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Sample records for experimental autoimmune myositis

  1. 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.

  2. Regional blood flow in experimental myositis ossificans

    International Nuclear Information System (INIS)

    Hierton, C.

    1983-01-01

    In a recent model for heterotopic bone formation, muscular oedema, swelling and necrosis is seen in the quadriceps muscle of rabbit hind limbs immobilized for at least 2 weeks when, from the second week, the immobilized limb is subjected to dayly forcible mobilization lasting about 5 min. According to this model, heterotopic calcification develops gradually from the second week of forcible mobilization and is located in the vastus intermedius region. Between the fourth and fifth week of immobilization and forcible mobilization, heterotopic bone formation is seen in virtually all cases. The histological findings are similar to those in human ectopic bone formation. In the present investigation the labelled microsphere technique was used to study the regional blood flow effects in the early development of myositis ossificans with this model. The results are quite different from those reported by other investigators on immobilization alone and point to a causal relation between regional blood flow and forcible mobilization of the immobilized rabbit hind limp. Prostaglandins as mediators between the traumatic inflammation, a part of the circulatory effects observed and the induction of a new bone is suggested. (author)

  3. TLR4-HMGB1 signaling pathway affects the inflammatory reaction of autoimmune myositis by regulating MHC-I.

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    Wan, Zemin; Zhang, Xiujuan; Peng, Anping; He, Min; Lei, Zhenhua; Wang, Yunxiu

    2016-12-01

    To analyze the effects of TLR4 on the expression of the HMGB1, MHC-I and downstream cytokines IL-6 and TNF-α, and to investigate the biological role of the TLR4-HMGB1 signaling pathway in the development of the autoimmune myositis. We built mice models with experimental autoimmune myositis (EAM) and used the inverted screen experiment to measure their muscle endurance; we also examined inflammatory infiltration of muscle tissues after HE staining; and we assessed the expression of MHC-I using immunohistochemistry. In addition, peripheral blood mononuclear cells (PBMC) were extracted and flow cytometry was utilized to detect the effect of IFN-γ on the expression of MHC-I. Furthermore, PBMCs were treated with IFN-γ, anti-TLR4, anti-HMGB1 and anti-MHC-I. Real-time PCR and western blotting were employed to examine the expressions of TLR4, HMGB1 and MHC-I in different groups. The ELISA method was also utilized to detect the expression of the downstream cytokines TNF-α and IL-6. The expressions of TLR4, HMGB1 and MHC-I in muscle tissues from mice with EAM were significantly higher than those in the control group (all PMHC-I, TNF-α and IL-6 in PBMCs significantly increased (all PMHC-I could significantly downregulate the expression of MHC-I (all PMHC-I and other pro-inflammatory cytokines. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Disease specificity of autoantibodies to cytosolic 5'-nucleotidase 1A in sporadic inclusion body myositis versus known autoimmune diseases.

    Science.gov (United States)

    Herbert, Megan K; Stammen-Vogelzangs, Judith; Verbeek, Marcel M; Rietveld, Anke; Lundberg, Ingrid E; Chinoy, Hector; Lamb, Janine A; Cooper, Robert G; Roberts, Mark; Badrising, Umesh A; De Bleecker, Jan L; Machado, Pedro M; Hanna, Michael G; Plestilova, Lenka; Vencovsky, Jiri; van Engelen, Baziel G; Pruijn, Ger J M

    2016-04-01

    The diagnosis of inclusion body myositis (IBM) can be challenging as it can be difficult to clinically distinguish from other forms of myositis, particularly polymyositis (PM). Recent studies have shown frequent presence of autoantibodies directed against cytosolic 5'-nucleotidase 1A (cN-1A) in patients with IBM. We therefore, examined the autoantigenicity and disease specificity of major epitopes of cN-1A in patients with sporadic IBM compared with healthy and disease controls. Serum samples obtained from patients with IBM (n=238), PM and dermatomyositis (DM) (n=185), other autoimmune diseases (n=246), other neuromuscular diseases (n=93) and healthy controls (n=35) were analysed for the presence of autoantibodies using immunodominant cN-1A peptide ELISAs. Autoantibodies directed against major epitopes of cN-1A were frequent in patients with IBM (37%) but not in PM, DM or non-autoimmune neuromuscular diseases (autoimmune diseases, particularly Sjögren's syndrome (SjS; 36%) and systemic lupus erythematosus (SLE; 20%). In summary, we found frequent anti-cN-1A autoantibodies in sera from patients with IBM. Heterogeneity in reactivity with the three immunodominant epitopes indicates that serological assays should not be limited to a distinct epitope region. The similar reactivities observed for SjS and SLE demonstrate the need to further investigate whether distinct IBM-specific epitopes exist. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

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

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    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...

  6. 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.

  7. Inclusion body myositis : a nationwide study

    NARCIS (Netherlands)

    Badrising, Umesh Arvind

    2006-01-01

    The studies reported in this thesis aimed to survey the prevalence of inclusion body myositis (IBM), to describe its clinical features and course, to investigate whether the major histocompatibility complex predisposed subjects to IBM and autoimmune disorders (AID), to investigate the possible

  8. 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...

  9. Interferon-gamma regulates oxidative stress during experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Espejo, Carmen; Penkowa, Milena; Sáez-Torres, Irene

    2002-01-01

    Experimental autoimmune encephalomyelitis (EAE) is an induced inflammatory and demyelinating disease of the central nervous system which shares many clinical and pathological features with and is considered the animal model of multiple sclerosis. There is extensive evidence that EAE is a Th1...

  10. Dermatomyositis Sine Myositis with Membranoproliferative Glomerulonephritis

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    Mohammad Bagher Owlia

    2012-01-01

    Full Text Available Dermatomyositis (DM is an autoimmune disease that is characterized by involvement of proximal musculature and skin. We report a 52-year-old woman with a 6-year history of dermatomyositis sine myositis, who developed lower extremity edema and proteinuria. Pathological examination of renal biopsy showed membranoproliferative glomerulonephritis. She received steroid, cyclophosphamide, and mycophenolate mofetil. Over the 9 to 10 months after the beginning of treatment, the proteinuria was improved.

  11. Autoantibodies to cytosolic 5'-nucleotidase 1A in inclusion body myositis

    NARCIS (Netherlands)

    Pluk, H.; Hoeve, B.J.A. van; Dooren, S.H. van; Stammen-Vogelzangs, J.; Heijden, A. van der; Schelhaas, H.J.; Verbeek, M.M.; Badrising, U.A.; Arnardottir, S.; Gheorghe, K.; Lundberg, I.E.; Boelens, W.C.; Engelen, B.G.M. van; Pruijn, Ger

    2013-01-01

    OBJECTIVE: Sporadic inclusion body myositis (sIBM) is an inflammatory myopathy characterized by both degenerative and autoimmune features. In contrast to other inflammatory myopathies, myositis-specific autoantibodies had not been found in sIBM patients until recently. We used human skeletal muscle

  12. 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.

  13. 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.

  14. Orbital myositis in scleritis

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    Boonman, Z F H M; de Keizer, R J W; Graniewski-Wijnands, H S; Watson, P G

    2003-01-01

    Aims: To investigate the association between scleritis and myositis. Methods: Retrospective, non-comparative case series. Records and ultrasonograms were examined of 132 patients, with a diagnosis of episcleritis or scleritis, who attended the ophthalmology department at Leiden University Medical Center between 1997 and 2000. 103 were eligible for comprehensive examination. Medical records were evaluated. Ultrasonography was performed in all patients diagnosed with episcleritis or scleritis. Clinical features, precipitating factors, systemic associations, ocular complications, treatment, and outcome of each patient were assessed. Results: Of the 103 patients, 27 (26.2%) had episcleritis and 76 (73.8%) had scleritis. Myositis was found to be present in 11 patients. It was present in 14.5% of all patients with scleritis and 30.5% of those in whom the posterior sclera was affected. The presence of the associated myositis did not worsen the visual prognosis and the presence of myositis was not associated with other systemic diseases. There were no cases of unilateral scleritis with bilateral orbital myositis. During an attack ocular complications were more common in patients with scleritis and myositis (64%) than in patients with scleritis alone (30.4%), indicating a more diffuse and potentially dangerous inflammation. There was no evidence that the inflammatory changes in the orbit had spread to involve the sclera, so it is assumed that the muscle changes are an extension of a generalised response to intense inflammation of the episclera and sclera. Conclusion: This study found a frequent association between myositis and scleritis. Prognosis for vision was not affected by coexistence of myositis. PMID:12488260

  15. 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.

  16. Inclusion-Body Myositis: Diagnosis

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    ... for MDA Blog Donate Search MDA.org Close Inclusion-Body Myositis (IBM) Share print email share facebook ... As with other muscle diseases, a doctor diagnoses inclusion-body myositis (IBM) by considering the individual’s personal ...

  17. Therapeutic effects of cisplatin on rat experimental autoimmune encephalomyelitis.

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    Li, Xiao-Bo; Schluesener, Hermann J

    2006-01-01

    Experimental autoimmune encephalomyelitis (EAE) is a prototypic Th1-mediated autoimmune inflammatory disease of the central nervous system (CNS), and serves as a model for the human demyelinating disease, multiple sclerosis. Cisplatin is a drug widely used in the treatment of a variety of human neoplasias, such as advanced bladder carcinoma, adrenal cortex carcinoma, breast cancer, head and neck or lung carcinoma. Cisplatin binds to DNA and interferes with cellular repair and other mechanism, which eventually result into cell death. It is known that cisplatin can induce immunosuppressive effects through inhibition of T cell activity. Therefore we analyzed the anti-inflammatory effects of cisplatin in a rat EAE model. EAE was induced in male LEW rats by immunizing with a synthetic peptide of guinea pig myelin basic protein. The development of EAE and neurological signs were evaluated by a standard protocol. Immunohistochemistry was applied to show immune cell infiltration into the CNS. Early treatment of EAE rats with cisplatin effectively ameliorated the development of disease and provided a significant protective effect compared to control rats. Further, histological analysis demonstrated that the formation of the typical perivascular cuffs and brain infiltration of monocytes and lymphocytes were complete absent in cisplatin treated rats, while abundant T cell infiltration was seen in the CNS of EAE rats. Our data show that cisplatin has protective effects in EAE, indicating that cisplatin could be a candidate in the treatment of human CNS autoimmunity.

  18. 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.

  19. Benign acute childhood myositis.

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    Rajajee, Sarala; Ezhilarasi, S; Rajarajan, K

    2005-05-01

    To describe the clinical and laboratory features of benign acute childhood myositis. 40 children of BACM were seen during October 2001 to February 2002, 22 (52%) were male with mean age of 5.3 years. Duration of illness was 3.97 days. Preceding symptoms included fever, leg pain, vomiting and inability to walk. A provisional diagnosis of viral myositis was made in 26 (66%). Guillian Barre Syndrome was the most common referral diagnosis. 11 (27.5%) children had leucopenia with lymphocytic response and 16 (40%) had thrombocytopenia. CRP was negative in 32 (80%). CPK was markedly elevated (more than 1000 IU/l) in 18 (45%) and more than 500 IU/l in 11 (27.5%) remaining between 200 to 500 IU/l. Associated features were hepatitis (elevated SGOT & SGPT) in 28 (70%) and shock in 5 (12.5%). Serological test were indicative of dengue virus (Elisa PAN BIO) in 20 (50%) of which 8 (25%) were primary dengue and 12 (30%) were secondary dengue. The outcome of therapy mainly supportive were excellent. Benign acute myositis occurs often in association with viral infection. In the present study, Dengue virus was positive in 20 (50%) children. Benign acute myositis can be differentiated from more serious causes of walking difficulty by presence of calf and thigh muscle tenderness on stretching, normal power and deep tendon reflex and elevated CPK.

  20. Fluoxetine promotes remission in acute experimental autoimmune encephalomyelitis in rats.

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    Yuan, Xi-qiu; Qiu, Guang; Liu, Xiao-jia; Liu, Shan; Wu, Yongming; Wang, Xinyu; Lu, Tianming

    2012-01-01

    This study was carried out to clarify the effects of the antidepressant fluoxetine, a selective serotonin reuptake inhibitor, for its potential use in autoimmune diseases like multiple sclerosis in a rat model of experimental autoimmune encephalomyelitis (EAE). The rat EAE model was induced by subcutaneous injection of guinea pig spinal cord homogenate. Rats received fluoxetine via daily intragastric administration, starting 2 weeks prior to immune induction (fluoxetine pretreatment). Clinical scores and pathological changes in EAE rats were analyzed. Changes in serum cytokine levels were assessed by ELISA. Fluoxetine pretreatment significantly promoted remission in EAE. Histologically, fluoxetine-induced neuroprotection was accompanied by reductions in inflammatory foci and in the degree of demyelination in the spinal cord of EAE rats. The increase in serum IFN-γ in the EAE model was also suppressed by fluoxetine administration. These findings suggest that the prophylactic use of fluoxetine can relieve symptoms during remission in the acute EAE model, and these neuroprotective effects are associated with its anti-inflammatory effects. Copyright © 2012 S. Karger AG, Basel.

  1. Exquisite peptide specificity of oral tolerance in experimental autoimmune encephalomyelitis.

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    Javed, N H; Gienapp, I E; Cox, K L; Whitacre, C C

    1995-08-01

    Experimental autoimmune encephalomyelitis (EAE), induced in Lewis rats by injection of myelin basic protein (MBP) and adjuvant, is a T cell-mediated autoimmune disease. Earlier studies from our laboratory have shown that oral administration of guinea pig MBP before encephalitogenic challenge induces T cell anergy and results in the suppression of clinical signs and CNS histopathologic changes of EAE. In contrast, oral administration of rat MBP did not confer a similar degree of protection. This study was undertaken to determine the tolerogenicity of the synthetic peptide 68-88 derived from guinea pig (GP) MBP and rat MBP. These peptides differ by a single amino acid at position 80. Lewis rats fed GP 68-88 were protected from EAE induced with GP 68-88 or rat 68-88. In contrast, feeding rats 68-88 did not protect the animals from challenge with either peptide. Measurement of the frequency of peptide-reactive Th1 cells showed results consistent with the clinical picture. The in vitro proliferative response was significantly suppressed following oral administration of either whole GP MBP, the GP peptide, or the rat peptide, irrespective of clinical status. These results extend our earlier observation at the whole molecule level that GP but not rat MBP confers oral tolerance. These findings suggest that small structural differences at the amino acid level can produce dramatic differences in clinical outcome, with important implications for the design of multiple sclerosis clinical trials.

  2. Interferon-gamma regulates oxidative stress during experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Espejo, Carmen; Penkowa, Milena; Sáez-Torres, Irene

    2002-01-01

    . Here we analyze the role of IFN-gamma during EAE by using both IFN-gamma receptor-knockout (IFN-gamma R(-/-)) and wild-type mice, both strains immunized with peptide 40-55 from rat myelin oligodendrocyte glycoprotein. The levels of oxidative stress were determined through the analysis......Experimental autoimmune encephalomyelitis (EAE) is an induced inflammatory and demyelinating disease of the central nervous system which shares many clinical and pathological features with and is considered the animal model of multiple sclerosis. There is extensive evidence that EAE is a Th1...... disease eliciting secretion of proinflammatory cytokines like IFN-gamma or TNF-alpha, and it has been suggested that cytokine-induced oxidative stress could have a role in EAE neuropathology. However, the individual roles of these and other cytokines in the pathogenesis of the disease are still uncertain...

  3. 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.

  4. Dietary naringenin supplementation attenuates experimental autoimmune encephalomyelitis by modulating autoimmune inflammatory responses in mice

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    Autoimmune disease is prevalent in humans. Since conventional therapies have limited efficacy and often come with significant side effects, nutrition may provide an alternative and complementary approach to improving the autoimmune disorders. Naringenin, a flavonoid found in citrus fruits, has been ...

  5. 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

  6. 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.

  7. Combined short-term immunotherapy for experimental autoimmune myasthenia gravis

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    Pestronk, A.; Drachman, D.B.; Teoh, R.; Adams, R.N.

    1983-08-01

    A therapeutic strategy was designed to eliminate the humoral immune response to acetylcholine receptor (AChR) in ongoing experimental autoimmune myasthenia gravis (EAMG). Rats with EAMG were treated with a protocol consisting of three components: (1) A single high dose of cyclophosphamide (200 mg/kg) was used to produce a rapid and sustained fall in the anti-AChR antibody levels by preferential destruction of antibody-producing B-lymphocytes. ''Memory'' lymphocytes were not eliminated by cyclophosphamide. (2) Irradiation (600 rads) was used to eliminate the ''memory'' cells. It eliminated the anamnestic response to a challenge with the antigen AChR. (3) Bone marrow transplantation was used to repopulate the hematopoietic system after the otherwise lethal dose of cyclophosphamide. We used bone marrow from syngeneic rats with active EAMG to simulate an autologous transplant. Rats with EAMG treated with this combined protocol showed a prompt and sustained fall in the anti-AChR antibody levels and had no anamnestic response to a challenge with AChR. Thus, an affected animal's own marrow could be stored and used later for repopulation after cyclophosphamide-irradiation treatment. This treatment eliminates the animal's ongoing immune responses and reconstitutes the immune system in its original state. The success of this approach suggests that, if their safety could be established, similar ''curative'' strategies might be developed for the treatment of patients with severe antibody-mediated autoimmune disorders, such as myasthenia gravis.

  8. CD1-dependent regulation of chronic central nervous system inflammation in experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Teige, Anna; Teige, Ingrid; Lavasani, Shahram

    2004-01-01

    The existence of T cells restricted for the MHC I-like molecule CD1 is well established, but the function of these cells is still obscure; one implication is that CD1-dependent T cells regulate autoimmunity. In this study, we investigate their role in experimental autoimmune encephalomyelitis (EA...

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

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    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.

  10. Ageing and recurrent episodes of neuroinflammation promote progressive experimental autoimmune encephalomyelitis in Biozzi ABH mice

    NARCIS (Netherlands)

    Peferoen, Laura A. N.; Breur, Marjolein; van de Berg, Sarah; Peferoen-Baert, Regina; Boddeke, Erik H. W. G. M.; van der Valk, Paul; Pryce, Gareth; van Noort, Johannes M.; Baker, David; Amor, Sandra

    2016-01-01

    Current therapies for multiple sclerosis (MS) reduce the frequency of relapses by modulating adaptive immune responses but fail to limit the irreversible neurodegeneration driving progressive disability. Experimental autoimmune encephalomyelitis (EAE) in Biozzi ABH mice recapitulates clinical

  11. Prolonged stimulation of a brainstem raphe region attenuates experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Madsen, Pernille M.; Sloley, Stephanie S.; Vitores, Alberto A.

    2017-01-01

    Multiple sclerosis (MS), a neuroinflammatory disease, has few treatment options, none entirely adequate. We studied whether prolonged electrical microstimulation of a hindbrain region (the nucleus raphe magnus) can attenuate experimental autoimmune encephalomyelitis, a murine model of MS induced ...

  12. Differential expression of metallothioneins in the CNS of mice with experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Espejo, C; Carrasco, J; Hidalgo, J

    2001-01-01

    during experimental autoimmune encephalomyelitis in interferon-gamma receptor knockout mice with two different genetic backgrounds: 129/Sv and C57BL/6x129/Sv.Mice with experimental autoimmune encephalomyelitis showed a significant induction of metallothioneins-I+II in the spinal cord white matter......, and to a lower extent in the brain. Interferon-gamma receptor knockout mice suffered from a more severe experimental autoimmune encephalomyelitis, and interestingly showed a higher metallothioneins-I+II induction in both white and grey matter of the spinal cord and in the brain. In contrast...... to the metallothioneins-I+II isoforms, metallothionein-III expression remained essentially unaltered during experimental autoimmune encephalomyelitis; interferon-gamma receptor knockout mice showed an altered metallothionein-III expression (a slight increase in the spinal cord white matter) only in the C57BL/6x129/Sv...

  13. PET Imaging of Disease Progression and Treatment Effects in the Experimental Autoimmune Encephalomyelitis Rat Model

    NARCIS (Netherlands)

    Faria, Daniele de Paula; Vlaming, Maria L. H.; Copray, Sjef C. V. M.; Tielen, Frans; Anthonijsz, Herma J. A.; Sijbesma, Jurgen W. A.; Buchpiguel, Carlos A.; Dierckx, Rudi A. J. O.; van der Hoorn, Jose W. A.; de Vries, Erik F. J.

    The experimental autoimmune encephalomyelitis model is a model of multiple sclerosis that closely mimics the disease characteristics in humans. The main hallmarks of multiple sclerosis are neuroinflammation (microglia activation, monocyte invasion, and T-cell infiltration) and demyelination. PET

  14. Idiopathic Inflammatory Myopathies; Association with Overlap Myositis and Syndromes: Classification, Clinical Characteristics, and Associated Autoantibodies

    Directory of Open Access Journals (Sweden)

    Pari Basharat

    2016-07-01

    Full Text Available Idiopathic inflammatory myopathies (IIM are traditionally identified as a group of disorders that target skeletal muscle due to autoimmune dysfunction. The IIM can be divided into subtypes based on certain clinical characteristics, and several classification schemes have been proposed. The predominant diagnostic criteria for IIM is the Bohan and Peter criteria, which subdivides IIM into primary polymyositis (PM, primary dermatomyositis (DM, myositis with another connective tissue disease, and myositis associated with cancer. However, this measure has been criticised for several reasons including lack of specific criteria to help distinguish between muscle biopsy findings of PM, DM, and immune-mediated necrotising myopathy, as well as the lack of identification of cases of overlap myositis (OM. Because of this issue, other classification criteria for IIM have been proposed, which include utilising myositis-associated antibodies and myositis-specific antibodies, as well as overlap features such as Raynaud’s phenomenon, polyarthritis, oesophageal abnormalities, interstitial lung disease, small bowel abnormalities such as hypomotility and malabsorption, and renal crises, amongst others. Indeed, the identification of autoantibodies associated with certain clinical phenotypes of myositis, in particular connective tissue disease-myositis overlap, has further helped divide IIM into distinct clinical subsets, which include OM and overlap syndromes (OS. This paper reviews the concepts of OM and OS as they pertain to IIM, including definitions in the literature, clinical characteristics, and overlap autoantibodies.

  15. The EuroMyositis registry

    DEFF Research Database (Denmark)

    Lilleker, James B; Vencovsky, Jiri; Wang, Guochun

    2018-01-01

    AIMS: The EuroMyositis Registry facilitates collaboration across the idiopathic inflammatory myopathy (IIM) research community. This inaugural report examines pooled Registry data. METHODS: Cross-sectional analysis of IIM cases from 11 countries was performed. Associations between clinical subtyp...

  16. Myositis ossificans in hemophilia

    Energy Technology Data Exchange (ETDEWEB)

    Vas, W.; Cockshott, W.P.; Martin, R.F.; Pai, M.K.; Walker, I.

    1981-10-01

    A review of the radiographs of 60 hemophilia patients showed nine (15%) with ectopic new bone formation. Three of these patients had multiple sites of involvement. The high frequency discovered in this series contrasts with the paucity of descriptions to be found in the literature. This process of myositis ossificans affects the lower half of the body and probably represents dysplastic metaplasia developing at the site of an intramuscular hematoma when remote from bone, as well as ossification of hemorrhagic lesions related to the periosteum. In conventional radiographs anatomic localization of bone foci is difficult, but use of computed tomography permits precise identification of the affected muscle. There is negligible disability associated with this condition.

  17. Myositis ossificans in hemophilia

    International Nuclear Information System (INIS)

    Vas, W.; Cockshott, W.P.; Martin, R.F.; Pai, M.K.; Walker, I.

    1981-01-01

    A review of the radiographs of 60 hemophilia patients showed nine (15%) with ectopic new bone formation. Three of these patients had multiple sites of involvement. The high frequency discovered in this series contrasts with the paucity of descriptions to be found in the literature. This process of myositis ossificans affects the lower half of the body and probably represents dysplastic metaplasia developing at the site of an intramuscular hematoma when remote from bone, as well as ossification of hemorrhagic lesions related to the periosteum. In conventional radiographs anatomic localization of bone foci is difficult, but use of computed tomography permits precise identification of the affected muscle. There is negligible disability associated with this condition. (orig.)

  18. Radiological evaluation of myositis ossificans

    International Nuclear Information System (INIS)

    Kwon, Yang Sook; Kim, Soo Han; Lim, Young Chae; Shin, Hyun Ja

    1986-01-01

    The 35 patients who have suffered from myositis ossificans were investigate for 11 years. They were post traumatic patients. They trauma was divided into 3 groups; spinal cord injury, direct injury (fracture) and mixed type involving both. We evaluated the age distribution, the frequency of myositis ossificans, predilection site, bilaterally and relation between predilection site and bilaterally to the type of trauma. The results are as follows; 1. The age distribution was highest in 4th decades (12 among 35 patients). 2. In regard to distribution of 35 patients, spinal cord injury were most common (15 cases, 43%), the fracture nextly common (14, 40%) and then mixed type (6, 17%). 3. Among 51 cases of myositis ossificans, the frequency was highest in spinal cord injury (25 cases, 49%), next was fracture (14, 27%). 4. The predilection site of myositis ossificans were thigh (18 cases, 35%), hip (17, 33%) and buttock (6, 12%). 5. In correlation between predilection site of myositis ossificans and level of spinal cord injury, hip is the most frequent site in thoracic injury. 6. The bilaterally of myositis ossificans is 39% (20 among 51 lesions).

  19. A case of late-onset, thymoma-associated myasthenia gravis with ryanodine receptor and titin antibodies and concomitant granulomatous myositis.

    Science.gov (United States)

    Stefanou, M I; Komorowski, L; Kade, S; Bornemann, A; Ziemann, U; Synofzik, M

    2016-09-13

    Myasthenia gravis is an autoimmune neuromuscular disorder, which has only rarely been reported to co-manifest with myositis. The diagnosis of concomitant myositis in patients with myasthenia gravis is clinically challenging, and requires targeted investigations for the differential diagnosis, including EMG, autoantibody assays, muscle biopsy and, importantly, imaging of the mediastinum for thymoma screening. This report presents a case-vignette of a 72-year-old woman with progressive proximal muscle weakness and myalgias, diagnosed with thymoma-associated myasthenia and bioptically verified granulomatous myositis, with positive autoantibody status for ryanodine receptor and titin antibodies. The diagnosis of concurrent myositis and myasthenia gravis, especially in the presence of ryanodine receptor and titin antibodies, should lead neurologists to adopt different treatment strategies compared to those applied in myasthenia or myositis alone. Moreover, further evidence is warranted that titin and, particularly, ryanodine receptor antibodies may co-occur or be pathophysiologically involved in myasthenia-myositis cases.

  20. 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.

  1. 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...

  2. 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

  3. The murine gammaherpesvirus-68 chemokine-binding protein M3 inhibits experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Millward, Jason M; Holst, Peter J; Høgh-Petersen, Mette

    2010-01-01

    M3 (AdM3) directly to the CNS to evaluate the capacity of this protein to inhibit neuroinflammation using the experimental autoimmune encephalomyelitis (EAE) model. Treatment with the AdM3 vector significantly reduced the clinical severity of EAE, attenuated CNS histopathology, and reduced numbers...

  4. 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...

  5. A role for VAV1 in experimental autoimmune encephalomyelitis and multiple sclerosis

    DEFF Research Database (Denmark)

    Jagodic, Maja; Colacios, Celine; Nohra, Rita

    2009-01-01

    region on rat chromosome 9 regulates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Using interval-specific congenic rat lines and association of single-nucleotide polymorphisms with inflammatory phenotypes, we localized the gene of influence to Vav1, which codes for a signal...

  6. 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...

  7. 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...

  8. 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

    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...

  9. Oxidative Injury and Iron Redistribution Are Pathological Hallmarks of Marmoset Experimental Autoimmune Encephalomyelitis

    NARCIS (Netherlands)

    Dunham, Jordon; Bauer, Jan; Campbell, Graham R.; Mahad, Don J.; van Driel, Nikki; van der Pol, Susanne M. A.; 't Hart, Bert A.; Lassmann, Hans; Laman, Jon D.; van Horssen, Jack; Kap, Yolanda S.

    Oxidative damage and iron redistribution are associated with the pathogenesis and progression of multiple sclerosis (MS), but these aspects are not entirely replicated in rodent experimental autoimmune encephalomyelitis (EAE) models. Here, we report that oxidative burst and injury as well as

  10. Inclusion body myositis. Clinical aspects

    NARCIS (Netherlands)

    Cox, Fieke Maria Elisabeth

    2014-01-01

    Sporadische inclusion body myositis (IBM) is een van de meest voor voorkomende verworven spierziekte die ontstaat na het 50e levensjaar. In dit proefschrift worden de klinische aspecten van sporadische IBM beschreven. Uit de studie met betrekking tot het natuurlijk beloop blijkt dat de ziekte niet

  11. 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......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...... to study the effects of increased MT levels, we administered Zn-MT-II intraperitoneally (i.p.) to rats during EAE. Clinically, Zn-MT-II treatment reduced the severity of EAE symptoms and mortality in a time- and dose-dependent manner. Histopathologically, Zn-MT-II increased reactive astrogliosis...... of action on macrophages, while T lymphocytes are affected locally in the CNS. During EAE, oxidative stress was decreased by Zn-MT-II, which could contribute to the diminished clinical scores observed. None of the effects caused by Zn-MT-II could be attributable to the zinc content. These results suggest MT...

  12. Keeping an Eye on Crohn’s Disease: Orbital Myositis as the Presenting Symptom

    Directory of Open Access Journals (Sweden)

    Carol A Durno

    1997-01-01

    Full Text Available Episodic periorbital swelling due to presumed orbital inflammation and myositis caused intermittent apparent proptosis and was the presenting symptom of ileocecal Crohn's disease (CD in a teenage female with a family history of autoimmune disorders and CD. Orbital myositis, a very rare extraintestinal manifestation of inflammatory bowel disease (IBD, likely represents a process of impaired immunoregulation related to the underlying intestinal inflammation. This rare manifestation of IBD simulates the more commonly encountered thyroid orbitopathy (ophthalmopathy, but IBD should be considered if all thyroid tests are negative. It is important to recognize that orbital myositis may be an extraintestinal manifestation of Crohn's disease so that the diagnosis can be made and appropriate therapy commenced.

  13. The more the merrier? Scoring, statistics and animal welfare in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Palle, Pushpalatha; Ferreira, Filipa M; Methner, Axel; Buch, Thorsten

    2016-12-01

    Experimental autoimmune encephalomyelitis (EAE) is a frequently used animal model for the investigation of autoimmune processes in the central nervous system. As such, EAE is useful for modelling certain aspects of multiple sclerosis, a human autoimmune disease that leads to demyelination and axonal destruction. It is an important tool for investigating pathobiology, identifying drug targets and testing drug candidates. Even though EAE is routinely used in many laboratories and is often part of the routine assessment of knockouts and transgenes, scoring of the disease course has not become standardized in the community, with at least 83 published scoring variants. Varying scales with differing parameters are used and thus limit comparability of experiments. Incorrect use of statistical analysis tools to assess EAE data is commonplace. In experimental practice the clinical score is used not only as an experimental readout, but also as a parameter to determine animal welfare actions. Often overlooked factors such as the animal's ability to sense its compromised motoric abilities, drastic though transient weight loss, and also the possibility of neuropathic pain, make the assessment of severity a difficult task and pose a problem for experimental refinement. © The Author(s) 2016.

  14. 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.

  15. Post-traumatic myositis ossificans

    Directory of Open Access Journals (Sweden)

    John M. Zietkiewicz

    2014-12-01

    Full Text Available Post-traumatic myositis ossificans (PTMO is characterised by abnormal heterotopic boneformation involving striated muscle. PTMO is usually associated with trauma and is most common in the second and third decades. An important teaching point is that in the early or subacute phase, clinical and imaging features can mimic a soft-tissue sarcoma. A combination of imaging modalities is required to evaluate the muscle lesion.

  16. Rare myositis-specific autoantibody associations among Hungarian patients with idiopathic inflammatory myopathy

    Directory of Open Access Journals (Sweden)

    Levente Bodoki

    2015-10-01

    Full Text Available Idiopathic inflammatory myopathies are systemic, chronic autoimmune diseases characterized by symmetrical, proximal muscle weakness. Homogeneous groups present with similar symptoms. The response to therapy and prognosis could be facilitated by myositis-specific autoantibodies, and in this way, give rise to immunoserological classification. The myositis-specific autoantibodies are directed against specific proteins found in the cytoplasm or in the nucleus of the cells. To date, literature suggests the rarity of the co-existence of two myositis-specific autoantibodies. In this study the authors highlight rare associations of myositis-specific autoantibodies. Three hundred and thirty-seven Hungarian patients with polymyositis or dermatomyositis were studied. Their clinical findings were noted retrospectively. Specific blood tests identified six patients with the rare co-existence of myositis-specific autoantibodies, anti-Jo-1 and anti-SRP, anti-Jo-1 and anti-Mi-2, anti-Mi-2 and anti-PL-12, anti-Mi-2 and anti-SRP, and anti-SRP and anti-PL-7, respectively. This case review aims to identify the clinical importance of these rare associations and their place within the immunoserological classification.

  17. Experimental transmission of systemic AA amyloidosis in autoimmune disease and type 2 diabetes mellitus model mice

    Science.gov (United States)

    Maeda, Mayuko; Murakami, Tomoaki; Muhammad, Naeem; Inoshima, Yasuo; Ishiguro, Naotaka

    2016-01-01

    AA amyloidosis is a protein misfolding disease characterized by extracellular deposition of amyloid A (AA) fibrils. AA amyloidosis has been identified in food animals, and it has been postulated that AA amyloidosis may be transmissible to different animal species. Since the precursor protein of AA fibrils is serum amyloid A (SAA), which is an inflammatory acute phase protein, AA amyloidosis is considered to be associated with inflammatory diseases such as rheumatoid arthritis. Chronic diseases such as autoimmune disease and type 2 diabetes mellitus could be potential factors for AA amyloidosis. In this study, to examine the relationship between the induction of AA amyloidosis and chromic abnormalities such as autoimmune disease or type 2 diabetes mellitus, amyloid fibrils from mice, cattle, or chickens were experimentally injected into disease model mice. Wild-type mice were used as controls. The concentrations of SAA, IL-6, and IL-10 in autoimmune disease model mice were higher than those of control mice. However, induction of AA amyloidosis in autoimmune disease and type 2 diabetes mellitus model mice was lower than that in control mice, and the amount of amyloid deposits in the spleens of both mouse models was lower than that of control mice according to Congo red staining and immunohistochemistry. These results suggest that factors other than SAA levels, such as an inflammatory or anti-inflammatory environment in the immune response, may be involved in amyloid deposition. PMID:27321428

  18. 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.

  19. Experimental transmission of systemic AA amyloidosis in autoimmune disease and type 2 diabetes mellitus model mice.

    Science.gov (United States)

    Maeda, Mayuko; Murakami, Tomoaki; Muhammad, Naeem; Inoshima, Yasuo; Ishiguro, Naotaka

    2016-11-01

    AA amyloidosis is a protein misfolding disease characterized by extracellular deposition of amyloid A (AA) fibrils. AA amyloidosis has been identified in food animals, and it has been postulated that AA amyloidosis may be transmissible to different animal species. Since the precursor protein of AA fibrils is serum amyloid A (SAA), which is an inflammatory acute phase protein, AA amyloidosis is considered to be associated with inflammatory diseases such as rheumatoid arthritis. Chronic diseases such as autoimmune disease and type 2 diabetes mellitus could be potential factors for AA amyloidosis. In this study, to examine the relationship between the induction of AA amyloidosis and chromic abnormalities such as autoimmune disease or type 2 diabetes mellitus, amyloid fibrils from mice, cattle, or chickens were experimentally injected into disease model mice. Wild-type mice were used as controls. The concentrations of SAA, IL-6, and IL-10 in autoimmune disease model mice were higher than those of control mice. However, induction of AA amyloidosis in autoimmune disease and type 2 diabetes mellitus model mice was lower than that in control mice, and the amount of amyloid deposits in the spleens of both mouse models was lower than that of control mice according to Congo red staining and immunohistochemistry. These results suggest that factors other than SAA levels, such as an inflammatory or anti-inflammatory environment in the immune response, may be involved in amyloid deposition.

  20. Induction of experimental autoimmune encephalomyelitis in Dark Agouti rats without adjuvant.

    Science.gov (United States)

    Stosic-Grujicic, S; Ramic, Z; Bumbasirevic, V; Harhaji, L; Mostarica-Stojkovic, M

    2004-04-01

    Experimental autoimmune encephalomyelitis (EAE) is a well-recognized model for multiple sclerosis (MS) in humans. However, adjuvants used with encephalitogens to induce EAE produce non-specific effects interfering with the mechanisms involved in the autoimmune response to the central nervous system (CNS) tissue. It is therefore important to establish a more suitable model of EAE for analysis of autoimmune phenomena resembling those operative in MS. Here we report that EAE can be induced regularly in Dark Agouti (DA) strain of rats with spinal cord tissue without any adjuvant, as judged by both clinical and histological parameters. The incidence and severity of EAE depended on the origin of the encephalitogen, the rat versus guinea pig spinal cord homogenate being more efficient. Furthermore, EAE could be reinduced in animals which had recovered from disease that had been induced actively with encephalitogen alone, suggesting the role of adjuvant-generated non-specific mechanisms in resistance to reinduction of EAE. Thus, EAE induced in DA rats with encephalitogen alone provides a reproducible model for defining pathogenically relevant events in CNS autoimmunity devoid of the potentially misleading effects of adjuvants.

  1. [Changes of mechanical pain threshold in rats with experimental autoimmune prostatitis].

    Science.gov (United States)

    Song, Guo-Hong; Aisikaer, Tulahong; He, Li-Juan; Julaiti, Saimaiti; Zhang, Qiu-Mei; Li, Wen-Yu

    2014-06-01

    To observe the changes of the mechanical pain threshold in the rat model of autoimmune prostatitis, explore the mechanism of autoimmune prostatitis pain and offer some animal experimental evidence for the drug therapy of the condition. Twenty male Wistar rats weighing 180 - 220 g were divided into a model and a control group. The autoimmune prostatitis model was established by subcutaneous injection of an extract of male rat prostate glands (RPG) at 60 mg/ml in Freund's complete adjuvant (FCA) and pertussis-diphtheria-tetanus vaccine at 0 and 30 days, respectively. Mechanical tactile hyperalgesia was measured once a week using Von Frey Filaments from the beginning of the study. At 8 weeks after modeling, the rats were sacrificed and the prostate tissues harvested for observation of histomorphological changes by HE staining. HE staining revealed different degrees of benign prostatitis in the model rats. Compared with the controls, the mechanical pain threshold in the model rats was significantly decreased with the increased time of modeling, from (65.52 +/- 6.27) g at 0 week to (23.67 +/- 4.09) g at 8 weeks (P < 0.01). Statistically significant differences were found in the variation trend at different time points between the two groups (P < 0.01). Autoimmune prostatitis models were successfully established in rats and hyperalgesia was induced after modeling.

  2. Production of reactive nitrogen intermediates (RNI) by peritoneal macrophages from rats with experimental autoimmune prostatitis (EAP).

    Science.gov (United States)

    Orsilles, M A; Depiante-Depaoli, M

    1995-08-01

    Peritoneal macrophages from experimental autoimmune prostatitis (EAP) rats were examined for their capacity to secrete reactive nitrogen intermediates (RNI), measured by the release of nitrite (NO2-). Under basal conditions, there was a significant increase of NO2- secretion by cells from autoimmune rats in relation to resident cells. After stimulation in vitro with lipopolysaccharide (LPS), the NO2- production was higher in cells from autoimmune rats compared to treated and nontreated controls. The NO2- production was dependent upon the presence of L-arginine in the culture medium. The addition of L-NG-monomethyl arginine, an inhibitor of nitric oxide synthesis, to the medium reduced the amount of measurable NO2-. Kinetic studies in cells from EAP rats showed that in basal conditions there was an significant release of NO2- at day 7 of immunization that was maintained during the whole period studied. After LPS stimulation, there was a similar behavior and maximum values were reached at day 28 of immunization. These results, together with the lesion observed in the prostate gland, suggest that RNI may be of pathogenic importance in the development of early tissue inflammation and autoimmune disease of the prostate.

  3. Simultaneous Combined Myositis, Inflammatory Polyneuropathy, and Overlap Myasthenic Syndrome

    Directory of Open Access Journals (Sweden)

    Stéphane Mathis

    2016-01-01

    Full Text Available Immune-mediated neuromuscular disorders include pathologies of the peripheral nervous system, neuromuscular junction, and muscles. If overlap syndromes (or the association of almost two autoimmune disorders are recognized, the simultaneous occurrence of several autoimmune neuromuscular disorders is rare. We describe two patients presenting the simultaneous occurrence of inflammatory neuropathy, myositis, and myasthenia gravis (with positive acetylcholine receptor antibodies. For each patient, we carried out a pathological analysis (nerve and muscle and an electrophysiological study (and follow-up. To our knowledge, this is the first description of such a triple immune-mediated neuromuscular syndrome. We compared our observations with a few other cases of simultaneous diagnosis of two inflammatory neuromuscular disorders.

  4. 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....

  5. 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

    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...... 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...... skewing in the frequency of born Arg-/- mice. Loss of Arg function did not affect development of experimental autoimmune encephalomyelitis, but reduced the number of splenic B-cells in Arg-/- mice following immunization with MOG peptide. Conclusions: Development of MOG-induced experimental autoimmune...

  6. Time-course expression of CNS inflammatory, neurodegenerative tissue repair markers and metallothioneins during experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Espejo, C; Penkowa, M; Demestre, M

    2005-01-01

    Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS). EAE and MS are characterized by CNS inflammation, demyelination and neurodegeneration. The inflammatory response occurring within the CNS leads to glial activation, dysfunction and death, as well...

  7. Phenotype of Antigen Unexperienced TH Cells in the Inflamed Central Nervous System in Experimental Autoimmune Encephalomyelitis.

    Science.gov (United States)

    Franck, Sophia; Paterka, Magdalena; Birkenstock, Jerome; Zipp, Frauke; Siffrin, Volker; Witsch, Esther

    2017-06-01

    Multiple sclerosis is a chronic, disseminated inflammation of the central nervous system which is thought to be driven by autoimmune T cells. Genetic association studies in multiple sclerosis and a large number of studies in the animal model of the disease support a role for effector/memory T helper cells. However, the mechanisms underlying relapses, remission and chronic progression in multiple sclerosis or the animal model experimental autoimmune encephalomyelitis, are not clear. In particular, there is only scarce information on the role of central nervous system-invading naive T helper cells in these processes. By applying two-photon laser scanning microscopy we could show in vivo that antigen unexperienced T helper cells migrated into the deep parenchyma of the inflamed central nervous system in experimental autoimmune encephalomyelitis, independent of their antigen specificity. Using flow cytometric analyses of central nervous system-derived lymphocytes we found that only antigen-specific, formerly naive T helper cells became activated during inflammation of the central nervous system encountering their corresponding antigen.

  8. 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.

  9. 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...... of apoptosis is the passive cell death or "cell death by neglect" pathway, which is under the control of the Bcl family of genes. To investigate the role of passive cell death pathway in EAE, we used mice with transgenic expression of the long form of the bcl-x gene (Bcl-x(L)) targeted to the T-cell lineage...... central nervous system (CNS) compared with controls. There was also a decreased number of apoptotic cells in the CNS of Bcl-x(L) transgenic mice when compared with littermates at all time points tested. This is the first report of an autoimmune disease model in Bcl-x(L) transgenic mice. Our data indicate...

  10. Magnetic resonance imaging of infectious myositis

    International Nuclear Information System (INIS)

    Yun, Ji Young; Kim, Jee Young; Kim, Sang Heum; Jung, Youn Ju; Cha, Eun Suk; Park, Joung Mi; Park, Young Ha

    1998-01-01

    To describe the findings of magnetic resonance imaging in infectious myositis and to determine their value for differentiation between ruberculous and bacterial myositis. Magnetic resonance images of ten proven cases of infectious myositis (five tuberculous and five bacterial) were retrospectively reviewed in the light of clinical and laboratory findings. On the basis of magnetic resonance images, signal intensity of the mass, the presence or absence of an abscess, signal intensity of the peripheral wall, patterns of contrast enhancement, and associated findings were evaluated. Compared with those of bacterial myositis, the symptoms of tuberculous myositis lasted longer but there were no difinite local inflammatory signs. In three of five cases of bacterial myositis there were specific medical records;trauma in two cases and systemic lupus erythematosus in one. All tuberculous myositis cases involved a single muscle, but bacterial myositis affected multipe muscles in three cases(60%). All but one case showed a mass in the involved muscles. In one bacterial case, there was diffuse swelling in the involved muscle. On T1-weighted images, eight infectious cases showed low signal intensity;two, of the bactrerial type, showed subtle increased signal intensity. all cases demonstrated high signal intensity on t2-weighted images. The signal intensity of peripheral wall was slightly increased on T1-weighted images, but low on T2-weighted. In four cases there was associated cellulitis, and in one case each, adjacent joint effusion and deep vein thrombosis were seen. After gadolinium infusion, peripheral rim enhancement was noted in nine cases and heterogeneous enhancement in one. After magnetic resonance imaging of infectious myositis, the characteristic finding was an abscessed lesion, with the peripheral wall showing high signal intensity on T1-weighted images and low signal intensity on T2 weighted. Although we found it difficult to differentiate bacterial from tuberculous

  11. Magnetic resonance imaging of infectious myositis

    Energy Technology Data Exchange (ETDEWEB)

    Yun, Ji Young; Kim, Jee Young; Kim, Sang Heum; Jung, Youn Ju; Cha, Eun Suk; Park, Joung Mi; Park, Young Ha [The Catholic Univ., College of Medicine, Suwon (Korea, Republic of)

    1998-09-01

    To describe the findings of magnetic resonance imaging in infectious myositis and to determine their value for differentiation between ruberculous and bacterial myositis. Magnetic resonance images of ten proven cases of infectious myositis (five tuberculous and five bacterial) were retrospectively reviewed in the light of clinical and laboratory findings. On the basis of magnetic resonance images, signal intensity of the mass, the presence or absence of an abscess, signal intensity of the peripheral wall, patterns of contrast enhancement, and associated findings were evaluated. Compared with those of bacterial myositis, the symptoms of tuberculous myositis lasted longer but there were no difinite local inflammatory signs. In three of five cases of bacterial myositis there were specific medical records;trauma in two cases and systemic lupus erythematosus in one. All tuberculous myositis cases involved a single muscle, but bacterial myositis affected multipe muscles in three cases(60%). All but one case showed a mass in the involved muscles. In one bacterial case, there was diffuse swelling in the involved muscle. On T1-weighted images, eight infectious cases showed low signal intensity;two, of the bactrerial type, showed subtle increased signal intensity. all cases demonstrated high signal intensity on t2-weighted images. The signal intensity of peripheral wall was slightly increased on T1-weighted images, but low on T2-weighted. In four cases there was associated cellulitis, and in one case each, adjacent joint effusion and deep vein thrombosis were seen. After gadolinium infusion, peripheral rim enhancement was noted in nine cases and heterogeneous enhancement in one. After magnetic resonance imaging of infectious myositis, the characteristic finding was an abscessed lesion, with the peripheral wall showing high signal intensity on T1-weighted images and low signal intensity on T2 weighted. Although we found it difficult to differentiate bacterial from tuberculous

  12. Inclusion-body myositis, a multifactorial muscle disease associated with aging: current concepts of pathogenesis.

    Science.gov (United States)

    Askanas, Valerie; Engel, W King

    2007-11-01

    Sporadic inclusion-body myositis, the most common muscle disease of older persons, has no known cause or persistently beneficial treatment. The unfolding pathogenesis could lead to new treatment strategies and it is now of growing interest among clinicians and basic scientists. About 100 papers related to the subject were published in 2006 and the first part of 2007 (we cite only articles most relevant to this review). This review focuses on the current concepts of the pathogenesis of sporadic inclusion-body myositis. Both degeneration and mononuclear-cell inflammation are components of the pathology, but how each relates to the pathogenesis remains unclear. We suggest that an intramuscle fiber degenerative component is primary, leading to muscle-fiber destruction, while the lymphocytic inflammatory component may only slightly contribute to sporadic inclusion-body myositis muscle-fiber damage. Intracellular accumulation of amyloid-beta precursor protein, amyloid-beta, and amyloid-beta oligomers in an aging muscle-fiber cellular milieu, and other abnormalities, appear to be key pathogenic factors. We summarize intracellular molecular events and their consequences, and correlate findings in sporadic inclusion-body myositis muscle biopsies with inclusion-body myositis experimental models in tissue culture and in transgenic mice. Treatment of sporadic inclusion-body myositis remains a challenge. Antiinflammatory approaches used so far are without major or enduring benefit. Possible new treatment avenues are suggested.

  13. Rapidly progressive myositis as the sole manifestation of a concurrent gastric carcinoma

    OpenAIRE

    Asadi, Mehrnaz; Javanbakht, Maryam; Khajavian, Sirin; Zand, Sara

    2010-01-01

    Inflammatory myopathies including polymyositis and dermatomyositis are autoimmune disorders presenting with characteristic muscle weakness. These diseases, especially dermatomyositis, have a well-known association with a wide variety of neoplasms including lung, breast, ovary and colon cancers. Here we report the case of a 58-year-old man who presented with a 3-week history of myositis and was simultaneously diagnosed with gastric cancer.

  14. Evaluation of Marijuana Compounds on Neuroimmune Endpoints in Experimental Autoimmune Encephalomyelitis.

    Science.gov (United States)

    Kaplan, Barbara L F

    2018-02-21

    Cannabinoid compounds refer to a group of more than 60 plant-derived compounds in Cannabis sativa, more commonly known as marijuana. Exposure to marijuana and cannabinoid compounds has been increasing due to increased societal acceptance for both recreational and possible medical use. Cannabinoid compounds suppress immune function, and while this could compromise one's ability to fight infections, immune suppression is the desired effect for therapies for autoimmune diseases. It is critical, therefore, to understand the effects and mechanisms by which cannabinoid compounds alter immune function, especially immune responses induced in autoimmune disease. Therefore, this unit will describe induction and assessment of the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), and its potential alteration by cannabinoid compounds. The unit includes three approaches to induce EAE, two of which provide correlations to two forms of MS, and the third specifically addresses the role of autoreactive T cells in EAE. © 2018 by John Wiley & Sons, Inc. Copyright © 2018 John Wiley & Sons, Inc.

