jacob P

    2017-02-01

    An increased susceptibility to autoimmune disease has been shown in patients with atopic dermatitis (AD), but data remain scarce and inconsistent. We examined the co-occurrence of selected autoimmune diseases in adult patients with AD. Nationwide health registers were used. Adult patients with a hospital diagnosis of AD in Denmark between 1997 and 2012 were included as cases (n = 8112) and matched with controls (n = 40,560). The occurrence of autoimmune diseases was compared in the 2 groups. Logistic regression was used to estimate odds ratios. AD was significantly associated with 11 of 22 examined autoimmune diseases. In addition, AD was associated with having multiple autoimmune comorbidities. Patients with a history of smoking had a significantly higher occurrence of autoimmune comorbidities compared to nonsmokers. This study was limited to adult patients with AD. No information about AD severity or degree of tobacco consumption was available. Results from a hospital population of AD patients cannot be generalized to the general population. Our results suggest a susceptibility of autoimmune diseases in adult patients with AD, especially in smokers. While we cannot conclude on causality based on these data, an increased awareness of autoimmune comorbidities in patients with AD may be warranted. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  16. Kaleidoscope of autoimmune diseases in HIV infection.

    Science.gov (United States)

    Roszkiewicz, Justyna; Smolewska, Elzbieta

    2016-11-01

    Within the last 30 years, the human immunodeficiency virus (HIV) infection has changed its status from inevitably fatal to chronic disorder with limited impact on life span. However, this breakthrough was mainly the effect of introduction of the aggressive antiviral treatment, which has led to the clinically significant increase in CD4+ cell count, resulting in fewer cases of the acquired immunodeficiency syndrome (AIDS) and improved management of opportunistic infections occurring in the course of the disease. The occurrence of a particular autoimmune disease depends on degree of immunosuppression of the HIV-positive patient. In 2002, four stages of autoimmunity were proposed in patients infected by HIV, based on the absolute CD4+ cell count, feature of AIDS as well as on the presence of autoimmune diseases. Spectrum of autoimmune diseases associated with HIV infection seems to be unexpectedly wide, involving several organs, such as lungs (sarcoidosis), thyroid gland (Graves' disease), liver (autoimmune hepatitis), connective tissue (systemic lupus erythematosus, rheumatoid arthritis, polyarteritis nodosa and other types of vasculitis, antiphospholipid syndrome) or hematopoietic system (autoimmune cytopenias). This paper contains the state of art on possible coincidences between HIV infection and a differential types of autoimmune diseases, including the potential mechanisms of this phenomenon. As the clinical manifestations of autoimmunization often mimic those inscribed in the course of HIV infection, health care providers should be aware of this rare but potentially deadly association and actively seek for its symptoms in their patients.

  17. Gender and autoimmune comorbidity in multiple sclerosis

    DEFF Research Database (Denmark)

    Magyari, Melinda; Koch-Henriksen, Nils; Pfleger, Claudia C

    2014-01-01

    BACKGROUND: The female preponderance in incidence of multiple sclerosis (MS) calls for investigations into sex differences in comorbidity with other autoimmune diseases (ADs). OBJECTIVES: To determine whether male and female patients with MS have a higher frequency of autoimmune comorbidity than...

  18. Monogenic autoimmune diseases of the endocrine system.

    Science.gov (United States)

    Johnson, Matthew B; Hattersley, Andrew T; Flanagan, Sarah E

    2016-10-01

    The most common endocrine diseases, type 1 diabetes, hyperthyroidism, and hypothyroidism, are the result of autoimmunity. Clustering of autoimmune endocrinopathies can result from polygenic predisposition, or more rarely, may present as part of a wider syndrome due to a mutation within one of seven genes. These monogenic autoimmune diseases show highly variable phenotypes both within and between families with the same mutations. The average age of onset of the monogenic forms of autoimmune endocrine disease is younger than that of the common polygenic forms, and this feature combined with the manifestation of other autoimmune diseases, specific hallmark features, or both, can inform clinicians as to the relevance of genetic testing. A genetic diagnosis can guide medical management, give an insight into prognosis, inform families of recurrence risk, and facilitate prenatal diagnoses. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Autoimmune diseases in women with Turner's syndrome