  15. HMGB1 expression patterns during the progression of experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Sun, Yan; Chen, Huoying; Dai, Jiapei; Zou, Huijuan; Gao, Ming; Wu, Hao; Ming, Bingxia; Lai, Lin; Xiao, Yifan; Xiong, Ping; Xu, Yong; Gong, Feili; Zheng, Fang

    2015-03-15

    High mobility group box 1 (HMGB1), a nonhistone chromatin associated protein, plays different roles according to the expression pattern such as the amount, cell location and sub-cellular location. It has been recently demonstrated that the systemic HMGB1 is associated with autoimmune encephalomyelitis. However, the dynamic change of HMGB1 expression pattern in spinal cords that may be involved in the progression of disease is not fully understood. In this study, the amount, cell location and subcellular location of HMGB1 in adult mice spinal cords during various stages of experimental autoimmune encephalomyelitis (EAE) are investigated. HMGB1 is expressed in the nuclei of spinal cord resident cells such as some astrocytes, microglia and a few neurons in normal situation. During EAE progression, the total and extracellular HMGB1 in the spinal cord are increased, more HMGB1 positive astrocytes and microglia are observed, and the intra-neurons HMGB1 in the ventral horn and around the central canal localize majorly in the cytoplasm accompanied by the increasing extracellular HMGB1. Blockade of HMGB1 in central nervous system (CNS) locally attenuates the severity of EAE significantly. Our findings indicate that the HMGB1 expression pattern in the spinal cord is associated with the progression of EAE. HMGB1 may be a potential target for autoimmune encephalomyelitis (multiple sclerosis in human) therapy. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Protoporphyrin Treatment Modulates Susceptibility to Experimental Autoimmune Encephalomyelitis in miR-155-Deficient Mice.

    Directory of Open Access Journals (Sweden)

    Jinyu Zhang

    Full Text Available We previously identified heme oxygenase 1 (HO-1 as a specific target of miR-155, and inhibition of HO-1 activity restored the capacity of miR-155-/- CD4+ T cells to promote antigen-driven inflammation after adoptive transfer in antigen-expressing recipients. Protoporphyrins are molecules recognized for their modulatory effect on HO-1 expression and function. In the present study, we investigated the effect of protoporphyrin treatment on the development of autoimmunity in miR-155-deficient mice. MiR-155-mediated control of HO-1 expression in promoting T cell-driven chronic autoimmunity was confirmed since HO-1 inhibition restored susceptibility to experimental autoimmune encephalomyelitis (EAE in miR-155-deficient mice. The increased severity of the disease was accompanied by an enhanced T cell infiltration into the brain. Taken together, these results underline the importance of miR-155-mediated control of HO-1 expression in regulating the function of chronically-stimulated T cells in EAE.

  17. Blockade of Extracellular ATP Effect by Oxidized ATP Effectively Mitigated Induced Mouse Experimental Autoimmune Uveitis (EAU.

    Directory of Open Access Journals (Sweden)

    Ronglan Zhao

    Full Text Available Various pathological conditions are accompanied by ATP release from the intracellular to the extracellular compartment. Extracellular ATP (eATP functions as a signaling molecule by activating purinergic P2 purine receptors. The key P2 receptor involved in inflammation was identified as P2X7R. Recent studies have shown that P2X7R signaling is required to trigger the Th1/Th17 immune response, and oxidized ATP (oxATP effectively blocks P2X7R activation. In this study we investigated the effect of oxATP on mouse experimental autoimmune uveitis (EAU. Our results demonstrated that induced EAU in B6 mice was almost completely abolished by the administration of small doses of oxATP, and the Th17 response, but not the Th1 response, was significantly weakened in the treated mice. Mechanistic studies showed that the therapeutic effects involve the functional change of a number of immune cells, including dendritic cells (DCs, T cells, and regulatory T cells. OxATP not only directly inhibits the T cell response; it also suppresses T cell activation by altering the function of DCs and Foxp3+ T cell. Our results demonstrated that inhibition of P2X7R activation effectively exempts excessive autoimmune inflammation, which may indicate a possible therapeutic use in the treatment of autoimmune diseases.

  18. The Adaptor Protein Rai/ShcC Promotes Astrocyte-Dependent Inflammation during Experimental Autoimmune Encephalomyelitis.

    Science.gov (United States)

    Ulivieri, Cristina; Savino, Maria Teresa; Luccarini, Ilaria; Fanigliulo, Emanuela; Aldinucci, Alessandra; Bonechi, Elena; Benagiano, Marisa; Ortensi, Barbara; Pelicci, Giuliana; D'Elios, Mario Milco; Ballerini, Clara; Baldari, Cosima Tatiana

    2016-07-15

    Th17 cells have been casually associated to the pathogenesis of autoimmune disease. We have previously demonstrated that Rai/ShcC, a member of the Shc family of adaptor proteins, negatively regulates Th17 cell differentiation and lupus autoimmunity. In this study, we have investigated the pathogenic outcome of the Th17 bias associated with Rai deficiency on multiple sclerosis development, using the experimental autoimmune encephalomyelitis (EAE) mouse model. We found that, unexpectedly, EAE was less severe in Rai(-/-) mice compared with their wild-type counterparts despite an enhanced generation of myelin-specific Th17 cells that infiltrated into the CNS. Nevertheless, when adoptively transferred into immunodeficient Rai(+/+) mice, these cells promoted a more severe disease compared with wild-type encephalitogenic Th17 cells. This paradoxical phenotype was caused by a dampened inflammatory response of astrocytes, which were found to express Rai, to IL-17. The results provide evidence that Rai plays opposite roles in Th17 cell differentiation and astrocyte activation, with the latter dominant over the former in EAE, highlighting this adaptor as a potential novel target for the therapy of multiple sclerosis. Copyright © 2016 by The American Association of Immunologists, Inc.

  19. RGS10 deficiency ameliorates the severity of disease in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Lee, Jae-Kyung; Kannarkat, George T; Chung, Jaegwon; Joon Lee, Hyun; Graham, Kareem L; Tansey, Malú G

    2016-02-01

    Regulator of G-protein signaling (RGS) family proteins, which are GTPase accelerating proteins (GAPs) that negatively regulate G-protein-coupled receptors (GPCRs), are known to be important modulators of immune cell activation and function. Various single-nucleotide polymorphisms in RGS proteins highly correlate with increased risk for multiple sclerosis (MS), an autoimmune, neurodegenerative disorder. An in-depth search of the gene expression omnibus profile database revealed higher levels of RGS10 and RGS1 transcripts in peripheral blood mononuclear cells (PBMCs) in MS patients, suggesting potential functional roles for RGS proteins in MS etiology and/or progression. To define potential roles for RGS10 in regulating autoimmune responses, we evaluated RGS10-null and wild-type (WT) mice for susceptibility to experimental autoimmune encephalomyelitis (EAE), a widely studied model of MS. Leukocyte distribution and functional responses were assessed using biochemical, immunohistological, and flow cytometry approaches. RGS10-null mice displayed significantly milder clinical symptoms of EAE with reduced disease incidence and severity, as well as delayed onset. We observed fewer CD3+ T lymphocytes and CD11b+ myeloid cells in the central nervous system (CNS) tissues of RGS10-null mice with myelin oligodendrocyte protein (MOG)35-55-induced EAE. Lymph node cells and splenocytes of immunized RGS10-null mice demonstrated decreased proliferative and cytokine responses in response to in vitro MOG memory recall challenge. In adoptive recipients, transferred myelin-reactive RGS10-null Th1 cells (but not Th17 cells) induced EAE that was less severe than their WT counterparts. These data demonstrate a critical role for RGS10 in mediating autoimmune disease through regulation of T lymphocyte function. This is the first study ever conducted to elucidate the function of RGS10 in effector lymphocytes in the context of EAE. The identification of RGS10 as an important regulator of

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

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    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.

  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. 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...

  3. 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......, oxidative stress, and apoptotic cell death during EAE were increased by MT-I+II deficiency. We now show for the first time that demyelination and axonal damage are significantly increased in MT-I+II deficient mice during EAE. Furthermore, oligodendroglial regeneration, growth cone formation, and tissue...

  4. 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......-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-controlled...

  5. 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...... and either CTLA4Ig or CTLA4IgY100F protected recipients from disease. In vitro studies confirmed the in vivo observations and showed that primed lymph node cells from protected animals had decreased proliferative responses to myelin basic protein as compared with controls, while lymphocytes from animals...

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

    Science.gov (United States)

    2018-02-01

    Following on from the Expression of Concern (10.1002/glia.22466) previously published by GLIA, the following Original Article has been retracted by the journal Editors and Publisher: Metallothionein I+II expression and their role in experimental autoimmune encephalomyelitis By Milena Penkowa and Juan Hidalgo GLIA (2000), 32(3), 247-263 DOI: 10.1002/1098-1136(200012)32:33.0.CO;2-T Discrepancies in the type and number of animals used in experiments performed by Milena Penkowa and reported in Table 1, identified during the course of investigations into Ms Penkowa's research, render the data and conclusions drawn from them unreliable. © 2017 Wiley Periodicals, Inc.

  8. Interleukin-12 promotes activation of effector cells that induce a severe destructive granulomatous form of murine experimental autoimmune thyroiditis.

    OpenAIRE

    Braley-Mullen, H.; Sharp, G. C.; Tang, H.; Chen, K.; Kyriakos, M.; Bickel, J. T.

    1998-01-01

    Granulomatous inflammatory lesions are a major histopathological feature of a wide spectrum of human infectious and autoimmune diseases. Experimental autoimmune thyroiditis (EAT) with granulomatous histopathological features can be induced by mouse thyroglobulin (MTg)-sensitized spleen cells activated in vitro with MTg and anti-interleukin-2 receptor (anti-IL-2R), anti-IL-2, or anti-interferon-gamma (anti-IFN-gamma) monoclonal antibody (MAb). These studies suggested that IFN-gamma-producing T...

  9. Vaccination with DNA Encoding an Immunodominant Myelin Basic Protein Peptide Targeted to Fc of Immunoglobulin G Suppresses Experimental Autoimmune Encephalomyelitis

    OpenAIRE

    Lobell, Anna; Weissert, Robert; Storch, Maria K.; Svanholm, Cecilia; de Graaf, Katrien L.; Lassmann, Hans; Andersson, Roland; Olsson, Tomas; Wigzell, Hans

    1998-01-01

    We explore here if vaccination with DNA encoding an autoantigenic peptide can suppress autoimmune disease. For this purpose we used experimental autoimmune encephalomyelitis (EAE), which is an autoaggressive disease in the central nervous system and an animal model for multiple sclerosis. Lewis rats were vaccinated with DNA encoding an encephalitogenic T cell epitope, guinea pig myelin basic protein peptide 68–85 (MBP68–85), before induction of EAE with MBP68–85 in complete Freund's adjuvant....

  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. 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.

  12. Liver Damage and Mortality in a Male Lewis Rat of Experimental Autoimmune Encephalomyelitis.

    Science.gov (United States)

    Ghaffarinia, Ameneh; Jalili, Cyrus; Mostafaie, Ali; Parvaneh, Shahram; Pakravan, Nafiseh

    2015-01-01

    Multiple sclerosis is an inflammatory disease of the central nervous system. This is due to migration of peripherally activated lymphocytes to central nervous system leading to inflammatory lesions. However, liver has an anti-inflammatory microenvironment. Myelin expression in the liver of transgenic mice suppresses inflammatory lesions within central nervous system. Considering the notion that the inflammatory events originate from periphery, we investigated if the liver was affected in an animal model for multiple sclerosis. Experimental autoimmune encephalomyelitis was induced in male Lewis rats using guinea pig spinal cord and complete Freund's adjuvant. Weight, clinical score, and survival rate were evaluated for 14 days post immunization. Liver sections were taken and stained with Hematoxylin and Eosin and examined with an Olympus microscope. Mortality was accompanied by liver damage. Sinusoidal congestion, pycnotic nuclei within hepatocytes, hepatocyte necrosis, and severe widespread congestion along with fat accumulation within hepatocytes (fatty degeneration) were observed in liver tissue sections. Liver damage occurs in experimental autoimmune encephalomyelitis. The perpetuation of self antigen leading to continuous migration of extrahepatically activated T cells makes an inflammatory milieu in the liver. It follows migration and development of more inflammatory cells and may paralyses tolerance inducing mechanisms. Apart from central nervous system lesion, liver injury may act as synergistic factor for debilitation and mortality.

  13. Linomide suppresses chronic-relapsing experimental autoimmune encephalomyelitis in DA rats.

    Science.gov (United States)

    Zhu, J; Diab, A; Mustafa, M; Levi, M; Wahren, B; Björk, J; Hedlund, G

    1998-10-08

    Linomide (quinoline-3-carboxamide) is a synthetic immunomodulator that suppresses several experimental autoimmune diseases. Here we report the effects of Linomide on chronic progressive and/or relapsing experimental autoimmune encephalomyelitis (PR-EAE), a CD4+ T cell mediated animal model of multiple sclerosis (MS). PR-EAE induced in DA rats by inoculation with homogenized guinea pig spinal cord and Freund's complete adjuvant, was strongly suppressed by Linomide administered daily subcutaneously from the day of inoculation. Linomide dose-dependently delayed the interval between immunization and onset of clinical PR-EAE, reduced severity and relapse of clinical PR-EAE, and shortened clinical PR-EAE. These clinical effects were associated with the down-modulation of CNS antigen-induced T cell responses and production of proinflammatory cytokines (IFN-gamma and TNF-alpha) as well as with upregulation of IL-4 (except in spleen MNC), IL-10 and TGF-beta in both spleen MNC and the spinal cord. These effects indicate that Linomide can suppress PR-EAE and may mediate its suppressive effects by regulation of cytokines.

  14. Study of the immune response to thyroglobulin through a model of experimental autoimmune thyroiditis

    International Nuclear Information System (INIS)

    Santos Castro, M. dos.

    1981-01-01

    The cellular and humoral immune response to thyroglobulin of different species was studied in guinea pigs. The experiments described suggested that the immune system can be activated against self-determinants. Human and pork thyroglobulin were able to induce the experimental thyroiditis as well as some immune responses, such as in vitro proliferative response, delayed hypersensitivity and antibodies. Although guinea pig thyroglobulin was unable to induce specific T-lymphocyte proliferation in vitro, delayed hypersensitivity response and antibodies, it was very efficient in inducing the autoimmune thyroiditis. On the contrary, bovine thyroglobulin did not induce experimental autoimmune thyroiditis despite producing good responses as determined by similar in vitro proliferative response, delayed hypersensitivity and on the humoral level. These results suggest that the assays utilised were not able to evaluate the relevant immune response to genesis of the thyroiditis. The determinant selection mechanisms operating in these immune responses are probably selecting determinants not responsible for self-recognition in vivo. It was suggested that the macrophage could be the cell responsible for the presentation of these determinants to the lymphocyte in an immunogenic form. (Author) [pt

  15. Corticosteroids in Myositis and Scleroderma

    Science.gov (United States)

    Postolova, Anna; Chen, Jennifer K; Chung, Lorinda

    2017-01-01

    Synopsis Idiopathic inflammatory myopathies (IIM) involve inflammation of the muscles and are classified based on the patterns of presentation and immunohistopathologic features on skin and muscle biopsy into four categories: dermatomyositis, polymyositis, inclusion body myositis, and immune mediated necrotizing myopathy. The term “scleroderma” refers to fibrosis of the skin. Localized scleroderma (morphea) is skin-limited, while systemic sclerosis (SSc) is associated with vascular and internal organ involvement. Although there is a paucity of randomized clinical trials, treatment with systemic corticosteroids (CS) is the standard of care for IIM with muscle and organ involvement. The extra-cutaneous features of systemic sclerosis are frequently treated with CS, however high doses have been associated with scleroderma renal crisis in high-risk patients. CS monotherapy is neither recommended for the cutaneous manifestations of dermatomyositis nor scleroderma. While CS can be effective first line agents, their significant side effect profile encourages concomitant treatment with other immunosuppressive medications to enable timely tapering. PMID:26611554

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

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    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.

  18. 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.

  19. The severity of experimental autoimmune cystitis can be ameliorated by anti-CXCL10 Ab treatment.

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    Udai P Singh

    Full Text Available Interstitial cystitis (IC, more recently called painful bladder syndrome (PBS is a complex disease associated with chronic bladder inflammation that primarily affects women. Its symptoms include frequent urinary urgency accompanied by discomfort or pain in the bladder and lower abdomen. In the United States, eight million people, mostly women, have IC/PBS. New evidence that autoimmune mechanisms are important in the pathogenesis of IC/PBS triggered interest.SWXJ mice immunized with a homogenate of similar mice's urinary bladders develop an autoimmune phenotype comparable to clinical IC with functional and histological alterations confined to the urinary bladder. Using the murine model of experimental autoimmune cystitis (EAC, we found that serum levels of CXCR3 ligand and local T helper type 1 (Th1 cytokine are elevated. Also, IFN-γ-inducible protein10 (CXCL10 blockade attenuated overall cystitis severity scores; reversed the development of IC; decreased local production of CXCR3 and its ligands, IFN-γ, and tumor necrosis factor-α (TNF-α; and lowered systemic levels of CXCR3 ligands. Urinary bladder CD4(+ T cells, mast cells, and neutrophils infiltrates were reduced following anti-CXCL10 antibody (Ab treatment of mice. Anti-CXCL10 Ab treatment also reversed the upregulated level of CXCR3 ligand mRNA at urinary bladder sites. The decreased number and percentage of systemic CD4(+ T cells in EAC mice returned to normal after anti-CXCL10 Ab treatment.Taken together, our findings provide important new information about the mechanisms underlying EAC pathogenesis, which has symptoms similar to those of IC/PBS. CXCL10 has the potential for use in developing new therapy for IC/PBS.

  20. Reduced experimental autoimmune encephalomyelitis after intranasal and oral administration of recombinant lactobacilli expressing myelin antigens.

    Science.gov (United States)

    Maassen, Catharina B M; Laman, Jon D; van Holten-Neelen, Conny; Hoogteijling, Linsy; Groenewegen, Lizet; Visser, Lizette; Schellekens, Marc M; Boersma, Wim J A; Claassen, Eric

    2003-12-01

    Oral administration of autoantigens is a safe and convenient way to induce peripheral T-cell tolerance in autoimmune diseases like multiple sclerosis (MS). To increase the efficacy of oral tolerance induction and obviate the need for large-scale purification of human myelin proteins, we use genetically modified lactobacilli expressing myelin antigens. A panel of recombinant lactobacilli was constructed producing myelin proteins and peptides, including human and guinea pig myelin basic protein (MBP) and proteolipid protein peptide 139-151 (PLP(139-151)). In this study we examined whether these Lactobacillus recombinants are able to induce oral and intranasal tolerance in an animal model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Lewis rats received soluble cell extracts of Lactobacillus transformants intranasally three times prior to induction of EAE. For the induction of oral tolerance, rats were fed live transformed lactobacilli for 20 days. Ten days after the first oral administration EAE was induced. Intranasal administration of extracts containing guinea pig MBP (gpMBP) or MBP(72-85) significantly inhibited EAE in Lewis rats. Extracts of control transformants did not reduce EAE. Live lactobacilli expressing guinea pig MBP(72-85) fused to the marker enzyme beta-glucuronidase (beta-gluc) were also able to significantly reduce disease when administered orally. In conclusion, these experiments provide proof of principle that lactobacilli expressing myelin antigens reduce EAE after mucosal (intranasal and oral) administration. This novel method of mucosal tolerance induction by mucosal administration of recombinant lactobacilli expressing relevant autoantigens could find applications in autoimmune disease in general, such as multiple sclerosis, rheumatoid arthritis and uveitis.

  1. Silencing miR-146a influences B cells and ameliorates experimental autoimmune myasthenia gravis.

    Science.gov (United States)

    Zhang, JunMei; Jia, Ge; Liu, Qun; Hu, Jue; Yan, Mei; Yang, BaiFeng; Yang, Huan; Zhou, WenBin; Li, Jing

    2015-01-01

    MicroRNAs have been shown to be important regulators of immune homeostasis as patients with aberrant microRNA expression appeared to be more susceptible to autoimmune diseases. We recently found that miR-146a was up-regulated in activated B cells in response to rat acetylcholine receptor (AChR) α-subunit 97-116 peptide, and this up-regulation was significantly attenuated by AntagomiR-146a. Our data also demonstrated that silencing miR-146a with its inhibitor AntagomiR-146a effectively ameliorated clinical myasthenic symptoms in mice with ongoing experimental autoimmune myasthenia gravis. Furthermore, multiple defects were observed after miR-146a was knocked down in B cells, including decreased anti-R97-116 antibody production and class switching, reduced numbers of plasma cells, memory B cells and B-1 cells, and weakened activation of B cells. Previously, miR-146a has been identified as a nuclear factor-κB-dependent gene and predicted to base pair with the tumour necrosis factor receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1) genes to regulate the immune response. However, our study proved that miR-146a inhibition had no effect on the expression of TRAF6 and IRAK1 in B cells. This result suggests that the function of miR-146a in B cells does not involve these two target molecules. We conclude that silencing miR-146a exerts its therapeutic effects by influencing the B-cell functions that contribute to the autoimmune pathogenesis of myasthenia gravis. © 2014 John Wiley & Sons Ltd.

  2. Gut-associated lymphoid tissue, gut microbes and susceptibility to experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Stanisavljević, S; Lukić, J; Momčilović, M; Miljković, M; Jevtić, B; Kojić, M; Golić, N; Mostarica Stojković, M; Miljković, D

    2016-06-01

    Gut microbiota and gut-associated lymphoid tissue have been increasingly appreciated as important players in pathogenesis of various autoimmune diseases, including multiple sclerosis. Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis that can be induced with an injection of spinal cord homogenate emulsified in complete Freund's adjuvant in Dark Agouti (DA) rats, but not in Albino Oxford (AO) rats. In this study, mesenteric lymph nodes (MLN), Peyer's patches (PP) and gut microbiota were analysed in these two rat strains. There was higher proportion of CD4(+) T cells and regulatory T cells in non-immunised DA rats in comparison to AO rats. Also, DA rat MLN and PP cells were higher producers of pro-inflammatory cytokines interferon-γ and interleukin-17. Finally, microbial analyses showed that uncultivated species of Turicibacter and Atopostipes genus were exclusively present in AO rats, in faeces and intestinal tissue, respectively. Thus, it is clear that in comparison of an EAE-susceptible with an EAE-resistant strain of rats, various discrepancies at the level of gut associated lymphoid tissue, as well as at the level of gut microbiota can be observed. Future studies should determine if the differences have functional significance for EAE pathogenesis.

  3. Erythropoietin-derived nonerythropoietic peptide ameliorates experimental autoimmune neuritis by inflammation suppression and tissue protection.

    Directory of Open Access Journals (Sweden)

    Yuqi Liu

    Full Text Available Experimental autoimmune neuritis (EAN is an autoantigen-specific T-cell-mediated disease model for human demyelinating inflammatory disease of the peripheral nervous system. Erythropoietin (EPO has been known to promote EAN recovery but its haematopoiesis stimulating effects may limit its clinic application. Here we investigated the effects and potential mechanisms of an EPO-derived nonerythropoietic peptide, ARA 290, in EAN. Exogenous ARA 290 intervention greatly improved EAN recovery, improved nerve regeneration and remyelination, and suppressed nerve inflammation. Furthermore, haematopoiesis was not induced by ARA 290 during EAN treatment. ARA 290 intervention suppressed lymphocyte proliferation and altered helper T cell differentiation by inducing increase of Foxp3+/CD4+ regulatory T cells and IL-4+/CD4+ Th2 cells and decrease of IFN-γ+/CD4+ Th1 cells in EAN. In addition, ARA 290 inhibited inflammatory macrophage activation and promoted its phagocytic activity. In vitro, ARA 290 was shown to promote Schwann cell proliferation and inhibit its inflammatory activation. In summary, our data demonstrated that ARA 290 could effectively suppress EAN by attenuating inflammation and exerting direct cell protection, indicating that ARA 290 could be a potent candidate for treatment of autoimmune neuropathies.

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

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    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.

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

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    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.

  6. 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.

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

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    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.

  8. 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......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...

  9. Total glucosides of peony attenuates experimental autoimmune encephalomyelitis in C57BL/6 mice.

    Science.gov (United States)

    Huang, Qiling; Ma, Xiaomeng; Zhu, Dong Liang; Chen, Li; Jiang, Ying; Zhou, Linli; Cen, Lei; Pi, Rongbiao; Chen, Xiaohong

    2015-07-15

    Total glucosides of peony (TGP), an active compound extracted from the roots of Paeonia lactiflora Pall, has wide pharmacological effects on nervous system. Here we examined the effects of TGP on experimental autoimmune encephalomyelitis (EAE), an established model of multiple sclerosis (MS). The results showed that TGP can reduce the severity and progression of EAE in C57 BL/6 mice. In addition, TGP also down-regulated the Th1/Th17 inflammatory response and prevented the reduced expression of brain-derived neurotrophic factor and 2',3'-cyclic nucleotide 3'-phosphodiesterase of EAE. These findings suggest that TGP could be a potential therapeutic agent for MS. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Pertussis toxin promotes relapsing-remitting experimental autoimmune encephalomyelitis in Lewis rats.

    Science.gov (United States)

    Mohajeri, Maryam; Sadeghizadeh, Majid; Javan, Mohammad

    2015-12-15

    Animal models simulate different aspects of human diseases and are essential to get a better understanding of the disease, studying treatments and producing new drugs. Experimental autoimmune encephalomyelitis (EAE) is a preferred model in multiple sclerosis research. Common EAE model in Lewis rats is induced using MBP peptide as a myelin antigen which results in a monophasic disease course. In the present study, EAE was induced in Lewis rats by homogenized guinea pig spinal cord along with or without pertussis toxin (PT). When PT was used, EAE turned into remitting-relapsing form and worsen the clinical symptoms. Higher inflammation and oxidative stress marker gene expression was observed when PT was administrated. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. The influence of cyclosporin A on experimental autoimmune thyroid disease in the rat

    International Nuclear Information System (INIS)

    McGregor, A.M.; Rennie, D.P.; Weetman, A.P.; Hassman, R.A.; Foord, S.M.; Dieguez, C.; Hall, R.

    1983-01-01

    Female PVG/c rats, thymectomised on weaning and given 4 courses of whole body irradiation to a total dose of 1000 rads, developed experimental autoimmune thyroid disease (EAITD) as assessed by histological evidence of thyroiditis and circulating levels of antithyroglobulin antibodies. Hypothyroidism resulted. Induction of the disease was associated with a highly significant fall in T lymphocyte numbers. Eight weeks after their last dose of irradiation the animals commenced treatment with cyclosporin A (10 mg/kg rat/day, intragastrically) and were treated for varying time intervals thereafter. The reversal of the T lymphocyte helper: suppressor ratio on cyclosporin A therapy was associated with a significant improvement in the disease process. The alterations in the T cell subsets and in the disease lasted only as long as the drug was administered and thereafter reverted towards that seen in the control groups of animals receiving no treatment

  12. Damage to the Optic Chiasm in Myelin Oligodendrocyte Glycoprotein–Experimental Autoimmune Encephalomyelitis Mice

    Directory of Open Access Journals (Sweden)

    Sheryl L. Herrera

    2014-01-01

    Full Text Available Optic chiasm lesions in myelin oligodendrocyte glycoprotein (MOG–experimental autoimmune encephalomyelitis (EAE mice were characterized using magnetic resonance imaging (MRI and validated using electron microscopy (EM. MR images were collected from 3 days after induction to remission, approximately 20 days after induction. Hematoxylin and eosin, solochrome cyanin–stained sections, and EM images were obtained from the optic chiasms of some mice approximately 4 days after disease onset when their scores were thought to be the highest. T 2 -weighted imaging and apparent diffusion coefficient map hyperintensities corresponded to abnormalities in the optic chiasms of EAE mice. Mixed inflammation was concentrated at the lateral surface. Degeneration of oligodendrocytes, myelin, and early axonal damage were also apparent. A marked increase in chiasm thickness was observed. T 2 -weighted and diffusion-weighted MRI can detect abnormalities in the optic chiasms of MOG-EAE mice. MRI is an important method in the study of this model toward understanding optic neuritis.

  13. Experimental autoimmune encephalomyelitis from a tissue energy perspective [version 1; referees: 2 approved

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    Roshni A Desai

    2017-11-01

    Full Text Available 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.

  14. Specific removal of autoantibodies by extracorporeal immunoadsorption ameliorates experimental autoimmune myasthenia gravis.

    Science.gov (United States)

    Lazaridis, Konstantinos; Dalianoudis, Ioannis; Baltatzidi, Vasiliki; Tzartos, Socrates J

    2017-11-15

    Myasthenia gravis (MG) is caused by autoantibodies, the majority of which target the muscle acetylcholine receptor (AChR). Plasmapheresis and IgG-immunoadsorption are useful therapy options, but are highly non-specific. Antigen-specific immunoadsorption would remove only the pathogenic autoantibodies, reducing the possibility of side effects while maximizing the benefit. We have extensively characterized such adsorbents, but in vivo studies are missing. We used rats with experimental autoimmune MG to perform antigen-specific immunoadsorptions over three weeks, regularly monitoring symptoms and autoantibody titers. Immunoadsorption was effective, resulting in a marked autoantibody titer decrease while the immunoadsorbed, but not the mock-treated, animals showed a dramatic symptom improvement. Overall, the procedure was found to be efficient, suggesting the subsequent initiation of clinical trials. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. 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

  16. Protracted, relapsing and demyelinating experimental autoimmune encephalomyelitis in DA rats immunized with syngeneic spinal cord and incomplete Freund's adjuvant

    DEFF Research Database (Denmark)

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

    1995-01-01

    Experimental autoimmune encephalomyelitis (EAE) is a model for multiple sclerosis (MS). However, MS is a chronic, relapsing and demyelinating disease, whereas EAE in rats is typically a brief and monophasic disorder showing little demyelination. We demonstrate here that DA rats develop severe...

  17. 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 mice...

  18. 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

    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...

  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

    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...

  20. Necrotising Myositis, the Deadly Impersonator

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    A. Rahman

    2014-01-01

    Full Text Available We report two cases of patients with necrotising myositis who presented initially with limb pain and swelling on a background of respiratory complaints. Patient 1, a previously well 38-year-old female, underwent various investigations in the emergency department for excessive lower limb pain and a skin rash. Patient 2, a 61-year-old female with a background of rheumatoid arthritis and hypertension, presented to accident and emergency feeling generally unwell and was treated for presumed respiratory sepsis. Both deteriorated rapidly and were referred to the plastic surgery team with soft tissue necrosis, impending multiorgan failure and toxaemia. Large areas of necrotic muscle and skin were debrided, which grew group A streptococci, Streptococcus pyogenes. Patient 1 had a high above knee amputation of the left leg with extensive debridement of the right. Despite aggressive surgical intervention and microbiological input with intensive care support, patient 2 died. These two cases highlight the importance of early diagnosis and prompt surgical and pharmacological intervention in managing this life-threatening disease. Pain is the primary symptom with skin changes being a late and subtle sign in a septic patient. The Laboratory Risk Indicator for Necrotising Fasciitis (LRINEC may be of use if there is concern to aid diagnosis of this life-threatening disease.

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

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    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

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

    Science.gov (United States)

    Carrillo-Salinas, Francisco J; Navarrete, Carmen; Mecha, Miriam; Feliú, Ana; Collado, Juan A; Cantarero, Irene; Bellido, María L; Muñoz, Eduardo; Guaza, Carmen

    2014-01-01

    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 therapeutic potential

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

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    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

  4. High salt drives Th17 responses in experimental autoimmune encephalomyelitis without impacting myeloid dendritic cells.

    Science.gov (United States)

    Jörg, Stefanie; Kissel, Jan; Manzel, Arndt; Kleinewietfeld, Markus; Haghikia, Aiden; Gold, Ralf; Müller, Dominik N; Linker, Ralf A

    2016-05-01

    Recently, we have shown that high dietary salt intake aggravates T helper cell (Th) 17 responses and neuroinflammation. Here, we employed in vitro assays for myeloid dendritic cell (mDC) maturation, DC cytokine production, T cell activation and ex vivo analyses in murine experimental autoimmune encephalomyelitis (EAE) to investigate whether the salt effect on Th17 cells is further mediated through DCs in vivo. In cell culture, an excess of 40mM sodium chloride did neither affect the generation, maturation nor the function of DCs, but, in different assays, significantly increased Th17 differentiation. During the initiation phase of MOG35-55 EAE, we did not observe altered DC frequencies or co-stimulatory capacities in lymphoid organs, while IL-17A production and Th17 cells in the spleen were significantly increased. Complementary ex vivo analyses of the spinal cord during the effector phase of EAE showed increased frequencies of Th17 cells, but did not reveal differences in phenotypes of CNS invading DCs. Finally, adaption of transgenic mice harboring a MOG specific T cell receptor to a high-salt diet led to aggravated clinical disease only after active immunization. Wild-type mice adapted to a high-salt diet in the effector phase of EAE, bypassing the priming phase of T cells, only displayed mildly aggravated disease. In summary, our data argue for a direct effect of NaCl on Th17 cells in neuroinflammation rather than an effect primarily exerted via DCs. These data may further fuel our understanding on the dietary impact on different immune cell subsets in autoimmune diseases, such as multiple sclerosis. Copyright © 2016. Published by Elsevier Inc.

  5. In acute experimental autoimmune encephalomyelitis, infiltrating macrophages are immune activated, whereas microglia remain immune suppressed.

    Science.gov (United States)

    Vainchtein, I D; Vinet, J; Brouwer, N; Brendecke, S; Biagini, G; Biber, K; Boddeke, H W G M; Eggen, B J L

    2014-10-01

    Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS) characterized by loss of myelin accompanied by infiltration of T-lymphocytes and monocytes. Although it has been shown that these infiltrates are important for the progression of MS, the role of microglia, the resident macrophages of the CNS, remains ambiguous. Therefore, we have compared the phenotypes of microglia and macrophages in a mouse model for MS, experimental autoimmune encephalomyelitis (EAE). In order to properly discriminate between these two cell types, microglia were defined as CD11b(pos) CD45(int) Ly-6C(neg) , and infiltrated macrophages as CD11b(pos) CD45(high) Ly-6C(pos) . During clinical EAE, microglia displayed a weakly immune-activated phenotype, based on the expression of MHCII, co-stimulatory molecules (CD80, CD86, and CD40) and proinflammatory genes [interleukin-1β (IL-1β) and tumour necrosis factor- α (TNF-α)]. In contrast, CD11b(pos) CD45(high) Ly-6C(pos) infiltrated macrophages were strongly activated and could be divided into two populations Ly-6C(int) and Ly-6C(high) , respectively. Ly-6C(high) macrophages contained less myelin than Ly-6C(int) macrophages and expression levels of the proinflammatory cytokines IL-1β and TNF-α were higher in Ly-6C(int) macrophages. Together, our data show that during clinical EAE, microglia are only weakly activated whereas infiltrated macrophages are highly immune reactive. © 2014 Wiley Periodicals, Inc.

  6. 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.

  7. Transplantation of autologous adipose stem cells lacks therapeutic efficacy in the experimental autoimmune encephalomyelitis model.

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    Xiujuan Zhang

    Full Text Available Multiple sclerosis (MS, characterized by chronic inflammation, demyelination, and axonal damage, is a complicated neurological disease of the human central nervous system. Recent interest in adipose stromal/stem cell (ASCs for the treatment of CNS diseases has promoted further investigation in order to identify the most suitable ASCs. To investigate whether MS affects the biologic properties of ASCs and whether autologous ASCs from MS-affected sources could serve as an effective source for stem cell therapy, cells were isolated from subcutaneous inguinal fat pads of mice with established experimental autoimmune encephalomyelitis (EAE, a murine model of MS. ASCs from EAE mice and their syngeneic wild-type mice were cultured, expanded, and characterized for their cell morphology, surface antigen expression, osteogenic and adipogenic differentiation, colony forming units, and inflammatory cytokine and chemokine levels in vitro. Furthermore, the therapeutic efficacy of the cells was assessed in vivo by transplantation into EAE mice. The results indicated that the ASCs from EAE mice displayed a normal phenotype, typical MSC surface antigen expression, and in vitro osteogenic and adipogenic differentiation capacity, while their osteogenic differentiation capacity was reduced in comparison with their unafflicted control mice. The ASCs from EAE mice also demonstrated increased expression of pro-inflammatory cytokines and chemokines, specifically an elevation in the expression of monocyte chemoattractant protein-1 and keratin chemoattractant. In vivo, infusion of wild type ASCs significantly ameliorate the disease course, autoimmune mediated demyelination and cell infiltration through the regulation of the inflammatory responses, however, mice treated with autologous ASCs showed no therapeutic improvement on the disease progression.

  8. 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.

  9. Application of dendritic cells stimulated with Trichinella spiralis excretory-secretory antigens alleviates experimental autoimmune encephalomyelitis.

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    Sofronic-Milosavljevic, L J; Radovic, I; Ilic, N; Majstorovic, I; Cvetkovic, J; Gruden-Movsesijan, A

    2013-06-01

    The parasitic nematode, Trichinella spiralis (T. spiralis), exerts an immunomodulatory effect on the host immune response through excretory-secretory products (ES L1) released from encysted muscle larvae. Our model of combined T. spiralis infection and experimental autoimmune encephalomyelitis (EAE) in Dark Agouti (DA) rats demonstrated a significant reduction in EAE severity in infected animals. Recently, we have created an immune status characteristic for the live infection by in vivo application of dendritic cells (DCs) stimulated with ES L1 products of T. spiralis muscle larvae. Moreover, these cells were able to ameliorate EAE when applied 7 days before EAE induction. ES L1-stimulated DCs increased production of IL-4, IL-10 and TGF-β, and decreased production of IFN-γ and IL-17, both at the systemic level and in target organs. A significant increase in the proportion of CD4+CD25+Foxp3+ T cells was found among spleen cells, and CNS infiltrates from DA rats treated with ES L1-stimulated DCs before EAE induction, compared to controls injected with unstimulated DCs. Regulatory T cells, together with elevated levels of IL-10 and TGF-β, are most likely involved in restraining the production of Th1 and Th17 cytokines responsible for autoimmunity and thus are responsible for the beneficial effect of ES L1-educated DCs on the course of EAE. Our results show that ES L1 antigen-stimulated DCs are able not only to provoke, but also to sustain anti-inflammatory and regulatory responses regardless of EAE induction, with subsequent amelioration of EAE, or even protection from the disease.

  10. Invariant NKT cells regulate experimental autoimmune uveitis through inhibition of Th17 differentiation.

    Science.gov (United States)

    Oh, Keunhee; Byoun, Ok-Jin; Ham, Don-Il; Kim, Yon Su; Lee, Dong-Sup

    2011-02-01

    Although NKT cells have been implicated in diverse immunomodulatory responses, the effector mechanisms underlying the NKT cell-mediated regulation of pathogenic T helper cells are not well understood. Here, we show that invariant NKT cells inhibited the differentiation of CD4(+) T cells into Th17 cells both in vitro and in vivo. The number of IL-17-producing CD4(+) T cells was reduced following co-culture with purified NK1.1(+) TCR(+) cells from WT, but not from CD1d(-/-) or Jα18(-/-) , mice. Co-cultured NKT cells from either cytokine-deficient (IL-4(-/-) , IL-10(-/-) , or IFN-γ(-/-) ) or WT mice efficiently inhibited Th17 differentiation. The contact-dependent mechanisms of NKT cell-mediated regulation of Th17 differentiation were confirmed using transwell co-culture experiments. On the contrary, the suppression of Th1 differentiation was dependent on IL-4 derived from the NKT cells. The in vivo regulatory capacity of NKT cells on Th17 cells was confirmed using an experimental autoimmune uveitis model induced with human IRBP(1-20) (IRBP, interphotoreceptor retinoid-binding protein) peptide. NKT cell-deficient mice (CD1d(-/-) or Jα18(-/-) ) demonstrated an increased disease severity, which was reversed by the transfer of WT or cytokine-deficient (IL-4(-/-) , IL-10(-/-) , or IFN-γ(-/-) ) NKT cells. Our results indicate that invariant NKT cells inhibited autoimmune uveitis predominantly through the cytokine-independent inhibition of Th17 differentiation. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. 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.

  12. Vorinostat Modulates the Imbalance of T Cell Subsets, Suppresses Macrophage Activity, and Ameliorates Experimental Autoimmune Uveoretinitis.

    Science.gov (United States)

    Fang, Sijie; Meng, Xiangda; Zhang, Zhuhong; Wang, Yang; Liu, Yuanyuan; You, Caiyun; Yan, Hua

    2016-03-01

    The purpose of the study was to investigate the anti-inflammatory efficiency of vorinostat, a histone deacetylase inhibitor, in experimental autoimmune uveitis (EAU). EAU was induced in female C57BL/6J mice immunized with interphotoreceptor retinoid-binding protein peptide. Vorinostat or the control treatment, phosphate-buffered saline, was administrated orally from 3 days before immunization until euthanasia at day 21 after immunization. The clinical and histopathological scores of mice were graded, and the integrity of the blood-retinal barrier was examined by Evans blue staining. T helper cell subsets were measured by flow cytometry, and the macrophage functions were evaluated with immunohistochemistry staining and immunofluorescence assays. The mRNA levels of tight junction proteins were measured by qRT-PCR. The expression levels of intraocular cytokines and transcription factors were examined by western blotting. Vorinostat relieved both clinical and histopathological manifestations of EAU in our mouse model, and the BRB integrity was maintained in vorinostat-treated mice, which had less vasculature leakage and higher mRNA and protein expressions of tight junction proteins than controls. Moreover, vorinostat repressed Th1 and Th17 cells and increased Th0 and Treg cells. Additionally, the INF-γ and IL-17A expression levels were significantly decreased, while the IL-10 level was increased by vorinostat treatment. Furthermore, due to the reduced TNF-α level, the macrophage activity was considerably inhibited in EAU mice. Finally, transcription factors, including STAT1, STAT3, and p65, were greatly suppressed by vorinostat treatment. Our data suggest that vorinostat might be a potential anti-inflammatory agent in the management of uveitis and other autoimmune inflammatory diseases.

  13. Anti-inflammatory and immunomodulatory potential of human immunoglobulin applied intrathecally in Lewis rat experimental autoimmune neuritis.

    Science.gov (United States)

    Pitarokoili, Kalliopi; Kohle, Felix; Motte, Jeremias; Fatoba, Oluwaseun; Pedreiturria, Xiomara; Gold, Ralf; Yoon, Min-Suk

    2017-08-15

    Intravenous human immunoglobulins dominate in the treatment of autoimmune neuropathies. We introduce intrathecal application as a new option for experimental autoimmune neuritis in Lewis rats. After immunisation with neuritogenic P2 peptide, we show a therapeutic and preventive effect of intrathecal human immunoglobulins (5-40mg/kg) on clinical and electrophysiological neuritis signs. Histology corroborated a lower degree of inflammation, demyelination, ICAM-1-dependent blood-nerve-barrier permeability and complement activation in the sciatic nerve. After preventive application, immunoglobulins induced a Th2 cytokine shift in the peripheral nerves already before clinical neuritis signs. Intrathecal immunoglobulin application could be a novel immunomodulatory option for autoimmune neuropathies. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Vaccination with DNA encoding an immunodominant myelin basic protein peptide targeted to Fc of immunoglobulin G suppresses experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Lobell, A; Weissert, R; Storch, M K; Svanholm, C; de Graaf, K L; Lassmann, H; Andersson, R; Olsson, T; Wigzell, H

    1998-05-04

    We explore here if vaccination with DNA encoding an autoantigenic peptide can suppress autoimmune disease. For this purpose we used experimental autoimmune encephalomyelitis (EAE), which is an autoaggressive disease in the central nervous system and an animal model for multiple sclerosis. Lewis rats were vaccinated with DNA encoding an encephalitogenic T cell epitope, guinea pig myelin basic protein peptide 68-85 (MBP68-85), before induction of EAE with MBP68-85 in complete Freund's adjuvant. Compared to vaccination with a control DNA construct, the vaccination suppressed clinical and histopathological signs of EAE, and reduced the interferon gamma production after challenge with MBP68-85. Targeting of the gene product to Fc of IgG was essential for this effect. There were no signs of a Th2 cytokine bias. Our data suggest that DNA vaccines encoding autoantigenic peptides may be useful tools in controlling autoimmune disease.

  15. Chloroquine treatment enhances regulatory T cells and reduces the severity of experimental autoimmune encephalomyelitis.

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    Rodolfo Thomé

    Full Text Available BACKGROUND: The modulation of inflammatory processes is a necessary step, mostly orchestrated by regulatory T (Treg cells and suppressive Dendritic Cells (DCs, to prevent the development of deleterious responses and autoimmune diseases. Therapies that focused on adoptive transfer of Treg cells or their expansion in vivo achieved great success in controlling inflammation in several experimental models. Chloroquine (CQ, an anti-malarial drug, was shown to reduce inflammation, although the mechanisms are still obscure. In this context, we aimed to access whether chloroquine treatment alters the frequency of Treg cells and DCs in normal mice. In addition, the effects of the prophylactic and therapeutic treatment with CQ on Experimental Autoimmune Encephalomyelitis (EAE, an experimental model for human Multiple Sclerosis, was investigated as well. METHODOLOGY/PRINCIPAL FINDINGS: EAE was induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein (MOG35-55 peptide. C57BL/6 mice were intraperitoneally treated with chloroquine. Results show that the CQ treatment provoked an increase in Treg cells frequency as well as a decrease in DCs. We next evaluated whether prophylactic CQ administration is capable of reducing the clinical and histopathological signs of EAE. Our results demonstrated that CQ-treated mice developed mild EAE compared to controls that was associated with lower infiltration of inflammatory cells in the central nervous system CNS and increased frequency of Treg cells. Also, proliferation of MOG35-55-reactive T cells was significantly inhibited by chloroquine treatment. Similar results were observed when chloroquine was administrated after disease onset. CONCLUSION: We show for the first time that CQ treatment promotes the expansion of Treg cells, corroborating previous reports indicating that chloroquine has immunomodulatory properties. Our results also show that CQ treatment suppress the inflammation in the CNS of

  16. Parental genes do not codominantly confer susceptibility to experimental autoimmune encephalomyelitis in F1 rats.

    Science.gov (United States)

    Lenz, D C; Wolf, N A; Swanborg, R H

    2001-03-01

    Lewis (LEW) and DA rats are highly susceptible to experimental autoimmune encephalomyelitis (EAE) induced with guinea pig myelin basic protein (MBP), but respond to different epitopes. The dominant epitope for LEW rats is MBP73-86, and disease is mediated primarily by Vbeta8.2 Th1 cells. DA rats lack conventional Vbeta8.2 T cells and do not respond to MBP73-86. Rather, DA rats respond to the cryptic epitope MBP63-81, which is not encephalitogenic for LEW rats. Responses to these neuroantigens were investigated in (DAxLEW) F1 hybrids to determine if experimental findings in inbred rats remain valid in more genetically complex models. Surprisingly, MBP63-81, a cryptic epitope for DA rats, induced moderate-to-severe EAE in F1 hosts, whereas MBP73-86, the dominant LEW epitope, was only weakly encephalitogenic in F1 hosts. The poor clinical response to MBP73-86 appears to be a consequence of an inability to expand Vbeta8.2 T cells. These results suggest that parental responses to neuroantigens are poor predictors for determining encephalitogenicity in F1 progeny.

  17. Recurrent Focal myositis: a rare inflammatory myopathy.

    Science.gov (United States)

    Teixeira, F; Peixoto, D; Costa, J A; Bogas, M; Taipa, R; Melo Pires, M; Afonso, C; Araújo, D

    2014-01-01

    Focal myositis is an acute and localized muscle inflammation of unknown aetiology. The clinical diagnosis is often difficult to obtain, since it can be confused with infections, vascular thrombosis or muscle tumours such as sarcomas. This leads to a significant delay in the diagnosis, resulting in the administration of inappropriate and potentially harmful treatments.  We report here a case of recurrent focal myositis in a woman where the diagnosis was only obtained after 6 years, despite multiple hospital admissions. This case reinforces the importance of clinical knowledge and experience to tackle challenging medical scenarios.

  18. Experimental autoimmune keratitis induced in rats by anti-cornea T-cell lines

    NARCIS (Netherlands)

    Verhagen, C.; Mor, F.; Kipp, J. B.; de Vos, A. F.; van der Gaag, R.; Cohen, I. R.

    1999-01-01

    Idiopathic inflammation of the cornea, keratitis, has been proposed to result from an autoimmune process, but thus far no convenient animal model of keratitis exists. An attempt was made to establish an animal model for keratitis, to investigate possible autoimmune mechanisms. T-cell lines were

  19. 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...

  20. Combination of cuprizone and experimental autoimmune encephalomyelitis to study inflammatory brain lesion formation and progression.

    Science.gov (United States)

    Rüther, Bernhard Josef; Scheld, Miriam; Dreymueller, Daniela; Clarner, Tim; Kress, Eugenia; Brandenburg, Lars-Ove; Swartenbroekx, Tine; Hoornaert, Chloé; Ponsaerts, Peter; Fallier-Becker, Petra; Beyer, Cordian; Rohr, Sven Olaf; Schmitz, Christoph; Chrzanowski, Uta; Hochstrasser, Tanja; Nyamoya, Stella; Kipp, Markus

    2017-12-01

    Brain-intrinsic degenerative cascades are a proposed factor driving inflammatory lesion formation in multiple sclerosis (MS) patients. We recently described a model combining noninflammatory cytodegeneration (via cuprizone) with the classic active experimental autoimmune encephalomyelitis (Cup/EAE model), which exhibits inflammatory forebrain lesions. Here, we describe the histopathological characteristics and progression of these Cup/EAE lesions. We show that inflammatory lesions develop at various topographical sites in the forebrain, including white matter tracts and cortical and subcortical grey matter areas. The lesions are characterized by focal demyelination, discontinuation of the perivascular glia limitans, focal axonal damage, and neutrophil granulocyte extravasation. Transgenic mice with enhanced green fluorescent protein-expressing microglia and red fluorescent protein-expressing monocytes reveal that both myeloid cell populations contribute to forebrain inflammatory infiltrates. EAE-triggered inflammatory cerebellar lesions were augmented in mice pre-intoxicated with cuprizone. Gene expression studies suggest roles of the chemokines Cxcl10, Ccl2, and Ccl3 in inflammatory lesion formation. Finally, follow-up experiments in Cup/EAE mice with chronic disease revealed that forebrain, but not spinal cord, lesions undergo spontaneous reorganization and repair. This study underpins the significance of brain-intrinsic degenerative cascades for immune cell recruitment and, in consequence, MS lesion formation. © 2017 Wiley Periodicals, Inc.

  1. The mechanism of effective electroacupuncture on T cell response in rats with experimental autoimmune encephalomyelitis.

    Directory of Open Access Journals (Sweden)

    Yumei Liu

    Full Text Available Previously, we demonstrated that electroacupuncture (EA decreased lymphocyte infiltration into the spinal cords of rats presenting with experimental autoimmune encephalomyelitis (EAE, a disease model used in the study of multiple sclerosis (MS. The aim of this study was to characterize the effects of EA on the EAE. Female Lewis rats were divided into either CFA, EAE, EA, or injection with naloxone after electroacupuncture (NAL groups. Electroacupuncture was administered every day for 21 days. To evaluate proliferation and apoptosis, lymphocytes from rats presenting with EAE were collected and cultured with β-endorphin. Immunohistochemisty, flow cytometry and radio-immunity methods were applied to detect the expression of β-endorphin. Results presented in this report demonstrate that the beneficial anti-inflammatory effects of EA on EAE were related to β-endorphin production that balances the Thl/Th2 and Th17/Treg responses. These results suggest that β-endorphin could be an important component in the development of EA-based therapies used for the treatment of EAE.

  2. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  4. 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

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

    Science.gov (United States)

    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

  6. 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...

  7. 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; Jung, Dong-In

    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.

  8. Augmentation of transfer of experimental autoimmune thyroiditis (EAT) in mice by irradiation of recipients

    International Nuclear Information System (INIS)

    Williams, W.V.; Kyriakos, M.; Sharp, G.C.; Braley-Mullen, H.

    1987-01-01

    Experimental autoimmune thyroiditis (EAT) can be adoptively transferred to normal syngeneic recipients using spleen cells from susceptible strains of mice primed in vivo with mouse thyroglobulin (MTg) and lipopolysaccharide (LPS) following in vitro activation of spleen cells by culture with MTg. Irradiation of recipient animals markedly augments the severity of thyroiditis induced in this system. Irradiation of recipients does not alter the time course of the development of thyroiditis, nor does it alter the requirement for both in vivo priming and in vitro activation of spleen cells for the development of EAT. Spleen cells from EAT-resistant strains of mice (e.g., Balb/c) do not induce EAT in irradiated recipients. Irradiated recipients develop significant levels of anti-MTg antibodies while unirradiated recipients have little detectable antibody response. The augmenting effect of irradiation can be substantially reversed by transferring naive spleen cells to recipients prior to the transfer of MTg/LPS-primed in vitro-activated spleen cells. In addition athymic CBA/Tufts nude mice develop more severe EAT than CBA/Tufts nude/+ littermates following transfer of activated CBA/J spleen cells. These data suggest that natural suppressor cells may regulate the development of EAT at the effector cell level

  9. 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.

  10. 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

    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......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...

  11. The experimental autoimmune encephalomyelitis disease course is modulated by nicotine and other cigarette smoke components.

    Directory of Open Access Journals (Sweden)

    Zhen Gao

    Full Text Available Epidemiological studies have reported that cigarette smoking increases the risk of developing multiple sclerosis (MS and accelerates its progression. However, the molecular mechanisms underlying these effects remain unsettled. We have investigated here the effects of the nicotine and the non-nicotine components in cigarette smoke on MS using the experimental autoimmune encephalomyelitis (EAE model, and have explored their underlying mechanism of action. Our results show that nicotine ameliorates the severity of EAE, as shown by reduced demyelination, increased body weight, and attenuated microglial activation. Nicotine administration after the development of EAE symptoms prevented further disease exacerbation, suggesting that it might be useful as an EAE/MS therapeutic. In contrast, the remaining components of cigarette smoke, delivered as cigarette smoke condensate (CSC, accelerated and increased adverse clinical symptoms during the early stages of EAE, and we identify a particular cigarette smoke compound, acrolein, as one of the potential mediators. We also show that the mechanisms underlying the opposing effects of nicotine and CSC on EAE are likely due to distinct effects on microglial viability, activation, and function.

  12. The experimental autoimmune encephalomyelitis (EAE) model of MS: utility for understanding disease pathophysiology and treatment

    Science.gov (United States)

    ROBINSON, ANDREW P.; HARP, CHRISTOPHER T.; NORONHA, AVERTANO; MILLER, STEPHEN D.

    2014-01-01

    While no single model can exactly recapitulate all aspects of multiple sclerosis (MS), animal models are essential in understanding the induction and pathogenesis of the disease and to develop therapeutic strategies that limit disease progression and eventually lead to effective treatments for the human disease. Several different models of MS exist, but by far the best understood and most commonly used is the rodent model of experimental autoimmune encephalomyelitis (EAE). This model is typically induced by either active immunization with myelin-derived proteins or peptides in adjuvant or by passive transfer of activated myelin-specific CD4+ T lymphocytes. Mouse models are most frequently used because of the inbred genotype of laboratory mice, their rapid breeding capacity, the ease of genetic manipulation, and availability of transgenic and knockout mice to facilitate mechanistic studies. Although not all therapeutic strategies for MS have been developed in EAE, all of the current US Food and Drug Administration (FDA)-approved immunomodulatory drugs are effective to some degree in treating EAE, a strong indicator that EAE is an extremely useful model to study potential treatments for MS. Several therapies, such as glatiramer acetate (GA: Copaxone), and natalizumab (Tysabri), were tested first in the mouse model of EAE and then went on to clinical trials. Here we discuss the usefulness of the EAE model in understanding basic disease pathophysiology and developing treatments for MS as well as the potential drawbacks of this model. PMID:24507518

  13. Differential regulation of CD4(+) T helper cell responses by curcumin in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Kanakasabai, Saravanan; Casalini, Eli; Walline, Crystal C; Mo, Caiqing; Chearwae, Wanida; Bright, John J

    2012-11-01

    Nutraceuticals and phytochemicals are important regulators of human health and diseases. Curcumin is a polyphenolic phytochemical isolated from the rhizome of the plant Curcuma longa (turmeric) that has been traditionally used for the treatment of inflammation and wound healing for centuries. Systematic analyses have shown that curcumin exerts its beneficial effects through antioxidant, antiproliferative and anti-inflammatory properties. We and others have shown earlier that curcumin ameliorates experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis. In this study, we show that C57BL/6 mice induced to develop EAE express elevated levels of interferon (IFN) γ and interleukin (IL)-17 in the central nervous system (CNS) and lymphoid organs that decreased significantly following in vivo treatment with curcumin. The EAE mice also showed elevated expression of IL-12 and IL-23 that decreased after treatment with curcumin. Ex vivo and in vitro treatment with curcumin resulted in a dose-dependent decrease in the secretion of IFNγ, IL-17, IL-12 and IL-23 in culture. The inhibition of EAE by curcumin was also associated with an up-regulation of IL-10, peroxisome proliferator activated receptor γ and CD4(+)CD25(+-)Foxp3(+) Treg cells in the CNS and lymphoid organs. These findings highlight that curcumin differentially regulates CD4(+) T helper cell responses in EAE. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Intrathecal Fas ligand infusion strengthens immunoprivilege of central nervous system and suppresses experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Zhu, Bing; Luo, Liqing; Chen, Yongliang; Paty, Donald W; Cynader, Max S

    2002-08-01

    Fas ligand (FasL) is an essential molecule strongly expressed in some immunoprivileged sites, but is expressed at very low levels in normal CNS. In this study, acute experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats with guinea pig myelin basic protein. Intrathecal infusion of recombinant FasL before EAE onset dose dependently suppressed acute EAE and alleviated pathological inflammation in lumbosacral spinal cord. This treatment greatly increased apoptosis in CNS inflammatory cells, but did not inhibit systemic immune response to myelin basic protein. Systemic administration of a similar dose of rFasL was ineffective. In vitro, encephalitogenic T cells were highly sensitive to rFasL-induced cell death, and activated macrophages were also susceptible. In addition, in vitro rFasL treatment potentiated the immunosuppressive property of rat cerebrospinal fluid. We conclude that intrathecal infusion of rFasL eliminated the initial wave of infiltrating T cells and macrophages, and therefore blocked the later recruitment of inflammatory cells into CNS. Although Fas receptor expression was observed on spinal cord neurons, astrocytes, and oligodendrocytes, no damage to these cells or to the myelin structure was detected after rFasL infusion.

  15. Effects of human recombinant-interferon β in experimental autoimmune encephalomyelitis in guinea pigs.

    Science.gov (United States)

    Aritake, Kosuke; Koh, Chang-Sung; Inoue, Atsushi; Yabuuchi, Fumie; Kitagaki, Kunihiko; Ikoma, Yukihiro; Hayashi, Shigehiro

    2010-11-01

    Although clinical data for beneficial effects of Betaferon, human recombinant-interferon (r-IFN) β-1b, are accumulating, what is less evident is how and why it works. The present study was carried out to examine whether Betaferon suppresses progression of experimental autoimmune encephalomyelitis (EAE). The EAE model was employed in guinea pigs in vivo, and mononuclear cell proliferation and 2',5'-oligoadenylate synthetase activity were assessed in vitro. Betaferon was more reactive in two assays of guinea pigs, mitogen-induced proliferation of peripheral blood mononuclear cells and 2',5'-oligoadenylate synthetase activity of blood, than in rats and rabbits. Guinea pigs were immunized actively by antigen, porcine myelin basic protein. The neurological deficits were assessed by clinical signs scored daily. Guinea pig Betaferon, replaced with guinea pig albumin (GPA), at 1.2 and 12.0 MIU/kg/day or vehicle was administered subcutaneously daily for 20 days in the immunized guinea pigs. GPA-Betaferon suppressed the manifestation of ataxia or more progression of chronic neurological deficits significantly at 1.2 MIU/kg (p guinea pigs with evidence for higher susceptibility of animal cells/tissues to the human cytokine, in contrast with rodents and rabbits.

  16. Transplantation of olfactory ensheathing cells promotes partial recovery in rats with experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Li, Jia; Chen, Weian; Li, Yu'an; Chen, Ying; Ding, Zhangna; Yang, Dehao; Zhang, Xu

    2015-01-01

    This study was to investigate the efficacy of olfactory ensheathing cell (OEC) transplantation on experimental autoimmune encephalomyelitis (EAE). EAE models were established by guinea pig spinal cord homogenate (GPSCH) immunization in Lewis rats. OECs were purified and cultured from the olfactory nerve layer of SD rats, and then transplanted to the EAE models through the vena caudalis (Group A) or into the lateral cerebral ventricle (Group B). Neurological function scores and body weights were daily recorded following transplantation, and histological analysis was performed to assess the pathological changes in EAE rats. Cultured cells mainly exhibited bipolar or tripolar morphology, and the majority of these cells were positive for NGFR p75 staining. Neurological function scoring and the body weight measurement showed that, OEC transplantation could significantly improve the performance of EAE rats, and similar results were observed for the transplantation through the vena caudalis and into the lateral cerebral ventricle. Moreover, the transplanted OECs accumulated to the lesions in the brains of EAE rats, in spite of the different transplantation approaches. However, no significant differences in histopathology (HE and LFB staining) were observed between the OEC-transplanted groups and the control group. OEC transplantation could exert beneficial effects in the treatment of EAE, no matter which the cells were transplanted through the vena caudalis or into the lateral cerebral ventricle. Our findings might provide evidence for the clinical treatment of multiple sclerosis with cell transplantation.

  17. [Protective effects of heat shock preconditioning on the experimental autoimmune encephalomyelitis rats].

    Science.gov (United States)

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

    2007-12-01

    To study the effects of heat shock preconditioning on the expression of heat shock protein-70 (HSP70) and apoptosis of the neuron in experimental autoimmune encephalomyelitis (EAE) rats. Thirty-six Wistar rats were randomly divided into control, EAE and heat shock preconditioning groups (n=12 each). The EAE animal model was induced with guinea pig myelin basic protein. Heat shock preconditioning was performed 24 hrs prior to the EAE model inducement. No treatment was done in the control group. The neurological signs were observed after immunization. The spinal cords were removed and stained with hematoxylin and eosin. HSP70 was detected by immunohistochemistry. Apoptosis of the neuron was measured by TUNEL. Heat shock preconditioning significantly alleviated clinical signs and neuronal injury. HSP70 expression in the heat shock preconditioning group was significantly higher than in the untreated EAE group (21.08 +/- 0.87 vs 10.17 +/- 0.51; P < 0.01). Heat shock preconditioning suppressed apoptosis of the neuron compared with the EAE group (apoptosis rate: 21.92 +/- 1.00% vs 58.92 +/- 1.67%; P < 0.01). Heat shock preconditioning might improve the neurological outcome in EAE rats, possibly through the induction of HSP70 synthesis and the reduction of apoptosis of the neuron in spinal cords.

  18. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats treated with fucoidan.

    Science.gov (United States)

    Kim, Heechul; Moon, Changjong; Park, Eun-jin; Jee, Youngheun; Ahn, Meejung; Wie, Myung Bok; Shin, Taekyun

    2010-03-01

    We examined whether fucoidan affected the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in rats. EAE was induced in Lewis rats that were immunized with guinea-pig myelin basic protein (MBP) and complete Freund's adjuvant. Fucoidan (50 mg/kg, daily) was administered to rats with EAE intraperitoneally, either in the EAE induction phase from either 1 day before immunization to day 7 post-immunization (PI), or the effector phase from day 8 to 14 PI, to test which phase of rat EAE is affected by fucoidan treatment.The onset, severity and duration of EAE paralysis in the fucoidan-treated group in the days 8-14 PI-treated rats, but not in days -1-7 PI-treated rats, were significantly delayed, suppressed and reduced, respectively, compared with the vehicle-treated controls. Treatment with fucoidan reduced the encephalitogenic response and TNF-alpha production during EAE. Moreover, the clinical amelioration coincided with decreased infiltration of inflammatory cells in the EAE-affected spinal cord. The ameliorative effect of fucoidan on clinical paralysis in EAE-affected rats may be mediated, in part, by the suppression of the autoreactive T cell response and inflammatory cytokine production. (c) 2009 John Wiley & Sons, Ltd.

  19. [Lipids and caplain in guinea pig tissues in the process of development of experimental autoimmune encephalomyelitis].

    Science.gov (United States)

    Morozova, R P; Pasichna, E P; Donchenko, H V; Kastrykina, T F; Silonov, S B; Palyvoda, O M; Delemenchuk, N V

    2007-01-01

    The character of some lipids level change--cholesterol and phospholipids--as basic lipid components of cell membranes in the guinea-pig brain and liver tissue, and in serum in conditions of development of experimental autoimmune encephalomyelitis (EAE) have been investigated on the 11th, 21st, 27th day after inoculation. It has been detected, that the level of the investigated lipids changes wavely and indifferent-direction in the brain tissue on the 21st day of EAE. Similar variability observed in the activity of proteolytic ferment calpain, which is authentically reduced in the brain tissue by the 11th hour and increases up to the test objective level in the subsequent periods of EAE development. In the liver the level of alpha-tocopherol is reduced, while the content of studied lipids does not change. The investigated parameters can be attributed to the factors, which play an essential role in structural stability of cell membranes and their variability in conditions of EAE development is related to the processes of nervous cells demyelinisation and, hence to occurrence of such pathology as multiple sclerosis in people.

  20. Expression of stress-response protein 60 in iritis associated with experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Kumagami, T; Kato, S; Ishikura, R; Nagata, M; Tamai, A; Ohama, E

    1999-01-01

    To study the expression of stress-response proteins in the inflamed iris of rats with experimental autoimmune encephalomyelitis (EAE). EAE was induced in Lewis rats by immunization with homogenized spinal cord of the guinea pig emulsified in complete Freund's adjuvant (CFA) (group EAE). Control rats included those immunized with only CFA (group CFA) and those that were untreated (group Normal). Immunohistochemical study for the localization of stress-response protein (srp) 27, srp 60, srp 72, ubiquitin, and alphaB-crystallin was performed. All rats in group EAE developed iritis, whereas none of the rats in group CFA and group Normal developed iritis. No expression of ubiquitin, alphaB-crystallin, srp 27, srp 60, or srp 72 was seen in the epithelium of the iris in group CFA rats. In the eyes of rats in group EAE, srp 60 was expressed in the epithelium of the iris in 20 of 22 (90.9%), ubiquitin in 4 of 22 (18.2%), and alphaB-crystallin in 3 of 22 (13.6%). In the group Normal rats, only ubiquitin was expressed in the epithelium of the iris in 1 of 6 (16.7%) eyes examined. These results suggest that srp 60 may be a potential uveitogenic antigen in the iris in EAE.

  1. Acquired resistance to experimental autoimmune encephalomyelitis is independent of V beta usage.

    Science.gov (United States)

    Johnson, B D; Nardella, J P; McConnell, T J; Mannie, M D

    1997-07-10

    In Lewis rats, activated encephalitogenic T-helper cells elicit a single bout of experimental autoimmune encephalomyelitis (EAE). Recovery from EAE is marked by reduced susceptibility to disease reinduction. The purpose of this study was to determine whether a dominant expression of V beta gene segments by encephalitogenic T cells was required for development of recovery-associated resistance. Several polyclonal and monoclonal T cell lines were derived from Lewis rats sensitized with R72-86, a synthetic peptide representing the 72- to 86-amino-acid sequence of rat myelin basic protein (RMBP). The results revealed broad heterogeneity among encephalitogenic T cells specific for R72-86 in regard to V beta expression and CDR3 sequence. Encephalitogenic clones exclusively bearing either V beta 4 or V beta 10 TCR or polyclonal T cells bearing heterogeneous TCR transferred EAE to recipient rats and elicited resistance to EAE as revealed by subsequent challenge with guinea pig (GP)MBP in complete Freund's adjuvant (CFA). Nonpathogenic V beta 3+ and V beta 8.6+ clones specific for the 68-86 and 55-66 regions of MBP, respectively, did not elicit effective protection from EAE. These data indicate that induction of postrecovery resistance to EAE does not depend upon a particular V beta usage.

  2. Therapeutic Potential of Pien Tze Huang on Experimental Autoimmune Encephalomyelitis Rat

    Directory of Open Access Journals (Sweden)

    Xuemei Qiu

    2018-01-01

    Full Text Available Multiple sclerosis (MS is a chronic inflammatory demyelinating disease of the central nervous system (CNS. There is still lack of commercially viable treatment currently. Pien Tze Huang (PZH, a traditional Chinese medicine, has been proved to have anti-inflammatory, neuroprotective, and immunoregulatory effects. This study investigated the possible therapeutic effects of PZH on experimental autoimmune encephalomyelitis (EAE rats, a classic animal model of MS. Male Lewis rats were immunized with myelin basic protein (MBP peptide to establish an EAE model and then treated with three doses of PZH. Clinical symptoms, organ coefficient, histopathological features, levels of proinflammatory cytokines, and chemokines as well as MBP and Olig2 were analyzed. The results indicated that PZH ameliorated the clinical severity of EAE rats. It also remarkably reduced inflammatory cell infiltration in the CNS of EAE rats. Furthermore, the levels of IL-17A, IL-23, CCL3, and CCL5 in serum and the CNS were significantly decreased; the p-P65 and p-STAT3 levels were also downregulated in the CNS, while MBP and Olig2 in the CNS of EAE rats had a distinct improvement after PZH treatment. In addition, PZH has no obvious toxicity at the concentration of 0.486 g/kg/d. This study demonstrated that PZH could be used to treat MS.

  3. [Umbilical cord mesenchymal stem cell transplantation for treatment of experimental autoimmune myasthenia gravis in rats].

    Science.gov (United States)

    Yu, Jing-Xia; Chen, Fang; Sun, Jun; Wang, Ji-Ming; Zhao, Qin-Jun; Ren, Xin-Jun; Ma, Feng-Xia; Yang, Shao-Guang; Han, Zhi-Bo; Han, Zhong-Chao

    2011-06-01

    Umbilical cord mesenchymal stem cell (UCMSC) transplantation has been widely used in the treatment of a variety of diseases due to their advantages such as abundant resources, low immunogenicity and large ex vivo expansion capacity. This study was aimed to investigate the effects of UCMSC on experimental autoimmune myasthenia gravis (EAMG) rats. The distribution of human-derived cells was observed by immunofluorescence method, the effect of MSC on B-cell in situ-secreted antibodies was assayed by ELISPOT, the secreted IFN-γ level was detected by using Transwell test. The results showed that UCMSC were able to migrate to inflammation region and lymph nudes, moreover human-derived cells could be detected in medulla zone of lymph nudes. In vitro in situ detection of AchR specific antibody secretion revealed that the full contact of MSC with lymphnode-derived lymphocytes could effectively inhibit production of AchR antibody. Transwell test indicated that the direct contact of UCMSC with CD4 T cells could effectively decrease production of IFN-γ, which modulated the unbalance between Th1/Th2 to a certain extent. It is concluded that UCMSC can regulate the immune system by direct cell-cell contact or/and release of cytokines, which bring a new insight into knowledge about MSC-based therapy for EAMG.

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

    Directory of Open Access Journals (Sweden)

    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.

  5. Magnetic resonance elastography reveals altered brain viscoelasticity in experimental autoimmune encephalomyelitis☆

    Science.gov (United States)

    Riek, Kerstin; Millward, Jason M.; Hamann, Isabell; Mueller, Susanne; Pfueller, Caspar F.; Paul, Friedemann; Braun, Jürgen; Infante-Duarte, Carmen; Sack, Ingolf

    2012-01-01

    Cerebral magnetic resonance elastography (MRE) measures the viscoelastic properties of brain tissues in vivo. It was recently shown that brain viscoelasticity is reduced in patients with multiple sclerosis (MS), highlighting the potential of cerebral MRE to detect tissue pathology during neuroinflammation. To further investigate the relationship between inflammation and brain viscoelasticity, we applied MRE to a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). EAE was induced and monitored by MRE in a 7-tesla animal MRI scanner over 4 weeks. At the peak of the disease (day 14 after immunization), we detected a significant decrease in both the storage modulus (G′) and the loss modulus (G″), indicating that both the elasticity and the viscosity of the brain are reduced during acute inflammation. Interestingly, these parameters normalized at a later time point (day 28) corresponding to the clinical recovery phase. Consistent with this, we observed a clear correlation between viscoelastic tissue alteration and the magnitude of perivascular T cell infiltration at both day 14 and day 28. Hence, acute neuroinflammation is associated with reduced mechanical cohesion of brain tissues. Moreover, the reduction of brain viscoelasticity appears to be a reversible process, which is restored when inflammation resolves. For the first time, our study has demonstrated the applicability of cerebral MRE in EAE, and showed that this novel imaging technology is highly sensitive to early tissue alterations resulting from the inflammatory processes. Thus, MRE may serve to monitor early stages of perivascular immune infiltration during neuroinflammation. PMID:24179740

  6. Synapsin I deletion reduces neuronal damage and ameliorates clinical progression of experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Guarnieri, Fabrizia C; Bellani, Serena; Yekhlef, Latefa; Bergamaschi, Andrea; Finardi, Annamaria; Fesce, Riccardo; Pozzi, Davide; Monzani, Elena; Fornasiero, Eugenio F; Matteoli, Michela; Martino, Gianvito; Furlan, Roberto; Taverna, Stefano; Muzio, Luca; Valtorta, Flavia

    2018-02-01

    The classical view of multiple sclerosis (MS) pathogenesis states that inflammation-mediated demyelination is responsible for neuronal damage and loss. However, recent findings show that impairment of neuronal functions and demyelination can be independent events, suggesting the coexistence of other pathogenic mechanisms. Due to the inflammatory milieu, subtle alterations in synaptic function occur, which are probably at the basis of the early cognitive decline that often precedes the neurodegenerative phases in MS patients. In particular, it has been reported that inflammation enhances excitatory synaptic transmission while it decreases GABAergic transmission in vitro and ex vivo. This evidence points to the idea that an excitation/inhibition imbalance occurs in the inflamed MS brain, even though the exact molecular mechanisms leading to this synaptic dysfunction are as yet not completely clear. Along this line, we observed that acute treatment of primary hippocampal neurons in culture with pro-inflammatory cytokines leads to an increased phosphorylation of synapsin I (SynI) by ERK1/2 kinase and to an increase in the frequency of spontaneous synaptic vesicle release events, which is prevented by SynI deletion. In vivo, the ablation of SynI expression is protective in terms of disease progression and neuronal damage in the experimental autoimmune encephalomyelitis mouse model of MS. Our results point to a possible key role in MS pathogenesis of the neuronal protein SynI, a regulator of excitation/inhibition balance in neuronal networks. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. 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.

  8. Vorinostat, a histone deacetylase inhibitor, suppresses dendritic cell function and ameliorates experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Ge, Zhenzhen; Da, Yurong; Xue, Zhenyi; Zhang, Kai; Zhuang, Hao; Peng, Meiyu; Li, Yan; Li, Wen; Simard, Alain; Hao, Junwei; Yao, Zhi; Zhang, Rongxin

    2013-03-01

    Vorinostat, a histone deacetylase inhibitor, has been used clinically as an anticancer drug and also has immunosuppressive properties. However, the underlying mechanisms of effects of vorinostat on central nervous system (CNS) inflammatory diseases remain incomplete. Here, this study investigates the effects of vorinostat on human CD14(+) monocyte-derived dendritic cells (DCs) and mouse immature DC in vitro. Furthermore, we explore the therapeutic effects and cellular mechanisms of vorinostat on animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) in vivo. Our findings demonstrate that vorinostat inhibited human CD14(+) monocyte-derived DCs differentiation, maturation, endocytosis, and further inhibited mDCs' stimulation of allogeneic T-cell proliferation. In addition, vorinostat inhibited DC-directed Th1- (Type 1T helper) and Th17-polarizing cytokine production. Furthermore, vorinostat ameliorated Th1- and Th17-mediated EAE by reducing CNS inflammation and demyelination. What's more, Th1 and Th17 cell functions were suppressed in vorinostat-treated EAE mice. Finally, vorinostat suppressed expression of costimulatory molecules of DC in EAE mice. These suggest therapeutic effects of vorinostat on EAE which may by suppress DCs and DCs-mediated Th1 and Th17 cell functions. Our findings warrant further investigation in the potential of vorinostat for the treatment of human multiple sclerosis. Copyright © 2012. Published by Elsevier Inc.

  9. 5. Myositis Ossificans – Two Case Presentations

    African Journals Online (AJOL)

    Esem

    Myositis Ossificans [MO], a florid ossification, may occur in muscles and soft tissue. It is also called by many different names. The lesion contains actively proliferating fibroblasts and osteoblasts and early in its development may be confused with a malignant tumor. It commonly affects vigorous young men and more so ...

  10. Coagulopathy triggered autoimmunity: experimental antiphospholipid syndrome in factor V Leiden mice

    Science.gov (United States)

    2013-01-01

    Background We investigated interactions between genetically and autoimmune-mediated coagulopathies by inducing experimental antiphospholipid syndrome (eAPS) in mice carrying the factor V Leiden (FVL) mutation. Methods eAPS was induced in heterozygous and homozygous FVL transgenic mice (C57BL/6 background) by immunization with β2-glycoprotein I (β2-GPI). Autoantibody levels were measured at 1 and 5 months post-immunization. Mice were tested at 4 months post-immunization for behavior and cognitive function in the staircase, elevated plus-maze, and swim T-maze tests. Brains were removed and analyzed by immunohistochemistry for inflammatory markers and neurodegenerative processes. Results A single immunization with β2-GPI induced significantly higher and longer-lasting immune responses, and this was dependent on the number of FVL alleles. At 1 and 5 months post-immunization, levels of antibodies rose from 1.17 ± 0.07 to 1.62 ± 0.17 (optical density units; ODU) in homozygous FVL mice, compared with stable levels of 0.59 ± 0.17 and 0.48 ± 0.16 ODU in heterozygous FVL mice and a drop from 1.62 ± 0.21 to 0.61 ± 0.13 ODU in wild-type mice. Behavioral and cognitive clinical features of eAPS were also correlated with FVL allele load, as assessed by the elevated plus-maze (altered anxiety), staircase (hyperactivity and higher exploration), and swim T-maze (impaired learning) tests. Histological studies identified significant neurodegenerative changes in both grey and white matter in the eAPS-FVL brains. In spite of the potential interaction of two prothrombotic disease states, there were no ischemic lesions seen in this group. Conclusions The results indicate that genetically mediated coagulopathies increase the risk of developing coagulation-targeted autoimmune responses, and suggest the importance of antibody-mediated neurodegenerative processes in the brain in APS. PMID:23566870

  11. Gray Matter Hypoxia in the Brain of the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis

    Science.gov (United States)

    Johnson, Thomas W.; Wu, Ying; Nathoo, Nabeela; Rogers, James A.; Wee Yong, V.; Dunn, Jeff F.

    2016-01-01

    Background Multiple sclerosis (MS) has a significant inflammatory component and may have significant gray matter (GM) pathophysiology. Brain oxygenation is a sensitive measurement of the balance between metabolic need and oxygen delivery. There is evidence that inflammation and hypoxia are interdependent. In this paper, we applied novel, implanted PO2 sensors to measure hypoxia in cortical and cerebellar GM, in an inflammation-induced mouse model of MS. Objective Quantify oxygenation in cortical and cerebellar GM in the awake, unrestrained experimental autoimmune encephalomyelitis (EAE) mouse model and to relate the results to symptom level and disease time-course. Methods C57BL/6 mice were implanted with a fiber-optic sensor in the cerebellum (n = 13) and cortex (n = 24). Animals were induced with stimulation of the immune response and sensitization to myelin oligodendrocyte glycoprotein (MOG). Controls did not have MOG. We measured PO2 in awake, unrestrained animals from pre-induction (baseline) up to 36 days post-induction for EAE and controls. Results There were more days with hypoxia than hyperoxia (cerebellum: 34/67 vs. 18/67 days; cortex: 85/112 vs. 22/112) compared to time-matched controls. The average decline in PO2 on days that were significantly lower than time-matched controls was -8.8±6.0 mmHg (mean ± SD) for the cerebellum and -8.0±4.6 for the cortex. Conversely, the average increase in PO2 on days that were significantly hyperoxic was +3.2±2.8 mmHg (mean ± SD) for the cerebellum and +0.8±2.1 for the cortex. Cortical hypoxia related to increased behavioral deficits. Evidence for hypoxia occurred before measurable behavioral deficits. Conclusions A highly inflammatory condition primed to a white matter (WM) autoimmune response correlates with significant hypoxia and increased variation in oxygenation in GM of both cerebellum and cortex in the mouse EAE model of MS. PMID:27907119

  12. Autoimmune Hepatitis

    Science.gov (United States)

    ... with type 1 autoimmune hepatitis commonly have other autoimmune disorders, such as celiac disease, an autoimmune disease in ... 2 can also have any of the above autoimmune disorders. What are the symptoms of autoimmune hepatitis? The ...

  13. MYOSITIS ASSOCIATED WITH MALIGNANT TUMORS

    Directory of Open Access Journals (Sweden)

    O. A. Antelava

    2016-01-01

    Full Text Available Idiopathic inflammatory myopathies (IIM are a heterogeneous group of acquired systemic diseases mainly involving skeletal muscles. The main representatives of IIM are polymyositis (PM and dermatomyositis (DM. Epidemiological surveys demonstrate that there is a relationship between PM/DM and malignant neoplasms (MNs, the detection risk of which is higher than that in the population of respective age groups. The rate of MNs in PM/DM ranges from 9 to 50%. The relationship to MNs is described in each subtype of IIM; however, these are most common in DM. The patients suffering from PM/DM associated with MNs have a worse prognosis than those without MNs. The early detection of MNs could improve the prognosis in these patients. The investigations published identify demographic, clinical, and laboratory factors increasing MN detection risks in patients with PM/DM. Just the same, they all cover small patient groups; the findings are heterogeneous and not well convincing, which calls for a further larger-scale study of this problem.Objective: to reveal and identify the specific features of paraneoplastic myositis (PnM.Subjects and methods. The investigation included 320 patients with a valid diagnosis of IIM, who had been followed up in the period of 1996 to 2016. The patients underwent laboratory tests, manual proximal muscle strength testing using a 10-point scale and electromyographic examination with needle electrodes.Results and discussion. PnM was detected in 32 (10% of the 320 patients with IIM. Among the patients with PnM, there were 6 (19% men and 26 (81% women. The mean age at the onset of PnM was 55.4 years. PnM manifested with characteristic musculocutaneous syndrome in 19 (59% patients; 18 (41% of them were found to have MNs within the first year after disease onset. The manifestation of MNs was preliminary to the picture of PM/DM in 13 (41% patients. The most commonly detected conditions were ovarian cancer (37.5%, MNs of the lung and breast

  14. Featured Article: Modulation of the OGF-OGFr pathway alters cytokine profiles in experimental autoimmune encephalomyelitis and multiple sclerosis.

    Science.gov (United States)

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

    2018-02-01

    The endogenous neuropeptide opioid growth factor, chemically termed [Met 5 ]-enkephalin, has growth inhibitory and immunomodulatory properties. Opioid growth factor is distributed widely throughout most tissues, is autocrine and paracrine produced, and interacts at the nuclear-associated receptor, OGFr. Serum levels of opioid growth factor are decreased in patients with multiple sclerosis and in animals with experimental autoimmune encephalomyelitis suggesting that the OGF-OGFr pathway becomes dysregulated in this disease. This study begins to assess other cytokines that are altered following opioid growth factor or low-dose naltrexone modulation of the OGF-OGFr axis in mice with experimental autoimmune encephalomyelitis using serum samples collected in mice treated for 10 or 20 days and assayed by a multiplex cytokine assay for inflammatory markers. Cytokines of interest were validated in mice at six days following immunization for experimental autoimmune encephalomyelitis. In addition, selected cytokines were validated with serum from MS patients treated with low-dose naltrexone alone or low-dose naltrexone in combination with glatiramer acetate (Copaxone®). Experimental autoimmune encephalomyelitis mice had elevated levels of 7 of 10 cytokines. Treatment with opioid growth factor or low-dose naltrexone resulted in elevated expression levels of the IL-6 cytokine, and significantly reduced IL-10 values, relative to saline-treated experimental autoimmune encephalomyelitis mice. TNF-γ values were increased in experimental autoimmune encephalomyelitis mice relative to normal, but were not altered by opioid growth factor or low-dose naltrexone. IFN-γ levels were reduced in opioid growth factor- or low-dose naltrexone-treated experimental autoimmune encephalomyelitis mice relative to saline-treated mice at 10 days, and elevated relative to normal values at 20 days. Validation studies revealed that within six days of immunization, opioid growth factor or low

  15. 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...... 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....

  16. Effects of Vaccination with Altered Peptide Ligand on Chronic Pain in Experimental Autoimmune Encephalomyelitis, an Animal Model of Multiple Sclerosis

    OpenAIRE

    Tian, David H.; Perera, Chamini J.; Apostolopoulos, Vasso; Moalem-Taylor, Gila

    2013-01-01

    Neuropathic pain is a chronic symptom of multiple sclerosis (MS) and affects nearly half of all MS sufferers. A key instigator of this pain is the pro-inflammatory response in MS. We investigated the behavioural effects of immunisation with a mutant peptide of myelin basic protein (MBP), termed altered peptide ligand (APL), known to initiate immune deviation from a pro-inflammatory state to an anti-inflammatory response in experimental autoimmune encephalomyelitis (EAE), an animal model of MS...

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

    Science.gov (United States)

    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.

  18. RAE-1 expression is induced during experimental autoimmune encephalomyelitis and is correlated with microglia cell proliferation.

    Science.gov (United States)

    Djelloul, Mehdi; Popa, Natalia; Pelletier, Florence; Raguénez, Gilda; Boucraut, José

    2016-11-01

    Retinoic acid early induced transcript-1 (RAE-1) glycoproteins are ligands of the activating immune receptor NKG2D. They are known as stress molecules induced in pathological conditions. We previously reported that progenitor cells express RAE-1 in physiological conditions and we described a correlation between RAE-1 expression and cell proliferation. In addition, we showed that Raet1 transcripts are induced in the spinal cord of experimental autoimmune encephalomyelitis (EAE) mice. EAE is a model for multiple sclerosis which is accompanied by microglia proliferation and activation, recruitment of immune cells and neurogenesis. We herein studied the time course expression of the two members of the Raet1 gene family present in C57BL/6 mice, namely Raet1d and Raet1e, in the spinal cord during EAE. We report that Raet1d and Raet1e genes are induced early upon EAE onset and reach a maximal expression at the peak of the pathology. We show that myeloid cells, i.e. macrophages as well as microglia, are cellular sources of Raet1 transcripts. We also demonstrate that only Raet1d expression is induced in microglia, whereas macrophages expressed both Raet1d and Raet1e. Furthermore, we investigated the dynamics of RAE-1 expression in microglia cultures. RAE-1 induction correlated with cell proliferation but not with M1/M2 phenotypic orientation. We finally demonstrate that macrophage colony-stimulating factor (M-CSF) is a major factor controlling RAE-1 expression in microglia. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Hyperinducibility of Ia antigen on astrocytes correlates with strain-specific susceptibility to experimental autoimmune encephalomyelitis

    International Nuclear Information System (INIS)

    Massa, P.T.; ter Meulen, V.; Fontana, A.

    1987-01-01

    In search of a phenotypic marker determining genetically controlled susceptibility to delayed-type hypersensitivity (DTH) reactions in the brain-in particular, experimental autoimmune encephalomyelitis (EAE)- the authors have compared the γ-interferon (IFN-γ) induction of Ia molecules on astrocytes and macrophages from rat and mouse strains that are susceptible or resistant to this disease. They focused on Ia expression because DTH reactions to self or foreign antigens are largely mediated by lymphocytes restricted by class II (Ia) antigens of the major histocompatibility complex (MHC). The data demonstrate that Lewis (fully susceptible) and Brown Norway (BN) (fully resistant) rats are very different in that Lewis astrocytes express much higher levels of Ia than BN astrocytes. Similar data were obtained from an analysis of EAE-susceptible and -resistant mouse strains (SJL and BALB/c, respectively), which suggest that this phenomenon may be universal and not limited to only one mammalian species. At least one gene responsible for Ia hyperinduction is located outside the rat RT-1 or the mouse MHC locus. Animals congenic at the RT-1 or MHC locus of the resistant strain but with background genes of the susceptible strain exhibit intermediate levels of Ia compared to fully resistant and susceptible rodents, which fits well with the reduced EAE susceptibility of these congenic animals. Furthermore, hyperinduction of Ia is astrocyte specific, since peritoneal macrophages of susceptible and resistant strains exhibit identical profiles of Ia induction. Thus, astrocyte Ia hyperinducibility may be a major strain- and tissue-specific factor that contributes to Ia-restricted DTH reactions in the brain

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

    Directory of Open Access Journals (Sweden)

    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

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

    Directory of Open Access Journals (Sweden)

    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

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

    Science.gov (United States)

    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. Role of ethanolamine phosphate in the hippocampus of rats with acute experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Aguado-Llera, D; Puebla-Jiménez, L; Barrios, V; Hernández-Pinto, A; Arilla-Ferreiro, E

    2011-01-01

    Here, we assessed the effects of acute experimental autoimmune encephalomyelitis (EAE) on the rat hippocampal somatostatinergic system and whether administration of an ethanolamine phosphate salt could prevent the appearance of the clinical signs and the impairment of the somatostatinergic system in this pathological condition. Female Lewis rats were injected in both hindlimb footpads with myelin basic protein from guinea pig brain and complete Freund's adjuvant and were sacrificed when limp tail (grade 1 EAE) or severe hindlimb paralysis (grade 3 EAE) were observed. One group was injected daily with ethanolamine phosphate, starting two days prior to immunization and for 15 days thereafter. The animals were sacrificed 15 days post-immunization. Acute EAE in grade 3 increased anti-myelin basic protein antibodies in rat serum as well as tumor necrosis factor-α and interferon-γ levels in hippocampal extracts. In addition, it decreased the somatostatin receptor density, somatostatin receptor subtype 2 mRNA and protein content, and the inhibitory effect of somatostatin on adenylyl cyclase activity in the hippocampus. The protein levels of the inhibitory G protein subunits αi(1-3), the G protein-coupled receptor kinase isoforms 2, 5 and 6, the phosphorylated cyclic AMP-binding protein and the somatostatin-like immunoreactivity content were unaltered in this brain area. Acute EAE in grade 1 did not modify any of these parameters. Ethanolamine phosphate administration prevented the clinical expression of acute EAE as well as the decrease in the somatostatin receptor density, somatostatin receptor subtype 2 expression and the capacity of somatostatin to inhibit adenylyl cyclase activity at the time-period studied. Furthermore, it blunted the rise in serum anti-myelin basic protein antibodies and hippocampal interferon-γ and tumor necrosis factor-α levels. Altogether, these data suggest that ethanolamine phosphate might provide protection against acute EAE. Copyright

  4. Neurointermediate pituitary lobectomy decreases the incidence and severity of experimental autoimmune encephalomyelitis in Lewis rats.

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    Quintanar-Stephano, Andrés; Chavira-Ramírez, Roberto; Kovacs, Kalman; Berczi, Istvan

    2005-01-01

    Acute experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease of the central nervous system, mediated by T lymphocytes. Immunization of Lewis rats with myelin antigens suspended in complete Freund's adjuvant induces EAE. In a previous study on rats we have found that neurointermediate pituitary lobectomy (NIL) decreased both the humoral and cell-mediated immune responses. Here we investigated the effect of NIL on the incidence and severity of EAE and on the function of the hypothalamic-pituitary-adrenal axis in Lewis rats. NIL, hypophysectomized (Hypox) and sham-operated (Sham) rats were immunized s.c. with guinea-pig brain extract suspended in complete Freund's adjuvant. Untreated rats were used as controls. Water intake, body weight gain, clinical and histopathologic incidence and severity of EAE were evaluated in the operated groups. On killing, plasma adrenocorticotropin and corticosterone levels were measured and adrenals, thymuses and spleens were weighed. Histopathologic lesions were counted in the brain and spinal cord. Water intake and body weight gain were significantly decreased in Sham and Hypox animals with EAE whereas higher intakes persisted in the NIL group. Plasma levels of adrenocorticotropin were within the normal range whereas corticosterone levels increased in Sham and occasionally in NIL animals. Thymus weights were decreased in NIL and Hypox groups. The clinical and histopathologic incidence and severity of EAE were significantly decreased in NIL animals as compared with Sham and Hypox rats. We concluded that NIL affects the cell-mediated immune response and plays a role in the development and progression of EAE in the Lewis rat.

  5. Epimedium flavonoids ameliorate experimental autoimmune encephalomyelitis in rats by modulating neuroinflammatory and neurotrophic responses.

    Science.gov (United States)

    Yin, Lin-Lin; Lin, Li-Li; Zhang, Lan; Li, Lin

    2012-10-01

    The present study was designed to determine whether epimedium flavonoids (EF) had effect on the development of experimental autoimmune encephalomyelitis (EAE) in rats and to elucidate its underlying mechanisms. EAE was induced by immunization of adult female Lewis rats with partially purified myelin basic protein (MBP) prepared from guinea-pig spinal cord homogenate. EF was administrated intragastrically once a day after immunization until day 14 post immunization (p.i.). Histopathological staining, enzyme-linked immunosorbent assay (ELISA), biochemical methods and western blotting approaches were used to evaluate the disease incidence and severity, neuroinflammatory and neurotrophic response in the central nervous system (CNS). Intragastrical administration of EF (20 and 60 mg/kg) significantly reduced clinical score of neurological deficit in EAE rats; alleviated demyelination and inflammatory infiltration; and inhibited astrocytes activation, production of proinflammatory molecules such as interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α), nitric oxide (NO) and nuclear transcription factor (NF-κB) in the spinal cord of EAE rats. Treatment with EF also enhanced the expression of 2', 3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) and nerve growth factor (NGF), increased the number of oligodendrocytes and protected the ultrastructure of myelin sheaths and axons in the spinal cord of EAE rats. Our results showed that EF inhibited the development of partial MBP-induced EAE in rats. This effect involved reducing neuroinflammation and enhancing myelination and neurotrophins and our findings suggest that EF may be useful for the treatment of multiple sclerosis. Copyright © 2012 Elsevier Ltd. All rights reserved.

  6. Anergy-associated T cell antigen presentation. A mechanism of infectious tolerance in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Mannie, M D; Rendall, S K; Arnold, P Y; Nardella, J P; White, G A

    1996-08-01

    CD4+ T cells promote immune responses against foreign Ags while actively suppressing responses against self Ags. To address how CD4+ T cells ensure self-tolerance, we focused on two CD4+ T helper cells specific for myelin basic protein (MBP). GP2.E5/R1 T cells recognized rat MBP (RMBP) as a partial agonist and mediated mild experimental autoimmune encephalomyelitis (EAE), whereas R2 T cells recognized RMBP with full efficacy and mediated severe EAE. GP2.E5/R1 T cells were more susceptible to anergy induction than R2 T cells. Anergic GP2.E5/R1 T cells lacked proliferative reactivity, but expressed both I-A glycoproteins and high levels of radioresistant APC activity. During induction of anergy, these T cells acquired the ability to present MBP. In a separate subsequent culture without further addition of Ag, anergic GP2.E5/R1 T cells elicited full proliferative and IL-2 production responses by R2 T cells. Unlike activations induced via irradiated splenocytes, irradiated anergic T cells elicited anergy in R2 T cells in the form of a postactivational phase of nonresponsiveness. Anergic GP2.E5/R1 T cells not only transferred anergy to pathogenic R2 T cells in vitro, but these anergic T cells also transferred resistance to EAE in Lewis rats subsequently challenged with guinea pig MBP in CFA. Antagonistic signaling by autologous RMBP was more tolerogenic than that of guinea pig MBP in both in vitro and in vivo models of infectious anergy. We conclude that in the presence of tolerogenic mAb, antagonistic signaling by a self protein elicited the coordinate expression of anergy and T cell-mediated APC activity as a mechanism for the genesis and spread of infectious tolerance.

  7. Cell Fusion along the Anterior-Posterior Neuroaxis in Mice with Experimental Autoimmune Encephalomyelitis.

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    Sreenivasa R Sankavaram

    Full Text Available It is well documented that bone marrow-derived cells can fuse with a diverse range of cells, including brain cells, under normal or pathological conditions. Inflammation leads to robust fusion of bone marrow-derived cells with Purkinje cells and the formation of binucleate heterokaryons in the cerebellum. Heterokaryons form through the fusion of two developmentally differential cells and as a result contain two distinct nuclei without subsequent nuclear or chromosome loss.In the brain, fusion of bone marrow-derived cells appears to be restricted to the complex and large Purkinje cells, raising the question whether the size of the recipient cell is important for cell fusion in the central nervous system. Purkinje cells are among the largest neurons in the central nervous system and accordingly can harbor two nuclei.Using a well-characterized model for heterokaryon formation in the cerebellum (experimental autoimmune encephalomyelitis - a mouse model of multiple sclerosis, we report for the first time that green fluorescent protein-labeled bone marrow-derived cells can fuse and form heterokaryons with spinal cord motor neurons. These spinal cord heterokaryons are predominantly located in or adjacent to an active or previously active inflammation site, demonstrating that inflammation and infiltration of immune cells are key for cell fusion in the central nervous system. While some motor neurons were found to contain two nuclei, co-expressing green fluorescent protein and the neuronal marker, neuron-specific nuclear protein, a number of small interneurons also co-expressed green fluorescent protein and the neuronal marker, neuron-specific nuclear protein. These small heterokaryons were scattered in the gray matter of the spinal cord.This novel finding expands the repertoire of neurons that can form heterokaryons with bone marrow-derived cells in the central nervous system, albeit in low numbers, possibly leading to a novel therapy for spinal cord

  8. 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.

  9. Prophylactic versus Therapeutic Fingolimod: Restoration of Presynaptic Defects in Mice Suffering from Experimental Autoimmune Encephalomyelitis.

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    Tommaso Bonfiglio

    Full Text Available Fingolimod, the first oral, disease-modifying therapy for MS, has been recently proposed to modulate glutamate transmission in the central nervous system (CNS of mice suffering from Experimental Autoimmune Encephalomyelitis (EAE and in MS patients. Our study aims at investigating whether oral fingolimod recovers presynaptic defects that occur at different stages of disease in the CNS of EAE mice. In vivo prophylactic (0.3 mg/kg for 14 days, from the 7th day post immunization, d.p.i, the drug dissolved in the drinking water fingolimod significantly reduced the clinical symptoms and the anxiety-related behaviour in EAE mice. Spinal cord inflammation, demyelination and glial cell activation are markers of EAE progression. These signs were ameliorated following oral fingolimod administration. Glutamate exocytosis was shown to be impaired in cortical and spinal cord terminals isolated from EAE mice at 21 ± 1 d.p.i., while GABA alteration emerged only at the spinal cord level. Prophylactic fingolimod recovered these presynaptic defects, restoring altered glutamate and GABA release efficiency. The beneficial effect occurred in a dose-dependent, region-specific manner, since lower (0.1-0.03 mg/kg doses restored, although to a different extent, synaptic defects in cortical but not spinal cord terminals. A delayed reduction of glutamate, but not of GABA, exocytosis was observed in hippocampal terminals of EAE mice at 35 d.p.i. Therapeutic (0.3 mg/kg, from 21 d.p.i. for 14 days fingolimod restored glutamate exocytosis in the cortex and in the hippocampus of EAE mice at 35 ± 1 d.p.i. but not in the spinal cord, where also GABAergic defects remained unmodified. These results improve our knowledge of the molecular events accounting for the beneficial effects elicited by fingolimod in demyelinating disorders.

  10. 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.

  11. Protective effect of intravitreal administration of tresperimus, an immunosuppressive drug, on experimental autoimmune uveoretinitis.