    DEFF Research Database (Denmark)

    Jørgensen, Kristian T; Rostgaard, Klaus; Bache, Iben

    2010-01-01

    OBJECTIVE: In terms of number of X chromosomes, women with Turner's syndrome cytogenetically resemble men. An increased risk of autoimmune diseases has been observed among women with Turner's syndrome. This study was undertaken to investigate whether the autoimmune disease profile in women...... with Turner's syndrome is characterized by diseases with a female or male predominance. METHODS: Using the Danish Cytogenetic Central Register, the Danish National Patient Register, and the Danish Civil Registration System, we estimated relative risk of 46 different autoimmune diseases in a cohort of 798...... Danish women with Turner's syndrome followed up for 12,461 person-years between 1980 and 2004. Standardized incidence ratios (SIRs) of first hospitalization for autoimmune disease and 95% confidence intervals (95% CIs) were used as measures of relative risk. RESULTS: The overall risk of autoimmune...

  20. Autoimmune mechanisms in pernicious anaemia & thyroid disease.

    Science.gov (United States)

    Osborne, David; Sobczyńska-Malefora, Agata

    2015-09-01

    Pernicious anaemia (PA) and some types of thyroid disease result from autoimmune processes. The autoimmune mechanisms in these conditions have not been fully elucidated. This review discusses the autoimmune mechanisms involved in PA and how these affect diagnosis and disease progression. In addition to gastric antibodies, antibodies to the vitamin B12 binding protein transcobalamin which can result in high serum B12 levels are also addressed with regard to how they affect clinical practice. The role of autoimmune susceptibility is investigated by comparing PA to one of its most common comorbidities, autoimmune thyroid disease (AITD). Thyroid disease (although not exclusively AITD) and B12 deficiency are both also implicated in the pathology of hyperhomocysteinemia, an elevated homocysteine in plasma. Since hyperhomocysteinemia is a risk factor for cardiovascular occlusive disease, this review also addresses how thyroid disease in particular leads to changes in homocysteine levels. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Immunological GABAergic interactions and therapeutic applications in autoimmune diseases.

    Science.gov (United States)

    Prud'homme, Gérald J; Glinka, Yelena; Wang, Qinghua

    2015-11-01

    Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. However, it is also produced in other sites; notably by pancreatic β cells and immune cells. The function of GABA in the immune system is at an early stage of study, but it exerts inhibitory effects that are relevant to autoimmune diseases. The study of GABAergic interactions in the immune system has centered on three main aspects: 1) the expression of GABA and the relevant GABAergic molecular machinery; 2) the in vitro response of immune cells; and 3) therapeutic applications in autoimmune diseases. T cells and macrophages can produce GABA, and express all the components necessary for a GABAergic response. There are two types of GABA receptors, but lymphocytes appear to express only type A (GABAAR); a ligand-gated chloride channel. Other immune cells may also express the type B receptor (GABABR); a G-protein coupled receptor. Activation of GABA receptors on T cells and macrophages inhibits responses such as production of inflammatory cytokines. In T cells, GABA blocks the activation-induced calcium signal, and it also inhibits NF-κB activation. In preclinical models, therapeutic application of GABA, or GABAergic (agonistic) drugs, protects against type 1 diabetes (T1D), experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA) and contact dermatitis. In addition, GABA exerts anti-apoptotic and proliferative effects on islet β cells, which may be applicable to islet transplantation. Autoimmunity against glutamic acid decarboxylase 65 (GAD65; synthesizes GABA) occurs in T1D. Antigen therapy of T1D with GAD65 or proinsulin in mice has protective effects, which are markedly enhanced by combined GABA therapy. Clinically, autoantibodies against GAD65 and/or GABA receptors play a pathogenic role in several neurological conditions, including stiff person syndrome (SPS), some forms of encephalitis, and autoimmune epilepsy. GABAergic drugs are widely used in

  2. Unresolved issues in theories of autoimmune disease using myocarditis as a framework

    Science.gov (United States)