    Science.gov (United States)

    Bousquet, Elodie; Camelo, Serge; Leroux les Jardins, Guillaume; Goldenberg, Brigitte; Naud, Marie-Christine; Besson-Lescure, Bernadette; Lebreton, Luc; Annat, Jocelyne; Behar-Cohen, Francine; de Kozak, Yvonne

    2011-07-20

    To test the efficiency of locally administrated tresperimus in experimental autoimmune uveoretinitis (EAU). EAU was induced in Lewis rats by S-antigen (S-Ag) immunization. Three intravitreal injections of tresperimus (prevention or prevention/treatment protocols) were performed at different time points after immunization. The pharmacokinetics of tresperimus was evaluated in the ocular tissues and plasma. The in vitro effect of tresperimus was evaluated on macrophages. EAU was graded clinically and histologically. Blood ocular barrier permeability was evaluated by protein concentration in ocular fluids. Immune response to S-Ag was examined by delayed type hypersensitivity, the expression of inflammatory cytokines in lymph nodes, ocular fluids and serum by multiplex ELISA, and in ocular cells by RT-PCR. In vitro, tresperimus significantly reduced the production of inflammatory cytokines by lipopolysaccharide-stimulated macrophages. In vivo, in the treatment protocol, efficient tresperimus levels were measured in the eye but not in the plasma up to 8 days after the last injection. Tresperimus efficiently reduced inflammation, retinal damage, and blood ocular barrier permeability breakdown. It inhibited nitric oxide synthase-2 and nuclear factor κBp65 expression in ocular macrophages. IL-2 and IL-17 were decreased in ocular media, while IL-18 was increased. By contrast, IL-2 and IL-17 levels were not modified in inguinal lymph nodes draining the immunization site. Moreover, cytokine levels in serum and delayed type hypersensitivity to S-Ag were not different in control and treated rats. In the prevention/treatment protocol, ocular immunosuppressive effects were also observed. Locally administered tresperimus appears to be a potential immunosuppressive agent in the management of intraocular inflammation.

  12. 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.

  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...... are a target of immune attack. TNF-alpha also regulates macrophage activity which could contribute to autoimmune inflammation. We have expressed TNF-alpha at disease-equivalent levels in the central nervous system of transgenic mice, using a myelin basic protein (MBP) promoter. These mice were normal...... 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...

  14. [Myositis ossificans circumscripta and its variants].

    Science.gov (United States)

    Wybier, M; Quillard, A; Parlier, C; Champsaur, P

    1997-01-01

    Myositis ossificans circumscripta (MOC) is a benign proliferation of fibrous tissue with large amounts of bone within soft tissues. Its clinical and radiological course is described and the value of CT and MR imaging is emphasized. Differential diagnosis includes soft tissue hematoma, infection or tumor. Florid reactive periostitis of the phalanges, turret exostosis, bizarre periosteal osteochondromatous proliferation in the hand and fibro-osseous pseudotumor of the digits are also described.

  15. MYOSITIS OSSIFICANS PROGRESSIVA-CURRENT CONCEPTS

    OpenAIRE

    Rohit; Madhuchandra; Sathish; Devadoss

    2014-01-01

    Myositis ossificans progressiva is a severe disabling disorder occurring as a rare sporadic or autosomal dominant disorder. 1 The incidence is about 1 in 2 million people with no particular predilictions. 2 It presents clinically with characteristic short great toes and heterotopic ossification involving multiple sites. 3 Current research points the defect to a receptor of Bone Morphogenic Protein which induces the ossification. The cumulative effect of the hetero...

  16. Fungal myositis in children: serial ultrasonographic findings

    Energy Technology Data Exchange (ETDEWEB)

    Kwon, Jung Hwa; Lee, Hee Jung; Choi, Jin Soo [Keimyung University School of Medicine, Daegu (Korea, Republic of)

    2003-08-01

    To evaluate serial ultrasonographic findings of fungal myositis in children. Eleven lesions caused by fungal myositis and occurring in six children were included in this study. Eight lesions in five children were histopathologically proven and the other three were clinically diagnosed. Serial ultrasonographic findings were retrospectively evaluated in terms of size, location, margin, internal echotexture and adjacent cortical change occurring during the follow-up period ranging from five days to two months. Three patients (50%) had multiple lesions. The sites of involvment were the thigh (n=4), calf (n=3), chest wall (n=2), abdominal wall (n=1) and forearm (n=1). Initially, diffuse muscular swelling was revealed, with ill-defined hypoechoic lesions confined to the muscle layer (n=8). Follow-up examination of eight lesions over a period of 5-10 days showed that round central echogenic lesions were surrounded by previous slightly echogenic lesions (n=6, 75%). Long-term follow-up of five lesions over a two-month period revealed periosteal thickening in one case (20%), and the peristence of echogenic solid nodules in four (80%). Pathologic examination showed that the central lesions correlated with a fungus ball and the peripheral slightly echogenic lesions corresponded to hematoma and necrosis. Serial ultrasonographic findings of fungal myositis in children revealed relatively constant features in each case. In particular, the findings of muscular necrosis and a fungus ball over a period of 5-14 days were thought to be characteristic.

  17. In Acute Experimental Autoimmune Encephalomyelitis, Infiltrating Macrophages Are Immune Activated, Whereas Microglia Remain Immune Suppressed

    NARCIS (Netherlands)

    Vainchtein, I. D.; Vinet, J.; Brouwer, N.; Brendecke, S.; Biagini, G.; Biber, K.; Boddeke, H. W. G. M.; Eggen, B. J. L.

    2014-01-01

    Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS) characterized by loss of myelin accompanied by infiltration of T-lymphocytes and monocytes. Although it has been shown that these infiltrates are important for the progression of MS, the role of

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

    Science.gov (United States)

    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. Reduced experimental autoimmune encephalomyelitis after intranasal and oral administration of recombinant lactobacilli expressing myelin antigens

    NARCIS (Netherlands)

    C.B.M. Maassen (Kitty); J.D. Laman (Jon); C. van Holten-Neelen; L. Hoogteijling (L.); L. Groenewegen (Lizet); L. Visser (Lizette); M.M. Schellekens (M.); W.G. Boersma (Wim); H.J.H.M. Claassen (Eric)

    2003-01-01

    textabstractOral administration of autoantigens is a safe and convenient way to induce peripheral T-cell tolerance in autoimmune diseases like multiple sclerosis (MS). To increase the efficacy of oral tolerance induction and obviate the need for large-scale purification of human myelin proteins, we

  1. Reduced experimental autoimmune encephalomyelitis after intranasal and oral administration of recombinant lactobacilli expressing meyelin antigens

    NARCIS (Netherlands)

    Maassen, C.B.M.; Holten-Neelen, van J.C.P.A.; Groenewegen, L.; Hoogteijling, L.; Visser, L.; Boersma, W.J.A.

    2003-01-01

    Oral administration of autoantigens is a safe and convenient way to induce peripheral T-cell tolerance in autoimmune diseases like multiple sclerosis (MS). To increase the efficacy of oral tolerance induction and obviate the need for large-scale purification of human myelin proteins, we use

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

    Science.gov (United States)

    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. Treatment of experimental autoimmune uveoretinitis with intravitreal injection of infliximab encapsulated in liposomes.

    Science.gov (United States)

    Zhang, Rui; Qian, Jiang; Li, Xiaofeng; Yuan, Yifei

    2017-12-01

    To evaluate the safety and efficacy of intravitreal injection of liposomes encapsulating infliximab in experimental autoimmune uveoretinitis (EAU) rats. Liposomes containing infliximab were prepared and characterised for mean particle size, entrapment efficiency, polydispersity index (PDI) and zeta potential. In vitro release profile and the stability of infliximab-lip were evaluated. EAU rats were intravitreally injected with saline, infliximab, infliximab-lip or unloaded liposomes. Clinical signs and ocular histological sections were graded. Infliximab concentrations were determined with competitive ELISA. Safety of the intravitreal injections was evaluated by electroretinography (ERG) and histopathological examination. Retinal biodistribution and clearance of rhodamine-conjugated liposomes containing infliximab were evaluated with a laser scanning confocal microscope. The mean particle size of infliximab liposomes was 351.3±58 nm and entrapment efficiency was 90.65%±2.68%. PDI and zeta potential of infliximab liposomes were 0.386 and -20.8±9.78 mV, respectively. Stability test data showed that the infliximab-lip was stable for 60 days at room temperature. In EAU rats, intravitreal injection of infliximab and infliximab-lip greatly reduced intraocular inflammation determined by clinical scores and histopathological analyses (n=4). The mean concentrations of infliximab decreased quickly in infliximab injection group and were lower than those in infliximab-lip injection group (n=4 eyes, pinfliximab-lip in ERG (n=4 rats, p>0.05) and histopathological sections compared with normal rats. Confocal microscopy showed that fluorescent liposomes were observed in almost every layer of the retina and remained detectable for >30 days after injection. Intravitreal injection of liposomal infliximab can prolong the persistence of the drug in vitreous body and demonstrated a satisfactory safety and significant therapeutic potentials in EAU. The use of biodegradable

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

    Science.gov (United States)

    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.

    Science.gov (United States)

    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. Short- and long-term effects of T-cell modulating agents in experimental autoimmunity

    International Nuclear Information System (INIS)

    Mellergaard, Johan; Havarinasab, Said; Hultman, Per

    2004-01-01

    Due to the easy and reliable induction of a disease condition with many of the features present in human autoimmunity, mercury-induced autoimmunity (mHgAI) in rodents is a favourable autoimmune model. Genetically susceptible (H-2 s ) mice develop in response to mercury (Hg) a systemic autoimmune condition with antinucleolar antibodies (ANoA) targeting the protein fibrillarin, transient polyclonal B-cell activation, hyperimmunoglobulinemia, and systemic immune-complex (IC) deposits. In order to study the short- and long-term effects of treatment with immunomodulating agents on the disease parameters in HgAI, groups of B10.S (H-2 s ) mice were given 6 mg HgCl 2 /l drinking water for 22 weeks. Three weeks initial treatment with cyclosporin A (CyA), a high dose of tacrolimus (HD tacrolimus), or anti-CD4 monoclonal antibody (a-CD4) inhibited induction of ANoA and IC deposit by Hg. This effect persisted for the subsequent 19 weeks when the mice were only treated with Hg. Initial treatment with anti-IL-4 monoclonal antibody (a-IL-4) for 3 weeks inhibited induction of IgE and IC deposits by Hg, but not ANoA. However, subsequent treatment with Hg without a-IL-4 for 19 weeks induced IC deposits. The T-cell modulating agents aggravated some of the HgAI disease parameters: a-CD4 stimulated the polyclonal B-cell activation, a-IL-4 increased the IgG antichromatin antibody response, and a low dose of tacrolimus (LD tacrolimus) enhanced the ANoA, the polyclonal B-cell activation, and the IC deposits. We conclude that a short initial treatment with a-CD4 or CyA efficiently protects against induction of systemic autoimmunity for an extended period of time. However, some of the T-cell modulating agents, especially a low dose of tacrolimus, aggravate autoimmune manifestations not only during ongoing treatment, but also after treatment with these agents has ceased

  8. Oral administration of probiotic bacteria, Lactobacillus casei and Bifidobacterium breve, does not exacerbate neurological symptoms in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Kobayashi, Toshihide; Kato, Ikuo; Nanno, Masanobu; Shida, Kan; Shibuya, Kazumoto; Matsuoka, Yoshiaki; Onoue, Masaharu

    2010-03-01

    To evaluate the safety of two probiotic bacterial strains, Lactobacillus casei strain Shirota (LcS) and Bifidobacterium breve strain Yakult (BbY), these probiotics were orally administered to Lewis rats with experimental autoimmune encephalomyelitis (EAE), the experimental model of human multiple sclerosis. We examined three experimental designs by combining different antigen types and probiotic administration periods: (1) EAE was induced with a homogenate of guinea pig spinal cord as the sensitizing antigen, and LcS was orally administered from one week before this sensitization until the end of the experiment; (2) EAE was induced using guinea pig originated myelin basic protein (MBP) as the sensitizing antigen, and LcS was orally administered from one week before this sensitization to the end of the experiment; (3) EAE was induced using guinea pig MBP as the sensitizing antigen, and the probiotic strains (LcS and BbY) were administered starting in infancy (two weeks old) and continued until the end of the experiment. In experiment 1, oral administration of LcS tended to suppress the development of neurological symptoms. Differences in neurological symptoms between the control group and the administration groups did not reach statistical significance in experiments 2 and 3. These results support the notion that neither LcS nor BbY exacerbates autoimmune disease.

  9. Myositis ossificans progressive: case report | Talbi | Pan African ...

    African Journals Online (AJOL)

    Myositis ossificans progressive: case report. Sofia Talbi, Nassira Aradoini, Iman El Mezouar, Fatima Ezzahra Abourazzak, Taoufik Harzy. Abstract. Myositis ossificansprogressiva (MOP) is an autosomal dominant disorder. There is a progressive ectopic ossification and skeletal malformation, mainly in the connective tissue of ...

  10. Myositis Ossificans Circumscripta of the Supra-orbital Region: A ...

    African Journals Online (AJOL)

    ANNALS

    Abstract. Myositis ossificans circumscripta is a pathological condition characterized by formation of bony tissue within the skeletal muscles following repeated trauma. A case of myositis ossificans circumscripta of the supra-orbital region in a 25-year-old man is presented and the pertinent literature is reviewed. To the best.

  11. Reduced experimental autoimmune encephalomyelitis after intranasal and oral administration of recombinant lactobacilli expressing myelin antigens

    OpenAIRE

    Maassen, Kitty; Laman, Jon; Holten-Neelen, C.; Hoogteijling, L.; Groenewegen, Lizet; Visser, Lizette; Schellekens, M.; Boersma, Wim; Claassen, Eric

    2003-01-01

    textabstractOral administration of autoantigens is a safe and convenient way to induce peripheral T-cell tolerance in autoimmune diseases like multiple sclerosis (MS). To increase the efficacy of oral tolerance induction and obviate the need for large-scale purification of human myelin proteins, we use genetically modified lactobacilli expressing myelin antigens. A panel of recombinant lactobacilli was constructed producing myelin proteins and peptides, including human and guinea pig myelin b...

  12. Insulinotropic and anti-inflammatory effects of rosiglitazone in experimental autoimmune diabetes.

    Science.gov (United States)

    Awara, Wageh M; el-Sisi, Alaa E; el-Refaei, Mohamed; el-Naa, Mona M; el-Desoky, Karima

    2005-01-01

    Cytokines and nitric oxide (NO) are involved in the pathogenesis of autoimmune diabetes mellitus (DM). Rosiglitazone is an insulin-sensitizing drug that is a ligand for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma). The anti-inflammatory and immunomodulating properties of PPAR-gamma have been documented. The aim of this study is to investigate the effectiveness of rosiglitazone in autoimmune DM and to clarify the possible mechanism(s) involved. Autoimmune DM was induced in adult male Balb/c mice by co-administration of cyclosporin A and multiple low doses of streptozotocin. Diabetic mice were treated daily with rosiglitazone (7 mg/kg, p.o.) for 21 days. Blood glucose level (BGL), serum insulin level and pancreatic levels of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and NO were measured. Histopathological examination and immunohistochemical determination of CD4 and CD8 T lymphocytes in the pancreatic islets were performed. In addition, analysis of pancreatic protein expression was carried out. The results showed that rosiglitazone treatment resulted in a significant decrease in the BGL and the pancreatic levels of TNF-alpha, IFN-gamma and NO compared to diabetic mice. The serum insulin level was significantly increased after rosiglitazone treatment compared to diabetic mice. The destroyed pancreatic islets were regenerated and became free from both CD4 and CD8 T cells after treatment. Furthermore, many changes in pancreatic protein expression were observed. These results suggest that rosiglitazone has a beneficial effect in the treatment of autoimmune diabetes, an effect that seemed to be a secondary consequence of its anti-inflammatory and immunomodulating properties and might be reflected at the level of protein expression.

  13. Myositis with endomysial cell invasion indicates inclusion body myositis even if other criteria are not fulfilled

    NARCIS (Netherlands)

    van de Vlekkert, J; Hoogendijk, J E; de Visser, M

    The objective of this study was to investigate if patients with endomysial mononuclear cell infiltrates invading non-necrotic fibers have a disease course consistent with inclusion body myositis (IBM), irrespective of other histopathological and clinical characteristics. All patients with a muscle

  14. Oral Administration of Lactococcus lactis Expressing Synthetic Genes of Myelin Antigens in Decreasing Experimental Autoimmune Encephalomyelitis in Rats.

    Science.gov (United States)

    Kasarello, Kaja; Kwiatkowska-Patzer, Barbara; Lipkowski, Andrzej W; Bardowski, Jacek K; Szczepankowska, Agnieszka K

    2015-05-31

    Multiple sclerosis is a human autoimmunological disease that causes neurodegeneration. One of the potential ways to stop its development is induction of oral tolerance, whose effect lies in decreasing immune response to the fed antigen. It was shown in animal models that administration of specific epitopes of the three main myelin proteins - myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), and proteolipid protein (PLP) - results in induction of oral tolerance and suppression of disease symptoms. Use of bacterial cells to produce and deliver antigens to gut mucosa seems to be an attractive method for oral tolerance induction in treatment of diseases with autoimmune background. Synthetic genes of MOG35-55, MBP85-97, and PLP139-151 myelin epitopes were generated and cloned in Lactococcus lactis under a CcpA-regulated promoter. The tolerogenic effect of bacterial preparations was tested on experimental autoimmune encephalomyelitis, which is the animal model of MS. EAE was induced in rats by intradermal injection of guinea pig spinal cord homogenate into hind paws. Rats were administered preparations containing whole-cell lysates of L. lactis producing myelin antigens using different feeding schemes. Our study demonstrates that 20-fold, but not 4-fold, intragastric administration of autoantigen-expressing L. lactis cells under specific conditions reduces the clinical symptoms of EAE in rats. The present study evaluated the use of myelin antigens produced in L. lactis in inhibiting the onset of experimental autoimmune encephalomyelitis in rats. Obtained results indicate that application of such recombinant cells can be an attractive method of oral tolerance induction.

  15. BCG and BCG/DNAhsp65 vaccinations promote protective effects without deleterious consequences for experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Zorzella-Pezavento, Sofia Fernanda Gonçalves; Guerino, Clara Pires Fujiara; Chiuso-Minicucci, Fernanda; França, Thais Graziela Donegá; Ishikawa, Larissa Lumi Watanabe; Masson, Ana Paula; Silva, Célio Lopes; Sartori, Alexandrina

    2013-01-01

    A prime-boost strategy conserving BCG is considered the most promising vaccine to control tuberculosis. A boost with a DNA vaccine containing the mycobacterial gene of a heat shock protein (pVAXhsp65) after BCG priming protected mice against experimental tuberculosis. However, anti-hsp65 immunity could worsen an autoimmune disease due to molecular mimicry. In this investigation, we evaluated the effect of a previous BCG or BCG/pVAXhsp65 immunization on experimental autoimmune encephalomyelitis (EAE) development. Female Lewis rats were immunized with BCG or BCG followed by pVAXhsp65 boosters. The animals underwent EAE induction and were daily evaluated for weight loss and clinical score. They were euthanized during recovery phase to assess immune response and inflammatory infiltration at the central nervous system. Previous immunization did not aggravate or accelerate clinical score or weight loss. In addition, this procedure clearly decreased inflammation in the brain. BCG immunization modulated the host immune response by triggering a significant reduction in IL-10 and IFN-γ levels induced by myelin basic protein. These data indicated that vaccination protocols with BCG or BCG followed by boosters with pVAXhsp65 did not trigger a deleterious effect on EAE evolution.

  16. BCG and BCG/DNAhsp65 Vaccinations Promote Protective Effects without Deleterious Consequences for Experimental Autoimmune Encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Sofia Fernanda Gonçalves Zorzella-Pezavento

    2013-01-01

    Full Text Available A prime-boost strategy conserving BCG is considered the most promising vaccine to control tuberculosis. A boost with a DNA vaccine containing the mycobacterial gene of a heat shock protein (pVAXhsp65 after BCG priming protected mice against experimental tuberculosis. However, anti-hsp65 immunity could worsen an autoimmune disease due to molecular mimicry. In this investigation, we evaluated the effect of a previous BCG or BCG/pVAXhsp65 immunization on experimental autoimmune encephalomyelitis (EAE development. Female Lewis rats were immunized with BCG or BCG followed by pVAXhsp65 boosters. The animals underwent EAE induction and were daily evaluated for weight loss and clinical score. They were euthanized during recovery phase to assess immune response and inflammatory infiltration at the central nervous system. Previous immunization did not aggravate or accelerate clinical score or weight loss. In addition, this procedure clearly decreased inflammation in the brain. BCG immunization modulated the host immune response by triggering a significant reduction in IL-10 and IFN-γ levels induced by myelin basic protein. These data indicated that vaccination protocols with BCG or BCG followed by boosters with pVAXhsp65 did not trigger a deleterious effect on EAE evolution.

  17. Pediatric nontraumatic myositis ossificans of the neck

    Energy Technology Data Exchange (ETDEWEB)

    Kokkosis, Angela A. [Stony Brook University Medical Center, Stony Brook University School of Medicine, Stony Brook, NY (United States); Balsam, Dvorah [Stony Brook University Medical Center, Department of Radiology, Stony Brook, NY (United States); Lee, Thomas K. [Stony Brook University Medical Center, Department of Pediatric Surgery, Stony Brook, NY (United States); Schreiber, Z.J. [Stony Brook University Medical Center, Department of Pathology, Stony Brook, NY (United States)

    2009-04-15

    Nontraumatic myositis ossificans circumscripta (MOC) is a rarely reported benign heterotopic ossification characterized by the aberrant formation of bone in extraskeletal soft tissues. Although a history of trauma can be elicited in 75% of MOC patients, the etiology is unclear in patients without inciting injury. MOC is associated with young male athletes, and is most often localized to the muscle groups of the extremities. Rare cases have been reported in children and adolescents of nontraumatic MOC in the neck. We present a 15-year-old adolescent with a rapidly growing, painful neck mass without traumatic stimulus. (orig.)

  18. Genetic resistance in experimental autoimmune encephalomyelitis. I. Analysis of the mechanism of LeR resistance using radiation chimeras

    International Nuclear Information System (INIS)

    Pelfrey, C.M.; Waxman, F.J.; Whitacre, C.C.

    1989-01-01

    Experimental autoimmune encephalomyelitis (EAE) is a cell-mediated autoimmune disease of the central nervous system that has been extensively studied in the rat. The Lewis rat is highly susceptible to the induction of EAE, while the Lewis resistant (LeR) rat is known to be resistant. In this paper, we demonstrate that the LeR rat, which was derived from the Lewis strain by inbreeding of fully resistant animals, is histocompatible with the Lewis strain. Radiation chimeras, a tool for distinguishing between immunologic and nonimmunologic resistance mechanisms, were utilized to analyze the cellular mechanisms involved in genetic resistance to EAE. By transplanting bone marrow cells from LeR rats into irradiated Lewis recipients, Lewis rats were rendered resistant to EAE induction. Likewise, transplanting Lewis bone marrow cells into irradiated LeR recipients rendered LeR rats susceptible. Mixed lymphoid cell chimeras using bone marrow, spleen, and thymus cells in Lewis recipient rats revealed individual lymphoid cell types and cell interactions that significantly affected the incidence and severity of EAE. Our results suggest that LeR resistance is mediated by hematopoietic/immune cells, and that cells located in the spleen appear to play a critical role in the resistance/susceptibility to EAE induction. Depletion of splenic adherent cells did not change the patterns of EAE resistance. In vivo cell mixing studies suggested the presence of a suppressor cell population in the LeR spleen preparations which exerted an inhibitory effect on Lewis autoimmune responses. Thus, the mechanism of LeR resistance appears to be different from that in other EAE-resistant animals

  19. Effect of DAB(389)IL-2 immunotoxin on the course of experimental autoimmune encephalomyelitis in Lewis rats.

    Science.gov (United States)

    Phillips, S Michael; Bhopale, Mahendra K; Constantinescu, Cris S; Ciric, Bogoljub; Hilliard, Brendan; Ventura, Elvira; Lavi, Ehud; Rostami, Abdolmohamad

    2007-12-15

    Activated T cells express the high affinity interleukin 2 receptor (IL-2R also CD25) that binds interleukin 2 (IL-2) and transduces signals important for the proliferation and survival of these cells. We investigated the effect of the genetically engineered immunotoxin DAB(389)IL-2 on experimental autoimmune encephalomyelitis (EAE), an autoimmune disease of the central nervous system (CNS) mediated by activated myelin-reactive T cells. EAE is the most commonly used animal model of the human disease multiple sclerosis (MS). DAB(389)IL-2 is a recombinant fusion product made of a portion of diphtheria toxin, which contains binding and translocation components of the toxin linked to IL-2. The diphtheria toxin targets and kills cells expressing the high affinity IL-2 receptor and has been successfully used in several autoimmune and neoplastic conditions. We observed a significant suppression of guinea-pig spinal cord homogenate (gpSCH)-MBP induced active EAE in Lewis rats at 2 x 1,600 kU of DAB(389)IL-2 given on days 7 and 9 post-immunization and complete suppression with the same dose on days 7, 8 and 9 or 7, 8, 9 and 10 after immunization during the active disease period. There were reduced mononuclear cell infiltrates of CD4(+), CD8(+), CD25(+) and alphabetaTCR(+) T cells in the spinal cord of treated rats. However, treatment at day 11 or 12 post-immunization led to severe, fatal disease. The toxin added to cultures in vitro or injected in vivo suppressed antigen- and mitogen-induced T cell proliferation. DAB(389)IL-2 treatment in vivo or exposure of encephalitogenic T cells in vitro prior to transfer did have a significant inhibitory effect on adoptive transfer EAE. Our data demonstrate that DAB(389)IL-2 immunotoxin can suppress active and passive EAE if applied at specific, early time points, but can have negative consequences at later time points.

  20. Dose-dependent mechanisms relate to nasal tolerance induction and protection against experimental autoimmune encephalomyelitis in Lewis rats.

    Science.gov (United States)

    Li, H L; Liu, J Q; Bai, X F; vn der Meide, P H; Link, H

    1998-07-01

    Nasal administration of soluble antigens is an exciting means of specifically down-regulating pathogenic T-cell reactivities in autoimmune diseases. The mechanisms by which nasal administration of soluble antigens suppresses autoimmunity are poorly understood. To define further the principles of nasal tolerance induction, we studied the effects of nasal administration of myelin basic protein (MBP) on experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. EAE is a CD4+ T-cell-mediated animal model for human multiple sclerosis. Nasal administration of guinea-pig (gp)-MBP at a dose as low as 30 micrograms/rat can completely prevent gp-MBP-induced EAE, whereas nasal administration of bovine (b)-MBP is not effective even at a much higher dosage. Cellular immune responses, as reflected by T-cell proliferation and interferon-gamma (IFN-gamma)-ELISPOT, were suppressed in rats receiving the two different doses (30 and 600 micrograms/rat) of gp-MBP, but not after administration of b-MBP. Rats tolerized with both doses of gp-MBP had also abrogated MBP-induced IFN-gamma mRNA expression in popliteal and inguinal lymph node mononuclear cells compared with rats receiving phosphate-buffered saline nasally. However, adoptive transfer revealed that only spleen mononuclear cells from rats pretreated with a low dose, but not from those pretreated with a high dose, of gp-MBP transferred protection to actively induced EAE. Low-dose (30 micrograms/rat) gp-MBP-tolerized rats also had high numbers of interleukin-4 (IL-4) mRNA-expressing lymph node cells, while high-dose (600 micrograms/rat) gp-MBP-tolerized rats had low numbers of IL-4 mRNA-expressing lymph node cells. Our data suggest an exquisite specificity of nasal tolerance. Dose-dependent mechanisms also relate to nasal tolerance induction and protection against EAE in the Lewis rat.

  1. CD27 natural killer cell subsets play different roles during the pre-onset stage of experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Gao, Ming; Yang, Yan; Li, Daling; Ming, Bingxia; Chen, Huoying; Sun, Yan; Xiao, Yifan; Lai, Lin; Zou, Huijuan; Xu, Yong; Xiong, Ping; Tan, Zheng; Gong, Feili; Zheng, Fang

    2016-08-01

    NK cells participate in the development of human multiple sclerosis (MS) and mouse experimental autoimmune encephalomyelitis (EAE), but the roles of different NK cell subsets in disease onset remain poorly understood. In this study, murine NK cells were divided into CD27(high) and CD27(low/-) subsets. The CD27(high) subset was decreased and the CD27(low/-) subset was increased in lymphoid organs during the pre-onset stage of EAE. Compared with the counterpart in naïve mice, the CD27(high) subset showed lower expression of Ly49D, Ly49H and NKG2D, and less production of IFN-γ, whereas the CD27(low/-) subset showed similar expression of the above mentioned surface receptors but higher cytotoxic activity in EAE mice. Compared with the CD27(high) subset, the CD27(low/-) subset exhibited increased promotion of DC maturation and no significant inhibition of T cells proliferation and Th17 cells differentiation in vitro Additionally, adoptive transfer of the CD27(low/-) subset, but not the CD27(high) subset, exacerbated the severity of EAE. Collectively, our data suggest the CD27 NK cell subsets play different roles in controlling EAE onset, which provide a new understanding for the regulation of NK cell subsets in early autoimmune disease. © The Author(s) 2016.

  2. 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.

  3. 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.

    2013-01-01

    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. PMID:22939403

  4. Proteasome Inhibitor Bortezomib Suppresses Nuclear Factor-Kappa B Activation and Ameliorates Eye Inflammation in Experimental Autoimmune Uveitis

    Directory of Open Access Journals (Sweden)

    Sheng-Min Hsu

    2015-01-01

    Full Text Available Bortezomib is a proteasome inhibitor used for hematologic cancer treatment. Since it can suppress NF-κB activation, which is critical for the inflammatory process, bortezomib has been found to possess anti-inflammatory activity. In this study, we evaluated the effect of bortezomib on experimental autoimmune uveitis (EAU in mice and investigated the potential mechanisms related to NF-κB inactivation. High-dose bortezomib (0.75 mg/kg, low-dose bortezomib (0.15 mg/kg, or phosphate buffered saline was given after EAU induction. We found that the EAU is ameliorated by high-dose bortezomib treatment when compared with low-dose bortezomib or PBS treatment. The DNA-binding activity of NF-κB was suppressed and expression of several key inflammatory mediators including TNF-α, IL-1α, IL-1β, IL-12, IL-17, and MCP-1 was lowered in the high-dose bortezomib-treated group. These results suggest that proteasome inhibition is a promising treatment strategy for autoimmune uveitis.

  5. Unimpaired Autoreactive T-Cell Traffic Within the Central Nervous System During Tumor Necrosis Factor Receptor-Mediated inhibition of Experimental Autoimmune Encephalomyelitis

    Science.gov (United States)

    Korner, Heinrich; Goodsall, Anna L.; Lemckert, Frances A.; Scallon, Bernard J.; Ghrayeb, John; Ford, Andrew L.; Sedgwick, Jonathon D.

    1995-11-01

    The critical role of tumor necrosis factor (TNF) as a mediator in autoimmune inflammatory processes is evident from in vivo studies with TNF-blocking agents. However, the mechanisms by which TNF, and possibly also its homologue lymphotoxin α, contributes to development of pathology in rheumatoid arthritis and Crohn disease and in animal models like experimental autoimmune encephalomyelitis is unclear. Possibilities include regulation of vascular adhesion molecules enabling leukocyte movement into tissues or direct cytokine-mediated effector functions such as mediation of tissue damage. Here we show that administration of a TNF receptor (55 kDa)-IgG fusion protein prevented clinical signs of actively induced experimental autoimmune encephalomyelitis. Significantly, the total number of CD4^+ T lymphocytes isolated from the central nervous system of clinically healthy treated versus diseased control animals was comparable. By using a CD45 congenic model of passively transferred experimental autoimmune encephalomyelitis to enable tracking of myelin basic protein-specific effector T lymphocytes, prevention of clinical signs of disease was again demonstrated in treated animals but without quantitative or qualitative impediment to the movement of autoreactive T lymphocytes to and within the central nervous system. Thus, despite the uninterrupted movement of specific T lymphocytes into the target tissue, subsequent disease development was blocked. This provides compelling evidence for a direct effector role of TNF/lymphotoxin α in autoimmune tissue damage.

  6. 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.

  7. 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.

  8. New findings and old controversies in the research of multiple sclerosis and its model experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Aharoni, Rina

    2013-05-01

    Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS that is heterogeneous in its clinical manifestation and progression, as well as in its pathological mechanisms. Animal models, in particular the various forms of experimental autoimmune encephalomyelitis, have been highly valuable for studying both disease pathology and drug development. Novel technologies, such as advanced imaging systems, as well as systematic research of CNS biopsies and postmortem samples from MS patients, have brought major progress in disease understanding. Consequently, in addition to the sclerotic demyelinated plaques in the white matter, changes in normal-appearing white matter tissue ('pre-plaque') and gray matter pathology are currently regarded as central disease components. This review aims to provide current insights on several central aspects in MS research. In particular, the interplay between inflammation and neurodegeneration mediating the disease, and therapeutic strategies attempting to induce immunomodulation and neuroprotective repair processes, are discussed.

  9. Deletion of UCP2 in iNOS deficient mice reduces the severity of the disease during experimental autoimmune encephalomyelitis.

    Directory of Open Access Journals (Sweden)

    Caroline Aheng

    Full Text Available Uncoupling protein 2 is a member of the mitochondrial anion carrier family that is widely expressed in neurons and the immune cells of humans. Deletion of Ucp2 gene in mice pre-activates the immune system leading to higher resistance toward infection and to an increased susceptibility to develop chronic inflammatory diseases as previously exemplified with the Experimental Autoimmune Encephalomyelitis (EAE, a mouse model for multiple sclerosis. Given that oxidative stress is enhanced in Ucp2-/- mice and that nitric oxide (NO also plays a critical function in redox balance and in chronic inflammation, we generated mice deficient for both Ucp2 and iNos genes and submitted them to EAE. Mice lacking iNos gene exhibited the highest clinical score (3.4+/-0.5 p<0.05. Surprisingly, mice deficient for both genes developed milder disease with reduced immune cell infiltration, cytokines and ROS production as compared to iNos-/- mice.

  10. Efficacy of Synthetic Peptide Corresponding to the ACTH-Like Sequence of Human Immunoglobulin G1 in Experimental Autoimmune Encephalomyelitis.

    Science.gov (United States)

    Turobov, Valery I; Danilkovich, Alexey V; Shevelev, Alexei B; Biryukova, Yulia K; Pozdniakova, Natalia V; Azev, Viatcheslav N; Murashev, Arkady N; Lipkin, Valery M; Udovichenko, Igor P

    2018-01-01

    Peptide immunocortin sequence corresponds to the amino acid residues 11-20 of the variable part of human immunoglobulin G1 (IgG1) heavy chain. Since immunocortin was shown previously to inhibit phagocytosis in peritoneal macrophages and ConA-induced T-lymphocytes proliferation in culture, we suggested that immunocortin administering may be of use for patients with self-immune syndrome. Immunocortin in concentration 10 μM inhibited proliferation of both antigen (myelin)-induced and ConA-induced LN lymphocytes isolated from the lymph nodes of Dark Agouti (DA) rats immunized with chorda shear. The biological trials of the synthetic immunocortin were carried out on the DA rats with induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. These in vivo experiments have shown that intraperitoneal injections of immunocortin in a daily dosage 100 μg per animal reduced symptoms of EAE in DA rats.

  11. Efficacy of Synthetic Peptide Corresponding to the ACTH-Like Sequence of Human Immunoglobulin G1 in Experimental Autoimmune Encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Valery I. Turobov

    2018-02-01

    Full Text Available Peptide immunocortin sequence corresponds to the amino acid residues 11–20 of the variable part of human immunoglobulin G1 (IgG1 heavy chain. Since immunocortin was shown previously to inhibit phagocytosis in peritoneal macrophages and ConA-induced T-lymphocytes proliferation in culture, we suggested that immunocortin administering may be of use for patients with self-immune syndrome. Immunocortin in concentration 10 μM inhibited proliferation of both antigen (myelin-induced and ConA-induced LN lymphocytes isolated from the lymph nodes of Dark Agouti (DA rats immunized with chorda shear. The biological trials of the synthetic immunocortin were carried out on the DA rats with induced experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis. These in vivo experiments have shown that intraperitoneal injections of immunocortin in a daily dosage 100 μg per animal reduced symptoms of EAE in DA rats.

  12. Transgenic expression of soluble human CD5 enhances experimentally-induced autoimmune and anti-tumoral immune responses.

    Directory of Open Access Journals (Sweden)

    Rafael Fenutría

    Full Text Available CD5 is a lymphoid-specific transmembrane glycoprotein constitutively expressed on thymocytes and mature T and B1a lymphocytes. Current data support the view that CD5 is a negative regulator of antigen-specific receptor-mediated signaling in these cells, and that this would likely be achieved through interaction with CD5 ligand/s (CD5L of still undefined nature expressed on immune or accessory cells. To determine the functional consequence of loss of CD5/CD5L interaction in vivo, a new transgenic mouse line was generated (shCD5EμTg, expressing a circulating soluble form of human CD5 (shCD5 as a decoy to impair membrane-bound CD5 function. These shCD5EμTg mice showed an enhanced response to autologous antigens, as deduced from the presentation of more severe forms of experimentally inducible autoimmune disease (collagen-induced arthritis, CIA; and experimental autoimmune encephalitis, EAE, as well as an increased anti-tumoral response in non-orthotopic cancer models (B16 melanoma. This enhancement of the immune response was in agreement with the finding of significantly reduced proportions of spleen and lymph node Treg cells (CD4+CD25+FoxP3+, and of peritoneal IL-10-producing and CD5+ B cells, as well as an increased proportion of spleen NKT cells in shCD5EμTg mice. Similar changes in lymphocyte subpopulations were observed in wild-type mice following repeated administration of exogenous recombinant shCD5 protein. These data reveal the relevant role played by CD5/CD5L interactions on the homeostasis of some functionally relevant lymphocyte subpopulations and the modulation of immune responses to autologous antigens.

  13. Plasma Exchange for Refractory MDA5 Myositis and ILD

    Science.gov (United States)

    2017-04-26

    59 MDW/SGVU SUBJECT: Professional Presentation Approval 18 APR 2017 1. Your paper, entitled Plasma Exchange for Refractorv MDAS myositis and ILD...submitted for review and approval.) Plasma exchange for refractory MDA5 myositis and ILD 6. TITLE OF MATERIAL TO BE PUBLISHED OR PRESENTED: Plasma ...MDWI 41-,08 PREVIOUS EDITIONS ARE OBSOLETE 50. DATE Page 3 of 3 Pages Sidari CCR Abstract Rough Drafts Title: Plasma exchange for refractory MDAS

  14. Myositis ossificans of the elbow after a trigger point injection.

    Science.gov (United States)

    Shin, Sang-Jin; Kang, Sung Shik

    2011-03-01

    Trigger point injection is a simple procedure that is widely performed for relieving pain. Even though there are several complications of trigger point injection, myositis ossificans has not been documented as one of its complications. We treated a patient who suffered from painful limitation of elbow motion and this was caused by myositis ossificans between the insertions of brachialis and supinator muscles after a trigger point injection containing lidocaine mixed with saline, and we also review the relevant medical literature.

  15. Myositis Ossificans of the Elbow after a Trigger Point Injection

    OpenAIRE

    Shin, Sang-Jin; Kang, Sung Shik

    2011-01-01

    Trigger point injection is a simple procedure that is widely performed for relieving pain. Even though there are several complications of trigger point injection, myositis ossificans has not been documented as one of its complications. We treated a patient who suffered from painful limitation of elbow motion and this was caused by myositis ossificans between the insertions of brachialis and supinator muscles after a trigger point injection containing lidocaine mixed with saline, and we also r...

  16. 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...

  17. 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...

  18. 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

    In this study we evaluated stimulation of the angiotensin AT2-receptor (AT2R) by the selective non-peptide agonist Compound 21 (C21) as a novel therapeutic concept for the treatment of multiple sclerosis using the model of experimental autoimmune encephalomyelitis (EAE) in mice. C57BL-6 mice were...

  19. Novel pathogenic epitopes of myelin oligodendrocyte glycoprotein induce experimental autoimmune encephalomyelitis in C57BL/6 mice

    Science.gov (United States)

    Delarasse, Cecile; Smith, Paul; Baker, David; Amor, Sandra

    2013-01-01

    Myelin oligodendrocyte glycoprotein (MOG), a minor protein of the central nervous system myelin, is recognized as a potential target in multiple sclerosis and neuromyelitis optica. The extracellular domain of MOG is commonly used in a wide range of mouse strains and other animals to induce experimental autoimmune encephalomyelitis (EAE), an autoimmune animal model of multiple sclerosis, because it is a target for antibody-mediated attack. Previous studies, using selected peptides, have indicated that MOG35–55 peptide is an encephalitogenic epitope in C57BL/6 (H-2b) mice. A more systematic analysis of both T-cell and B-cell responses following immunization of C57BL/6 mice with either recombinant extracellular mouse MOG protein (1–116) or with overlapping peptides spanning the whole sequence of MOG, before assessment of responses to 15 mer and 23 mer peptides was undertaken. The studies identified T-cell responses within the MOG35–55 (extracellular domain) but also two new immunogenic and encephalitogenic T-cell epitopes within residues MOG113–127, MOG120–134 (localized in the transmembrane region) and MOG183–197 (in the second hydrophobic MOG domain). In addition, residue MOG113–127 was found to be a B-cell epitope, suggesting that this may be a useful adjunct for the induction of EAE as well as for immunological studies in C57BL/6 mice, which are increasingly being used to study immune function through the use of transgenic and gene knockout technology. PMID:23876060

  20. Implication of the intestinal microbiome as a potential surrogate marker of immune responsiveness to experimental therapies in autoimmune diabetes.

    Science.gov (United States)

    Needell, James C; Dinarello, Charles A; Ir, Diana; Robertson, Charles E; Ryan, Sarah M; Kroehl, Miranda E; Frank, Daniel N; Zipris, Danny

    2017-01-01

    Type 1 diabetes (T1D) is an autoimmune proinflammatory disease with no effective intervention. A major obstacle in developing new immunotherapies for T1D is the lack of means for monitoring immune responsiveness to experimental therapies. The LEW1.WR1 rat develops autoimmunity following infection with the parvovirus Kilham rat virus (KRV) via mechanisms linked with activation of proinflammatory pathways and alterations in the gut bacterial composition. We used this animal to test the hypothesis that intervention with agents that block innate immunity and diabetes is associated with a shift in the gut microbiota. We observed that infection with KRV results in the induction of proinflammatory gene activation in both the spleen and pancreatic lymph nodes. Furthermore, administering animals the histone deacetylase inhibitor ITF-2357 and IL-1 receptor antagonist (Anakinra) induced differential STAT-1 and the p40 unit of IL-12/IL-23 gene expression. Sequencing of bacterial 16S rRNA genes demonstrated that both ITF-2357 and Anakinra alter microbial diversity. ITF-2357 and Anakinra modulated the abundance of 23 and 8 bacterial taxa in KRV-infected animals, respectively, of which 5 overlapped between the two agents. Lastly, principal component analysis implied that ITF-2357 and Anakinra induce distinct gut microbiomes compared with those from untreated animals or rats provided KRV only. Together, the data suggest that ITF-2357 and Anakinra differentially influence the innate immune system and the intestinal microbiota and highlight the potential use of the gut microbiome as a surrogate means of assessing anti-inflammatory immune effects in type 1 diabetes.

  1. 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.

  2. Experimental autoimmune encephalomyelitis in the Wistar rat: dependence of MBP-specific T cell responsiveness on B7 costimulation.

    Science.gov (United States)

    Zhou, Jing; Zhang, Jia-Sheng; Ma, Bao-Li; Mamula, Mark J

    2002-05-01

    Experimental autoimmune encephalomyelitis (EAE) is an animal model of human multiple sclerosis that requires the activation of autoreactive T cells for the expression of pathology. EAE has been most frequently studied in the Lewis rat model as well as in several murine models of EAE including the PLJ and B10PL strains. In the present study we describe a novel model of EAE induced in the Wistar rat strain by immunization with guinea pig spinal cord antigens and pertussis toxin (PT). T cell responses were induced to myelin basic protein. Autoreactive T cells could be totally blocked by the in vitro treatment with CTLA4Ig, a protein that blocks the costimulation of autoreactive T cells. The addition of IL-2 could reverse the inhibition seen in vitro with CTLA4Ig. The effects of inhibition of B7 costimulation were also examined by an analysis of cytokine responses and IL-2 receptor on T cells. CTLA4Ig treatment in vitro reduced the expression of IL-2 receptor on T cells, enhanced T cell apoptosis and decreased the synthesis of IL-2, IFN-gamma and TNF-alpha. CTLA4Ig treatment had no effect on IL-10 synthesis by T cells, a cytokine implicated in the functions of regulatory T cell subsets. Overall, our studies support the rationale of B7 blocking therapies as a potential treatment for models of multiple sclerosis. The induction of EAE in the Wistar rat provides yet another novel model in which to examine the regulation of T cell autoimmunity.

  3. Molecular and genetic requirements for preferential recruitment of TCRBV8S2+ T cells in Lewis rat experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Weissert, R; Svenningsson, A; Lobell, A; de Graaf, K L; Andersson, R; Olsson, T

    1998-01-15

    The underlying mechanisms behind the preferential expression of select TCRBV products in certain autoimmune illnesses, such as multiple sclerosis and some models of experimental autoimmune encephalomyelitis (EAE), have principally remained enigmatic. In this study, we examined the mutual role of nonself- vs self-origin of antigenic myelin basic protein (MBP) peptides and given MHC haplotypes in relation to the relative frequency of activated TCRBV8S2+ T lymphocytes in the Lewis (LEW) rat EAE model. Inbred MHC (RT1) congenic LEW rats (LEW (RT1l), LEW.1AV1 (RT1av1), and LEW.1W (RT1u)) were immunized with the 63 to 88 peptide of the guinea pig MBP (MBPGP63-88). Additionally, LEW rats were immunized with the corresponding autologous rat sequence (MBPRAT63-88). Although EAE ensued in all MBP peptide/LEW rat strain combinations, only LEW rats immunized with the heterologous MBPGP63-88 peptide elicited T cell responses encompassing a bias toward TCRBV8S2 expression, as determined by flow cytometric analyses. Reduction of TCRBV8S2+ T cells led to mitigation of disease severity in LEW rats immunized with MBPGP63-88, but not with MBPRAT63-88, indicating that critical encephalitogenic characteristics are associated with this T cell subset. We conclude that the preferential recruitment of TCRBV8S2+ T cells in the LEW rat EAE model is due to selective, high-avidity recognition of the nonself-MBPGP63-88 in the context of the RT1.Bl molecule. This inference lends support to the notion that the highly restricted TCR repertoire of the self-MBP-reactive T cells in certain genetically predisposed multiple sclerosis patients may have its source in a multistep molecular mimicry event.

  4. 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.

  5. Effect of a cocoa flavonoid-enriched diet on experimental autoimmune arthritis.

    Science.gov (United States)

    Ramos-Romero, Sara; Pérez-Cano, Francisco J; Pérez-Berezo, Teresa; Castellote, Cristina; Franch, Angels; Castell, Margarida

    2012-02-01

    Previously we established that a cocoa-enriched diet in young rats reduces specific antibody production and the T helper (Th) lymphocyte proportion in lymphoid tissues. The aim of the present study was to ascertain the modulatory ability of a cocoa flavonoid-enriched diet on collagen-induced arthritis (CIA), which is mediated by anti-collagen autoantibody response and Th lymphocyte activation. Female Louvain (LOU) rats were fed with a cocoa-enriched diet, beginning 2 weeks before CIA induction. Hind-paw swelling and serum cytokine and anti-collagen antibody concentrations were determined. Anti-collagen antibody-secreting cell counts and lymphocyte subset proportions were established in inguinal lymph nodes (ILN). Reactive oxygen species (ROS), nitric oxide (NO) and TNFα produced by peritoneal macrophages were determined. Although arthritic cocoa-fed rats showed a similar hind-paw swelling time course as the arthritic animals fed a standard diet, the cocoa intake was able to decrease specific IgG2a, IgG2b and IgG2c titres. Moreover, cocoa intake in CIA rats reduced ROS production, TNFα and NO release from peritoneal macrophages, and decreased the Th:cytotoxic T cell ratio in ILN. In conclusion, a cocoa flavonoid-enriched diet in LOU rats with CIA produced no effect on hind-paw swelling but was able to modulate the specific antibody response and also the Th lymphocyte proportion, as well as the synthesis of pro-inflammatory mediators from peritoneal macrophages. Therefore, a cocoa-enriched diet could be a good adjuvant therapy in disorders with oxidative stress or autoimmune pathogenesis.

  6. 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......-gamma neutralization strongly influenced the Th1/Th2 balance in BN rats, it did not affect the disease outcome. These data demonstrate that a Th1-dominated immune response is not necessarily associated with disease severity in EAMG, not only in rats with disparate MHC haplotype but also in the same rat strain......, and suggest that in a situation where complement-fixing Ab can be generated as a consequence of either Th1- or Th2-mediated T cell help, deviation of the immune response will not be an adequate strategy to prevent this Ab-mediated autoimmune disease....

  7. 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.

  8. Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin antigens: IV. Suppression of chronic relapsing disease in the Lewis rat and strain 13 guinea pig.

    Science.gov (United States)

    Brod, S A; al-Sabbagh, A; Sobel, R A; Hafler, D A; Weiner, H L

    1991-06-01

    Oral administration of proteins is a long-recognized method of inducing antigen-specific peripheral immune tolerance. We previously showed that oral administration of myelin basic protein suppresses monophasic experimental autoimmune encephalomyelitis in the Lewis rat when it is given in association with immunization and prior to disease onset. As a potential therapy for human autoimmune disease, it is crucial to determine whether oral tolerance can ameliorate an ongoing immune response. We therefore asked whether oral administration of myelin antigens, after sensitization and disease expression has occurred, could affect immunological, clinical, or pathological features of experimental autoimmune encephalomyelitis. Chronic relapsing experimental autoimmune encephalomyelitis was induced in the Lewis rat and strain 13 guinea pig by immunization with whole guinea pig cord homogenate, complete Freund's adjuvant, and Mycobacterium tuberculosis. Following recovery from the first attack, animals were orally given bovine myelin, guinea pig myelin, or guinea pig myelin basic protein three times per week for up to 3 months. Animals receiving myelin products orally had decreased severity and frequency of clinical relapses, decreased delayed-type hypersensitivity responses to myelin antigens, diminished inflammation in the central nervous system (CNS), and decreased areas of CNS demyelination. In the rat, guinea pig myelin basic protein was as effective as guinea pig myelin in ameliorating the disease and also resulted in decreased serum anti-myelin basic protein antibody levels. No exacerbation of disease or worsening of pathological findings occurred in the animals given myelin products. These results demonstrate that oral administration of myelin antigens can suppress chronic relapsing experimental autoimmune encephalomyelitis and have direct relevance to therapy of human demyelinating disorders such as multiple sclerosis.

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

    Directory of Open Access Journals (Sweden)

    Fakharzadeh S

    2014-08-01

    Full Text Available Saideh Fakharzadeh,1 Mohammad Ali Sahraian,2 Maryam Hafizi,1 Somayeh Kalanaky,1 Zahra Masoumi,1 Mehdi Mahdavi,1 Nasser Kamalian,3 Alireza Minagar,4 Mohammad Hassan Nazaran1 1Department of Research and Development, Sodour Ahrar Shargh Company, Tehran, Iran; 2MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; 3Department of Pathology, Medical School of Tehran University of Medical Sciences, Tehran, Iran; 4Department of Neurology, LSU Health Sciences Centre, Shreveport, LA, USA 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

  10. Daily supplementation of D-ribose shows no therapeutic benefits in the MHC-I transgenic mouse model of inflammatory myositis.

    Directory of Open Access Journals (Sweden)

    William Coley

    Full Text Available BACKGROUND: Current treatments for idiopathic inflammatory myopathies (collectively called myositis focus on the suppression of an autoimmune inflammatory response within the skeletal muscle. However, it has been observed that there is a poor correlation between the successful suppression of muscle inflammation and an improvement in muscle function. Some evidence in the literature suggests that metabolic abnormalities in the skeletal muscle underlie the weakness that continues despite successful immunosuppression. We have previously shown that decreased expression of a purine nucleotide cycle enzyme, adenosine monophosphate deaminase (AMPD1, leads to muscle weakness in a mouse model of myositis and may provide a mechanistic basis for muscle weakness. One of the downstream metabolites of this pathway, D-ribose, has been reported to alleviate symptoms of myalgia in patients with a congenital loss of AMPD1. Therefore, we hypothesized that supplementing exogenous D-ribose would improve muscle function in the mouse model of myositis. We treated normal and myositis mice with daily doses of D-ribose (4 mg/kg over a 6-week time period and assessed its effects using a battery of behavioral, functional, histological and molecular measures. RESULTS: Treatment with D-ribose was found to have no statistically significant effects on body weight, grip strength, open field behavioral activity, maximal and specific forces of EDL, soleus muscles, or histological features. Histological and gene expression analysis indicated that muscle tissues remained inflamed despite treatment. Gene expression analysis also suggested that low levels of the ribokinase enzyme in the skeletal muscle might prevent skeletal muscle tissue from effectively utilizing D-ribose. CONCLUSIONS: Treatment with daily oral doses of D-ribose showed no significant effect on either disease progression or muscle function in the mouse model of myositis.

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

    Science.gov (United States)

    Huang, Hai-Peng; Pan, Hong; Wang, Hong-Feng

    2016-03-01

    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.

  12. "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.

  13. Autoimmune disorders

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000816.htm Autoimmune disorders To use the sharing features on this page, please enable JavaScript. An autoimmune disorder occurs when the body's immune system attacks and ...

  14. Inhibition of Myeloperoxidase at the Peak of Experimental Autoimmune Encephalomyelitis Restores Blood-Brain-Barrier Integrity and Ameliorates Disease Severity.

    Science.gov (United States)

    Zhang, Hao; Ray, Avijit; Miller, Nichole M; Hartwig, Danielle; Pritchard, Kirkwood A; Dittel, Bonnie N

    2015-11-12

    Oxidative stress is thought to contribute to disease pathogenesis in the central nervous system (CNS) disease multiple sclerosis (MS). Myeloperoxidase (MPO), a potent peroxidase that generates toxic radicals and oxidants, is increased in the CNS during MS. However, the exact mechanism whereby MPO drives MS pathology is not known. We addressed this question by inhibiting MPO in mice with experimental autoimmune encephalomyelitis (EAE) using our non-toxic MPO inhibitor KYC. We found that therapeutic administration of KYC for five days starting at the peak of disease significantly attenuated EAE disease severity, reduced myeloid cell numbers and permeability of the blood-brain-barrier (BBB). These data indicate that inhibition of MPO by KYC restores BBB integrity thereby limiting migration of myeloid cells into the CNS that drive EAE pathogenesis. In addition, these observations indicate that KYC may be an effective therapeutic agent for the treatment of MS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  15. 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.

  16. 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.

  17. Hyaluronan Anchored to Activated CD44 on Central Nervous System Vascular Endothelial Cells Promotes Lymphocyte Extravasation in Experimental Autoimmune Encephalomyelitis*

    Science.gov (United States)

    Winkler, Clayton W.; Foster, Scott C.; Matsumoto, Steven G.; Preston, Marnie A.; Xing, Rubing; Bebo, Bruce F.; Banine, Fatima; Berny-Lang, Michelle A.; Itakura, Asako; McCarty, Owen J. T.; Sherman, Larry S.

    2012-01-01

    The extravasation of lymphocytes across central nervous system (CNS) vascular endothelium is a key step in inflammatory demyelinating diseases including multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). The glycosaminoglycan hyaluronan (HA) and its receptor, CD44, have been implicated in this process but their precise roles are unclear. We find that CD44−/− mice have a delayed onset of EAE compared with wild type animals. Using an in vitro lymphocyte rolling assay, we find that fewer slow rolling (<1 μm/s) wild type (WT) activated lymphocytes interact with CD44−/− brain vascular endothelial cells (ECs) than with WT ECs. We also find that CD44−/− ECs fail to anchor HA to their surfaces, and that slow rolling lymphocyte interactions with WT ECs are inhibited when the ECs are treated with a pegylated form of the PH20 hyaluronidase (PEG-PH20). Subcutaneous injection of PEG-PH20 delays the onset of EAE symptoms by ∼1 day and transiently ameliorates symptoms for 2 days following disease onset. These improved symptoms correspond histologically to degradation of HA in the lumen of CNS blood vessels, decreased demyelination, and impaired CD4+ T-cell extravasation. Collectively these data suggest that HA tethered to CD44 on CNS ECs is critical for the extravasation of activated T cells into the CNS providing new insight into the mechanisms promoting inflammatory demyelinating disease. PMID:22865853

  18. 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.

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

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    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.

  20. Microwave & Magnetic (M2) Proteomics Reveals CNS-Specific Protein Expression Waves that Precede Clinical Symptoms of Experimental Autoimmune Encephalomyelitis

    Science.gov (United States)

    Raphael, Itay; Mahesula, Swetha; Purkar, Anjali; Black, David; Catala, Alexis; Gelfond, Jonathon A. L.; Forsthuber, Thomas G.; Haskins, William E.

    2014-09-01

    Central nervous system-specific proteins (CSPs), transported across the damaged blood-brain-barrier (BBB) to cerebrospinal fluid (CSF) and blood (serum), might be promising diagnostic, prognostic and predictive protein biomarkers of disease in individual multiple sclerosis (MS) patients because they are not expected to be present at appreciable levels in the circulation of healthy subjects. We hypothesized that microwave & magnetic (M2) proteomics of CSPs in brain tissue might be an effective means to prioritize putative CSP biomarkers for future immunoassays in serum. To test this hypothesis, we used M2 proteomics to longitudinally assess CSP expression in brain tissue from mice during experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Confirmation of central nervous system (CNS)-infiltrating inflammatory cell response and CSP expression in serum was achieved with cytokine ELISPOT and ELISA immunoassays, respectively, for selected CSPs. M2 proteomics (and ELISA) revealed characteristic CSP expression waves, including synapsin-1 and α-II-spectrin, which peaked at day 7 in brain tissue (and serum) and preceded clinical EAE symptoms that began at day 10 and peaked at day 20. Moreover, M2 proteomics supports the concept that relatively few CNS-infiltrating inflammatory cells can have a disproportionally large impact on CSP expression prior to clinical manifestation of EAE.

  1. Amelioration of experimental autoimmune encephalomyelitis in C57BL/6 mice by photobiomodulation induced by 670 nm light.

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    Kamaldeen A Muili

    Full Text Available The approved immunomodulatory agents for the treatment of multiple sclerosis (MS are only partially effective. It is thought that the combination of immunomodulatory and neuroprotective strategies is necessary to prevent or reverse disease progression. Irradiation with far red/near infrared light, termed photobiomodulation, is a therapeutic approach for inflammatory and neurodegenerative diseases. Data suggests that near-infrared light functions through neuroprotective and anti-inflammatory mechanisms. We sought to investigate the clinical effect of photobiomodulation in the Experimental Autoimmune Encephalomyelitis (EAE model of multiple sclerosis.The clinical effect of photobiomodulation induced by 670 nm light was investigated in the C57BL/6 mouse model of EAE. Disease was induced with myelin oligodendrocyte glycoprotein (MOG according to standard laboratory protocol. Mice received 670 nm light or no light treatment (sham administered as suppression and treatment protocols. 670 nm light reduced disease severity with both protocols compared to sham treated mice. Disease amelioration was associated with down-regulation of proinflammatory cytokines (interferon-γ, tumor necrosis factor-α and up-regulation of anti-inflammatory cytokines (IL-4, IL-10 in vitro and in vivo.These studies document the therapeutic potential of photobiomodulation with 670 nm light in the EAE model, in part through modulation of the immune response.

  2. Chronic caffeine treatment attenuates experimental autoimmune encephalomyelitis induced by guinea pig spinal cord homogenates in Wistar rats.

    Science.gov (United States)

    Chen, Guo Qian; Chen, Yan Yan; Wang, Xin Shi; Wu, Sai Zhen; Yang, Hui Min; Xu, Hui Qin; He, Jin Cai; Wang, Xiao Tong; Chen, Jiang Fan; Zheng, Rong Yuan

    2010-01-14

    Dysfunction of adenosinergic systems has been implicated in the development of multiple sclerosis in humans and experimental autoimmune encephalomyelitis (EAE) in animals. Caffeine, a non-selective antagonist of adenosine receptors, has been shown to provide protection against myelin oligodendroglia glycoprotein (MOG)-induced EAE in mice. In this study, we showed that chronic caffeine similarly imparts neuroprotection against EAE induced in rats by guinea pig spinal cord homogenates (GPSCH). GPSCH-induced EAE is characterized by extensive tissue inflammation with a typical chronic disease course. We showed that caffeine decreases the incidence of EAE and attenuates EAE pathology at behavioral, histological (inflammatory cell infiltration and demyelination) and neurochemical (expression of inflammatory cytokines) levels. The attenuation of GPSCH-induced pathology by chronic caffeine treatment was observed at doses of 10 and 30 mg/kg and during both peak and recovery phases of EAE. Furthermore, it was showed that chronic treatment with caffeine up-regulated A1 receptor and TGF-beta mRNAs and suppressed interferon-gamma mRNA in EAE rats. Together with previous reports, our data demonstrates that chronic treatment with caffeine exerts a neuroprotective effect against EAE, possibly through an A(1) receptor-mediated shift from Th1 to Th2 cell function, and provides a neurobiological basis for epidemiological investigation into the possible relationship between caffeine consumption and development of multiple sclerosis in humans.

  3. Idazoxan attenuates spinal cord injury by enhanced astrocytic activation and reduced microglial activation in rat experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Wang, Xin-Shi; Chen, Yan-Yan; Shang, Xiao-Feng; Zhu, Zhen-Guo; Chen, Guo-Qian; Han, Zhao; Shao, Bei; Yang, Hui-Min; Xu, Hui-Qin; Chen, Jiang-Fan; Zheng, Rong-Yuan

    2009-02-09

    Idazoxan, an imidazoline 2 receptor (I(2)R) ligand, has been shown to protect against brain injury in several animal models of neurological disorders. In the present study we investigated the effect of idazoxan on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. EAE was induced by immunizing Wistar rats with guinea pig spinal cord homogenates emulsified in CFA, followed by daily treatment of idazoxan (0, 0.5 mg/kg, 1.5 mg/kg, 4.5 mg/kg, i.p, bid) for 10 days. The results showed that the treatment of idazoxan (1.5 mg/kg and 4.5 mg/kg) significantly decreased the incidence and alleviated inflammatory cell infiltration and demyelination in spinal cords and cerebral cortex. Furthermore, the protective effect of idazoxan on EAE was associated with the enhanced astrocytic activation and attenuated microglial activation and with the subsequent down-regulated expression of proinflammatory cytokines IL-12p40 and IFN-gamma and up-regulated expression of anti-inflammatory cytokines IL-10 and TGF-beta(1). Thus, the daily treatment of the I(2)R ligand idazoxan for 10 days attenuates EAE pathology by differential modulation of astrocytic and microglial activations, raising a possibility that the I(2)R ligand may be a novel strategy for treating EAE.

  4. Effects of vaccination with altered peptide ligand on chronic pain in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis

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    David H Tian

    2013-10-01

    Full Text Available Neuropathic pain is a chronic symptom of multiple sclerosis (MS and affects nearly half of all MS sufferers. A key instigator of this pain is the pro-inflammatory response in MS. We investigated the behavioural effects of immunisation with a mutant peptide of myelin basic protein (MBP, termed altered peptide ligand (APL, known to initiate immune deviation from a pro-inflammatory state to an anti-inflammatory response in experimental autoimmune encephalomyelitis (EAE, an animal model of MS. Male and female Lewis rats were injected with vehicle control or with varying doses of 50 or 100 µg guinea pig MBP in combination with or without APL. APL-treated animals established significantly lower disease severity compared to encephalitogenic MBP-treated animals. Animals with EAE developed mechanical, but not thermal pain hypersensitivity. Mechanical pain sensitivities were either improved or normalised during periods of clinical disease in male and female APL-treated animals as compared to the encephalitogenic group. No significant changes to thermal latency were observed upon co-immunisation with APL. Together these data indicate that APL ameliorates disease states and selectively mediates an analgesic effect on EAE animals.

  5. Effects of vaccination with altered Peptide ligand on chronic pain in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis.

    Science.gov (United States)

    Tian, David H; Perera, Chamini J; Apostolopoulos, Vasso; Moalem-Taylor, Gila

    2013-01-01

    Neuropathic pain is a chronic symptom of multiple sclerosis (MS) and affects nearly half of all MS sufferers. A key instigator of this pain is the pro-inflammatory response in MS. We investigated the behavioral effects of immunization with a mutant peptide of myelin basic protein (MBP), termed altered peptide ligand (APL), known to initiate immune deviation from a pro-inflammatory state to an anti-inflammatory response in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Male and female Lewis rats were injected with vehicle control or with varying doses of 50 or 100 μg guinea pig MBP in combination with or without APL. APL-treated animals established significantly lower disease severity compared to encephalitogenic MBP-treated animals. Animals with EAE developed mechanical, but not thermal pain hypersensitivity. Mechanical pain sensitivities were either improved or normalized during periods of clinical disease in male and female APL-treated animals as compared to the encephalitogenic group. No significant changes to thermal latency were observed upon co-immunization with APL. Together these data indicate that APL ameliorates disease states and selectively mediates an analgesic effect on EAE animals.

  6. [Expression of the stress-response protein 60 in iritis in experimental autoimmune encephalomyelitis--an immunohistochemical study].

    Science.gov (United States)

    Kumagami, T; Kato, S; Ohama, E

    1997-04-01

    Uveitis of unknown etiology is known to occur in association with various systemic disorders. We did an immunohistochemical study on the expression of stress-response proteins (srp's) in iritis associated with experimental autoimmune encephalomyelitis (EAE), which is regarded as a model of multiple sclerosis. EAE was induced in Lewis rats by sensitization with homogenized spinal cord of guinea pig in complete Freund's adjuvant (CFA) (Group EAE). For controls, we used rats sensitized with CFA only (Group CFA) and untreated rats (normal controls). All rats developed iritis in Group EAE. In Group CFA, no rats developed iritis. No expression of ubiquitin, alpha B-crystallin, srp 27, srp 60, or srp 72 was seen in the epithelium of the iris of the rats in Group CFA. In the rats in Group EAE, srp 60 was expressed in the epithelium of the iris in 20/22 (90.9%) of the eyes examined, ubiquitin in 4/22 (18.2%), and alpha B-crystallin in 3/22 (13.6%). In the untreated rats, only ubiquitin was expressed in the epithelium of the iris in 1/6 (16.7%) of the eyes examined. These results suggest that srp 60, 60 kDa srp, plays an important role in the occurrence of iritis associated with EAE.

  7. Studies on T-cell receptors involved in experimental autoimmune encephalomyelitis using the complementary peptide recognition approach.

    Science.gov (United States)

    Xian, C J; Simmons, R D; Willenborg, D O; Vandenbark, A A; Hashim, G A; Carnegie, P R

    1995-08-01

    Based upon Blalock's complementary recognition approach, a complementary or antisense peptide (CP) was designed to the experimental autoimmune encephalomyelitis (EAE) epitope peptide, rat myelin basic protein (MBP) peptide 72-82. This peptide (EAE CP) was shown to have some sequence similarities to T-cell receptors (TCR) and MHC II molecules in a sequence homology search. Solid-phase binding assays demonstrated specific and high affinity binding (3 and 4 microM) between the EAE CP and the rat and guinea pig EAE epitope peptides (Rt72-82 and Gp69-82), respectively. This EAE CP was also found to be immunogenic in rats in an ear swelling test for delayed type hypersensitivity (DTH) reactions and an ELISA for antibody responses. However, a rabbit antibody generated to EAE CP was shown to be unable to stain the V beta 8+ EAE susceptible T-cells in immunofluorescence analyses. This EAE CP was also used in attempts to down-regulate EAE and the results showed that prior immunization with EAE CP in complete Freund's adjuvant could not prevent the Lewis rats from developing EAE. Although the data on sense-antisense peptide interaction were positive and the EAE CP was immunogenic, the inability of EAE CP to regulate EAE indicates that the CP approach may not be generally applicable.

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

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    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.

  9. Oral delivery of ACE2/Ang-(1-7) bioencapsulated in plant cells protects against experimental uveitis and autoimmune uveoretinitis.

    Science.gov (United States)

    Shil, Pollob K; Kwon, Kwang-Chul; Zhu, Ping; Verma, Amrisha; Daniell, Henry; Li, Qiuhong

    2014-12-01

    Hyperactivity of the renin-angiotensin system (RAS) resulting in elevated Angiotensin II (Ang II) contributes to all stages of inflammatory responses including ocular inflammation. The discovery of angiotensin-converting enzyme 2 (ACE2) has established a protective axis of RAS involving ACE2/Ang-(1-7)/Mas that counteracts the proinflammatory and hypertrophic effects of the deleterious ACE/AngII/AT1R axis. Here we investigated the hypothesis that enhancing the systemic and local activity of the protective axis of the RAS by oral delivery of ACE2 and Ang-(1-7) bioencapsulated in plant cells would confer protection against ocular inflammation. Both ACE2 and Ang-(1-7), fused with the non-toxic cholera toxin subunit B (CTB) were expressed in plant chloroplasts. Increased levels of ACE2 and Ang-(1-7) were observed in circulation and retina after oral administration of CTB-ACE2 and Ang-(1-7) expressing plant cells. Oral feeding of mice with bioencapsulated ACE2/Ang-(1-7) significantly reduced endotoxin-induced uveitis (EIU) in mice. Treatment with bioencapsulated ACE2/Ang-(1-7) also dramatically decreased cellular infiltration, retinal vasculitis, damage and folding in experimental autoimmune uveoretinitis (EAU). Thus, enhancing the protective axis of RAS by oral delivery of ACE2/Ang-(1-7) bioencapsulated in plant cells provide an innovative, highly efficient and cost-effective therapeutic strategy for ocular inflammatory diseases.

  10. 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.

  11. MuSK induced experimental autoimmune myasthenia gravis does not require IgG1 antibody to MuSK.

    Science.gov (United States)

    Küçükerden, Melike; Huda, Ruksana; Tüzün, Erdem; Yılmaz, Abdullah; Skriapa, Lamprini; Trakas, Nikos; Strait, Richard T; Finkelman, Fred D; Kabadayı, Sevil; Zisimopoulou, Paraskevi; Tzartos, Socrates; Christadoss, Premkumar

    2016-06-15

    Sera of myasthenia gravis (MG) patients with muscle-specific receptor kinase-antibody (MuSK-Ab) predominantly display the non-complement fixing IgG4 isotype. Similarly, mouse IgG1, which is the analog of human IgG4, is the predominant isotype in mice with experimental autoimmune myasthenia gravis (EAMG) induced by MuSK immunization. The present study was performed to determine whether IgG1 anti-MuSK antibody is required for immunized mice to develop EAMG. Results demonstrated a significant correlation between clinical severity of EAMG and levels of MuSK-binding IgG1+, IgG2+ and IgG3+ peripheral blood B cells in MuSK-immunized wild-type (WT) mice. Moreover, MuSK-immunized IgG1 knockout (KO) and WT mice showed similar EAMG severity, serum MuSK-Ab levels, muscle acetylcholine receptor concentrations, neuromuscular junction immunoglobulin and complement deposit ratios. IgG1 and IgG3 were the predominant anti-MuSK isotypes in WT and IgG1 KO mice, respectively. These observations demonstrate that non-IgG1 isotypes can mediate MuSK-EAMG pathogenesis. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Soluble Vascular Cell Adhesion Molecule-1 (VCAM-1 as a Biomarker in the Mouse Model of Experimental Autoimmune Myocarditis (EAM.

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    U Grabmaier

    Full Text Available Vascular cell adhesion molecule-1 (VCAM-1 is strongly upregulated in hearts of mice with coxsackie virus-induced as well as in patients with viral infection-triggered dilated cardiomyopathy. Nevertheless, the role of its soluble form as a biomarker in inflammatory heart diseases remains unclear. Therefore, we investigated whether plasma levels of soluble VCAM-1 (sVCAM-1 directly correlated with disease activity and progression of cardiac dysfunction in the mouse model of experimental autoimmune myocarditis (EAM. EAM was induced by immunization of BALB/c mice with heart-specific myosin-alpha heavy chain peptide together with complete Freund`s adjuvant. ELISA revealed strong expression of cardiac VCAM-1 (cVCAM-1 throughout the course of EAM in immunized mice compared to control animals. Furthermore, sVCAM-1 was elevated in the plasma of immunized compared to control mice at acute and chronic stages of the disease. sVCAM-1 did not correlate with the degree of acute cardiac inflammation analyzed by histology or cardiac cytokine expression investigated by ELISA. Nevertheless, heart to body weight ratio correlated significantly with sVCAM-1 at chronic stages of EAM. Cardiac systolic dysfunction studied with positron emission tomography indicated a weak relationship with sVCAM-1 at the chronic stage of the disease. Our data provide evidence that plasma levels of sVCAM-1 are elevated throughout all stages of the disease but showed no strong correlation with the severity of EAM.

  13. Susceptibility to experimental autoimmune encephalomyelitis (model of multiple sclerosis) and anxiety in genetically heterogeneous rats

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    Martínez Membrives, Esther

    2013-01-01

    Las respuestas al estrés del eje hipotalámico-pituitario-adrenal (HPA) juegan un papel decisivo tanto en la conducta ansiosa como en el funcionamiento del sistema inmune (IS). Es sabido que los niveles elevados de glucocorticoides (GC) desempeñan un papel protector ante la encefalomielitis experimental autoinmune (EAE), fiable modelo animal de la esclerosis múltiple. En esta Tesis, nos propusimos investigar si un determinado perfil ansioso podría corresponderse con un perfil específico de sen...

  14. Clinical aspects of autoimmune rheumatic diseases.

    Science.gov (United States)

    Goldblatt, Fiona; O'Neill, Sean G

    2013-08-31

    Multisystem autoimmune rheumatic diseases are heterogeneous rare disorders associated with substantial morbidity and mortality. Efforts to create international consensus within the past decade have resulted in the publication of new classification or nomenclature criteria for several autoimmune rheumatic diseases, specifically for systemic lupus erythematosus, Sjögren's syndrome, and the systemic vasculitides. Substantial progress has been made in the formulation of new criteria in systemic sclerosis and idiopathic inflammatory myositis. Although the autoimmune rheumatic diseases share many common features and clinical presentations, differentiation between the diseases is crucial because of important distinctions in clinical course, appropriate drugs, and prognoses. We review some of the dilemmas in the diagnosis of these autoimmune rheumatic diseases, and focus on the importance of new classification criteria, clinical assessment, and interpretation of autoimmune serology. In this era of improvement of mortality rates for patients with autoimmune rheumatic diseases, we pay particular attention to the effect of leading complications, specifically cardiovascular manifestations and cancer, and we update epidemiology and prognosis. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. MHC class II expression and potential antigen-presenting cells in the retina during experimental autoimmune uveitis.

    Science.gov (United States)

    Lipski, Deborah A; Dewispelaere, Rémi; Foucart, Vincent; Caspers, Laure E; Defrance, Matthieu; Bruyns, Catherine; Willermain, François

    2017-07-18

    Controversy exists regarding which cell types are responsible for autoantigen presentation in the retina during experimental autoimmune uveitis (EAU) development. In this study, we aimed to identify and characterize the retinal resident and infiltrating cells susceptible to express major histocompatibility complex (MHC) class II during EAU. EAU was induced in C57BL/6 mice by adoptive transfer of autoreactive lymphocytes from IRBP1-20-immunized animals. MHC class II expression was studied by immunostainings on eye cryosections. For flow cytometry (FC) analysis, retinas were dissected and enzymatically digested into single-cell suspensions. Three MHC class II + retinal cell populations were sorted by FC, and their RNA processed for RNA-Seq. Immunostainings demonstrate strong induction of MHC class II expression in EAU, especially in the inner retina at the level of inflamed vessels, extending to the outer retinal layers and the subretinal space in severely inflamed eyes. Most MHC class II + cells express the hematopoietic marker IBA1. FC quantitative analyses demonstrate that MHC class II induction significantly correlates with disease severity and is associated with upregulation of co-stimulatory molecule expression. In particular, most MHC class II hi cells express co-stimulatory molecules during EAU. Further phenotyping identified three MHC class II + retinal cell populations: CD45 - CD11b - non-hematopoietic cells with low MHC class II expression and CD45 + CD11b + hematopoietic cells with higher MHC class II expression, which can be further separated into Ly6C + and Ly6C - cells, possibly corresponding to infiltrating macrophages and resident microglia. Transcriptome analysis of the three sorted populations leads to a clear sample clustering with some enrichment in macrophage markers and microglial cell markers in Ly6C + and Ly6C - cells, respectively. Functional annotation analysis reveals that both hematopoietic cell populations are more competent in MHC class

  16. Bee Venom Acupuncture Alleviates Experimental Autoimmune Encephalomyelitis by Upregulating Regulatory T Cells and Suppressing Th1 and Th17 Responses.

    Science.gov (United States)

    Lee, Min Jung; Jang, Minhee; Choi, Jonghee; Lee, Gihyun; Min, Hyun Jung; Chung, Won-Seok; Kim, Jong-In; Jee, Youngheun; Chae, Younbyoung; Kim, Sung-Hoon; Lee, Sung Joong; Cho, Ik-Hyun

    2016-04-01

    The protective and therapeutic mechanism of bee venom acupuncture (BVA) in neurodegenerative disorders is not clear. We investigated whether treatment with BVA (0.25 and 0.8 mg/kg) at the Zusanli (ST36) acupoints, located lateral from the anterior border of the tibia, has a beneficial effect in a myelin basic protein (MBP)(68-82)-induced acute experimental autoimmune encephalomyelitis (EAE) rat model. Pretreatment (every 3 days from 1 h before immunization) with BVA was more effective than posttreatment (daily after immunization) with BVA with respect to clinical signs (neurological impairment and loss of body weight) of acute EAE rats. Treatment with BVA at the ST36 acupoint in normal rats did not induce the clinical signs. Pretreatment with BVA suppressed demyelination, glial activation, expression of cytokines [interferon (IFN)-γ, IL-17, IL-17A, tumor necrosis factor-alpha (TNF-α), and IL-1β], chemokines [RANTES, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein (MIP)-1α], and inducible nitric oxide synthase (iNOS), and activation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB (p65 and phospho-IκBα) signaling pathways in the spinal cord of acute EAE rats. Pretreatment with BVA decreased the number of CD4(+), CD4(+)/IFN-γ(+), and CD4(+)/IL-17(+) T cells, but increased the number of CD4(+)/Foxp3(+) T cells in the spinal cord and lymph nodes of acute EAE rats. Treatment with BVA at six placebo acupoints (SP9, GB39, and four non-acupoints) did not have a positive effect in acute EAE rats. Interestingly, onset and posttreatment with BVA at the ST36 acupoint markedly attenuated neurological impairment in myelin oligodendrocyte glycoprotein (MOG)(35-55)-induced chronic EAE mice compared to treatment with BVA at six placebo acupoints. Our findings strongly suggest that treatment with BVA with ST36 acupoint could delay or attenuate the development and progression of EAE by upregulating regulatory T cells and

  17. Bilateral increase in expression and concentration of tachykinin in a unilateral rabbit muscle overuse model that leads to myositis.

    Science.gov (United States)

    Song, Yafeng; Stål, Per S; Yu, Ji-Guo; Forsgren, Sture

    2013-04-12

    Tachykinins can have pro-inflammatory as well as healing effects during tissue reorganization and inflammation. Recent studies report an up-regulation in the expression of the substance P (SP)-preferred receptor, the neurokinin-1 receptor, in marked muscle inflammation (myositis). There is, however, only very little information on the expression patterns and levels of tachykinins in this situation. The tachykinin system was analyzed using a rabbit experimental model of muscle overuse, whereby unilateral muscle exercise in combination with electrical stimulation led to muscle derangement and myositis in the triceps surae muscle (experimental length 1-6 weeks). Evaluations were made for both parts of the muscle (soleus and gastrocnemius muscles) in experimental and non-experimental (contralateral) sides. Morphologic evaluation, immunohistochemistry, in situ hybridization and enzyme immunoassay (EIA) analyses were applied. Myositis and muscle derangement occurred focally not only in the experimental side but also in the non-experimental side. In the inflammatory areas (focal myositis areas), there were frequent nerve fibers showing tachykinin-like immunoreactivity and which were parts of nerve fascicles and which were freely dispersed in the tissue. Cells in the inflammatory infiltrates showed tachykinin-like immunoreactivity and tachykinin mRNA expression. Specific immunoreactivity and mRNA expression were noted in blood vessel walls of both sides, especially in focally affected areas. With increasing experimental length, we observed an increase in the degree of immunoreactivity in the vessel walls. The EIA analyses showed that the concentration of tachykinin in the tissue on both sides increased in a time-dependent manner. There was a statistical correlation in the concentration of tachykinin and the level of tachykinin immunoreactivity in the blood vessel walls between experimental and non-experimental sides. The observations show an up-regulation of the tachykinin

  18. Bilateral increase in expression and concentration of tachykinin in a unilateral rabbit muscle overuse model that leads to myositis

    OpenAIRE

    Song, Yafeng; St?l, Per S; Yu, Ji-Guo; Forsgren, Sture

    2013-01-01

    Background: Tachykinins can have pro-inflammatory as well as healing effects during tissue reorganization and inflammation. Recent studies report an up-regulation in the expression of the substance P (SP)-preferred receptor, the neurokinin-1 receptor, in marked muscle inflammation (myositis). There is, however, only very little information on the expression patterns and levels of tachykinins in this situation. Methods: The tachykinin system was analyzed using a rabbit experimental model of mu...

  19. Polyglandular autoimmune syndrome type I – a novel AIRE mutation in a North American patient

    Science.gov (United States)

    Huibregtse, Kelly Egan; Wolfgram, Peter; Winer, Karen K.; Connor, Ellen L.

    2015-01-01

    Autoimmune polyglandular syndrome type 1 (APS-1), also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare autoimmune disease that results from autosomal recessive mutations of the human autoimmune regulatory (AIRE) gene. We present the case of a 17-year-old North American girl of primarily Norwegian descent with a novel AIRE gene mutation causing APS-1. In addition to the classic triad of chronic candidiasis, hypoparathyoidism and autoimmune adrenocortical insufficiency, she also has vitiligo, intestinal malabsorption, autoimmune hepatitis, autoimmune hypothyroidism, myositis, myalgias, chronic fatigue, and failure to thrive. Genetic testing revealed heterozygosity for c.20_115de196 and c.967_979del13 mutations in the AIRE gene. The AIRE gene c.20_115de196 mutation has not been previously reported. PMID:24945421

  20. Polyglandular autoimmune syndrome type I - a novel AIRE mutation in a North American patient.

    Science.gov (United States)

    Huibregtse, Kelly Egan; Wolfgram, Peter; Winer, Karen K; Connor, Ellen L

    2014-11-01

    Autoimmune polyglandular syndrome type 1 (APS-1), also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare autoimmune disease that results from autosomal recessive mutations of the human autoimmune regulatory (AIRE) gene. We present the case of a 17-year-old North American girl of primarily Norwegian descent with a novel AIRE gene mutation causing APS-1. In addition to the classic triad of chronic candidiasis, hypoparathyoidism and autoimmune adrenocortical insufficiency, she also has vitiligo, intestinal malabsorption, autoimmune hepatitis, autoimmune hypothyroidism, myositis, myalgias, chronic fatigue, and failure to thrive. Genetic testing revealed heterozygosity for c.20_115de196 and c.967_979del13 mutations in the AIRE gene. The AIRE gene c.20_115de196 mutation has not been previously reported.

  1. 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.

  2. Pseudomalignant myositis ossificans involving multiple masticatory muscles: Imaging evaluation

    International Nuclear Information System (INIS)

    Kamalapur, Muralidhar G; Patil, Pritam B; Joshi, Shyamsundar; Shastri, Dinesh

    2014-01-01

    Myositis ossificans is a rare cause of trismus. We present a case of pseudomalignant myositis ossificans involving medial pterygoid, lateral pterygoid, and temporalis muscles. Patient presented with gross limitation in mouth opening. There was no history of trauma. Computed tomography (CT) images revealed a bone density mass located in the region of medial and lateral pterygoid muscles on the right and temporalis muscle on the left. Magnetic resonance imaging (MRI) showed similar findings. Radiological diagnosis was pseudomalignant myositis ossificans. The masses were resected and histopathologic examination confirmed the above diagnosis. This report describes the characteristic CT and MRI features. The unique feature of this case is the absence of history of trauma with involvement of multiple masticatory muscles, which, to the best of our knowledge, has not been reported before

  3. Myositis as the initial presentation of panarteritis nodosa.

    Science.gov (United States)

    Calvo, Romina; Negri, Melina; Ortiz, Alberto; Roverano, Susana; Paira, Sergio

    2017-07-26

    A 47-year-old man presented with weight loss, bilateral calf pain, fever, hypertension, orchitis and oligoarthritis. Lab tests: anemia and elevated muscle enzymes. Resonance magnetic imaging: hyperintensity in gastrocnemius muscles (myositis). Histologic exam of the muscles: inflammatory infiltrate with atrophy and perifascicular regeneration. methylprednisone (bolus) and cyclophosphamide. Muscle pain and swelling and difficulty in walking are common in panarteritis nodosa (PAN), whereas histologically demonstrated myositis is not. Even more rare is myositis as the initial presentation of this vasculitis. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  4. Brain leukocyte infiltration initiated by peripheral inflammation or experimental autoimmune encephalomyelitis occurs through pathways connected to the CSF-filled compartments of the forebrain and midbrain.

    OpenAIRE

    Schmitt, Charlotte; Strazielle, Nathalie; Ghersi-Egea, Jean-François

    2012-01-01

    Abstract Background Cerebrospinal fluid (CSF) has been considered as a preferential pathway of circulation for immune cells during neuroimmune surveillance. In order to evaluate the involvement of CSF-filled spaces in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, we performed a time-course analysis of immune cell association with the CSF-containing ventricles, velae, and cisterns in two active models of this disease. Methods Guinea-pig spi...

  5. 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

  6. 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

  7. Sodium and chloride channelopathies with myositis: coincidence or connection?

    Science.gov (United States)

    Matthews, E.; Miller, J.A.L.; Macleod, M.R.; Ironside, J.; Ambler, G.; Labrum, R.; Sud, R.; Holton, J.L.; Hanna, M.G.

    2011-01-01

    Introduction A proximal myopathy develops in some patients with muscle channelopathies, but the causative molecular mechanisms are unknown. Methods We reviewed retrospectively all clinical and muscle biopsy findings of three patients with channelopathy and additional myositis. Direct DNA sequencing was performed. Results Pathogenic mutations were identified in each case. Biopsies illustrated inflammatory infiltrates. Conclusions Clinicians should consider muscle biopsy in channelopathy patients with severe myalgia and/or subacute weakness and accompanying elevated CK. Chance association of myositis and channelopathy is statistically unlikely. An alternative hypothesis suggests that inflammatory insults could contribute to myopathy in some patients. PMID:21698652

  8. [Circumscribed myositis ossificans of the elbow: about a case].

    Science.gov (United States)

    Nhamoucha, Yassine; Alaoui, Othmane; Alaoui, Charifa; Abdellaoui, Hicham; Tazi, Mohammed; Oukhoya, Mohammed; Chater, Lamyae; Atarraf, Karima; Arroud, Mounir; Afifi, Abderahman

    2016-01-01

    Circumscribed myositis ossificans (CMO) is a heterotopic ossification of the striated muscles. Its location at the level of the elbow is rare. It occurs in young patients, often following trauma as it can also develop without experiencing any traumatic event. Its predominant location is at the level of the larger muscles limbs root (gluteus, deltoid) or of the areas which are most exposed to direct shocks (the quadriceps in more than 40% of post-traumatic cases). Our study aims to highlight the aspects of a circumscribed myositis ossificans in conventional radiology and tomodensitometry to avoid potential diagnostic confusion with a malignant bone tumor.

  9. Treatment with the antipsychotic agent, risperidone, reduces disease severity in experimental autoimmune encephalomyelitis.

    Directory of Open Access Journals (Sweden)

    David O'Sullivan

    Full Text Available 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 (MS4, 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.

  10. 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.

  11. A SELDI mass spectrometry study of experimental autoimmune encephalomyelitis: sample preparation, reproducibility, and differential protein expression patterns.

    Science.gov (United States)

    Azzam, Sausan; Broadwater, Laurie; Li, Shuo; Freeman, Ernest J; McDonough, Jennifer; Gregory, Roger B

    2013-05-01

    Experimental autoimmune encephalomyelitis (EAE) is an autoimmune, inflammatory disease of the central nervous system that is widely used as a model of multiple sclerosis (MS). Mitochondrial dysfunction appears to play a role in the development of neuropathology in MS and may also play a role in disease pathology in EAE. Here, surface enhanced laser desorption ionization mass spectrometry (SELDI-MS) has been employed to obtain protein expression profiles from mitochondrially enriched fractions derived from EAE and control mouse brain. To gain insight into experimental variation, the reproducibility of sub-cellular fractionation, anion exchange fractionation as well as spot-to-spot and chip-to-chip variation using pooled samples from brain tissue was examined. Variability of SELDI mass spectral peak intensities indicates a coefficient of variation (CV) of 15.6% and 17.6% between spots on a given chip and between different chips, respectively. Thinly slicing tissue prior to homogenization with a rotor homogenizer showed better reproducibility (CV = 17.0%) than homogenization of blocks of brain tissue with a Teflon® pestle (CV = 27.0%). Fractionation of proteins with anion exchange beads prior to SELDI-MS analysis gave overall CV values from 16.1% to 18.6%. SELDI mass spectra of mitochondrial fractions obtained from brain tissue from EAE mice and controls displayed 39 differentially expressed proteins (p≤ 0.05) out of a total of 241 protein peaks observed in anion exchange fractions. Hierarchical clustering analysis showed that protein fractions from EAE animals with severe disability clearly segregated from controls. Several components of electron transport chain complexes (cytochrome c oxidase subunit 6b1, subunit 6C, and subunit 4; NADH dehydrogenase flavoprotein 3, alpha subcomplex subunit 2, Fe-S protein 4, and Fe-S protein 6; and ATP synthase subunit e) were identified as possible differentially expressed proteins. Myelin Basic Protein isoform 8 (MBP8) (14.2 k

  12. 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

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2015-01-01

    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. PMID:25796590

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

    Directory of Open Access Journals (Sweden)

    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.

  16. Secondary B cell receptor diversification is necessary for T cell mediated neuro-inflammation during experimental autoimmune encephalomyelitis.

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    Georgina Galicia

    Full Text Available Clinical studies of B cell depletion in Multiple Sclerosis (MS have revealed that B Lymphocytes are involved in the neuro-inflammatory process, yet it remains unclear how B cells can exert pro- and anti-inflammatory functions during MS. Experimental Autoimmune Encephalomyelitis (EAE is an animal model of MS whereby myelin-specific T cells become activated and subsequently migrate to the Central Nervous System (CNS where they perform pro-inflammatory functions such as cytokine secretion. Typically EAE is induced by immunization of mice of a susceptible genetic background with peptide antigen emulsified in Complete Freund's Adjuvant. However, novel roles for B-lymphocytes in EAE may also be explored by immunization with full-length myelin oligodendrocyte glycoprotein (MOG that contains the B cell conformational epitope. Here we show that full length MOG immunization promotes a chronic disease in mice that depends on antigen-driven secondary diversification of the B cell receptor.Activation-Induced Deaminase (AID is an enzyme that is essential for antigen-driven secondary diversification of the B cell receptor. We immunized AID(-/- mice with the extracellular domain (amino acids 1-120 of recombinant human MOG protein (rhMOG and examined the incidence and severity of disease in AID(-/- versus wild type mice. Corresponding with these clinical measurements, we also evaluated parameters of T cell activation in the periphery and the CNS as well as the generation of anti-MOG antibodies (Ab.AID(-/- mice exhibit reduced severity and incidence of EAE. This suggests that the secondary diversification of the B cell receptor is required for B cells to exert their full encephalogenic potential during rhMOG-induced EAE, and possibly also during MS.

  17. Prenatal maternal immune activation increases anxiety- and depressive-like behaviors in offspring with experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Majidi-Zolbanin, J; Doosti, M-H; Kosari-Nasab, M; Salari, A-A

    2015-05-21

    Multiple sclerosis (MS) is thought to result from a combination of genetics and environmental factors. Several lines of evidence indicate that significant prevalence of anxiety and depression-related disorders in MS patients can influence the progression of the disease. Although we and others have already reported the consequences of prenatal maternal immune activation on anxiety and depression, less is known about the interplay between maternal inflammation, MS and gender. We here investigated the effects of maternal immune activation with Poly I:C during mid-gestation on the progression of clinical symptoms of experimental autoimmune encephalomyelitis (EAE; a mouse model of MS), and then anxiety- and depressive-like behaviors in non-EAE and EAE-induced offspring were evaluated. Stress-induced corticosterone and tumor necrosis factor-alpha (TNF-α) levels in EAE-induced offspring were also measured. Maternal immune activation increased anxiety and depression in male offspring, but not in females. This immune challenge also resulted in an earlier onset of the EAE clinical signs in male offspring and enhanced the severity of the disease in both male and female offspring. Interestingly, the severity of the disease was associated with increased anxiety/depressive-like behaviors and elevated corticosterone or TNF-α levels in both sexes. Overall, these data suggest that maternal immune activation with Poly I:C during mid-pregnancy increases anxiety- and depressive-like behaviors, and the clinical symptoms of EAE in a sex-dependent manner in non-EAE or EAE-induced offspring. Finally, the progression of EAE in offspring seems to be linked to maternal immune activation-induced dysregulation in neuro-immune-endocrine system. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  18. Establishment of a Novel Autoimmune Experimental Model of Bladder Pain Syndrome/Interstitial Cystitis in C57BL/6 Mice.

    Science.gov (United States)

    Jin, Xing-Wei; Liu, Bo-Ke; Zhang, Xiang; Zhao, Zhong-Hua; Shao, Yuan

    2017-06-01

    The aim of this study is to identify whether vaccinating twice with bladder homogenate can establish a new model of experimental autoimmune cystitis (EAC) in C57BL/6 strain mice. C57BL/6 mice were vaccinated with bladder homogenate in complete Freund's adjuvant (CFA) and boost immunized with bladder homogenate in incomplete Freund's adjuvant (IFA) after 2 weeks were used as the EAC model. Mice immunized with phosphate-buffered saline (PBS) in CFA or IFA were used as the control. Micturition habits and suprapubic-pelvic pain threshold were measured 4 weeks after primary immunization. Bladder to body weight ratios and expression of inflammatory cytokines and neurokinin 1 receptor (NK1R) were then examined. Histologic and immunohistochemical examination of the bladder was carried out, and IL-1β, IFN-γ, and TNF-α production by the kidneys, liver, and lungs was also tested. Double-immunized mice were extensively sensitive to pressure applied on the pelvic area (P < 0.001). Compared to single-immunized mice or controls, double-immunized mice showed more micturition frequency, lower urine output per micturition, higher bladder to body weight ratio, and significant elevation in the expression of inflammatory cytokines, including IL-1β, IL-4, IL-6, IL-10, IFN-γ, and TNF-α (all P < 0.05). NK1R gene expression was significantly increased in double-immunized mice compared to the other three groups (P < 0.001). A nonspecific immune response occurred in the liver but was much weaker than bladder inflammation. Our dual immunization EAC model in C57BL/6 mice can effectively mimic the symptoms and pathophysiologic characteristics of BPS/IC and thus can be widely used to investigate the pathogenesis and therapeutic strategies of BPS/IC.

  19. 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.)

  20. 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.

  1. Anti-S-nitrosocysteine antibodies are a predictive marker for demyelination in experimental autoimmune encephalomyelitis: implications for multiple sclerosis.

    Science.gov (United States)

    Boullerne, Anne I; Rodriguez, Jose J; Touil, Tarik; Brochet, Bruno; Schmidt, Stephan; Abrous, Nora D; Le Moal, Michel; Pua, Jeffrey R; Jensen, Mark A; Mayo, Willy; Arnason, Barry G W; Petry, Klaus G

    2002-01-01

    Multiple sclerosis (MS) is characterized by inflammation within the CNS. This inflammatory response is associated with production of nitric oxide (NO) and NO-related species that nitrosylate thiols. We postulated that MS patients would exhibit an antibody (Ab) response directed against proteins containing S-nitrosocysteine (SNO-cysteine) and showed that anti-NO-cysteine Abs of the IgM isotype are in fact present in the sera of some MS patients (Boullerne et al., 1995). We report here the presence of a seemingly identical Ab response directed against SNO-cysteine in an acute model of MS, experimental autoimmune encephalomyelitis (EAE) induced in Lewis rats with the 68-84 peptide of guinea pig myelin basic protein (MBP(68-84)). Serum levels of anti-SNO-cysteine Abs peaked 1 week before the onset of clinical signs and well before the appearance of anti-MBP(68-84) Abs. The anti-SNO-cysteine Ab peak titer correlated with the extent of subsequent CNS demyelination, suggesting a link between Ab level and CNS lesion formation. In relapsing-remitting MS patients, we found elevated anti-SNO-cysteine Ab at times of relapse and normal values in most patients judged to be in remission. Two-thirds of patients with secondary progressive MS had elevated anti-SNO-cysteine Ab levels, including those receiving interferon beta-1b. The data show that a rise in circulating anti-SNO-cysteine Ab levels precedes onset of EAE. Anti-SNO-cysteine Abs are also elevated at times of MS attacks and in progressive disease, suggesting a possible role for these Abs, measurable in blood, as a biological marker for clinical activity.

  2. Exacerbation of experimental autoimmune encephalomyelitis in P2X7R-/- mice: evidence for loss of apoptotic activity in lymphocytes.

    Science.gov (United States)

    Chen, Lanfen; Brosnan, Celia F

    2006-03-01

    The purinergic receptor P2X7R is a nucleotide-gated ion channel that has been proposed to function as a major regulator of inflammation. In this study we examined the role of this receptor in regulating inflammation in the CNS by determining the effects of the loss of this receptor (P2X7R-/-) on experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. We show here that P2X7R-/- mice developed more severe clinical and pathological expression of EAE than wild type (WT) controls and that spleen and lymph node cells from P2X7R-/- mice proliferated more vigorously to Ag in vitro. Bone marrow (BM) radiation chimeras revealed that enhanced susceptibility to EAE was detected in chimeric mice of WT host engrafted with P2X7R-/- BM cells, indicating that the genotype of the BM cells regulated disease susceptibility. Coculture of P2X7R-/- macrophages with WT lymphocytes and vice versa showed that enhanced proliferative activity resided within the P2X7R-/- lymphocyte population and correlated with reduced levels of IFN-gamma and NO and apoptosis of lymphocytes. mRNA and protein for IFN-gamma were also significantly reduced in the CNS of P2X7R-/- mice with EAE. FACS analysis of cells isolated from the CNS showed significantly fewer annexin V/propidium iodide-positive lymphocytes in the CNS of P2X7R-/- mice early in the disease, and TUNEL staining of inflamed CNS tissues supported this result. From these data we conclude that enhanced susceptibility of P2X7R-/- mice to EAE reflects a loss of apoptotic activity in lymphocytes, supporting an important role for this receptor in lymphocyte homeostasis.

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

    Directory of Open Access Journals (Sweden)

    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

  4. 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.

  5. Cytokines in relapsing experimental autoimmune encephalomyelitis in DA rats: persistent mRNA expression of proinflammatory cytokines and absent expression of interleukin-10 and transforming growth factor-beta

    DEFF Research Database (Denmark)

    Issazadeh-Navikas, Shohreh; Lorentzen, J C; Mustafa, M I

    1996-01-01

    Experimental autoimmune encephalomyelitis (EAE) in rats is typically a brief and monophasic disease with sparse demyelination. However, inbred DA rats develop a demyelinating, prolonged and relapsing encephalomyelitis after immunization with rat spinal cord in incomplete Freund's adjuvant...

  6. A fusion protein consisting of IL-16 and the encephalitogenic peptide of myelin basic protein constitutes an antigen-specific tolerogenic vaccine that inhibits experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Mannie, Mark D; Abbott, Derek J

    2007-08-01

    To test a novel concept for the generation of tolerogenic vaccines, fusion proteins were constructed encompassing a tolerogenic or biasing cytokine and the major encephalitogenic peptide of guinea pig myelin basic protein (GPMBP; i.e., neuroantigen or NAg). The cytokine domain was predicted to condition APC while simultaneously targeting the covalently linked encephalitogenic peptide to the MHC class II Ag processing pathway of those conditioned APC. Rats were given three s.c. injections of cytokine-NAg in saline 1-2 wk apart and then at least 1 wk later were challenged with NAg in CFA. The rank order of tolerogenic activity in the Lewis rat model of EAE was NAgIL16 > IL2NAg > IL1RA-NAg, IL13NAg >or= IL10NAg, GPMBP, GP69-88, and saline. NAgIL16 was also an effective inhibitor of experimental autoimmune encephalomyelitis when administered after an encephalitogenic challenge during the onset of clinical signs. Covalent linkage of the NAg and IL-16 was required for inhibition of experimental autoimmune encephalomyelitis. These data identify IL-16 as an optimal cytokine partner for the generation of tolerogenic vaccines and indicate that such vaccines may serve as Ag-specific tolerogens for the treatment of autoimmune disease.