    Root-Bernstein, Robert; Fairweather, DeLisa

    2014-01-01

    Many theories of autoimmune disease have been proposed since the discovery that the immune system can attack the body. These theories include the hidden or cryptic antigen theory, modified antigen theory, T cell bypass, T cell-B cell mismatch, epitope spread or drift, the bystander effect, molecular mimicry, anti-idiotype theory, antigenic complementarity, and dual-affinity T cell receptors. We critically review these theories and relevant mathematical models as they apply to autoimmune myocarditis. All theories share the common assumption that autoimmune diseases are triggered by environmental factors such as infections or chemical exposure. Most, but not all, theories and mathematical models are unifactorial assuming single-agent causation of disease. Experimental and clinical evidence and mathematical models exist to support some aspects of most theories, but evidence/models that support one theory almost invariably supports other theories as well. More importantly, every theory (and every model) lacks the ability to account for some key autoimmune disease phenomena such as the fundamental roles of innate immunity, sex differences in disease susceptibility, the necessity for adjuvants in experimental animal models, and the often paradoxical effect of exposure timing and dose on disease induction. We argue that a more comprehensive and integrated theory of autoimmunity associated with new mathematical models is needed and suggest specific experimental and clinical tests for each major theory that might help to clarify how they relate to clinical disease and reveal how theories are related. PMID:25484004

  3. Helminth Immunomodulation in Autoimmune Disease

    Directory of Open Access Journals (Sweden)

    John J. Miles

    2017-04-01

    Full Text Available Helminths have evolved to become experts at subverting immune surveillance. Through potent and persistent immune tempering, helminths can remain undetected in human tissues for decades. Redirecting the immunomodulating “talents” of helminths to treat inflammatory human diseases is receiving intensive interest. Here, we review therapies using live parasitic worms, worm secretions, and worm-derived synthetic molecules to treat autoimmune disease. We review helminth therapy in both mouse models and clinical trials and discuss what is known on mechanisms of action. We also highlight current progress in characterizing promising new immunomodulatory molecules found in excretory/secretory products of helminths and their potential use as immunotherapies for acute and chronic inflammatory diseases.

  4. Autoimmune pancreatitis: a case report.

    Science.gov (United States)

    Salari, Masoumeh; Hosseini, Mousareza; Nekooei, Sirous; Ataei Azimi, Sajad; Farzanehfar, Mohammad Reza

    2014-01-01

    Autoimmune pancreatitis is a fibro-inflammatory form of chronic pancreatitis. It is diagnosed by the combination of imaging studies such as a CT scan and pancreatography, laboratory analyses that include IgG4 and/or autoantibodies, histopathological evaluations and positive response to corticosteroid therapy. We report the case of a 41-year-old female with a history of jaundice and increasing abdominal pain for two weeks prior to her clinic visit. Laboratory results were significant for an increase in alkaline phosphatase (ALP) and erythrocyte sedimentation rate (ESR). Magnetic resonance cholangiopancreatography (MRCP) confirmed areas of stenosis and dilatation in the pancreatic duct and in the intra- and extra-hepatic bile ducts similar to primary sclerosantcholangitis. Laboratory analyses showed increased levels of IgG4 with thepresence of antinuclear antibodies.

  5. Antiretinal antibody- proven autoimmune retinopathy

    Directory of Open Access Journals (Sweden)

    Sharanya Abraham

    2017-01-01

    Full Text Available A young female presented with bilateral subacute onset of progressive decrease in night vision and reduced peripheral field of vision. The short duration and rapid progression of symptoms along with the lack of family history of night blindness prompted a diagnosis of autoimmune retinopathy (AIR. Fundus fluorescein angiography, optical coherence tomography, visual fields, and electroretinogram were suggestive of AIR. A differential diagnosis of retinitis pigmentosa (RP was also made. Antiretinal autoantibodies were detected in the blood sample. Treatment was with oral steroids and subsequently oral immunosuppressive agents. Visual acuity was maintained, fundus examination reverted to normal, and investigations repeated at every visit were stable with improvement in visual fields. Our case suggests that AIR, if diagnosed early and treated appropriately, may have a good outcome and should be considered in patients with an atypical presentation of RP.