  7. Linomide suppresses acute experimental autoimmune encephalomyelitis in Lewis rats by counter-acting the imbalance of pro-inflammatory versus anti-inflammatory cytokines.

    Science.gov (United States)

    Diab, A; Michael, L; Wahren, B; Deng, G M; Björk, J; Hedlund, G; Zhu, J

    1998-05-15

    Linomide (quinoline-3-carboxamide) is a synthetic immunomodulator that suppresses several experimental autoimmune diseases. Here we report the effects of Linomide on experimental autoimmune encephalomyelitis (EAE), a CD4+ T cell-mediated animal model of multiple sclerosis (MS). EAE induced in Lewis rats by inoculation with homogenized guinea pig spinal cord and Freund's complete adjuvant was strongly suppressed by Linomide administered daily subcutaneously from the day of inoculation. Linomide dose-dependently delayed the interval between immunization and onset of clinical EAE, and reduced severity of EAE symptoms. These clinical effects were associated with dose-dependent down-modulation of myelin antigens-induced T cell responses and by suppression of the proinflammatory cytokines IFN-gamma and TNF-alpha, and upregulation IL-4, IL-10 and TGF-beta as evaluated by in situ hybridization for mRNA expression in spleen mononuclear cells and spinal cord sections. These findings suggest that Linomide could be useful in certain T cell dependent autoimmune diseases.

  8. Brucellosis presenting as piriformis myositis: a case report

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    Romanos Odysseas

    2011-03-01

    Full Text Available Abstract Introduction Myositis is a rare bacterial muscle infection. Involvement of the piriformis muscle has been rarely reported in the literature. In this report we describe a case of piriformis myositis due to Brucella melitensis, which to the best of our knowledge is the first such case presented in the literature. Case presentation We report the case of a 19-year-old Caucasian man who presented to our institution with fever and right hip pain. Brucellosis was suspected, but the clinical suspicion was for spondylodiscitis. A pelvic magnetic resonance imaging scan allowed prompt diagnosis of inflammatory involvement of the right piriformis muscle. Blood culture results were positive for B. melitensis. Our patient was treated with antibiotics, and follow-up magnetic resonance imaging scans showed resolution of the inflammation. Conclusion Brucellosis can present as piriformis myositis. The clinical diagnosis of piriformis myositis is difficult, as it can mimic other common entities such as referred back pain from spondylodiscitis. Magnetic resonance imaging is the method of choice for establishing the diagnosis in the early stages of the disease, as late diagnosis can lead to abscess formation and the need for drainage.

  9. Management of a femoral fracture complicated by clostridial myositis

    International Nuclear Information System (INIS)

    Thomson, M.J.; Eger, C.E.

    1997-01-01

    A clinical case of clostridial myositis secondary to a comminuted femoral fracture is described. This case is unusual because, despite the severe degree of obvious muscle necrosis and gas production, the dog had minimal signs of systemic toxicity. Union of the fracture was achieved but six months postoperatively muscular contracture had resulted in permanent stifle extension

  10. Case Report - Myositis Ossificans: Two Case Presentations | Lungu ...

    African Journals Online (AJOL)

    While literature shows that MO is common in the flexor muscles of the arm, the hamstrings and quadriceps femoris, it is noted that other muscles of the thigh and around the hip joint can also be affected as demonstrated in the two cases presented here. Keywords: Myositis ossificans [MO], benign lesion, hip area and hip ...

  11. Richtlijn 'dermatomyositis, polymyositis en sporadische "inclusion body"-myositis'

    NARCIS (Netherlands)

    Hoogendijk, J. E.; Bijlsma, J. W. J.; van Engelen, B. G. M.; Lindeman, E.; van Royen-Kerkhof, A.; de Rie, M. A.; de Visser, M.; Jennekens, F. G. I.

    2005-01-01

    This guideline presents recommendations for the diagnosis and treatment of dermatomyositis, polymyositis and sporadic inclusion body myositis (sIBM) according to the best available evidence. Characteristic skin abnormalities can be sufficient for the diagnosis of dermatomyositis. In case of doubt, a

  12. [The practice guideline 'Dermatomyositis, polymyositis and sporadic inclusion body myositis'

    NARCIS (Netherlands)

    Hoogendijk, J.E.; Bijlsma, J.W.J.; Engelen, B.G.M. van; Lindeman, E.J.M.; Royen-Kerkhof, A. van; Rie, M.A. de; Visser, M. de; Jennekens, F.G.I.

    2005-01-01

    This guideline presents recommendations for the diagnosis and treatment of dermatomyositis, polymyositis and sporadic inclusion body myositis (sIBM) according to the best available evidence. Characteristic skin abnormalities can be sufficient for the diagnosis of dermatomyositis. In case of doubt, a

  13. Myositis ossificans of the quadriceps femoris in a soccer player

    Science.gov (United States)

    Marques, Jose Pedro; Pinheiro, João Páscoa; Santos Costa, Joana; Moura, Diogo

    2015-01-01

    A young soccer player was diagnosed with myositis ossificans 6 weeks after a muscle strain in the right thigh. Radiographic and sonographic investigations initially helped to confirm diagnosis and later supported clinical improvement. We present our approach to the case and discuss pathophysiology, prevention and treatment of this rare condition. PMID:26264943

  14. 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

  15. Moringin activates Wnt canonical pathway by inhibiting GSK3β in a mouse model of experimental autoimmune encephalomyelitis

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    Giacoppo S

    2016-10-01

    Full Text Available Sabrina Giacoppo,1 Thangavelu Soundara Rajan,1 Gina Rosalinda De Nicola,2 Renato Iori,2 Placido Bramanti,1 Emanuela Mazzon1 1IRCCS Centre Neurolesi “Bonino-Pulejo”, Messina, Italy; 2Council for Agricultural Research and Economics, Research Centre for Industrial Crops (CREA-CIN, Bologna, Italy Abstract: Aberrant canonical Wnt–β-catenin signaling has been reported in multiple sclerosis (MS, although the results are controversial. The present study aimed to examine the role of the Wnt–β-catenin pathway in experimental MS and also to test moringin (4-[α-L-rhamnopyranosyloxy]-benzyl isothiocyanate, resulting from exogenous myrosinase hydrolysis of the natural phytochemical glucomoringin 4(α-L-rhamnosyloxy-benzyl glucosinolate as a modulator of neuroinflammation via the β-catenin–PPARγ axis. Experimental autoimmune encephalomyelitis (EAE, the most common model of MS, was induced in C57BL/6 mice by immunization with MOG35–55. Released moringin (10 mg/kg glucomoringin +5 µL myrosinase/mouse was administered daily for 1 week before EAE induction and continued until mice were killed on day 28 after EAE induction. Our results clearly showed that the Wnt–β-catenin pathway was downregulated in the EAE model, whereas moringin pretreatment was able to avert this. Moringin pretreatment normalizes the aberrant Wnt–β-catenin pathway, resulting in GSK3β inhibition and β-catenin upregulation, which regulates T-cell activation (CD4 and FoxP3, suppresses the main inflammatory mediators (IL-1β, IL-6, and COX2, through activation of PPARγ. In addition, moringin attenuates apoptosis by reducing the expression of the Fas ligand and cleaved caspase 9, and in parallel increases antioxidant Nrf2 expression in EAE mice. Taken together, our results provide an interesting discovery in identifying moringin as a modulator of the Wnt–β-catenin signaling cascade and as a new potential therapeutic target for MS treatment. Keywords: Wnt

  16. Characteristics of mouse adipose tissue-derived stem cells and therapeutic comparisons between syngeneic and allogeneic adipose tissue-derived stem cell transplantation in experimental autoimmune thyroiditis.

    Science.gov (United States)

    Choi, Eun Wha; Shin, Il Seob; Park, So Young; Yoon, Eun Ji; Kang, Sung Keun; Ra, Jeong Chan; Hong, Sung Hwa

    2014-01-01

    Previously, we found that the intravenous administration of human adipose tissue-derived mesenchymal stem cells was a promising therapeutic option for autoimmune thyroiditis even when the cells were transplanted into a xenogeneic model without an immunosuppressant. Therefore, we explored the comparison between the therapeutic effects of syngeneic and allogeneic adipose tissue-derived stem cells on an experimental autoimmune thyroiditis mouse model. Experimental autoimmune thyroiditis was induced in C57BL/6 mice by immunization with porcine thyroglobulin. Adipose tissue-derived stem cells derived from C57BL/6 mice (syngeneic) or BALB/c mice (allogeneic) or saline as a vehicle control were administered intravenously four times weekly. Blood and tissue samples were collected 1 week after the last transplantation. Adipose tissue-derived stem cells from mice were able to differentiate into multiple lineages in vitro; however, mouse adipose tissue-derived stem cells did not have immunophenotypes identical to those from humans. Syngeneic and allogeneic administrations of adipose tissue-derived stem cells reduced thyroglobulin autoantibodies and the inflammatory immune response, protected against lymphocyte infiltration into the thyroid, and restored the Th1/Th2 balance without any adverse effects. However, different humoral immune responses were observed for infused cells from different stem cell sources. The strongest humoral immune response was induced by xenogeneic transplantation, followed by allogeneic and syngeneic administration, in that order. The stem cells were mostly found in the spleen, not the thyroid. This migration might be because the stem cells primarily function in systemic immune modulation, due to being given prior to disease induction. In this study, we confirmed that there were equal effects of adipose tissue-derived stem cells in treating autoimmune thyroiditis between syngeneic and allogeneic transplantations.

  17. GCN2 kinase plays an important role triggering the remission phase of experimental autoimmune encephalomyelitis (EAE) in mice.

    Science.gov (United States)

    Orsini, Heloisa; Araujo, Leandro P; Maricato, Juliana T; Guereschi, Marcia G; Mariano, Mario; Castilho, Beatriz A; Basso, Alexandre S

    2014-03-01

    Experimental autoimmune encephalomyelitis (EAE) has been widely employed as a model to study multiple sclerosis (MS) and indeed has allowed some important advances in our comprehension of MS pathogenesis. Several pieces of evidence suggest that infiltrating Th1 and Th17 lymphocytes are important players leading to CNS demyelination and lesion during the peak of murine EAE. Subsequently, effector T cell responses rapidly decline and the recovery phase of the disease strongly correlates with the expression of anti-inflammatory cytokines and the enrichment of Foxp3+ regulatory T (Treg) cells within the target organ. However, the mechanisms leading to the increased presence of Treg cells and to the remission phase of the disease are still poorly understood. Recent researches demonstrated that chemically induced amino-acid starvation response might suppress CNS immune activity. Here we verified an important participation of the general control nonrepressible 2 (GCN2), a key regulator kinase of the amino-acid starvation response, in the development of the remission phase of EAE in C57BL/6 mice. By immunizing wild type C57BL/6 (WT) and GCN2 knock-out mice (GCN2 KO) with myelin oligodendrocyte glycoprotein peptide (MOG35-55), it was noticed that GCN2 KO mice did not develop the remission phase of the disease and this was associated with higher levels of CNS inflammation and increased presence of effector T cells (Th1/Th17). These animals also showed lower frequency of Treg cells within the CNS as compared to WT animals. Higher expression of indoleamine 2,3-dioxygenase (IDO) and higher frequency of plasmacytoid dendritic cells (pDCs) were found at the peak of the disease in the CNS of WT animals. Our results suggest that the GCN2 kinase-dependent sensing of IDO activity represents an important trigger to the EAE remission phase. The IDO-mediated immunoregulatory events may include the arresting of effector T cell responses and the differentiation/expansion of Treg cells

  18. Clinical and serological characteristics of 125 Dutch myositis patients. Myositis specific autoantibodies aid in the differential diagnosis of the idiopathic inflammatory myopathies.

    NARCIS (Netherlands)

    Hengstman, G.J.D.; Brouwer, R.; Vree Egberts, W.T.M.; Seelig, H.P.; Jongen, P.J.H.; Venrooij, W.J.W. van; Engelen, B.G.M. van

    2002-01-01

    The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of systemic diseases that include the familiar disease entities of dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM). A subset of patients has unique autoantibodies which are specific for IIM (myositis

  19. Codelivery of antigen and an immune cell adhesion inhibitor is necessary for efficacy of soluble antigen arrays in experimental autoimmune encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Joshua O Sestak

    2014-01-01

    Full Text Available Autoimmune diseases such as multiple sclerosis (MS are typified by the misrecognition of self-antigen and the clonal expansion of autoreactive T cells. Antigen-specific immunotherapies (antigen-SITs have long been explored as a means to desensitize patients to offending self-antigen(s with the potential to retolerize the immune response. Soluble antigen arrays (SAgAs are composed of hyaluronic acid (HA cografted with disease-specific autoantigen (proteolipid protein peptide and an ICAM-1 inhibitor peptide (LABL. SAgAs were designed as an antigen-SIT that codeliver peptides to suppress experimental autoimmune encephalomyelitis (EAE, a murine model of MS. Codelivery of antigen and cell adhesion inhibitor (LABL conjugated to HA was essential for SAgA treatment of EAE. Individual SAgA components or mixtures thereof reduced proinflammatory cytokines in cultured splenocytes from EAE mice; however, these treatments showed minimal to no in vivo therapeutic effect in EAE mice. Thus, carriers that codeliver antigen and a secondary “context” signal (e.g., LABL in vivo may be an important design criteria to consider when designing antigen-SIT for autoimmune therapy.

  20. BJ-1108, a 6-Amino-2,4,5-trimethylpyridin-3-ol analogue, regulates differentiation of Th1 and Th17 cells to ameliorate experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Kang, Youra; Timilshina, Maheshwor; Nam, Tae-Gyu; Jeong, Byeong-Seon; Chang, Jae-Hoon

    2017-02-28

    CD4 + T cells play an important role in the initiation of an immune response by providing help to other cells. Among the helper T subsets, interferon-γ (IFN-γ)-secreting T helper 1 (Th1) and IL-17-secreting T helper 17 (Th17) cells are indispensable for clearance of intracellular as well as extracellular pathogens. However, Th1 and Th17 cells are also associated with pathogenesis and contribute to the progression of multiple inflammatory conditions and autoimmune diseases. In the current study, we found that BJ-1108, a 6-aminopyridin-3-ol analogue, significantly inhibited Th1 and Th17 differentiation in vitro in a concentration-dependent manner, with no effect on proliferation or apoptosis of activated T cells. Moreover, BJ-1108 inhibited differentiation of Th1 and Th17 cells in ovalbumin (OVA)-specific OT II mice. A complete Freund's adjuvant (CFA)/OVA-induced inflammatory model revealed that BJ-1108 can reduce generation of proinflammatory Th1 and Th17 cells. Furthermore, in vivo studies showed that BJ-1108 delayed onset of disease and suppressed experimental autoimmune encephalomyelitis (EAE) disease progression by inhibiting differentiation of Th1 and Th17 cells. BJ-1108 treatment ameliorates inflammation and EAE by inhibiting Th1 and Th17 cells differentiation. Our findings suggest that BJ-1108 is a promising novel therapeutic agent for the treatment of inflammation and autoimmune disease.

  1. Eosinophils in Autoimmune Diseases.

    Science.gov (United States)

    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.

  2. Eosinophils in Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    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.

  3. Vaccines, adjuvants and autoimmunity.

    Science.gov (United States)

    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.

  4. 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......-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...

  5. The effects of fasudil on the permeability of the rat blood-brain barrier and blood-spinal cord barrier following experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Huang, X N; Fu, J; Wang, W Z

    2011-10-28

    Dysfunction of the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) is a primary characteristic of multiple sclerosis (MS). We evaluated the protective effects of fasudil, a selective ROCK inhibitor, in a model of experimental autoimmune encephalomyelitis (EAE) that was induced by guinea-pig spinal cord. In addition, we studied the effects of fasudil on BBB and BSCB permeability. We found that fasudil partly alleviated EAE-dependent damage by decreasing BBB and BSCB permeability. These results provide rationale for the development of selective inhibitors of Rho kinase as a novel therapy for MS. Copyright © 2011 Elsevier B.V. All rights reserved.

  6. Insulin-like growth factor I treatment reduces demyelination and up-regulates gene expression of myelin-related proteins in experimental autoimmune encephalomyelitis.

    OpenAIRE

    Yao, D L; Liu, X; Hudson, L D; Webster, H D

    1995-01-01

    To compare effects of insulin-like growth factor I (IGF-I) and placebo treatment on lesions that resemble those seen during active demyelination in multiple sclerosis, we induced experimental autoimmune encephalomyelitis in Lewis rats with an emulsion containing guinea pig spinal cord and Freund's adjuvant. On day 12-13, pairs of rats with the same degree of weakness were given either IGF-I or placebo intravenously twice daily for 8 days. After 8 days of placebo or IGF-I (200 micrograms/day o...

  7. Autoimmune gastritis.

    Science.gov (United States)

    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.

  8. Non-traumatic myositis ossificans circumscripta: A diagnosis trap.

    Science.gov (United States)

    El Bardouni, Ahmed; Boufettal, Monsef; Zouaidia, Fouad; Kharmaz, Mohamed; Berrada, Mohamed S; Mahassini, Najat; El Yaacoubi, Moradh

    2014-12-01

    Myositis ossificans circumscripta (MOC) is a benign condition of non-neoplastic heterotopic bone formation in the muscle or soft tissue. Trauma plays a role in the development of MOC, thus, non-traumatic MOC is very rare. Although MOC may occur anywhere in the body, the lesions are localized predominantly in the high-risk sites of injury, such as the thigh, buttock, and elbow. MOC can easily be mistaken for osteomyelitis or a malignant tumor, specifically osteosarcoma or soft-tissue sarcoma. We report a rare case of non-traumatic myositis ossificans circumscripta of thigh which appear clinically and radiologically as a malignant neoplasm. Despite its rarity, MOC should be contemplated in the differential diagnosis of malignant tumors.

  9. Myositis, Vasculitis, Hepatic Dysfunction in Adult-Onset Still's Disease

    Directory of Open Access Journals (Sweden)

    Hidekatsu Yanai

    2009-01-01

    Full Text Available Although hepatic dysfunction is common in adult-onset Still's disease (AOSD, sometimes it is difficult to differentiate hepatic dysfunction due to AOSD itself from drug-induced hepatic dysfunction. Further, myalgia often occurs in patients with AOSD; however, AOSD patients complicated with myositis are rare. We report a 43-year-old Japanese man with AOSD who developed myositis and hepatic dysfunction which were deteriorated by multiple nonsteroidal antiinflammatory drugs (NSAIDs and were dramatically ameliorated by a low-dose steroid therapy. A skin biopsy of salmon pink rash which is characteristic for AOSD showed leukocytoclastic vasculitis, and the markers for vasculitis, plasma von Willebrand factor, and vascular endothelial growth factor levels were elevated in this patient, suggesting an association between AOSD and systemic vasculitis.

  10. Myocarditis in auto-immune or auto-inflammatory diseases.

    Science.gov (United States)

    Comarmond, Cloé; Cacoub, Patrice

    2017-08-01

    Myocarditis is a major cause of heart disease in young patients and a common precursor of heart failure due to dilated cardiomyopathy. Some auto-immune and/or auto-inflammatory diseases may be accompanied by myocarditis, such as sarcoidosis, Behçet's disease, eosinophilic granulomatosis with polyangiitis, myositis, and systemic lupus erythematosus. However, data concerning myocarditis in such auto-immune and/or auto-inflammatory diseases are sparse. New therapeutic strategies should better target the modulation of the immune system, depending on the phase of the disease and the type of underlying auto-immune and/or auto-inflammatory disease. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Inclusion body myositis: diagnosis, pathogenesis, and treatment options.

    Science.gov (United States)

    Solorzano, Guillermo E; Phillips, Lawrence H

    2011-05-01

    Inclusion body myositis (IBM) is the most common acquired myopathy in people older than 50 years. IBM typically presents with distal upper extremity weakness accompanied by proximal lower extremity muscle weakness. Associated clinical findings include asymmetric weakness, foot drop, and dysphagia. The pathogenesis of IBM is not clear. In this article the authors briefly discuss postulated pathogenic mechanisms. Although no proven pharmacotherapy exists, some promising candidates are discussed. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. 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

  13. In vivo evidence for CD4+ and CD8+ suppressor T cells in vaccination-induced suppression of murine experimental autoimmune thyroiditis

    International Nuclear Information System (INIS)

    Flynn, J.C.; Kong, Y.C.

    1991-01-01

    In several experimental autoimmune diseases, including experimental autoimmune thyroiditis (EAT), vaccination with attenuated autoantigen-specific T cells has provided protection against subsequent induction of disease. However, the mechanism(s) of vaccination-induced suppression remains to be clarified. Since the authors have previously shown that suppression generated by pretreatment with mouse thyroglobulin (MTg) or thyroid-stimulating hormone in EAT is mediated by CD4+, not CD8+, suppressor T cells, they examined the role of T cell subsets in vaccination-induced suppression of EAT. Mice were vaccinated with irradiated, MTg-primed, and MTg-activated spleen cells and then challenged. Pretreatment with these cells suppressed EAT induced by immunization with MTg and adjuvant, but not by adoptive transfer of thyroiditogenic cells, suggesting a mechanism of afferent suppression. The activation of suppressor mechanisms did not require CD8+ cells, since mice depleted of CD8+ cells before vaccination showed reduced EAT comparable to control vaccinated mice. Furthermore, depletion of either the CD4+ or the CD8+ subset after vaccination did not significantly abrogate suppression. However, suppression was eliminated by the depletion of both CD4+ and CD8+ cells in vaccinated mice. These results provide evidence for the cooperative effects of CD4+ and CD8+ T cells in vaccination-induced suppression of EAT

  14. Development of an anti-IL-12 p40 auto-vaccine: protection in experimental autoimmune encephalomyelitis at the expense of increased sensitivity to infection.

    Science.gov (United States)

    Uyttenhove, Catherine; Arendse, Berenice; Stroobant, Vincent; Brombacher, Frank; Van Snick, Jacques

    2004-12-01

    IL-12 and IL-23, which share the IL-12 p40 subunit, have been ascribed central roles in many autoimmune disorders. We describe here an anti-IL-12 (alphaIL-12) auto-vaccine that potentially blocks both factors in vivo. Immunization of mice with mouse IL-12 coupled to OVA or Pan DR epitope (PADRE) peptide induced Ab directed against the IL-12 p40 subunit, which prevented IFN-gamma production in response to IL-12 administration in vivo. Experimental autoimmune encephalomyelitis, an IL-23-dependent disease model, induced in SJL mice with a proteolipid protein (PLP) peptide was almost undetectable after alphaIL-12 vaccination. Myelin oligodendrocyte glycoprotein (MOG)-induced disease in C57BL/6 mice was also significantly inhibited. This protection correlated with inhibited Th1 cytokine responses in vitro and with an increase in the IgG1/IgG2a anti-PLP Ab balance. Detrimental consequences of alphaIL-12 vaccination were evaluated in C57BL/6 mice infected with Leishmania major (L.m.). While delayed-type hypersensitivity (DTH) suppression and immunoglobulin as well as interleukin production patterns reflected a major shift toward a Th2-type response, L.m. growth was still significantly retarded as compared to that seen in susceptible BALB/c mice. However, vaccinated animals ultimately failed to control parasite expansion. These results suggest that some chronic autoimmune diseases may benefit from alphaIL-12 vaccination at the expense of reduced, but not completely abrogated, cell-mediated immunity.

  15. A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using a Targeted Fusion Protein, mCTA1–T146

    Science.gov (United States)

    Consonni, Alessandra; Sharma, Sapna; Schön, Karin; Lebrero-Fernández, Cristina; Rinaldi, Elena; Lycke, Nils Yngve; Baggi, Fulvio

    2017-01-01

    Reinstating tissue-specific tolerance has attracted much attention as a means to treat autoimmune diseases. However, despite promising results in rodent models of autoimmune diseases, no established tolerogenic therapy is clinically available yet. In the experimental autoimmune myasthenia gravis (EAMG) model several protocols have been reported that induce tolerance against the prime disease-associated antigen, the acetylcholine receptor (AChR) at the neuromuscular junction. Using the whole AChR, the extracellular part or peptides derived from the receptor, investigators have reported variable success with their treatments, though, usually relatively large amounts of antigen has been required. Hence, there is a need for better formulations and strategies to improve on the efficacy of the tolerance-inducing therapies. Here, we report on a novel targeted fusion protein carrying the immunodominant peptide from AChR, mCTA1–T146, which given intranasally in repeated microgram doses strongly suppressed induction as well as ongoing EAMG disease in mice. The results corroborate our previous findings, using the same fusion protein approach, in the collagen-induced arthritis model showing dramatic suppressive effects on Th1 and Th17 autoaggressive CD4 T cells and upregulated regulatory T cell activities with enhanced IL10 production. A suppressive gene signature with upregulated expression of mRNA for TGFβ, IL10, IL27, and Foxp3 was clearly detectable in lymph node and spleen following intranasal treatment with mCTA1–T146. Amelioration of EAMG disease was accompanied by reduced loss of muscle AChR and lower levels of anti-AChR serum antibodies. We believe this targeted highly effective fusion protein mCTA1–T146 is a promising candidate for clinical evaluation in myasthenia gravis patients. PMID:28959261

  16. 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.

  17. Dendritic cells and anergic type I NKT cells play a crucial role in sulfatide-mediated immune regulation in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Maricic, Igor; Halder, Ramesh; Bischof, Felix; Kumar, Vipin

    2014-08-01

    CD1d-restricted NKT cells can be divided into two groups: type I NKT cells use a semi-invariant TCR, whereas type II express a relatively diverse set of TCRs. A major subset of type II NKT cells recognizes myelin-derived sulfatides and is selectively enriched in the CNS tissue during experimental autoimmune encephalomyelitis (EAE). We have shown that activation of sulfatide-reactive type II NKT cells by sulfatide prevents induction of EAE. In this article, we have addressed the mechanism of regulation, as well as whether a single immunodominant form of synthetic sulfatide can treat ongoing chronic and relapsing EAE in SJL/J mice. We have shown that the activation of sulfatide-reactive type II NKT cells leads to a significant reduction in the frequency and effector function of myelin proteolipid proteins 139-151/I-A(s)-tetramer(+) cells in lymphoid and CNS tissues. In addition, type I NKT cells and dendritic cells (DCs) in the periphery, as well as CNS-resident microglia, are inactivated after sulfatide administration, and mice deficient in type I NKT cells are not protected from disease. Moreover, tolerized DCs from sulfatide-treated animals can adoptively transfer protection into naive mice. Treatment of SJL/J mice with a synthetic cis-tetracosenoyl sulfatide, but not α-galactosylceramide, reverses ongoing chronic and relapsing EAE. Our data highlight a novel immune-regulatory pathway involving NKT subset interactions leading to inactivation of type I NKT cells, DCs, and microglial cells in suppression of autoimmunity. Because CD1 molecules are nonpolymorphic, the sulfatide-mediated immune-regulatory pathway can be targeted for development of non-HLA-dependent therapeutic approaches to T cell-mediated autoimmune diseases. Copyright © 2014 by The American Association of Immunologists, Inc.

  18. Modification of the FoxP3 transcription factor principally affects inducible T regulatory cells in a model of experimental autoimmune encephalomyelitis.

    Directory of Open Access Journals (Sweden)

    Johan Verhagen

    Full Text Available T regulatory (Treg cells expressing the transcription factor FoxP3 play a key role in protection against autoimmune disease. GFP-FoxP3 reporter mice have been used widely to study the induction, function and stability of both thymically- and peripherally-induced Treg cells. The N-terminal modification of FoxP3, however, affects its interaction with transcriptional co-factors; this can alter Treg cell development and function in certain self-antigen specific animal models. Interestingly, Treg cell function can be negatively or positively affected, depending on the nature of the model. In this study, we focused on the effect of the GFP-FoxP3 reporter on Treg cell development and function in the Tg4 mouse model. In this model, T cells express a transgenic T cell receptor (TCR specific for the Myelin Basic Protein (MBP peptide Ac1-9, making the animals susceptible to experimental autoimmune encephalomyelitis (EAE, a disease akin to multiple sclerosis in humans. Unlike diabetes-susceptible mice, Tg4 FoxP3(gfp mice did not develop spontaneous autoimmune disease and did not demonstrate augmented susceptibility to induced disease. Concurrently, thymic generation of natural Treg cells was not negatively affected. The induction of FoxP3 expression in naive peripheral T cells was, however, significantly impaired as a result of the transgene. This study shows that the requirements for the interaction of FoxP3 with co-factors, which governs its regulatory ability, differ not only between natural and inducible Treg cells but also between animal models of diseases such as diabetes and EAE.

  19. Patients' Experience of Myositis and Further Validation of a Myositis-specific Patient Reported Outcome Measure - Establishing Core Domains and Expanding Patient Input on Clinical Assessment in Myositis. Report from OMERACT 12.

    Science.gov (United States)

    Regardt, Malin; Basharat, Pari; Christopher-Stine, Lisa; Sarver, Catherine; Björn, Anita; Lundberg, Ingrid E; Wook Song, Yeong; Bingham, Clifton O; Alexanderson, Helene

    2015-12-01

    The Outcome Measures in Rheumatology (OMERACT) myositis working group was established to examine patient-reported outcomes (PRO) as well as to validate patient-reported outcome measures (PROM) in myositis. Qualitative studies using focus group interviews and cognitive debriefing of the myositis-specific Myositis Activities Profile (MAP) were used to explore the experience of adults living with polymyositis (PM) and dermatomyositis (DM). Preliminary results underscore the importance of patient input in the development of PROM to ensure content validity. Results from multicenter focus groups indicate the range of symptoms experienced including pain, fatigue, and impaired cognitive function, which are not currently assessed in myositis. Preliminary cognitive debriefing of the MAP indicated that while content was deemed relevant and important, several activities were not included; and that questionnaire construction and wording may benefit from revision. A research agenda was developed to continue work toward optimizing PRO assessment in myositis with 2 work streams. The first would continue to conduct and analyze focus groups until saturation in the thematic analysis was achieved to develop a framework that encompassed the patient-relevant aspects of myositis. The second would continue cognitive debriefing of the MAP to identify potential areas for revision. There was agreement that further work would be needed for inclusion body myositis and juvenile dermatomyositis, and that the inclusion of additional contributors such as caregivers and individuals from the pharmaceutical/regulatory spheres would be desirable. The currently used PROM do not assess symptoms or the effects of disease that are most important to patients; this emphasizes the necessity of patient involvement. Our work provides concrete examples for PRO identification.

  20. Nutrition, geoepidemiology, and autoimmunity.

    Science.gov (United States)

    Selmi, Carlo; Tsuneyama, Koichi

    2010-03-01

    As well represented by the impaired immune function of malnourished individuals encountered in developing countries and the incidence of specific diseases following local nutrient deficiencies, nutrition and immunity have been linked to each other for centuries while the specific connection between dietary factors and autoimmunity onset or modulation is a more recent acquisition. Autoimmune diseases manifest limited prevalence rates in developing countries while numerous immunity-related claims have been proposed in the field of functional foods. Nevertheless, over the past years multiple lines of evidence have supported a major role for specific dietary factors (including vitamin D, vitamin A, selenium, zinc, omega-3 fatty acids, probiotics, and flavanols) in determining the immune responses involved in infections, allergies, and autoimmune diseases. Interestingly, the link between nutrition and autoimmunity may well contribute to the geoepidemiology observed for numerous conditions. In general terms, most data that will be discussed herein were obtained in experimental or animal models while human data from real-life clinical settings or randomized clinical trials remain largely unsatisfactory. Our current knowledge on the beneficial impact of nutrition on autoimmunity prompts us to encourage the search for evidence-based nutrition to support the everyday diet choices of patients. 2009 Elsevier B.V. All rights reserved.

  1. Scintigraphic evaluation of Lyme disease: Gallium-67 imaging of Lyme myositis

    Energy Technology Data Exchange (ETDEWEB)

    Kengen, R.A.; v.d. Linde, M.; Sprenger, H.G.; Piers, D.A. (Univ. Hospital, Groningen (Netherlands))

    1989-10-01

    A patient suffering from Lyme disease had cardiac conduction abnormalities, symptoms of arthritis, and myalgia. A Ga-67 image showed evidence of endomyocarditis, but intense skeletal muscle uptake pointed to Lyme myositis. Reference is made to two other case reports of Lyme myositis.

  2. Myositis ossificans circumscripta, secondary to high-velocity gunshot and fragment wound that causes sciatica.

    Science.gov (United States)

    Gokkus, Kemal; Sagtas, Ergin; Suslu, Feride Ekimler; Aydin, Ahmet Turan

    2013-10-17

    This report concerns an unusual cause of sciatica. The case presented is of a young man with myositis ossificans that resulted in sciatica and was treated with en bloc excision and low-dose radiotherapy and indomethacine. The aim of this study was to explain the different diagnostic properties of myositis ossificans around the hip and non-classic causes of sciatica.

  3. Understanding Autoimmune Diseases

    Science.gov (United States)

    ... What are they? Points To Remember About Autoimmune Diseases Autoimmune diseases refer to problems with the immune system, ... Infectious Diseases Website: https://www.niaid.nih.gov/diseases-conditions/autoimmune-diseases American Autoimmune Related Diseases Association Website: https:// ...

  4. 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 in cryosect......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...

  5. Two Cases of Orbital Myositis as a Rare Feature of Lyme Borreliosis

    Directory of Open Access Journals (Sweden)

    Arnaud Sauer

    2011-01-01

    Full Text Available Myositis has been reported as a rare manifestation of Lyme disease, and the Lyme disease spirochetes can be an important consideration in the differential diagnosis of unusual cases of myositis, especially in patients who live in or travel to endemic areas. We report the case of two patients who presented with focal orbital myositis which are rare localization for Lyme disease. Myositis were confirmed by magnetic resonance imaging. Diagnosis criteria for Borrelia burgdorferi (B. burgdorferi infection was supported by (i medical history (tick bite in an endemic area, (ii systemic clinical findings (Erythema migrans, neurological manifestation or arthritis, (iii positive Lyme serology and/or the detection of B. burgdorferi DNA by polymerase chain reaction, as well as (iv exclusion of other infectious and inflammatory causes. The current cases are reviewed in the context of findings from previous myositis descriptions.

  6. 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......Autoimmune hypophysitis (AH) - often referred to as lymphocytic hypophysitis - is a rare disease that affects the pituitary gland and causes inflammation. The disease enlarges the pituitary gland and the clinical presentations are lack of pituitary function and headaches. AH is mostly seen in women...

  7. 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......Autoimmune hypophysitis (AH) - often referred to as lymphocytic hypophysitis - is a rare disease that affects the pituitary gland and causes inflammation. The disease enlarges the pituitary gland and the clinical presentations are lack of pituitary function and headaches. AH is mostly seen in women...... immunosuppressive treatment or surgery....

  8. A T Helper Cell 2 (Th2) Immune Response against Non-self Antigens Modifies the Cytokine Profile of Autoimmune T Cells and Protects against Experimental Allergic Encephalomyelitis

    Science.gov (United States)

    Falcone, Marika; Bloom, Barry R.

    1997-01-01

    Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system (CNS), and the most commonly used experimental model for multiple sclerosis. It is mediated by autoreactive T cell clones exhibiting a T helper cell (Th) 1 cytokine profile. Nonencephalitogenic T lymphocytes specific for self or exogenous antigens have been found to suppress encephalitogenic T cell responses and to protect against autoimmune disease. The mechanisms by which exogenous antigens modulate autoimmunity are not fully understood. In this study, we tested the hypothesis that a Th2-type immune response against an exogenous, nonself antigen, keyhole limpet hemocyanin (KLH), by releasing IL-4 in the microenvironment, could shift the cytokine profile of encephalitogenic T cells from an inflammatory Th1 to a protective Th2 type. SJL/J mice were preimmunized with the KLH in incomplete Freund's adjuvant to induce a population of Th2 memory cells that would be expected to release Th2 cytokines when activated by the specific antigen at the time of EAE induction. Four weeks later, mice received an encephalitogenic challenge containing guinea pig myelin in complete Freund's adjuvant with or without KLH. All KLH primed animals not receiving the exogenous antigen at the time of EAE induction developed a severe clinical disease indistinguishable from control mice not KLH primed. In contrast, animals preimmunized and challenged with the encephalitogenic inoculum containing KLH showed either no, or markedly reduced, clinical signs. Enzyme-linked immunospot analysis demonstrated that KLH-specific T cells in the primed mice were producing IL-4 characteristic of Th2 cells. In the KLH-primed and restimulated mice, the cytokine profile of the autoreactive, myelin basic protein–specific T cells was shifted from an inflammatory Th1 towards a protective Th2 type. We infer that the presence of IL-4 secreted by KLH-specific memory Th2 cells in the lymphoid system microenvironment

  9. A T helper cell 2 (Th2) immune response against non-self antigens modifies the cytokine profile of autoimmune T cells and protects against experimental allergic encephalomyelitis.

    Science.gov (United States)

    Falcone, M; Bloom, B R

    1997-03-03

    Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system (CNS), and the most commonly used experimental model for multiple sclerosis. It is mediated by autoreactive T cell clones exhibiting a T helper cell (Th) 1 cytokine profile. Nonencephalitogenic T lymphocytes specific for self or exogenous antigens have been found to suppress encephalitogenic T cell responses and to protect against autoimmune disease. The mechanisms by which exogenous antigens modulate autoimmunity are not fully understood. In this study, we tested the hypothesis that a Th2-type immune response against an exogenous, nonself antigen, keyhole limpet hemocyanin (KLH), by releasing IL-4 in the microenvironment, could shift the cytokine profile of encephalitogenic T cells from an inflammatory Th1 to a protective Th2 type. SJL/J mice were preimmunized with the KLH in incomplete Freund's adjuvant to induce a population of Th2 memory cells that would be expected to release Th2 cytokines when activated by the specific antigen at the time of EAE induction. Four weeks later, mice received an encephalitogenic challenge containing guinea pig myelin in complete Freund's adjuvant with or without KLH. All KLH primed animals not receiving the exogenous antigen at the time of EAE induction developed a severe clinical disease indistinguishable from control mice not KLH primed. In contrast, animals preimmunized and challenged with the encephalitogenic inoculum containing KLH showed either no, or markedly reduced, clinical signs. Enzyme-linked immunospot analysis demonstrated that KLH-specific T cells in the primed mice were producing IL-4 characteristic of Th2 cells. In the KLH-primed and restimulated mice, the cytokine profile of the autoreactive, myelin basic protein-specific T cells was shifted from an inflammatory Th1 towards a protective Th2 type. We infer that the presence of IL-4 secreted by KLH-specific memory Th2 cells in the lymphoid system microenvironment in

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

    DEFF Research Database (Denmark)

    Rasmussen, Stine; Wang, Yue; Kivisäkk, Pia

    2007-01-01

    callosal projecting neurons. There was significant impairment of retrograde labeling of NeuN-positive callosal projecting neurons and reduction in the labelling of their transcallosal axons. These data demonstrate a novel paradigm of cortical and callosal neuropathology in a mouse model of MS, perpetuated......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 lesions found in MS. Unlike the T-cell infiltrates that peak during acute disease, we found that microglia activation persists through the chronic disease phase. Microglia activation correlated with abnormal phosphorylation of neurofilaments in the cortex and stripping of synaptic proteins in cortical...

  11. 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...

  12. 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

  13. Non-traumatic myositis ossificans circumscripta: A diagnosis trap

    OpenAIRE

    El Bardouni, Ahmed; Boufettal, Monsef; Zouaidia, Fouad; Kharmaz, Mohamed; Berrada, Mohamed S.; Mahassini, Najat; El Yaacoubi, Moradh

    2014-01-01

    Myositis ossificans circumscripta (MOC) is a benign condition of non-neoplastic heterotopic bone formation in the muscle or soft tissue. Trauma plays a role in the development of MOC, thus, non-traumatic MOC is very rare. Although MOC may occur anywhere in the body, the lesions are localized predominantly in the high-risk sites of injury, such as the thigh, buttock, and elbow. MOC can easily be mistaken for osteomyelitis or a malignant tumor, specifically osteosarcoma or soft-tissue sarcoma. ...

  14. 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.

  15. 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.

  16. 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......RNA for interferon-gamma (IFN-gamma), but not for transforming growth factor-beta (TGF-beta) or interleukin-10 (IL-10). In contrast, the other MHC haplotypes (h, l, u) associated with low CD4/CD8 ratios and mRNA expression for TGF-beta and IL-10, but not for IFN-gamma. DA non-MHC genes determined the intensity...... of inflammation since the number of cells expressing MHC class II, CD4 and interleukin-2 receptor (IL-2R) was higher in DA rats than in LEW.1AV1 and PVG.1AV1 rats which also carry the av1 haplotype. We conclude that the MHC haplotype of DA rats favors a prolonged proinflammatory autoimmune response associated...

  17. 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

  18. 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

    to limit central nervous system (CNS) inflammation. In lymphoid organs, primed MBP 63-88 reactive T cells showed an interesting time-dependent evolution of their cytokine production in vitro. Thus, early after immunization there was a conspicuous MBP 63-88-induced production of both IFN-gamma and IL-4......-beta) both in sections of spinal cords and the antigen-induced expression of these cytokines by lymphoid cells after stimulation with a dominant encephalitogenic peptide of MBP (MBP 63-88) during the course of actively induced experimental autoimmune encephalomyelitis (EAE) in Lewis rats. In spinal cords...... autoimmunity systemically....

  19. [Autoimmune channelopathies].

    Science.gov (United States)

    Michaud, M; Delrieu, J; Astudillo, L

    2011-12-01

    Autoimmune channelopathies are rare neuromuscular diseases that have been characterized clinically for several decades but for which the evidence of associated antibodies has only been recently demonstrated. Ion channels have an important role of activation, inhibition and regulation in neuromuscular transmission. Myasthenia gravis, generally associated with the presence of anti-acetylcholine receptor antibody, is the best-known channelopathy. Other anti-channel antibodies, including voltage-dependent, are associated with several neurological diseases, as illustrated by anti-voltage-gated calcium channels found in Lambert-Eaton myasthenic syndrome and paraneoplastic cerebellar ataxia, and anti-voltage-gated potassium channels found in neuromyotonia, Morvan's syndrome and limbic encephalitis. The treatment of autoimmune channelopathies is logically based on corticosteroids, immunosuppressant drugs, intravenous immunoglobulins and plasmapheresis. Copyright © 2011 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  20. 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

  1. 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.

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

    Directory of Open Access Journals (Sweden)

    Hiromi Shoda

    Full Text Available 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.

  3. Differential expression of neurotrophic factors and inflammatory cytokines by myelin basic protein-specific and other recruited T cells infiltrating the central nervous system during experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Muhallab, S; Lundberg, C; Gielen, A W; Lidman, O; Svenningsson, A; Piehl, F; Olsson, T

    2002-03-01

    Recent evidence suggests that autoimmune reactions in the central nervous system (CNS) not only have detrimental consequences but can also be neuroprotective, and that this effect is mediated by the expression of neuronal growth factors by infiltrating leucocytes. Here we dissect these two phenomena in guinea pig myelin basic protein peptide (gpMBP 63-88)-induced experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. Real-time TaqMan polymerase chain reaction (PCR) was used to measure mRNA for the nerve growth factors, brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-3. As reference, the well-known proinflammatory mediator molecules interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha were quantified. In whole lumbar cord tissue, both the nerve growth factors and the proinflammatory cytokines, IFN-gamma and TNF-alpha, displayed similar expression patterns, peaking at the height of the disease. Among the infiltrating inflammatory cells isolated and sorted from the CNS, alphabeta+/T-cell receptor (TCR)BV8S2+, but not alphabeta+/TCRBV8S2-, recognized the encephalitogenic MBP peptide. Interestingly, these two populations displayed contrasting expression patterns of nerve growth factors and proinflammatory cytokines with higher inflammatory cytokine mRNA levels in alphabeta+/TCRBV8S2+ cells at all time intervals, whereas the levels of BDNF and NT3 were higher in alphabeta+/TCRBV8S2- cells. We conclude that a potentially important neuroprotective facet of CNS inflammation dominantly prevails within other non-MBP peptide-specific lymphoid cells and that there are independent regulatory mechanisms for neurotrophin and inflammatory cytokine expression during EAE.

  4. Multivalent Soluble Antigen Arrays Exhibit High Avidity Binding and Modulation of B Cell Receptor-Mediated Signaling to Drive Efficacy against Experimental Autoimmune Encephalomyelitis.

    Science.gov (United States)

    Hartwell, Brittany L; Pickens, Chad J; Leon, Martin; Berkland, Cory

    2017-06-12

    A pressing need exists for antigen-specific immunotherapies (ASIT) that induce selective tolerance in autoimmune disease while avoiding deleterious global immunosuppression. Multivalent soluble antigen arrays (SAgA PLP:LABL ), consisting of a hyaluronic acid (HA) linear polymer backbone cografted with multiple copies of autoantigen (PLP) and cell adhesion inhibitor (LABL) peptides, are designed to induce tolerance to a specific multiple sclerosis (MS) autoantigen. Previous studies established that hydrolyzable SAgA PLP:LABL , employing a degradable linker to codeliver PLP and LABL, was therapeutic in experimental autoimmune encephalomyelitis (EAE) in vivo and exhibited antigen-specific binding with B cells, targeted the B cell receptor (BCR), and dampened BCR-mediated signaling in vitro. Our results pointed to sustained BCR engagement as the SAgA PLP:LABL therapeutic mechanism, so we developed a new version of the SAgA molecule using nonhydrolyzable conjugation chemistry, hypothesizing it would enhance and maintain the molecule's action at the cell surface to improve efficacy. "Click SAgA" (cSAgA PLP:LABL ) uses hydrolytically stable covalent conjugation chemistry (Copper-catalyzed Azide-Alkyne Cycloaddition (CuAAC)) rather than a hydrolyzable oxime bond to attach PLP and LABL to HA. We explored cSAgA PLP:LABL B cell engagement and modulation of BCR-mediated signaling in vitro through flow cytometry binding and calcium flux signaling assays. Indeed, cSAgA PLP:LABL exhibited higher avidity B cell binding and greater dampening of BCR-mediated signaling than hydrolyzable SAgA PLP:LABL . Furthermore, cSAgA PLP:LABL exhibited significantly enhanced in vivo efficacy compared to hydrolyzable SAgA PLP:LABL , achieving equivalent efficacy at one-quarter of the dose. These results indicate that nonhydrolyzable conjugation increased the avidity of cSAgA PLP:LABL to drive in vivo efficacy through modulated BCR-mediated signaling.

  5. 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...... 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....

  6. 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

  7. 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

  8. 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...

  9. 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

  10. NKT cells can help mediate the protective effects of 1,25-dihydroxyvitamin D3 in experimental autoimmune encephalomyelitis in mice.

    Science.gov (United States)

    Waddell, Amanda; Zhao, Jun; Cantorna, Margherita T

    2015-05-01

    Active vitamin D [1,25-dihydroxyvitamin D3 (1,25D3)] blocks the development of experimental autoimmune diseases. However, the molecular and immunobiological mechanisms underlying 1,25D3's anti-inflammatory properties are not fully understood. We employed a murine model of experimental autoimmune encephalomyelitis (EAE) in order to determine the role of NKT cells in 1,25D3-mediated protection from EAE. Wild-type (WT) mice or mice lacking all NKT cells (CD1d(-/-)) or invariant NKT cells (Jα18(-/-)) were fed control or 1,25D3-supplemented diets. All mice fed with the control diet developed severe EAE. 1,25D3 treatment of WT mice protected them from developing EAE. CD1d(-/-) and Jα18(-/-) mice treated with 1,25D3 were not protected to the same extent as WT mice. Myelin oligodendrocyte glycoprotein-specific IL-17 and IFN-γ production was significantly reduced in 1,25D3 WT mice compared with WT but was not decreased in 1,25D3 CD1d(-/-) mice compared with CD1d(-/-) mice. IL-4(-/-) mice were utilized to determine how IL-4 deficiency affects susceptibility to EAE. IL-4(-/-) mice were not protected from developing EAE by α-galactosylceramide (α-GalCer) or 1,25D3 treatment. Furthermore, 1,25D3 treatment of splenocytes in vitro decreased α-GalCer-induced IL-17 and increased IL-4, IL-5 and IL-10 production. 1,25D3 alters the cytokine profile of invariant NKT cells in vitro. These studies demonstrate that NKT cells are important mediators of 1,25D3-induced protection from EAE in mice and NKT cell-derived IL-4 may be an important factor in providing this protection. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  11. Spontaneous recovery of dermatomyositis and unspecified myositis in three adult patients

    NARCIS (Netherlands)

    Van de Vlekkert, J.; Hoogendijk, J. E.; Frijns, C. J. M.; de Visser, M.

    2008-01-01

    Dermatomyositis (DM), polymyositis and unspecified myositis are idiopathic inflammatory myopathies in which prednisone is usually started as soon as the diagnosis has been established. Therefore, little is known about the natural history of these diseases and spontaneous recovery may escape

  12. INTERSTITIAL LUNG-DISEASE AND MYOSITIS IN A PATIENT WITH SIMULTANEOUSLY OCCURRING SARCOIDOSIS AND SCLERODERMA

    NARCIS (Netherlands)

    GROEN, H; POSTMA, DS; KALLENBERG, CGM

    1993-01-01

    A patient initially presented with sarcoidosis in combination with myositis of sarcoid origin and Raynaud's phenomenon. During the course of his disease, he additionally developed scleroderma. Bronchoalveolar lavage, performed because of increase of interstitial markings in the presence of enlarged

  13. Associated Autoimmune Diseases

    Science.gov (United States)

    ... celiac disease are type 1 diabetes and autoimmune thyroid disease. The tendency to develop autoimmune diseases is believed ... confusion, weight loss, and coma (if left untreated). Thyroid Disease There are two common forms of autoimmune thyroid ...

  14. 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 ...

  15. Inclusion-body myositis presenting with facial diplegia.

    Science.gov (United States)

    Ghosh, Partha S; Laughlin, Ruple S; Engel, Andrew G

    2014-02-01

    The hallmark clinical presentation of inclusion-body myositis (IBM) is slowly progressive weakness that characteristically affects the quadriceps and finger and wrist finger flexor muscles. Facial weakness can also occur, but it is typically mild and not a prominent finding. We describe the clinical features, laboratory investigations, and muscle biopsy findings in a 58-year old man who presented with a 6-year history of marked progressive symmetrical facial weakness. Examination also showed shoulder abduction and hip extensor weakness. The patient's serum creatine kinase level was 655 U/L, and electromyography showed fibrillation potentials and myopathic motor unit potentials. A biopsy specimen of the left biceps muscle was pathognomonic for IBM. This patient did not have a typical presentation for IBM but rather fulfilled the pathological criteria for IBM. To our knowledge, facial diplegia has not been reported previously as a presenting manifestation of IBM. Copyright © 2013 Wiley Periodicals, Inc.

  16. Physical function and muscle strength in sporadic inclusion body myositis

    DEFF Research Database (Denmark)

    Jørgensen, Anders N; Aagaard, Per; Nielsen, Jakob L

    2017-01-01

    INTRODUCTION: In this study, self-reported physical function, functional capacity, and isolated muscle function were investigated in sporadic inclusion body myositis (sIBM) patients. METHODS: The 36-item Short Form (SF-36) Health Survey and 2-min walk test (2MWT), timed up & go test (TUG), and 30-s...... chair stand performance were evaluated. In addition, patients were tested for knee extensor muscle strength (isokinetic dynamometer) and leg extension power (Nottingham power rig). RESULTS: TUG performance was the strongest predictor of self-reported physical function (r(2) = 0.56, P ... to sensitively predict self-perceived physical function in sIBM patients. Notably, between-limb asymmetry in lower limb muscle strength had a substantial negative impact on motor tasks involving gait function. Muscle Nerve, 2017....

  17. Different Sarcocystis spp. are present in bovine eosinophilic myositis.

    Science.gov (United States)

    Vangeel, Lieve; Houf, Kurt; Geldhof, Peter; De Preter, Katleen; Vercruysse, Jozef; Ducatelle, Richard; Chiers, Koen

    2013-11-08

    It has been suggested that Sarcocystis species are associated with bovine eosinophilic myositis (BEM). To date, parasite identification in this myopathy has been based on morphological techniques. The aim of the present study was to use molecular techniques to identify Sarcocystis species inside lesions of BEM. Histologically, BEM lesions of 97 condemned carcasses were examined for the presence of Sarcocystis species. Intralesional and extralesional cysts were collected using laser capture microdissection and the species was determined with a PCR-based technique based on 18S rDNA. Intralesional sarcocysts or remnants were found in BEM lesions in 28% of the carcasses. The majority (82%) of intralesional Sarcocystis species were found to be S. hominis. However S. cruzi and S. hirsuta were also found, as well as an unidentified species. It can be concluded that Sarcocystis species present in lesions of BEM are not restricted to one species. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Inclusion-body myositis: clinical, diagnostic, and pathologic aspects.

    Science.gov (United States)

    Engel, W King; Askanas, Valerie

    2006-01-24

    The diagnostic aspects of sporadic inclusion-body myositis (s-IBM), and a few comments on our own approach to its treatment, are presented to foster the goals of this symposium, which was organized to provoke new ideas concerning the cause and treatment of this currently unsolvable disease. s-IBM is the most common, progressive, debilitating muscle disease beginning in persons over age 50 years, and it is more common in men. Diagnostic parameters reviewed are clinical, muscle-biopsy histochemistry, electrophysiologic and CSF evaluations. Overall, the degenerative phenomena in s-IBM muscle fibers seem to be the major cause of the progressive, unstoppable weakness, rather than the lymphocytic inflammation. Available treatments are of only slight, temporary benefit for only some s-IBM patients, indicating a desperate need for definitive therapies.

  19. Group G streptococcal myositis in a patient with myeloproliferative neoplasm

    Directory of Open Access Journals (Sweden)

    Monica Midha, MD MBS

    2016-01-01

    Full Text Available While many cases of streptococcal infection are due to Lancefield groups A and B, there has been a rise in reported cases of infections due to group G streptococcus. We present a case of an individual with a hematologic malignancy who developed myositis secondary to group G streptococcus, with no clearly identifiable source of infection. The patient was managed with antibiotic therapy rather than surgical intervention due to high surgical risk related to severe thrombocytopenia. Targeted antibiotics initiated early in the course of disease may prevent the need for surgical intervention. Early diagnosis and treatment are critical to avoid the high morbidity and mortality of life-threatening infections caused by group G streptococcus.

  20. Myositis complicating benzathine penicillin-G injection in a case of rheumatic heart disease

    Directory of Open Access Journals (Sweden)

    Joshua R. Francis

    2016-01-01

    Full Text Available A 7-year old boy developed myositis secondary to intramuscular injection of benzathine penicillin-G in the context of secondary prophylaxis for rheumatic heart disease. Side effects of intramuscular delivery of benzathine penicillin-G are well described and include injection site pain and inflammation, but myositis, as depicted on magnetic resonance imaging in this case, has not previously been described.

  1. MR findings of infectious myositis caused by vibrio vulnificus: case report

    International Nuclear Information System (INIS)

    Lee, Joon Ho; Na, Jae Boem

    2003-01-01

    Vibrio vulnificus infection is a fatal disease occurring after the consumption of seafood in patients with underlying liver disease. Inflammation of the skin, subcutanous fat and fascia disseminates from the lower extremity to the trunk and upper extremity. Infection myositis caused by vibrio vulnificus is rare, and its MR findings have not been reported. We report these in a case of infectious myositis caused by vibrio vulnificus involving both lower extremities

  2. 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...... stained in perivascular infiltrates in frozen sections from the brains of animals with active EAE was 10-fold higher.(ABSTRACT TRUNCATED AT 250 WORDS)...

  3. 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.

  4. 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.

  5. 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.

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

    Science.gov (United States)

    Esposito, Giovanna; D'angeli, Luca; Bartoli, Antonietta; Chaabane, Linda; Terreno, Enzo

    2013-02-01

    Positron Emission Tomography (PET) with 18F-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 18F-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.

  7. 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.

  8. Sodium salicylate-induced amelioration of experimental autoimmune encephalomyelitis in Lewis rats is associated with the suppression of inducible nitric oxide synthase and cyclooxygenases.

    Science.gov (United States)

    Moon, Changjong; Ahn, Meejung; Jee, Youngheun; Heo, Seungdam; Kim, Seungjoon; Kim, Hyungmin; Sim, Ki-Bum; Koh, Chang-Sung; Shin, Young-Gyun; Shin, Taekyun

    2004-02-12

    We studied the effects of oral administration of sodium salicylate on the expression of the pro-inflammatory mediators, nitric oxide synthase (iNOS) and cyclooxygenase- (COX-) 1 and 2, in rats with experimental autoimmune encephalomyelitis (EAE). Sodium salicylate (200 mg/kg) was administered orally for 13 days after the induction of EAE by immunization with guinea pig myelin basic protein and complete Freund's adjuvant. The onset (P<0.0001) and severity (P<0.05) of EAE paralysis in salicylate-treated animals were delayed and suppressed significantly compared with vehicle-treated controls. Western blot analysis showed that expression of COX-2 and iNOS, but not COX-1, decreased significantly in the spinal cords of salicylate-treated rats compared with vehicle-treated controls (P<0.05) and this finding was paralleled by immunohistochemical observations. These results suggest that the amelioration by salicylate of paralysis in rats with EAE is mediated in part by the suppression of COX and iNOS.

  9. Valproic Acid attenuates disease symptoms and increases endogenous myelin repair by recruiting neural stem cells and oligodendrocyte progenitors in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Pazhoohan, Saeed; Satarian, Leila; Asghari, Ali-Akbar; Salimi, Mehdi; Kiani, Sahar; Mani, Ali-Reza; Javan, Mohammad

    2014-01-01

    inefficient remyelination of demyelinated plaques in multiple sclerosis (ms) leads to secondary axon degeneration and progressive disability. therapies that potentiate remyelination would be of immense help for managing MS. Here, we report the effects of valproic acid (VPA) on focal experimental autoimmune encephalomyelitis (fEAE). fEAE was induced in Wistar rats by immunizing the animals with guinea pig spinal cord homogenate emulsified in complete Freund's adjuvant and with pertussis toxin (PT) injection into the spinal cord at the level of T8 vertebra on day 18 after immunization. VPA 300 mg/kg was applied for 4 days after or 8 days before PT administration. Behavioral evaluation, histological assessment and immunohistofluorescence assays were used to evaluate the outcomes. VPA administration had no effect on the development of symptoms, but after discontinuing VPA, animals showed faster recovery. Eight days of pretreatment with VPA accelerated the recovery phase of EAE and increased the number of remyelinated axons in the lesion area. VPA pretreatment also increased the recruitment of neural stem cells and oligodendrocyte precursors within the lesion. Results suggest VPA as a potential therapy for remyelinating the lesions in MS and for faster recovery from disease relapses. The effect of VPA seems to be mediated by endogenous progenitors recruitment. Copyright © 2013 S. Karger AG, Basel.

  10. Time-Dependent Increases in Protease Activities for Neuronal Apoptosis in Spinal Cords of Lewis Rats During Development of Acute Experimental Autoimmune Encephalomyelitis

    Science.gov (United States)

    Das, Arabinda; Guyton, M. Kelly; Matzelle, Denise D.; Ray, Swapan K.; Banik, Naren L.

    2008-01-01

    Multiple sclerosis (MS) is characterized by axonal demyelination and neurodegeneration, the latter having been inadequately explored in the MS animal model experimental autoimmune encephalomyelitis (EAE). The purpose of this study was to examine the time-dependent correlation between increased calpain and caspase activities and neurodegeneration in spinal cord tissues from Lewis rats with acute EAE. An increase in TUNEL-positive neurons and internucleosomal DNA fragmentation in EAE spinal cords suggested that neuronal death was a result of apoptosis on days 8–10 following induction of EAE. Increases in calpain expression in EAE correlated with activation of pro-apoptotic proteases, leading to apoptotic cell death beginning on day 8 of EAE, which occurred before the appearance of visible clinical symptoms. Increases in calcineurin expression and decreases in phospho-Bad (p-Bad) suggested Bad activation in apoptosis during acute EAE. Increases in the Bax:Bcl-2 ratio and activation of caspase-9 showed the involvement of mitochondria in apoptosis. Further, caspase-8 activation suggested induction of the death receptor–mediated pathway for apoptosis. Endoplasmic reticulum stress leading to caspase-3 activation was also observed, indicating that multiple apoptotic pathways were activated following EAE induction. In contrast, cell death was mostly a result of necrosis on the later day (day 11), when EAE entered a severe stage. From these findings, we conclude that increases in calpain and caspase activities play crucial roles in neuronal apoptosis during the development of acute EAE. PMID:18521931

  11. Ginger extract modulates the expression of IL-12 and TGF-β in the central nervous system and serum of mice with experimental autoimmune encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Abdollah Jafarzadeh

    2017-01-01

    Full Text Available Objective: The main function of IL-12 is differentiation of naive T cells intoTh1 cells and TGF-β is a powerful immunoregulatory cytokine. The immunomodulatory and anti-inflammatory properties of ginger have also been reported in some studies. The aim of this study was to evaluate the effects of ginger extract on the expression of IL-12 and TGF-β in a model of experimental autoimmune encephalomyelitis (EAE.Materials and Methods: EAE was induced in C57BL/6 mice by immunization with myelin oligodendroglial glycoprotein emulsified in complete Freund's adjuvant. The mice were administered intra-peritoneally with ginger extracts or PBS, from day +3 to +30. On day 31, mice were scarified and the expression of IL-12 and TGF-β mRNA in the spinal cord were determined by using real time-PCR. The serum levels of cytokines were measured by ELISA.Results: In PBS-treated EAE mice, the expression of IL-12 P35 and IL-12 P40 mRNA in the CNS and the mean serum levels of IL-12 were significantly higher than those of healthy group (p

  12. 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.

  13. Sagittal Plane Kinematic Gait Analysis in C57BL/6 Mice Subjected to MOG35-55 Induced Experimental Autoimmune Encephalomyelitis.

    Science.gov (United States)

    Fiander, Maximillian Dj; Chedrawe, Matthew Aj; Lamport, Anna-Claire; Akay, Turgay; Robertson, George S

    2017-11-04

    Kinematic gait analysis in the sagittal plane has frequently been used to characterize motor deficits in multiple sclerosis (MS). We describe the application of these techniques to identify gait deficits in a mouse model of MS, known as experimental autoimmune encephalomyelitis (EAE). Paralysis and motor deficits in mice subjected to EAE are typically assessed using a clinical scoring scale. However, this scale yields only ordinal data that provides little information about the precise nature of the motor deficits. EAE disease severity has also been assessed by rotarod performance, which provides a measure of general motor coordination. By contrast, kinematic gait analysis of the hind limb in the sagittal plane generates highly precise information about how movement is impaired. To perform this procedure, reflective markers are placed on a hind limb to detect joint movement while a mouse is walking on a treadmill. Motion analysis software is used to measure movement of the markers during walking. Kinematic gait parameters are then derived from the resultant data. We show how these gait parameters can be used to quantify impaired movements of the hip, knee, and ankle joints in EAE. These techniques may be used to better understand disease mechanisms and identify potential treatments for MS and other neurodegenerative disorders that impair mobility.

  14. Intramuscular inoculation of cattle with Sarcocystis antigen results in focal eosinophilic myositis.

    Science.gov (United States)

    Vangeel, L; Houf, K; Geldhof, P; Nollet, H; Vercruysse, J; Ducatelle, R; Chiers, K

    2012-02-10

    Bovine eosinophilic myositis (BEM) is a subclinical myopathy characterized by multifocal white to grey-green discolorations in skeletal muscles, heart, tongue and oesophagus. These lesions are found at slaughter or during meat cutting and result in considerable economic losses. The etiology and pathogenesis are unclear, although it has been suggested, that Sarcocystis species are involved. To elucidate their role, two calves were repeatedly injected intramuscularly with adjuvanted Sarcocystis antigen. The morphological changes at the injection sites in these calves were histologically and immunohistochemically compared to spontaneous lesions from 44 BEM condemned carcasses sampled in slaughterhouses. Experimental intramuscular injection of Sarcocystis antigen resulted in lesions at the injection sites that were similar to the lesions of natural cases of BEM. They were characterized by massive infiltration of eosinophilic granulocytes, reactive macrophages (MAC387(+) cells), T-cells (CD3(+)) and B-cells (CD20(+)). Both in the experimental and in the natural cases, COX-2 expression was present in endothelial cells adjacent to lesional areas. MHC class II(+) staining was found amongst others in muscle cells surrounding the lesion. These results show that Sarcocystis antigens can induce an inflammatory response in bovine muscle having the characteristics of natural BEM. Copyright © 2011 Elsevier B.V. All rights reserved.

  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.

    Directory of Open Access Journals (Sweden)

    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. 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.

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

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    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

  18. Experimental autoimmune encephalomyelitis: Association with mutual regulation of RelA (p65)/NF-κB and phospho-IκB in the CNS

    International Nuclear Information System (INIS)

    Hwang, Insun; Ha, Danbee; Ahn, Ginnae; Park, Eunjin; Joo, Haejin; Jee, Youngheun

    2011-01-01

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

  19. 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

  20. Effects of beta 2 adrenergic agonists on axonal injury and mitochondrial metabolism in experimental autoimmune encephalomyelitis rats.

    Science.gov (United States)

    Zhang, Z W; Qin, X Y; Che, F Y; Xie, G; Shen, L; Bai, Y Y

    2015-10-28

    The primary aims of this study were to investigate mitochondrial metabolism during experimental allergic encephalomyelitis (EAE) animal model axonal injury and to determine the correlation among neurological function scores, pathological changes, and the activities of the BB isoenzyme of creatine kinase (CK-BB), catalase (CAT), and calpain in the brain tissues of EAE rats. Another goal was to preliminarily define the mechanism of mitochondrial metabolism resulting from the effect of beta 2 adrenergic agonists in the process of EAE animal model axonal damage. EAE was induced in specific pathogen free Wistar rats by guinea pig spinal cord homogenate, complete Freund's adjuvant, and pertussis vaccine. We recorded the behavioral change in EAE rats, detected pathological changes in central nervous tissue, and observed the changes of the CK-BB, CAT, and calpain in the EAE rat brain and spinal cord. The results indicated that the average neurologic function score increased in the EAE group compared to that of the controls (P < 0.01). In addition, CAT and CK-BB activities significantly decreased and the calpain activity significantly increased compared with those of the control group (P < 0.05). The decrease of the activity of central nervous CK-BB and CAT content, as well as the increase of calpain activity at the highest time point were considered to be the consequences of EAE. Furthermore, the results revealed that use of salbutamol could alleviate disease symptoms and reduce the recurrence of the EAE disease.

  1. Total glucosides of paeony suppresses experimental autoimmune uveitis in association with inhibition of Th1 and Th2 cell function in mice.

    Science.gov (United States)

    Huang, Xue-Tao; Wang, Bin; Zhang, Wen-Hua; Peng, Man-Qiang; Lin, Ding

    2018-01-01

    Total glucosides of paeony (TGP) are active components extracted from the roots of Paeonia lactiflora Pall. In this study, we investigated the role and mechanisms of TGP in experimental autoimmune uveitis (EAU) model of mice. The C57BL/6 mice were randomly divided into three groups: sham group, EAU-control group, and EAU-TGP group. Clinical score of images of the eye fundus were taken on 7, 14, 21, and 28 days after induction of EAU. The concentrations of proinflammatory cytokines in intraocular fluid were measured at 14 days after EAU induction with the use of a multiplex assay system. Flow cytometry was used to analyze the frequency of CD4+, CD8+, interferon-gamma (IFN-γ), and CD4+/CD8+ ratio in spleen and lymph nodes. Western blotting was used to measure expressions of mitogen-activated protein kinase (MAPK) pathway-related proteins in retina. Clinical scores for uveitis were lower in TGP-treated EAU mice than those without TGP treatment. Importantly, the concentrations of cytokines induced by T-helper 1 (Th1) and T-helper 2 (Th2) cells in intraocular fluid were reduced in EAU mice treated with TGP. Furthermore, the frequency of CD4+, IFN-γ, and CD4+/CD8+ ratio was decreased and the frequency of CD8+ was increased in spleen and lymph nodes of mice treated with TGP. The anti-inflammatory effects of TGP were mediated by inhibiting the MAPK signaling pathways. Our results showed that TGP suppressed uveitis in mice via the inhibition of Th1 and Th2 cell function. Thus, TGP may be a promising therapeutic strategy for uveitis, as well as other ocular inflammatory diseases.

  2. 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.

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

    Science.gov (United States)

    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. 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.

  5. 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.

  6. Brain leukocyte infiltration initiated by peripheral inflammation or experimental autoimmune encephalomyelitis occurs through pathways connected to the CSF-filled compartments of the forebrain and midbrain.

    Science.gov (United States)

    Schmitt, Charlotte; Strazielle, Nathalie; Ghersi-Egea, Jean-François

    2012-08-07

    Cerebrospinal fluid (CSF) has been considered as a preferential pathway of circulation for immune cells during neuroimmune surveillance. In order to evaluate the involvement of CSF-filled spaces in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, we performed a time-course analysis of immune cell association with the CSF-containing ventricles, velae, and cisterns in two active models of this disease. Guinea-pig spinal cord homogenate-induced EAE in rat and myelin oligodendrocyte glycoprotein-induced EAE in mouse were used. Leukocyte distribution and phenotypes were investigated by immunohistochemistry in serial sections of brain areas of interest, as well as in CSF withdrawn from rat. Immune cells associated with the choroid plexuses were quantified. Freund's adjuvant-induced peripheral inflammation in the absence of brain antigen led to a subtle but definite increase in the number of myeloid cells in the extraventricular CSF spaces. In both rats and mice, EAE was characterized by a sustained and initial infiltration of lymphocytes and monocytes within forebrain/midbrain fluid-filled compartments such as the velum interpositum and ambient cisterns, and certain basal cisterns. Leukocytes further infiltrated periventricular and pericisternal parenchymal areas, along perivascular spaces or following a downward CSF-to-tissue gradient. Cells quantified in CSF sampled from rats included lymphocytes and neutrophils. The distinctive pattern of cell distribution suggests that both the choroid plexus and the vessels lying in the velae and cisterns are gates for early leukocyte entry in the central nervous system. B-cell infiltration observed in the mouse model was restricted to CSF-filled extraventricular compartments. These results identified distinctive velae and cisterns of the forebrain and midbrain as preferential sites of immune cell homing following peripheral and early central inflammation and point to a role of CSF

  7. IL-2/neuroantigen fusion proteins as antigen-specific tolerogens in experimental autoimmune encephalomyelitis (EAE): correlation of T cell-mediated antigen presentation and tolerance induction.

    Science.gov (United States)

    Mannie, Mark D; Clayson, Barbara A; Buskirk, Elizabeth J; DeVine, Jarret L; Hernandez, Jose J; Abbott, Derek J

    2007-03-01

    The purpose of this study was to assess whether the Ag-targeting activity of cytokine/neuroantigen (NAg) fusion proteins may be associated with mechanisms of tolerance induction. To assess this question, we expressed fusion proteins comprised of a N-terminal cytokine domain and a C-terminal NAg domain. The cytokine domain comprised either rat IL-2 or IL-4, and the NAg domain comprised the dominant encephalitogenic determinant of the guinea pig myelin basic protein. Subcutaneous administration of IL2NAg (IL-2/NAg fusion protein) into Lewis rats either before or after an encephalitogenic challenge resulted in an attenuated course of experimental autoimmune encephalomyelitis. In contrast, parallel treatment of rats with IL4NAg (IL-4/NAg fusion protein) or NAg lacked tolerogenic activity. In the presence of IL-2R(+) MHC class II(+) T cells, IL2NAg fusion proteins were at least 1,000 times more potent as an Ag than NAg alone. The tolerogenic activity of IL2NAg in vivo and the enhanced potency in vitro were both dependent upon covalent linkage of IL-2 and NAg. IL4NAg also exhibited enhanced antigenic potency. IL4NAg was approximately 100-fold more active than NAg alone in the presence of splenic APC. The enhanced potency of IL4NAg also required covalent linkage of cytokine and NAg and was blocked by soluble IL-4 or by a mAb specific for IL-4. Other control cytokine/NAg fusion proteins did not exhibit a similar enhancement of Ag potency compared with NAg alone. Thus, the IL2NAg and IL4NAg fusion proteins targeted NAg for enhanced presentation by particular subsets of APC. The activities of IL2NAg revealed a potential relationship between NAg targeting to activated T cells, T cell-mediated Ag presentation, and tolerance induction.

  8. Brain leukocyte infiltration initiated by peripheral inflammation or experimental autoimmune encephalomyelitis occurs through pathways connected to the CSF-filled compartments of the forebrain and midbrain

    Directory of Open Access Journals (Sweden)

    Schmitt Charlotte

    2012-08-01

    Full Text Available Abstract Background Cerebrospinal fluid (CSF has been considered as a preferential pathway of circulation for immune cells during neuroimmune surveillance. In order to evaluate the involvement of CSF-filled spaces in the pathogenesis of experimental autoimmune encephalomyelitis (EAE, a model of multiple sclerosis, we performed a time-course analysis of immune cell association with the CSF-containing ventricles, velae, and cisterns in two active models of this disease. Methods Guinea-pig spinal cord homogenate-induced EAE in rat and myelin oligodendrocyte glycoprotein-induced EAE in mouse were used. Leukocyte distribution and phenotypes were investigated by immunohistochemistry in serial sections of brain areas of interest, as well as in CSF withdrawn from rat. Immune cells associated with the choroid plexuses were quantified. Results Freund’s adjuvant-induced peripheral inflammation in the absence of brain antigen led to a subtle but definite increase in the number of myeloid cells in the extraventricular CSF spaces. In both rats and mice, EAE was characterized by a sustained and initial infiltration of lymphocytes and monocytes within forebrain/midbrain fluid-filled compartments such as the velum interpositum and ambient cisterns, and certain basal cisterns. Leukocytes further infiltrated periventricular and pericisternal parenchymal areas, along perivascular spaces or following a downward CSF-to-tissue gradient. Cells quantified in CSF sampled from rats included lymphocytes and neutrophils. The distinctive pattern of cell distribution suggests that both the choroid plexus and the vessels lying in the velae and cisterns are gates for early leukocyte entry in the central nervous system. B-cell infiltration observed in the mouse model was restricted to CSF-filled extraventricular compartments. Conclusion These results identified distinctive velae and cisterns of the forebrain and midbrain as preferential sites of immune cell homing following

  9. [Inhibiton of experimental autoimmune encephalomyelitis in Lewis rats by nasal administration of encephalitogenic MBP peptides: synergistic effects of MBP 68-86 and 87-99].

    Science.gov (United States)

    Sun, Bo; Yang, Shuo; Peng, Hai-sheng; Qiao, Hui; Cao, Jing-yan; Jin, Lian-hong; Li, Hu-lun

    2007-02-01

    To explore the synergistic effect of MBP 68-86 and 87-99, on the inhibition of experimental autoimmune encephalomyelitis (EAE) in Lewis rat by nasal administration. Three different MBP peptides(MBP 68-86, 87-99, and the non-encephalitogenic peptide 110-128) were synthesized and administrated nasally to Lewis rat on day-11, -10, -9, -8 and -7 prior to immunization with the guinea pig MBP (gp-MBP)+CFA, which was used to induce EAE. The protective effect on Lewis rat from EAE by the MBP peptides was evaluated. Protection was achieved with the encephalitogenic peptides MBP 68-86 and 87-99, MBP 68-86 being more potent, but not with MBP 110-128. Neither MBP 68-86 nor 87-99 used alone conferred complete protection to gp-MBP-induced EAE. In contrast, nasal administration of a mixture of MBP 68-86 and 87-99 completely blocked gp-MBP-induced EAE even at lower dosage than being used alone. Rats tolerized with MBP 68-86+87-99 nasally showed decreased T cell responses to MBP, reflected by lymphocyte proliferation and IFN-gamma ELISPOT assays. Rats tolerized with MBP 68-86+87-99 also had abrogated MBP-reactive IFN-gamma and TNF-alpha mRNA expression in lymph node cells compared to rats receiving MBP 110-128 nasally, while similar low levels of MBP-reactive TGF-beta and IL-4 mRNA expressing cells were observed in the two groups. Nasal administration of encephalitogenic MBP peptides can induce antigen-specific T cell tolerance and confer incomplete protection to gp-MBP-induced EAE, and MBP 68-86 and 87-99 have synergistic effects. Non-regulatory mechanisms are proposed to be responsible for tolerance development after nasal peptide administration.

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

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    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.

  11. 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

  12. Intestinal Barrier Dysfunction Develops at the Onset of Experimental Autoimmune Encephalomyelitis, and Can Be Induced by Adoptive Transfer of Auto-Reactive T Cells

    Science.gov (United States)

    Nouri, Mehrnaz; Bredberg, Anders; Weström, Björn; Lavasani, Shahram

    2014-01-01

    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. PMID:25184418

  13. 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.

  14. Proteomic and biochemical analyses reveal the activation of unfolded protein response, ERK-1/2 and ribosomal protein S6 signaling in experimental autoimmune myocarditis rat model

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    Kim Chan

    2011-10-01

    Full Text Available Abstract Background To investigate the molecular and cellular pathogenesis underlying myocarditis, we used an experimental autoimmune myocarditis (EAM-induced heart failure rat model that represents T cell mediated postinflammatory heart disorders. Results By performing unbiased 2-dimensional electrophoresis of protein extracts from control rat heart tissues and EAM rat heart tissues, followed by nano-HPLC-ESI-QIT-MS, 67 proteins were identified from 71 spots that exhibited significantly altered expression levels. The majority of up-regulated proteins were confidently associated with unfolded protein responses (UPR, while the majority of down-regulated proteins were involved with the generation of precursor metabolites and energy metabolism in mitochondria. Although there was no difference in AKT signaling between EAM rat heart tissues and control rat heart tissues, the amounts and activities of extracellular signal-regulated kinase (ERK-1/2 and ribosomal protein S6 (rpS6 were significantly increased. By comparing our data with the previously reported myocardial proteome of the Coxsackie viruses of group B (CVB-mediated myocarditis model, we found that UPR-related proteins were commonly up-regulated in two murine myocarditis models. Even though only two out of 29 down-regulated proteins in EAM rat heart tissues were also dysregulated in CVB-infected rat heart tissues, other proteins known to be involved with the generation of precursor metabolites and energy metabolism in mitochondria were also dysregulated in CVB-mediated myocarditis rat heart tissues, suggesting that impairment of mitochondrial functions may be a common underlying mechanism of the two murine myocarditis models. Conclusions UPR, ERK-1/2 and S6RP signaling were activated in both EAM- and CVB-induced myocarditis murine models. Thus, the conserved components of signaling pathways in two murine models of acute myocarditis could be targets for developing new therapeutic drugs or

  15. Autoimmune Pancreatitis.

    Science.gov (United States)

    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.

  16. FLOW RESTRICTED RESISTANCE TRAINING ATTENUATES MYOSTATIN GENE EXPRESSION IN A PATIENT WITH INCLUSION BODY MYOSITIS

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    A.R. Santos

    2014-07-01

    Full Text Available Inclusion body myositis is a rare idiopathic inflammatory myopathy that produces extreme muscle weakness. Blood flow restricted resistance training has been shown to improve muscle strength and muscle hypertrophy in inclusion body myositis. Objective: The aim of this study was to evaluate the effects of a resistance training programme on the expression of genes related to myostatin (MSTN signalling in one inclusion body myositis patient. Methods: A 65-year-old man with inclusion body myositis underwent blood flow restricted resistance training for 12 weeks. The gene expression of MSTN, follistatin, follistatin-like 3, activin II B receptor, SMAD-7, MyoD, FOXO-3, and MURF-2 was quantified. Results: After 12 weeks of training, a decrease (25% in MSTN mRNA level was observed, whereas follistatin and follistatin-like 3 gene expression increased by 40% and 70%, respectively. SMAD-7 mRNA level was augmented (20%. FOXO-3 and MURF-2 gene expression increased by 40% and 20%, respectively. No change was observed in activin II B receptor or MyoD gene expression. Conclusions: Blood flow restricted resistance training attenuated MSTN gene expression and also increased expression of myostatin endogenous inhibitors. Blood flow restricted resistance training evoked changes in the expression of genes related to MSTN signalling pathway that could in part explain the muscle hypertrophy previously observed in a patient with inclusion body myositis.

  17. Myositis ossificans around shoulder following military training programme

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    Mustafa C Kir

    2011-01-01

    Full Text Available The myositis ossificans around shoulder in military recruits are not reported yet. Three young male soldiers presented with complaints of palpable mass at the anterior aspect of shoulder; tenderness around the superior part of deltopectoral groove close to acromioclavicular joint; and restriction of shoulder motion. They also noticed ecchymosis and pain around the coracoid process and anterior shoulder region during regular firing exercises. Plain X-rays and computerized tomography showed extra-capsular, dense, irregular structure in the space between pectoralis and deltoid muscles which correlated with heterotopic bone. One patient refused surgical intervention because of the completion of his military serving period. Surgical excision was performed for the other two patients. During surgical exploration, both ossified masses were found in deltopectoral region and mostly in fibers of clavicular and acromial parts of deltoid muscle. Pathological reports confirmed the structure of masses as mature trabecular bone. Postoperatively indomethacin treatment and active shoulder exercises were started until the full range of motion was regained. Mini soft bag was used on the rifle contact area of the shoulder. No complications or recurrences were observed during the 24 months of followup period.

  18. In vivo multi-modal imaging of experimental autoimmune uveoretinitis in transgenic reporter mice reveals the dynamic nature of inflammatory changes during disease progression.

    Science.gov (United States)

    Chen, Xiangting; Kezic, Jelena M; Forrester, John V; Goldberg, Gabrielle L; Wicks, Ian P; Bernard, Claude C; McMenamin, Paul G

    2015-01-27

    Experimental autoimmune uveoretinitis (EAU) is a widely used experimental animal model of human endogenous posterior uveoretinitis. In the present study, we performed in vivo imaging of the retina in transgenic reporter mice to investigate dynamic changes in exogenous inflammatory cells and endogenous immune cells during the disease process. Transgenic mice (C57Bl/6 J Cx 3 cr1 (GFP/+) , C57Bl/6 N CD11c-eYFP, and C57Bl/6 J LysM-eGFP) were used to visualize the dynamic changes of myeloid-derived cells, putative dendritic cells and neutrophils during EAU. Transgenic mice were monitored with multi-modal fundus imaging camera over five time points following disease induction with the retinal auto-antigen, interphotoreceptor retinoid binding protein (IRBP1-20). Disease severity was quantified with both clinical and histopathological grading. In the normal C57Bl/6 J Cx 3 cr1 (GFP/+) mouse Cx3cr1-expressing microglia were evenly distributed in the retina. In C57Bl/6 N CD11c-eYFP mice clusters of CD11c-expressing cells were noted in the retina and in C57Bl/6 J LysM-eGFP mice very low numbers of LysM-expressing neutrophils were observed in the fundus. Following immunization with IRBP1-20, fundus examination revealed accumulations of Cx3cr1-GFP(+) myeloid cells, CD11c-eYFP(+) cells and LysM-eGFP(+) myelomonocytic cells around the optic nerve head and along retinal vessels as early as day 14 post-immunization. CD11c-eYFP(+) cells appear to resolve marginally earlier (day 21 post-immunization) than Cx3cr1-GFP(+) and LysM-eGFP(+) cells. The clinical grading of EAU in transgenic mice correlated closely with histopathological grading. These results illustrate that in vivo fundus imaging of transgenic reporter mice allows direct visualization of various exogenously and endogenously derived leukocyte types during EAU progression. This approach acts as a valuable adjunct to other methods of studying the clinical course of EAU.

  19. 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.

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

    Science.gov (United States)

    Verhagen, Johan; Gabryšová, Leona; Shepard, Ella R; Wraith, David C

    2014-01-01

    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.

  1. Inhibition of experimental autoimmune encephalomyelitis in Lewis rats by nasal administration of encephalitogenic MBP peptides: synergistic effects of MBP 68-86 and 87-99.

    Science.gov (United States)

    Liu, J Q; Bai, X F; Shi, F D; Xiao, B G; Li, H L; Levi, M; Mustafa, M; Wahren, B; Link, H

    1998-08-01

    Induction of mucosal tolerance by inhalation of soluble peptides with defined T cell epitopes is receiving much attention as a means of specifically down-regulating pathogenic T cell reactivities in autoimmune and allergic disorders. Experimental autoimmune encephalomyelitis (EAE) induced in the Lewis rat by immunization with myelin basic protein (MBP) and Freund's adjuvant (CFA) is mediated by CD4+ T cells specific for the MBP amino acid sequences 68-86 and 87-99. To further define the principles of nasal tolerance induction, we generated three different MBP peptides (MBP 68-86, 87-99 and the non-encephalitogenic peptide 110-128), and evaluated whether their nasal administration on day -11, -10, -9, -8 and -7 prior to immunization with guinea pig MBP (gp-MBP) + CFA confers protection to Lewis rat EAE. Protection was achieved with the encephalitogenic peptides MBP 68-86 and 87-99, MBP 68-86 being more potent, but not with MBP 110-128. Neither MBP 68-86 nor 87-99 at doses used conferred complete protection to gp-MBP-induced EAE. In contrast, nasal administration of a mixture of MBP 68-86 and 87-99 completely blocked gp-MBP-induced EAE even at lower dosage compared to that being used for individual peptides. Rats tolerized with MBP 68-86 + 87-99 nasally showed decreased T cell responses to MBP reflected by lymphocyte proliferation and IFN-gamma ELISPOT assays. Rats tolerized with MBP 68-86 + 87-99 also had abrogated MBP-reactive IFN-gamma and tumor necrosis factor-alpha mRNA expression in lymph node cells compared to rats receiving MBP 110-128 nasally, while similar low levels of MBP-reactive transforming growth factor-beta and IL-4 mRNA expressing cells were observed in the two groups. Nasal administration of MBP 68-86 + 87-99 only slightly inhibited guinea pig spinal cord homogenate-induced EAE, and passive transfer of spleen mononuclear cells from MBP 68-86 + 87-99-tolerized rats did not protect naïve rats from EAE. Finally, we show that nasal administration of

  2. Autoimmunity and Gastric Cancer

    Science.gov (United States)

    Bizzaro, Nicola; Antico, Antonio; Villalta, Danilo

    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 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. PMID:29373557

  3. 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.

  4. Radiation recall phenomenon presenting as myositis triggered by carboplatin plus paclitaxel and related literature review

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    Chi Hoon Maeng

    2014-01-01

    Full Text Available While most case reports to date are radiation recall dermatitis, radiation recall myositis, which is a distinct form of radiation recall phenomenon caused by carboplatin plus paclitaxel, has not been reported. We treated a 57-year-old female patient who suffered from recurrent cervical cancer. When the patient developed a new left sacral metastasis, salvage radiotherapy (total dose 60 Gy was administered. Four weeks later, chemotherapy using carboplatin plus paclitaxel was initiated. Four months after chemotherapy, the patient complained of severe pain in her left buttock. On magnetic resonance imaging (MRI, edematous changes and increased signal densities of left gluteus maximus and medius muscles were noted suggesting myositis. The border of the high signal intensity territory of the muscles was sharp and clearly corresponded with the recent irradiation field. We concluded that the patient had radiation recall myositis triggered by paclitaxel-carboplatin. Symptoms were controlled by analgesics, and there was no recurrence.

  5. International consensus on preliminary definitions of improvement in adult and juvenile myositis.

    Science.gov (United States)

    Rider, Lisa G; Giannini, Edward H; Brunner, Hermine I; Ruperto, Nicola; James-Newton, Laura; Reed, Ann M; Lachenbruch, Peter A; Miller, Frederick W

    2004-07-01

    To use a core set of outcome measures to develop preliminary definitions of improvement for adult and juvenile myositis as composite end points for therapeutic trials. Twenty-nine experts in the assessment of myositis achieved consensus on 102 adult and 102 juvenile paper patient profiles as clinically improved or not improved. Two hundred twenty-seven candidate definitions of improvement were developed using the experts' consensus ratings as a gold standard and their judgment of clinically meaningful change in the core set of measures. Seventeen additional candidate definitions of improvement were developed from classification and regression tree analysis, a data-mining decision tree tool analysis. Six candidate definitions specifying percentage change or raw change in the core set of measures were developed using logistic regression analysis. Adult and pediatric working groups ranked the 13 top-performing candidate definitions for face validity, clinical sensibility, and ease of use, in which the sensitivity and specificity were >/=75% in adult, pediatric, and combined data sets. Nominal group technique was used to facilitate consensus formation. The definition of improvement (common to the adult and pediatric working groups) that ranked highest was 3 of any 6 of the core set measures improved by >/=20%, with no more than 2 worse by >/=25% (which could not include manual muscle testing to assess strength). Five and 4 additional preliminary definitions of improvement for adult and juvenile myositis, respectively, were also developed, with several definitions common to both groups. Participants also agreed to prospectively test 6 logistic regression definitions of improvement in clinical trials. Consensus preliminary definitions of improvement were developed for adult and juvenile myositis, and these incorporate clinically meaningful change in all myositis core set measures in a composite end point. These definitions require prospective validation, but they are now

  6. Immune modulation by a tolerogenic myelin oligodendrocyte glycoprotein (MOG)10-60 containing fusion protein in the marmoset experimental autoimmune encephalomyelitis model

    NARCIS (Netherlands)

    Kap, Y. S.; van Driel, N.; Arends, R.; Rouwendal, G.; Verolin, M.; Blezer, E.; Lycke, N.; 't Hart, Bert A.

    Current therapies for multiple sclerosis (MS), a chronic autoimmune neuroinflammatory disease, mostly target general cell populations or immune molecules, which may lead to a compromised immune system. A more directed strategy would be to re-enforce tolerance of the autoaggressive T cells that drive

  7. Immune modulation by a tolerogenic myelin oligodendrocyte glycoprotein (MOG)10-60 containing fusion protein in the marmoset experimental autoimmune encephalomyelitis model

    NARCIS (Netherlands)

    Y.S. Kap (Yolanda); N. van Driel (Nikki); R. Arends (Roel); G. Rouwendal; M. Verolin; E. Blezer (Erwin); N. Lycke; B.A. 't Hart (Bert)

    2015-01-01

    textabstractSummary: Current therapies for multiple sclerosis (MS), a chronic autoimmune neuroinflammatory disease, mostly target general cell populations or immune molecules, which may lead to a compromised immune system. A more directed strategy would be to re-enforce tolerance of the

  8. Immune modulation by a tolerogenic myelin oligodendrocyte glycoprotein (MOG)10-60 containing fusion protein in the marmoset experimental autoimmune encephalomyelitis model

    NARCIS (Netherlands)

    Kap, Y. S.; van Driel, N.; Arends, R.; Rouwendal, G.; Verolin, M.; Blezer, E.; Lycke, N.; 't Hart, B. A.

    2015-01-01

    Summary: Current therapies for multiple sclerosis (MS), a chronic autoimmune neuroinflammatory disease, mostly target general cell populations or immune molecules, which may lead to a compromised immune system. A more directed strategy would be to re-enforce tolerance of the autoaggressive T cells

  9. Adult Niemann-Pick disease type B with myositis ossificans: a case report

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    Russka Shumnalieva

    2016-07-01

    Full Text Available Niemann-Pick Disease (NPD is a rare autosomal recessive lysosomal lipid storage disorder. The disease is caused by gene mutations that affect the metabolism of sphingolipids. The dysfunctions cause sphingomyelin to accumulate in different organs. NPD includes forms with low and high levels of sphingomyelin. We report a case of a 34 year-old man with a family history of NPD type B who presented with hepatosplenomegaly, neurological deficiency, bone abnormalities, and myositis ossificans. The clinical, biochemical, and imaging data confirmed the combined diagnosis of NPD type B with myositis ossificans.

  10. Fatal Tuberculous Myositis in an Immunocompromised Adult With Primary Sjögren's Syndrome

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    Chi-Chang Huang

    2010-09-01

    Full Text Available Tuberculous myositis, which mimics rheumatic symptoms, is an extremely rare disease. Clinical ambiguity easily leads to misdiagnosis and delayed initial treatment. We present the case of a 55-year-old man who had primary Sjögren's syndrome and active cutaneous vasculitis treated with steroid and immunosuppressive drugs. He presented with a swollen, painful, hot left thigh. Although anti-tuberculosis medications were administered soon after a positive acid-fast stain of incisional muscular tissue, he died of rapidly progressive tuberculous myositis and multiorgan failure following 18 days of hospitalization. This case is presented to increase the awareness of this rare entity in clinical practice.

  11. Restrained Th17 response and myeloid cell infiltration into the central nervous system by human decidua-derived mesenchymal stem cells during experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Bravo, Beatriz; Gallego, Marta I; Flores, Ana I; Bornstein, Rafael; Puente-Bedia, Alba; Hernández, Javier; de la Torre, Paz; García-Zaragoza, Elena; Perez-Tavarez, Raquel; Grande, Jesús; Ballester, Alicia; Ballester, Sara

    2016-03-17

    Multiple sclerosis is a widespread inflammatory demyelinating disease. Several immunomodulatory therapies are available, including interferon-β, glatiramer acetate, natalizumab, fingolimod, and mitoxantrone. Although useful to delay disease progression, they do not provide a definitive cure and are associated with some undesirable side-effects. Accordingly, the search for new therapeutic methods constitutes an active investigation field. The use of mesenchymal stem cells (MSCs) to modify the disease course is currently the subject of intense interest. Decidua-derived MSCs (DMSCs) are a cell population obtained from human placental extraembryonic membranes able to differentiate into the three germ layers. This study explores the therapeutic potential of DMSCs. We used the experimental autoimmune encephalomyelitis (EAE) animal model to evaluate the effect of DMSCs on clinical signs of the disease and on the presence of inflammatory infiltrates in the central nervous system. We also compared the inflammatory profile of spleen T cells from DMSC-treated mice with that of EAE control animals, and the influence of DMSCs on the in vitro definition of the Th17 phenotype. Furthermore, we analyzed the effects on the presence of some critical cell types in central nervous system infiltrates. Preventive intraperitoneal injection of DMSCs resulted in a significant delay of external signs of EAE. In addition, treatment of animals already presenting with moderate symptoms resulted in mild EAE with reduced disease scores. Besides decreased inflammatory infiltration, diminished percentages of CD4(+)IL17(+), CD11b(+)Ly6G(+) and CD11b(+)Ly6C(+) cells were found in infiltrates of treated animals. Early immune response was mitigated, with spleen cells of DMSC-treated mice displaying low proliferative response to antigen, decreased production of interleukin (IL)-17, and increased production of the anti-inflammatory cytokines IL-4 and IL-10. Moreover, lower RORγT and higher GATA-3

  12. 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

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

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    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

  14. 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...

  15. [Autoimmune diseases with the presence of anti-ku antibodies - analysis of three cases].

    Science.gov (United States)

    Wielosz, Ewa; Majdan, Maria; Jeleniewicz, Radosław; Mazurek, Marcin

    2016-01-01

    a-Ku are rare antibodies, which are reported in course of connective tissue diseases. Their prevalence ranges from 0 to 10% , 2%, on average. The main symptoms associated with the presence of a-Ku antibodies include: myositis, arthritis, Raynaud`s phenomenon and skin lesions. The above features are often defined as autoimmune clinical syndrome associated with a-Ku antibodies. In recent years, three cases with the presence of a-Ku antibodies were observed at the Department of Rheumatology and Connective Tissue Diseases. Case 1, a 77-year-old man, with the diagnosis of mixed connective tissue disease according to Raynaud`s phenomenon, myositis, arthritis and presence of a-ribonucleoprotein antibodies. Moreover, secondary Sjögren syndrome (SS) and myasthenia gravis were diagnosed. Case 2, a 56-year-old woman with longstanding history of Raynaud`s phenomenon, sclerodactyly, myositis and arthritis. Based on clinical manifestations and additional tests, systemic sclerosis and myositis were diagnosed. Case 3, a 46-year-old woman with SS diagnosis, long-standing history of Raynaud`s phenomenon, arthralgia and polyneuropathy. Moreover, HCV infection with the presence of cryoglobulin was confirmed. The presence of a-Ku antibodies in high titers was found in all cases. The clinical conditions improved after steroid and immunosuppressive therapy. In conclusion, clinical syndromes with the presence of a-Ku antibodies are associated with a wide range of non-specific symptoms, regarding muscle, joint and skin involvement, in particular. The conditions are more often diagnosed in the elderly; in the majority of cases, they are characterized by mild courses, good response to steroid therapy and good prognosis.

  16. Autoimmune Hemolytic Anemia.

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    Liebman, Howard A; Weitz, Ilene C

    2017-03-01

    Autoimmune hemolytic anemia is an acquired autoimmune disorder resulting in the production of antibodies directed against red blood cell antigens causing shortened erythrocyte survival. The disorders can present as a primary disorder (idiopathic) or secondary to other autoimmune disorders, malignancies, or infections. Treatment involves immune modulation with corticosteroids and other agents. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Myositis-specific and myositis-associated autoantibody profiles and their clinical associations in a large series of patients with polymyositis and dermatomyositis

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    Marcela Gran Pina Cruellas

    2013-07-01

    Full Text Available OBJECTIVE: To analyze the prevalence of myositis-specific and myositis-associated autoantibodies and their clinical correlations in a large series of patients with dermatomyositis/polymyositis. METHOD: This cross-sectional study enrolled 127 dermatomyositis cases and 95 polymyositis cases. The disease-related autoantibody profiles were determined using a commercially available blood testing kit. RESULTS: The prevalence of myositis-specific autoantibodies in all 222 patients was 34.4%, whereas myositis-associated autoantibodies were found in 41.4% of the patients. The most frequently found autoantibody was anti-Ro-52 (36.9%, followed by anti-Jo-1 (18.9%, anti-Mi-2 (8.1%, anti-Ku (4.1%, anti-SRP (3.2%, anti-PL-7 (3.2%, anti-PL-12 (2.7%, anti-PM/Scl75 (2.7%, and anti-PM/Scl100 (2.7%. The distributions of these autoantibodies were comparable between polymyositis and dermatomyositis, except for a higher prevalence of anti-Jo-1 in polymyositis. Anti-Mi-2 was more prevalent in dermatomyositis. Notably, in the multivariate analysis, anti-Mi-2 and anti-Ro-52 were associated with photosensitivity and pulmonary disorders, respectively, in dermatomyositis. Anti-Jo-1 was significantly correlated with pulmonary disorders in polymyositis. Moreover, anti-Ro-52 was associated with anti-Jo-1 in both diseases. No significant correlation was observed between the remaining autoantibodies and the clinical and/or laboratory findings. CONCLUSIONS: Our data are consistent with those from other published studies involving other populations, although certain findings warrant consideration. Anti-Ro-52 and anti-Jo-1 were strongly associated with one another. Anti-Ro-52 was correlated with pulmonary disorders in dermatomyositis, whereas anti-Jo-1 was correlated with pulmonary alterations in polymyositis.

  18. ''Dropped-head'' syndrome due to isolated myositis of neck extensor muscles: MRI findings

    International Nuclear Information System (INIS)

    Gaeta, Michele; Mazziotti, Silvio; Blandino, Alfredo; Toscano, Antonio; Rodolico, Carmelo; Mazzeo, Anna

    2006-01-01

    MRI findings of a patient with dropped-head syndrome due to focal myositis of the neck extensor muscles are presented. MRI showed oedematous changes and marked enhancement of the neck extensor muscles. After therapy MRI demonstrated disappearance of the abnormal findings. (orig.)

  19. Medical and Surgical Treatment in Pediatric Orbital Myositis Associated with Coxsackie Virus

    Directory of Open Access Journals (Sweden)

    Pedro Gil

    2015-01-01

    Full Text Available Purpose. To report a case of orbital myositis associated with Coxsackie virus and its medical and surgical approach. Methods. Complete ophthalmological examination and imaging and analytical investigation were performed. Results. A 6-year-old male presented with subacute painless binocular horizontal diplopia. Examination revealed bilateral best-corrected visual acuity (BCVA of 20/20 and right eye 45-prism-dioptre (PD esotropia in near and distance fixations, with no motility restrictions. Serologic screening was positive for Coxsackie virus acute infection and computerized tomography (CT suggested right eye medial rectus orbital myositis. An oral corticosteroid 1.0 mg/kg/day regimen was started. A new CT after two months showed symmetrical lesions in both medial rectus muscles. Corticosteroids were increased to 1.5 mg/kg/day. After imagiological resolution on the 4th month, alternating 45 PD esotropia persisted. Bilateral 7 mm medial rectus recession was performed after 1 year without spontaneous recovery. At 1-year follow-up, the patient is orthophoric with 200′′ stereopsis and bilateral 20/20 BCVA. Conclusions. To our knowledge, this is the first reported case of orbital myositis associated with Coxsackie virus. This is also the first reported case of isolated strabismus surgery after orbital myositis in pediatric age, highlighting the favourable aesthetic and functional outcomes even in cases of late ocular motility disorders.

  20. Statin-induced focal myositis of the upper extremity. A report of two cases

    Energy Technology Data Exchange (ETDEWEB)

    Wagner, M., E-mail: wagner.radiologie@herzchirurgie.de [Department of Radiology, Herz- und Gefaessklinik GmbH, Salzburger Leite 1, D-97616 Bad Neustadt an der Saale (Germany); Muehldorfer-Fodor, M.; Prommersberger, K.J. [Department of Handsurgery, Herz- und Gefaessklinik GmbH, Bad Neustadt an der Saale (Germany); Schmitt, R. [Department of Radiology, Herz- und Gefaessklinik GmbH, Salzburger Leite 1, D-97616 Bad Neustadt an der Saale (Germany)

    2011-02-15

    Statins are widely used to lower increased cholesterol levels with the aim to prevent major cardiovascular events. However, they bare the risk of myotoxic side effects. We report on two patients with focal weakness and pain in the upper extremities. In both patients, abnormal MRI signal heights in the muscle groups involved were indicative of the final diagnosis of focal myositis during statin therapy.

  1. Medical and Surgical Treatment in Pediatric Orbital Myositis Associated with Coxsackie Virus.

    Science.gov (United States)

    Gil, Pedro; Gil, João; Paiva, Catarina; Castela, Guilherme; Castela, Rui

    2015-01-01

    Purpose. To report a case of orbital myositis associated with Coxsackie virus and its medical and surgical approach. Methods. Complete ophthalmological examination and imaging and analytical investigation were performed. Results. A 6-year-old male presented with subacute painless binocular horizontal diplopia. Examination revealed bilateral best-corrected visual acuity (BCVA) of 20/20 and right eye 45-prism-dioptre (PD) esotropia in near and distance fixations, with no motility restrictions. Serologic screening was positive for Coxsackie virus acute infection and computerized tomography (CT) suggested right eye medial rectus orbital myositis. An oral corticosteroid 1.0 mg/kg/day regimen was started. A new CT after two months showed symmetrical lesions in both medial rectus muscles. Corticosteroids were increased to 1.5 mg/kg/day. After imagiological resolution on the 4th month, alternating 45 PD esotropia persisted. Bilateral 7 mm medial rectus recession was performed after 1 year without spontaneous recovery. At 1-year follow-up, the patient is orthophoric with 200'' stereopsis and bilateral 20/20 BCVA. Conclusions. To our knowledge, this is the first reported case of orbital myositis associated with Coxsackie virus. This is also the first reported case of isolated strabismus surgery after orbital myositis in pediatric age, highlighting the favourable aesthetic and functional outcomes even in cases of late ocular motility disorders.

  2. Humanized in vivo Model for Autoimmune Diabetes

    Science.gov (United States)

    2010-05-07

    guinea - pig polyclonal anti-insulin (1:100 dilution, Abcam Ab7842-500, Cambridge, MA) and a secondary goat anti- guinea - pig Alexa-fluor 568 (1:100 dilu...which is reported to accelerate experimental autoimmune encephalomyelitis (a mouse model of multiple sclerosis). Our reasoning was that, as T cells...HL, Sobel RA, Kuchroo VK. IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4

  3. Vitiligo and Autoimmune Thyroid Disorders

    Directory of Open Access Journals (Sweden)

    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.

  4. CX3CL1 (fractalkine and CX3CR1 expression in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis: kinetics and cellular origin

    Directory of Open Access Journals (Sweden)

    Olsson Tomas

    2005-07-01

    Full Text Available Abstract Background Multiple sclerosis (MS is a chronic inflammatory disease of the central nervous system (CNS. It is associated with local activation of microglia and astroglia, infiltration of activated macrophages and T cells, active degradation of myelin and damage to axons and neurons. The proposed role for CX3CL1 (fractalkine in the control of microglia activation and leukocyte infiltration places this chemokine and its receptor CX3CR1 in a potentially strategic position to control key aspects in the pathological events that are associated with development of brain lesions in MS. In this study, we examine this hypothesis by analyzing the distribution, kinetics, regulation and cellular origin of CX3CL1 and CX3CR1 mRNA expression in the CNS of rats with an experimentally induced MS-like disease, myelin oligodendrocyte glycoprotein (MOG-induced autoimmune encephalomyelitis (EAE. Methods The expression of CX3CL1 and its receptor CX3CR1 was studied with in situ hybridization histochemical detection of their mRNA with radio labeled cRNA probes in combination with immunohistochemical staining of phenotypic cell markers. Both healthy rat brains and brains from rats with MOG EAE were analyzed. In defined lesional stages of MOG EAE, the number of CX3CR1 mRNA-expressing cells and the intensity of the in situ hybridization signal were determined by image analysis. Data were statistically evaluated by ANOVA, followed by Tukeyprimes multiple comparison test. Results Expression of CX3CL1 mRNA was present within neuronal-like cells located throughout the neuraxis of the healthy rat. Expression of CX3CL1 remained unaltered in the CNS of rats with MOG-induced EAE, with the exception of an induced expression in astrocytes within inflammatory lesions. Notably, the brain vasculature of healthy and encephalitic animals did not exhibit signs of CX3CL1 mRNA expression. The receptor, CX3CR1, was expressed by microglial cells in all regions of the healthy brain

  5. Sirolimus for Autoimmune Disease of Blood Cells

    Science.gov (United States)

    2017-11-02

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

  6. Single dose of glycoengineered anti-CD19 antibody (MEDI551) disrupts experimental autoimmune encephalomyelitis by inhibiting pathogenic adaptive immune responses in the bone marrow and spinal cord while preserving peripheral regulatory mechanisms.

    Science.gov (United States)

    Chen, Ding; Blazek, Monica; Ireland, Sara; Ortega, Sterling; Kong, Xiangmei; Meeuwissen, Anouk; Stowe, Ann; Carter, Laura; Wang, Yue; Herbst, Ronald; Monson, Nancy L

    2014-11-15

    Plasma cells and the autoreactive Abs they produce are suspected to contribute to the pathogenesis of multiple sclerosis, but recent attempts to target these components of humoral immunity have failed. MEDI551, an anti-CD19 Ab that depletes mature B cells including plasma cells may offer a compelling alternative that reduces pathogenic adaptive immune responses while sparing regulatory mechanisms. Indeed, our data demonstrate that a single dose of MEDI551, given before or during ongoing experimental autoimmune encephalomyelitis, disrupts development of the disease. Leukocyte infiltration into the spinal cord is significantly reduced, as well as short-lived and long-lived autoreactive CD138(+) plasma cells in the spleen and bone marrow, respectively. In addition, potentially protective CD1d(hi)CD5(+) regulatory B cells show resistance to depletion, and myelin-specific Foxp3(+) regulatory T cells are expanded. Taken together, these results demonstrate that MEDI551 disrupts experimental autoimmune encephalomyelitis by inhibiting multiple proinflammatory components whereas preserving regulatory populations. Copyright © 2014 by The American Association of Immunologists, Inc.

  7. 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

  8. Non-traumatic myositis ossificans mimicking a malignant neoplasm in an 83-year-old woman: a case report

    Directory of Open Access Journals (Sweden)

    Nishio Jun

    2010-08-01

    Full Text Available Abstract Introduction Myositis ossificans is a benign, self-limiting condition that usually affects young, athletically active men. To the best of our knowledge, this case report describes the oldest recorded patient with myositis ossificans. Case presentation Our patient was an 83-year-old Japanese woman who presented with a one week history of a palpable mass in the left thigh. She had a history of surgery for transverse colon cancer and lung cancer at the ages of 73 and 80, respectively. Clinical and radiological examinations suggested a malignant neoplasm such as metastatic carcinoma or extraskeletal osteosarcoma. A diagnosis of myositis ossificans was made by core needle biopsy. Our patient was asymptomatic and had no recurrence at one year follow-up. Conclusion Clinicians should consider myositis ossificans as a possible diagnosis for a soft tissue mass in the limb of an older patient, thereby avoiding unnecessarily aggressive therapy.

  9. 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

  10. [Thymoma and autoimmune diseases].

    Science.gov (United States)

    Jamilloux, Y; Frih, H; Bernard, C; Broussolle, C; Petiot, P; Girard, N; Sève, P

    2018-01-01

    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.

  11. 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...... and another to an autoimmune steady state characterized by widespread tissue damage and immune activation. We show how a triggering event may move the system from the healthy to the autoimmune state and how transient immunosuppressive treatment can move the system back to the healthy state....

  12. A novel antigen-toxin chimeric protein: myelin basic protein-pseudomonas exotoxin (MBP-PE 40) for treatment of experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Brenner, T; Steinberger, I; Soffer, D; Beraud, E; Ben-Nun, A; Lorberboum-Galski, H

    1999-06-01

    Myelin basic protein (MBP), is a major component of the central nervous system (CNS) myelin. MBP can stimulate T cells that migrate into the CNS, initiating a cascade of events that result in perivascular infiltration and demyelination. EAE is an inflammatory and demyelinating autoimmune disease of the CNS that serves as a model for the human disease Multiple Sclerosis (MS). Taking advantage of the fact that EAE can be mediated by T cells, able to recognize MBP or its peptides, we developed a new approach to target anti-MBP T cells by fusing an MBP-sequence to a toxin. In the new chimeric protein, an oligonucleotide coding for the guinea pig MBP encephalitogenic moiety (residues 68-88) was fused to a cDNA encoding a truncated form of the PE gene (PE40). The chimeric gene termed MBP-PE was expressed in E. coli and highly purified. MBP-PE chimeric protein was cytotoxic to various anti-MBP T cells. Moreover, treatment with the novel MBP-toxin blocked the clinical signs of EAE as well as CNS inflammation and demyelination. A chimeric protein such as MBP-PE40 presents a novel prototype of chimeric proteins, composed of antigen/peptide-toxin, that could prove to be an efficient and specific immunotherapeutic agent for autoimmune diseases in which a known antigen is involved.

  13. Stochastic Effects in Autoimmune Dynamics

    Directory of Open Access Journals (Sweden)

    Farzad Fatehi

    2018-02-01

    Full Text Available Among various possible causes of autoimmune disease, an important role is played by infections that can result in a breakdown of immune tolerance, primarily through the mechanism of “molecular mimicry”. In this paper we propose and analyse a stochastic model of immune response to a viral infection and subsequent autoimmunity, with account for the populations of T cells with different activation thresholds, regulatory T cells, and cytokines. We show analytically and numerically how stochasticity can result in sustained oscillations around deterministically stable steady states, and we also investigate stochastic dynamics in the regime of bi-stability. These results provide a possible explanation for experimentally observed variations in the progression of autoimmune disease. Computations of the variance of stochastic fluctuations provide practically important insights into how the size of these fluctuations depends on various biological parameters, and this also gives a headway for comparison with experimental data on variation in the observed numbers of T cells and organ cells affected by infection.

  14. American Autoimmune Related Diseases Association

    Science.gov (United States)

    ... List Common Thread Women & Autoimmunity Diagnosis Tips Coping Tools Support Groups Education Modules Caregivers Patient/Caregiver Relationship The Male Caregiver AD Knowledge Base Autoimmune Disease List Common ...

  15. 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.

  16. Update in endocrine autoimmunity.

    Science.gov (United States)

    Anderson, Mark S

    2008-10-01

    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. Rapid progress has recently been made in our understanding of the genetic factors involved in endocrine autoimmune diseases. Studies on monogenic autoimmune diseases that include endocrine phenotypes like autoimmune polyglandular syndrome type 1 and immune dysregulation, polyendocrinopathy, enteropathy, X-linked have helped reveal the role of key regulators in the maintenance of immune tolerance. Highly powered genetic studies have found and confirmed many new genes outside of the established role of the human leukocyte antigen locus with these diseases, and indicate an essential role of immune response pathways in these diseases. Progress has also been made in identifying new autoantigens and the development of new animal models for the study of endocrine autoimmunity. Finally, although hormone replacement therapy is still likely to be a mainstay of treatment in these disorders, there are new agents being tested for potentially treating and reversing the underlying autoimmune process. Although autoimmune endocrine disorders are complex in etiology, these recent advances should help contribute to improved outcomes for patients with, or at risk for, these disorders.

  17. Disruption of the β2-integrin CD11d (αDβ2) gene fails to protect against experimental autoimmune encephalomyelitis

    Science.gov (United States)

    Adams, Jillian E.; Webb, Matthew S.; Hu, Jane; Staunton, Don; Barnum, Scott R.

    2009-01-01

    The fourth member of the β2-integrin family of adhesion molecules, CD11d (αDβ2), is expressed on a wide variety of immune cells, however its function in autoimmune diseases, including EAE remains unknown. We induced EAE in wild type and CD11d-/- C57BL/6 mice using myelin oligodendrocyte glycoprotein (MOG35-55) peptide. The clinical course and histopathology of EAE was identical in both groups of mice throughout the disease course. There were no significant differences in the infiltration of leukocyte subsets into the central nervous system or in the production of cytokines from T cells isolated from the spleen or spinal cord from both groups of mice. Our data demonstrate that CD11d is not required for the development of EAE and, to date, is the only β2-integrin molecule whose deletion does not result in attenuated disease. PMID:17254640

  18. 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

    examined the utility of using in vitro and in vivo ligand binding to the PBR as a measure of lesion activity in autoimmune CNS demyelinating diseases. Applying a combined autoradiography and immunohistochemical approach to spinal cord and brain tissues from mice with EAE, we found a correlation at sites...... tomography (PET) imaging with [11C]-PK11195 showed ligand uptake only at sites of active MS lesions defined by magnetic resonance imaging criteria. Our results indicate the potential to develop markers suitable for both in vitro and in vivo use, which will serve to help correlate phenotypic and functional...... of inflammatory lesions between [3H]-PK11195 binding and immunoreactivity for the activated microglial/macrophage marker Mac-1/CD11b. In MS tissues, [3H]-PK11195 binding correlated with sites of immunoreactivity for the microglial/macrophage marker CD68, at the edges of chronic active plaques. Positron emission...

  19. Association of inclusion body myositis with T cell large granular lymphocytic leukaemia

    DEFF Research Database (Denmark)

    Greenberg, Steven A; Pinkus, Jack L; Amato, Anthony A

    2016-01-01

    SEE HOHLFELD AND SCHULZE-KOOPS DOI101093/BRAIN/AWW053 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Inclusion body myositis and T cell large granular lymphocytic leukaemia are rare diseases involving pathogenic cytotoxic CD8+ T cells. After encountering four patients with both disorders, we...... on follow-up testing in 15 patients a median of 350 days later. T cell aberrant loss of CD5 or gain of expression of CD16 and CD94 were common (19/42, 45%). In comparison, 2/15 (14%) age-matched patients with dermatomyositis, polymyositis, or necrotizing myopathy, and 0/20 (0%) age-matched healthy subjects...... prospectively screened 38 patients with inclusion body myositis for the presence of expanded large granular lymphocyte populations by standard clinical laboratory methods (flow cytometry, examination of blood smears, and T cell receptor gene rearrangements), and performed muscle immunohistochemistry for CD8, CD...

  20. A case of acute orbital myositis which was difficult to diagnose at first

    International Nuclear Information System (INIS)

    Yamamoto, Kiyoshi; Terabayashi, Tadasu; Mori, Hiroshi; Niida, Hirohito; Sugiyama, Yoshiaki; Nakagawa, Masato

    1988-01-01

    We report a case of acute orbital myositis. A 61-year-old woman exhibited acute orbital pain, diplopia, and left proptosis. Examination revealed a 5-mm left proptosis, left chemosis, and limitations in all directions of the movement of the left eye. Visual acuity was unimpaired, however, and the neurological examination was otherwise normal. CT demonstrated a left inferior orbital mass. We suspected an acute orbital pseudotumor based on the rapid onset and the clinical symptoms. We treated her with systemic corticosteroids. Four weeks later CT documented a reduced left orbital mass; there seemed to be left only an inferior rectus muscle enlargement. We diagnosed acute orbital myositis, a subgroup of orbital pseudotumors, based upon the rapid clinical presentation, the CT features, and the resolution after treatment with systemic corticosteroids. (author)

  1. MR imaging and ultrasonography findings of early myositis ossificans: a case report

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Kyung Ryeol [Jeju National University Hospital, Department of Radiology, Jeju-si, Jeju Special Self-Governing Province (Korea, Republic of); Park, So Young; Jin, Wook [Kyung Hee University Hospital at Gangdong, Department of Radiology, Seoul (Korea, Republic of); Won, Kyu Yeoun [Kyung Hee University Hospital at Gangdong, Department of Pathology, Seoul (Korea, Republic of)

    2016-10-15

    Myositis ossificans (MO) is a benign soft tissue lesion with non-neoplastic heterotopic bone formation. MO in the intermediate and mature stages can be easily diagnosed if characteristic imaging findings such as a peripheral zonal pattern of ossification with variable thickness is observed. However, it is difficult to correctly diagnose early MO because it can mimic malignancy clinically, radiologically, and histopathologically. We report a case of early pseudosarcomatous phase of non-traumatic MO with atypical imaging findings. A 59-year-old woman presented with pain followed by a mass in the left thigh within a week. MR imaging and ultrasonography showed an intramuscular lesion with preserved muscle fascicles in the vastus lateralis muscle. Intralesional ossification or calcification was not seen on ultrasonography. A diagnosis of myositis ossificans was made by ultrasonographically guided biopsy. (orig.)

  2. [Ocular myositis as a rare cause of vision loss].

    Science.gov (United States)

    Rollnik, J D; Requadt, H

    2017-04-01

    Ocular myositis is a rare disease characterized by painful diplopia but loss of vision rarely occurs. The article reviews the literature focusing on the differential diagnostics. We report the case of an 80-year-old women suffering from slowly progressive loss of vision in the left eye. Diplopia was only present at the beginning and there was only moderate pain. Computed tomography and magnetic resonance imaging revealed a swelling of the left medial, lateral and inferior rectus muscles of the orbit leading to compression of the optic nerve in the orbital cone. An intravenous prednisolone stoss therapy (1000 mg per day for 3 consecutive days) was initiated, followed by oral medication of 100 mg per day then tapering over 10 weeks. Vision improved and no relapses were observed. Physicians should be aware of this rare disease to ensure quick diagnosis and treatment of ocular myositis.

  3. A rare case of Enterococcus faecalis-induced orbital cellulitis and myositis.

    Science.gov (United States)

    Kohli, Piyush; Ichhpujani, Parul; Bansal, Rakesh Kumar; Kumar, Suresh

    2016-08-01

    Orbital cellulitis is an infection of soft tissue behind the orbital septum. Common pathogens isolated include Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus pneumoniae. It is a straightforward diagnosis and usually responds to empirical treatment without any sequela. We report a case of orbital cellulitis caused by Enterococcus faecalis, which was complicated by myositis of levator palpebrae superioris. To the best of our knowledge, only one case report exists dating way back to 1986.

  4. Vaccine-induced myositis with intramuscular sterile abscess formation: MRI and ultrasound findings

    Energy Technology Data Exchange (ETDEWEB)

    Polat, Ahmet Veysel; Bekci, Tumay; Selcuk, Mustafa Bekir [Ondokuz Mayis University, Department of Radiology, Faculty of Medicine, Samsun (Turkey); Dabak, Nevzat [Ondokuz Mayis University, Department of Orthopaedics and Traumatology, Faculty of Medicine, Samsun (Turkey); Ulu, Esra Meltem Kayahan [Samsun Medical Park Hospital, Department of Radiology, Samsun (Turkey)

    2015-12-15

    Although limb swelling is a well-known complication of vaccination, its rarity and wide band of differential diagnosis of limb swelling make it a diagnostic challenge. In this case report, we describe three cases of vaccine-induced myositis with intramuscular sterile abscess formation in patients with limb swelling and their magnetic resonance imaging and ultrasonography findings. Both radiologists and clinicians should be familiar with this rare entity, its clinical and imaging spectrum, and follow-up strategies. (orig.)

  5. A rare case of Enterococcus faecalis-induced orbital cellulitis and myositis

    Directory of Open Access Journals (Sweden)

    Piyush Kohli

    2016-01-01

    Full Text Available Orbital cellulitis is an infection of soft tissue behind the orbital septum. Common pathogens isolated include Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus pneumoniae. It is a straightforward diagnosis and usually responds to empirical treatment without any sequela. We report a case of orbital cellulitis caused by Enterococcus faecalis, which was complicated by myositis of levator palpebrae superioris. To the best of our knowledge, only one case report exists dating way back to 1986.

  6. Mosaic Tetrasomy 9p: A Mendelian Condition Associated With Pediatric-Onset Overlap Myositis.

    Science.gov (United States)

    Frémond, Marie-Louise; Gitiaux, Cyril; Bonnet, Damien; Guiddir, Tamazoust; Crow, Yanick J; de Pontual, Loïc; Bader-Meunier, Brigitte

    2015-08-01

    Pediatric-onset inflammatory myositis (IM) and systemic lupus erythematosus (SLE) are rare inflammatory diseases. Both result from the complex interaction of genetic and environmental factors. An increasing number of Mendelian conditions predisposing to the development of SLE have been recently identified. These include monogenic conditions, referred to as the type I interferonopathies, associated with a primary upregulation of type I interferon (IFN), a key cytokine in the pathogenesis of SLE and some cases of IM. Here, we report on a pediatric-onset inflammatory overlap phenotype in a 6-year-old girl who was shown to carry mosaic tetrasomy 9p. The patient presented with myositis overlapping with lupuslike features. Myositis was characterized by a proximal muscular weakness and HLA class I antigen myofiber overexpression on muscle biopsy. Lupus-like manifestations consisted of pericarditis, pleuritis, and positive antinuclear and anti-SSA (Sjögren-syndrome A) antibodies. Complete remission was achieved with corticosteroids and mycophenolate mofetyl. Analysis of tetrasomy 9p showed mosaic tetrasomy in the 9p24.3q12 region, including the type I IFN cluster, and increased expression of IFN-stimulated genes. These data suggest that mosaic tetrasomy 9p can be associated with an upregulation of type I IFN signaling, predisposing to inflammatory myositis and lupus-like features. Thus, unexplained muscle or other organ involvement in patients carrying mosaic tetrasomy of the type IFN cluster of chromosome 9p should lead to the search for IM and/or lupuslike disease, and karyotype should be performed in patients with SLE or IM with mental retardation. Copyright © 2015 by the American Academy of Pediatrics.

  7. Adult bacterial myositis: report of a single-center series of 26 cases

    Directory of Open Access Journals (Sweden)

    Fernando Gallucci

    2016-09-01

    Full Text Available Bacterial infections involving muscle are quite uncommon and generally require specific predisposing factors. Bacterial myositis is more rarely described in the typical kind of patients observed in Internal Medicine (presence of multiple co-morbidities, partial/limited immune-deficiency, advanced age. Twenty-six patients suffering from bacterial myositis (8 women and 18 men; mean age 58.5 years, range 27-82 observed in a single Internal Medicine Unit were reported. Muscles involved were ileopsoas, thigh, paravertebral, gluteus, calf, forearm and rectus abdomen. Simultaneous presence of arthritis was registered in 17 patients and all patients presented relevant comorbidity. Main cultured bacteria were Staphylococcus aureus, Escherichia coli, other Gram-negative bacteria, Streptococcus spp. Multi-drug-resistance was observed in 14 out 26 (53.8%. Computed tomography, ultrasound and magnetic resonance imaging were utilized for diagnostic purposes. Antibiotic treatment was administered to all patients. Surgical debridement and drainage were performed in 12 patients; 7 patients were treated with percutaneous aspiration and drainage. At discharge, relevant functional impairment was present in 17 patients (65.3%. Four patients died (in-hospital mortality 7.6%, global mortality at three months 15.3%. Management of bacterial myositis is difficult and its prognosis is poor. In the near future, this demanding infection will be more frequently observed in Internal Medicine setting as comorbidity, which is very often the main characteristic of these patients.

  8. Outcome of Benign Acute Childhood Myositis: The Experience of 2 Large Tertiary Care Pediatric Hospitals.

    Science.gov (United States)

    Rosenberg, Tom; Heitner, Shmuel; Scolnik, Dennis; Levin Ben-Adiva, Einav; Rimon, Ayelet; Glatstein, Miguel

    2016-08-20

    The aims of the study were to determine the evolution of benign acute childhood myositis in children and to assess the relationship between creatine phosphokinase (CPK) values and myoglobinuria. A retrospective study of patients with benign acute childhood myositis seen in 2 tertiary care university-affiliated pediatric hospitals during overlapping 4-year periods. Demographic data, historical details, clinical, and laboratory results were extracted from the charts of children younger than 16 years with a CPK greater than 3 times normal. Complications, treatments, and outcomes were recorded. Fifty-four children were included, 43 (80%) were male, and mean age was 7.3 years (median [range], 6 [3-16] years), none showed abnormal neurological findings, manifested hematuria, or developed renal failure. Mean CPK level at presentation was 1872 IU/L (range, 511-8086 IU/L). None developed renal failure, and there were no adverse outcomes on follow-up. Acute childhood myositis is a predominantly benign disease. Neurological examination is usually normal and rhabdomyolysis is rare. Although severe pathological comorbid conditions must be excluded, a complete history and examination, coupled with simple blood and urine tests, can help minimize unnecessary diagnostic investigations.

  9. Necrotizing myositis causes restrictive hypoventilation in a mouse model for human enterovirus 71 infection.

    Science.gov (United States)

    Xiu, Jing-hui; Zhu, Hao; Xu, Yan-feng; Liu, Jiang-ning; Xia, Xian-zhu; Zhang, Lian-feng

    2013-06-28

    Enterovirus 71 (EV71) infections are associated with a high prevalence of hand, foot and mouth disease (HFMD) in children and occasionally cause lethal complications. Most infections are self-limiting. However, resulting complications, including aseptic meningitis, encephalitis, poliomyelitis-like acute flaccid paralysis, and neurological pulmonary edema or hemorrhage, are responsible for the lethal symptoms of EV71 infection, the pathogenesis of which remain to be clarified. In the present study, 2-week-old Institute of Cancer Research (ICR) mice were infected with a mouse-adapted EV71 strain. These infected mice demonstrated progressive paralysis and died within 12 days post infection (d.p.i.). EV71, which mainly replicates in skeletal muscle tissues, caused severe necrotizing myositis. Lesions in the central nervous system (CNS) and other tissues were not observed. Necrotizing myositis of respiratory-related muscles caused severe restrictive hypoventilation and subsequent hypoxia, which could explain the fatality of EV71-infected mice. This finding suggests that, in addition to CNS injury, necrotic myositis may also be responsible for the paralysis and death observed in EV71-infected mice.

  10. Inhibition of myeloperoxidase by N-acetyl lysyltyrosylcysteine amide reduces experimental autoimmune encephalomyelitis-induced injury and promotes oligodendrocyte regeneration and neurogenesis in a murine model of progressive multiple sclerosis.

    Science.gov (United States)

    Yu, Guoliang; Zheng, Shikan; Zhang, Hao

    2018-02-07

    It is known that oxidative stress produced by proinflammatory myeloid cells plays an important role in demyelination and neuronal injury in progressive multiple sclerosis (MS). Myeloperoxidase (MPO) is a pro-oxidative enzyme released from myeloid cells during inflammation. It has been shown that MPO-dependent oxidative stress plays important roles in inducing tissue injury in many inflammatory diseases. In this report, we treated NOD experimental autoimmune encephalomyelitis (EAE) mice, a murine model of progressive MS, with N-acetyl lysyltyrosylcysteine amide (KYC), a novel specific MPO inhibitor. Our data showed that KYC treatment not only attenuated MPO-mediated oxidative stress but also reduced demyelination and axonal injury in NOD EAE mice. More importantly, we found that KYC treatment increased oligodendrocyte regeneration and neurogenesis in NOD EAE mice. Taken together, our data suggests that targeting MPO should be a good therapeutic approach for reducing oxidative injury and preserving neuronal function in progressive MS patients.

  11. Impaired hapten sensitization in patients with autoimmune disease

    DEFF Research Database (Denmark)

    Bangsgaard, N; Engkilde, K; Menné, T

    2011-01-01

    An inverse relation between contact allergy and autoimmune diseases is suggested from epidemiological studies. The aim of this study was to investigate susceptibility and reactivity in patients with psoriasis, patients with diabetes and healthy controls in an experimental sensitization study. We...... in individuals with autoimmune diseases such as psoriasis....

  12. Autologous hematopoietic stem cell transplantation for autoimmune diseases.

    NARCIS (Netherlands)

    Gratwohl, A.; Passweg, J.R.; Bocelli-Tyndall, C.; Fassas, A.; Laar, J.M. van; Farge, D.; Andolina, M.; Arnold, R.; Carreras, E.; Finke, J.; Kotter, I.; Kozak, T.; Lisukov, I.; Lowenberg, B.; Marmont, A.; Moore, J.; Saccardi, R.; Snowden, J.A.; Hoogen, F.H.J. van den; Wulffraat, N.M.; Zhao, X.; Tyndall, A.

    2005-01-01

    Experimental data and early phase I/II studies suggest that high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) can arrest progression of severe autoimmune diseases. We have evaluated the toxicity and disease response in 473 patients with severe autoimmune

  13. Clinical Manifestations and Myositis-Specific Autoantibodies Associated with Physical Dysfunction after Treatment in Polymyositis and Dermatomyositis: An Observational Study of Physical Dysfunction with Myositis in Japan

    Directory of Open Access Journals (Sweden)

    Hidenaga Kawasumi

    2016-01-01

    Full Text Available Objective. The physical function of PM/DM patients after remission induction therapy remains unknown adequately. The aim of our study was to evaluate the present status of physical dysfunction and to clarify the clinical manifestations and myositis-specific autoantibodies (MSAs associated with physical dysfunction after treatment in PM/DM. Methods. We obtained clinical data including the age at disease onset, gender, disease duration, laboratory data prior to initial treatment, and the specific treatment administered. We evaluated disease activity and physical dysfunction after treatment using the core set provided by the International Myositis Assessment and Clinical Studies Group. Results. 57% of the 77 enrolled patients with PM/DM had troubles in daily living after treatment. At the enrolment, disease activity evaluated by physicians was only revealed in 20% of patients. In a multivariate analysis, the age at disease onset, female gender, and CK levels before treatment were significantly associated with the severity of physical dysfunction after treatment. Anti-SRP positivity was associated with more severe physical dysfunction after treatment than anti-ARS or anti-MDA5. Conclusions. Half of the PM/DM patients showed physical dysfunction after treatment. Age at disease onset, gender, CK level before treatment, and anti-SRP were significant predictors associated with physical dysfunction after treatment in PM/DM.

  14. Psoriasis and autoimmunity.

    Science.gov (United States)

    Sticherling, Michael

    2016-12-01

    Psoriasis is one of the most common chronic inflammatory human skin diseases. Though clinically well characterized, the exact etiological and pathogenic mechanisms are still not known in detail. Current knowledge indicates distinct overlap to other inflammatory as well as autoimmune disorders. However, the one or more relevant autoantigens could not be characterized so-far. On the other side, several autoimmune diseases were shown to be associated with psoriasis. In addition, serological autoimmune phenomena, namely diverse circulating specific autoantibodies could be demonstrated in the past. A matter of current debate is if psoriasis is a primary autoimmune disease or secondarily evolving into autoimmunity as seen in other chronic inflammatory diseases. Related to this aspect is the concept of autoinflammation versus autoimmunity where psoriasis shares mechanisms of both entities. Though T-cells remain among the most important cellular players in the pathogenesis of psoriasis and current therapeutic strategies successfully target these cells or their products irrespective of these concepts, autoimmunity if relevant will add to the treatment armamentarium by using protective and prophylactic antigen-specific modalities. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. 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.

  16. Nickel-induced allergy and contact dermatitis: does it induce autoimmunity and cutaneous sclerosis? An experimental study in Brown Norway rats.

    Science.gov (United States)

    Al-Mogairen, Sultan M; Meo, Sultan Ayoub; Al-Arfaj, Abdurhman S; Hamdani, Muhammad; Husain, Sufia; Al-Mohimed, Bandar; Adam, M; Al-Hammad, A; El Rab, Mohammed O Gad

    2010-07-01

    Nickel sensitization is a growing problem and the most common cause of allergic contact dermatitis. The aim of this study was to investigate whether nickel chloride can induce autoimmunity and cutaneous sclerosis in immunosensitive rats. Nickel chloride, in a dose of 4.5 mg in 0.2 ml NS, was administered by the oral and subcutaneous routes to 20 Brown Norway rats. Autoantibodies (ANA, anti-RNP, anti-SCL70 and anti-centromere) were measured and compared in pre- and post-challenge serum samples. Histological studies were also performed in skin biopsies obtained from six positively responding rats and compared with an equal number of control rats at the 14th week post-challenge. Serum ANA was high in a significant number of rats in both the oral (P nickel-treated groups (P = 0.02), while the anti-SCL70 was high in a significant number of rats in only the orally nickel-treated group (P = 0.04). Histologically, subcutaneous and oral nickel-treated groups showed sclerodermic features of the skin (P = 0.22, P = 0.5), respectively. It may be concluded that nickel chloride can induce scleroderma-related autoantibodies and cutaneous sclerosis. More prolonged duration of exposure is probably associated with greater risk. This is the first study showing the potential risk of nickel in triggering the development of cutaneous sclerosis in susceptible hosts.

  17. Peripheral phosphodiesterase 4 inhibition produced by 4-[2-(3,4-Bis-difluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl]-3-methylpyridine-1-oxide (L-826,141) prevents experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Moore, Craig S.; Earl, Nathalie; Frenette, Richard

    2006-01-01

    Administration of phosphodiesterase 4 (PDE4) inhibitors suppresses the pathogenesis associated with experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In the present study, we compared the effects of rolipram and 4-[2-(3,4-bis-difluoromethoxyphenyl)-2...

  18. Stress proteins, autoimmunity, and autoimmune disease.

    Science.gov (United States)

    Winfield, J B; Jarjour, W N

    1991-01-01

    At birth, the immune system is biased toward recognition of microbial antigens in order to protect the host from infection. Recent data suggest that an important initial line of defense in this regard involves autologous stress proteins, especially conserved peptides of hsp60, which are presented to T cells bearing gamma delta receptors by relatively nonpolymorphic class lb molecules. Natural antibodies may represent a parallel B cell mechanism. Through an evolving process of "physiological" autoreactivity and selection by immunodominant stress proteins common to all prokaryotes, B and T cell repertoires expand during life to meet the continuing challenge of infection. Because stress proteins of bacteria are homologous with stress proteins of the host, there exists in genetically susceptible individuals a constant risk of autoimmune disease due to failure of mechanisms for self-nonself discrimination. That stress proteins actually play a role in autoimmune processes is supported by a growing body of evidence which, collectively, suggests that autoreactivity in chronic inflammatory arthritis involves, at least initially, gamma delta cells which recognize epitopes of the stress protein hsp60. Alternate mechanisms for T cell stimulation by stress proteins undoubtedly also exist, e.g., molecular mimicry of the DR beta third hypervariable region susceptibility locus for rheumatoid arthritis by a DnaJ stress protein epitope in gram-negative bacteria. While there still is confusion with respect to the most relevant stress protein epitopes, a central role for stress proteins in the etiology of arthritis appears likely. Furthermore, insight derived from the work thus far in adjuvant-induced arthritis already is stimulating analyses of related phenomena in autoimmune diseases other than those involving joints. Only limited data are available in the area of humoral autoimmunity to stress proteins. Autoantibodies to a number of stress proteins have been identified in SLE and

  19. Depletion of CD4+CD25+ regulatory T cells exacerbates sodium iodide-induced experimental autoimmune thyroiditis in human leucocyte antigen DR3 (DRB1*0301) transgenic class II-knock-out non-obese diabetic mice.

    Science.gov (United States)

    Flynn, J C; Meroueh, C; Snower, D P; David, C S; Kong, Y M

    2007-03-01

    Both genetic and environmental factors contribute to autoimmune disease development. Previously, we evaluated genetic factors in a humanized mouse model of Hashimoto's thyroiditis (HT) by immunizing human leucocyte antigen DR3 (HLA-DR3) and HLA-DQ8 transgenic class II-knock-out non-obese diabetic (NOD) mice. DR3+ mice were susceptible to experimental autoimmune thyroiditis (EAT) induction by both mouse thyroglobulin (mTg) and human (h) Tg, while DQ8+ mice were weakly susceptible only to hTg. As one environmental factor associated with HT and tested in non-transgenic models is increased sodium iodide (NaI) intake, we examined the susceptibility of DR3+ and/or DQ8+ mice to NaI-induced disease. Mice were treated for 8 weeks with NaI in the drinking water. At 0 x 05% NaI, 23% of DR3+, 0% of DQ8+ and 20% of DR3+DQ8+ mice had thyroid destruction. No spleen cell proliferation to mTg was observed. Most mice had undetectable anti-mTg antibodies, but those with low antibody levels usually had thyroiditis. At 0.3% NaI, a higher percentage of DR3+ and DR3+DQ8+ mice developed destructive thyroiditis, but it was not statistically significant. However, when DR3+ mice had been depleted of CD4+CD25+ regulatory T cells prior to NaI treatment, destructive thyroiditis (68%) and serum anti-mTg antibodies were exacerbated further. The presence of DQ8 molecules does not alter the susceptibility of DR3+DQ8+ mice to NaI-induced thyroiditis, similar to earlier findings with mTg-induced EAT. Susceptibility of DR3+ mice to NaI-induced EAT, in both the presence and absence of regulatory T cells, demonstrates the usefulness of HLA class II transgenic mice in evaluating the roles of environmental factors and immune dysregulation in autoimmune thyroid disease.

  20. Self-resolving focal non-ossifying myositis: a poorly known clinical and imaging entity diagnosed with MRI

    International Nuclear Information System (INIS)

    Perlepe, Vasiliki; Dallaudière, Benjamin; Omoumi, Patrick; Hristova, Lora; Rezzazadeh, Afshin; Vande Berg, Bruno; Malghem, Jacques; Lecouvet, Frederic

    2015-01-01

    Focal myositis is a rare benign inflammatory pseudotumor, presenting as a painful nodular mass within a muscle, and characterized by spontaneous resolution within weeks. To assess the clinical and imaging findings of focal nodular myositis simulating a neoplasm at clinical examination, with no history of trauma. This study describes the locations and appearance at ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) of this condition in a series of five patients. MRI and US displayed a solid intramuscular “tumor” and suggested a continuum between the proximal and distal muscle fibers that appeared thickened within the nodular lesion, a sign that has been reported in myositis ossificans. MRI showed edema in adjacent muscles and soft tissues, as well as intense enhancement of the mass. Intense vascular flows were seen at Doppler analysis. CT did not reveal the appearance of peripheral ossifications, ruling out the diagnosis of myositis ossificans. In some patients, the diagnosis of sarcoma had been suggested as possible by the radiologist. Imaging follow-up with MRI showed complete resolution of the masses over several weeks, thus avoiding a biopsy; no recurrence was observed at long-term follow-up (more than 24 months). This paper highlights MRI and US findings in focal non-ossifying myositis, and emphasizes the role of MRI in suggesting this diagnosis, leading to the careful follow-up of the lesion until its resolution, and ruling out more aggressive lesions

  1. Prolactin and Autoimmunity

    Directory of Open Access Journals (Sweden)

    Vânia Vieira Borba

    2018-02-01

    Full Text Available The great asymmetry of autoimmune diseases between genders represents one of the most enigmatic observations among the mosaic of autoimmunity. Sex hormones are believed to play a crucial role on this dimorphism. The higher prevalence of autoimmunity among women at childbearing ages, disease onset/relapses during pregnancy, and post-partum are some of the arguments that support this hypothesis. Certainly, motherhood represents one of the most remarkable challenges for the immune system, which not only has to allow for the conceptus, but also has to deal with complex endocrine alterations. Hormonal homeostasis is known to exert a crucial influence in achieving a competent and healthy immune system. Prolactin (PRL has a bioactive function acting as a hormone and a cytokine. It interferes with immune system modulation, mainly inhibiting the negative selection of autoreactive B lymphocytes. Likewise, hyperprolactinemia has been described in relation to the pathogenesis and activity of several autoimmune disorders. Dopamine is an effective inhibitor of PRL secretion due to either a direct influence on the hypophysis or stimulation of postsynaptic dopamine receptors in the hypothalamus, arousing the release of the PRL inhibitory factor. Hence, dopamine agonists have proven to offer clinical benefits among autoimmune patients and represent a promising therapy to be explored. In this review, we attempt to provide a critical overview of the link between PRL, autoimmune diseases, and motherhood.

  2. Autoimmune diseases: MIF as a therapeutic target

    NARCIS (Netherlands)

    Greven, Dorothee; Leng, Lin; Bucala, Richard

    2010-01-01

    Areas covered in this review: Our aim is to discuss MIF-directed therapies as a novel therapeutic approach. The review covers literature from the past 10 years. What the reader will gain: MIF inhibition has been shown to be efficacious in many experimental and pre-clinical studies of autoimmune

  3. 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.

  4. Muscle Biopsy Findings in Combination With Myositis-Specific Autoantibodies Aid Prediction of Outcomes in Juvenile Dermatomyositis.

    Science.gov (United States)

    Deakin, Claire T; Yasin, Shireena A; Simou, Stefania; Arnold, Katie A; Tansley, Sarah L; Betteridge, Zoe E; McHugh, Neil J; Varsani, Hemlata; Holton, Janice L; Jacques, Thomas S; Pilkington, Clarissa A; Nistala, Kiran; Wedderburn, Lucy R

    2016-11-01

    Juvenile dermatomyositis (DM) is a rare and severe autoimmune condition characterized by rash and proximal muscle weakness. While some patients respond to standard treatment, others do not. This study was carried out to investigate whether histopathologic findings and myositis-specific autoantibodies (MSAs) have prognostic significance in juvenile DM. Muscle biopsy samples (n = 101) from patients in the UK Juvenile Dermatomyositis Cohort and Biomarker Study were stained, analyzed, and scored for severity of histopathologic features. In addition, autoantibodies were measured in the serum or plasma of patients (n = 90) and longitudinal clinical data were collected (median duration of follow-up 4.9 years). Long-term treatment status (on or off medication over time) was modeled using generalized estimating equations. Muscle biopsy scores differed according to MSA subgroup. When the effects of MSA subgroup were accounted for, increased severity of muscle histopathologic features was predictive of an increased risk of remaining on treatment over time: for the global pathology score (histopathologist's visual analog scale [hVAS] score), 1.48-fold higher odds (95% confidence interval [95% CI] 1.12-1.96; P = 0.0058), and for the total biopsy score (determined with the standardized score tool), 1.10-fold higher odds (95% CI 1.01-1.21; P = 0.038). A protective effect was identified in patients with anti-Mi-2 autoantibodies, in whom the odds of remaining on treatment were 7.06-fold lower (95% CI 1.41-35.36; P = 0.018) despite muscle biopsy scores indicating more severe disease. In patients with anti-nuclear matrix protein 2 autoantibodies, anti-transcription intermediary factor 1γ autoantibodies, or no detectable autoantibody, increased histopathologic severity alone, without adjustment for the effect of MSA subtype, was predictive of the risk of remaining on treatment: for the hVAS global pathology score, 1.61-fold higher odds (95% CI 1.16-2.22; P = 0

  5. Susceptibility and resistance to experimental autoimmune encephalomyelitis and neuritis in the guinea pig correlate with the induction of procoagulant and anticoagulant activities.

    Science.gov (United States)

    Geczy, C L; Roberts, I M; Meyer, P; Bernard, C C

    1984-12-01

    Activation of macrophage procoagulant activity (MPCA) is involved in the manifestation of EAE and EAN in susceptible guinea pigs and provides a mechanism for the deposition of fibrin, which is a feature of histologic lesions of EAE. Peritoneal exudate cells (PEC) from susceptible (strain 13) guinea pigs immunized with either central or peripheral nervous tissue antigens produce procoagulant activity when incubated with the immunogen in vitro. The production of the procoagulant is quantitative and antigen-specific and is maximal at the time of clinical signs of the disease. After recovery, the production of procoagulant activity decreased. The MPCA test was able to discriminate the biochemical differences existing between chicken and mammalian peripheral nerve proteins, thus providing a quantitative and sensitive indicator of cell-mediated immunity in EAE and EAN. The autoimmune response to brain and nerve antigens in nonsusceptible (strain 2) guinea pigs was coincident with the antigen-specific production of a cell-bound anticoagulant activity by stimulated mononuclear cells. The production of anticoagulant activity followed the same sequence of time changes after immunization as that of the MPCA in susceptible guinea pigs, and high immunizing doses of nerve antigens induced high levels of anticoagulant activity. The same cells produced high levels of procoagulant when incubated with tuberculin or lipopolysaccharide. The recalcification time of normal plasma was prolonged by the anticoagulant, and the decreased clotting time of plasma induced by the procoagulant activity obtained by incubating sensitized strain 13 PEC with myelin basic protein was suppressed by the anticoagulant produced by culturing sensitized strain 2 PEC with myelin basic protein. Preliminary evidence indicates that the anticoagulant has properties similar to antithrombin III. The anticoagulant could play a role in the control of effector cell function, and therefore in recovery from clinical

  6. Myositis-specific autoantibodies and their association with malignancy in Italian patients with polymyositis and dermatomyositis.

    Science.gov (United States)

    Ceribelli, Angela; Isailovic, Natasa; De Santis, Maria; Generali, Elena; Fredi, Micaela; Cavazzana, Ilaria; Franceschini, Franco; Cantarini, Luca; Satoh, Minoru; Selmi, Carlo

    2017-02-01

    This study aims to characterize myositis-specific antibodies in a well-defined cohort of patients with idiopathic inflammatory myopathy and to determine their association with cancer. Sera from 40 patients with polymyositis, dermatomyositis, and controls were tested by protein and RNA immunoprecipitation to detect autoantibodies, and immunoprecipitation-Western blot was used for anti-MJ/NXP-2, anti-MDA5, and anti-TIF1γ/α identification. Medical records were re-evaluated with specific focus on cancer. Anti-MJ/NXP-2 and anti-TIF1γ/α were the most common antibodies in dermatomyositis. In six dermatomyositis cases, we found five solid forms of cancer and one Hodgkin's lymphoma in long-term remission. Among patients with cancer-associated dermatomyositis, three were positive for anti-TIF1γ/α, two for anti-Mi-2, and one for anti-MJ/NXP-2. The strongest positivity of anti-TIF1γ was seen in two active forms of cancer, and this antibody was either negative or positive at low titers in the absence of cancer or in the 7-year remission Hodgkin's lymphoma. Four out of twenty (20 %) patients with polymyositis had solid cancer, but no specific association with autoantibodies was identified; further, none of the four cases of antisynthetase syndrome had a history of cancer. No serum myositis-associated autoantibody was observed in control sera, resulting in positive predictive value 75 %, negative predictive value 78.5 %, sensitivity 50 %, specificity 92 %, and area under the ROC curve 0.7083 for the risk of paraneoplastic DM in anti-TIF1γ/α (+) patients. Myositis-specific autoantibodies can be identified thanks to the use of immunoprecipitation, and their association with cancer is particularly clear for anti-TIF1γ/α in dermatomyositis. This association should be evaluated in a prospective study by immunoprecipitation in clinical practice.

  7. 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.

  8. Avulsion Fracture and Myositis Ossificans in a Professional Teenage Dancer: A Case Report.

    Science.gov (United States)

    Tosun, Ozgur; Koralp, Muhabbet D; Tosun, Aliye; Celebi, Levent; Bulakbaşi, Nail

    2015-06-01

    Fractures of the transverse processes in the lumbar vertebrae occur as the result of major forces such as direct blunt trauma, violent lateral flexion-extension forces, avulsion of the psoas muscle, or Malgaigne fractures of the pelvis. Dancers make repeated and forceful hyperextension and flexions of the spine, which may cause fractures of the transverse processes of the lumbar vertebrae. Repeated trauma of muscles in dancers may cause avulsion fractures and myositis ossificans. Herein, we report MRI and CT findings of an avulsion from the right transverse process of the L2 and L3 vertebrae in a 16-year-old professional teenage dancer, who responded to conservative treatment.

  9. NEUTROPHILIC MYOSITIS ASSOCIATED WITH PYODERMA GANGRENOSUM IN A BREAK-DANCER

    Directory of Open Access Journals (Sweden)

    Hisashi Tamiya

    2013-10-01

    Full Text Available Neutrophilic myositis is an extremely rare condition, cases of which have been reported in association with neutrophilic dermatosis, inflammatory bowel disease and malignant hematological disease. The disorder is histologically characterized by a sterile infiltration of neutrophils throughout muscle, with necrosis of muscle fibres. We here report the case of a young male who also had associated pyoderma gangrenosum, and who presented with necrotizing fasciitis-like manifestations. In this case, although there were no other underlying disorders, compulsive exertional stress due to break-dancing was thought to be a precipitant. Debridement of the necrotic tissues combined with oral corticosteroid treatment was effective.

  10. Proliferative myositis of the latissimus dorsi presenting in a 20-year-old male athlete

    LENUS (Irish Health Repository)

    Mc Hugh, N

    2017-08-01

    We describe the case of a 20-year-old rower presenting with an uncommon condition of Proliferative Myositis (PM) affecting the Latissimus Dorsi (LD). PM is a rare, benign tumour infrequently developing in the upper back. Its rapid growth and firm consistency may mistake it for sarcoma at presentation. Therefore, careful multidisciplinary work-up is crucial, and should involve appropriate radiological and histopathological investigations. Here, we propose the aetiology of LD PM to be persistent myotrauma induced by repetitive rowing motions. Symptoms and rate of progression ultimately determine the management which includes surveillance and\\/or conservative resection. There have been no documented cases of recurrence or malignant transformation.

  11. [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.

  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. Headache in autoimmune diseases.

    Science.gov (United States)

    John, Seby; Hajj-Ali, Rula A

    2014-03-01

    Autoimmune diseases are a group of heterogeneous inflammatory disorders characterized by systemic or localized inflammation, leading to ischemia and tissue destruction. These include disorders like systemic lupus erythematosus and related diseases, systemic vasculitides, and central nervous system (CNS) vasculitis (primary or secondary). Headache is a very common manifestation of CNS involvement of these diseases. Although headache characteristics can be unspecific and often non-diagnostic, it is important to recognize because headache can be the first manifestation of CNS involvement. Prompt recognition and treatment is necessary not only to treat the headache, but also to help prevent serious neurological sequelae that frequently accompany autoimmune diseases. In this review, we discuss headache associated with autoimmune diseases along with important mimics. © 2014 American Headache Society.

  14. Bell's palsy and autoimmunity.

    Science.gov (United States)

    Greco, A; Gallo, A; Fusconi, M; Marinelli, C; Macri, G F; de Vincentiis, M

    2012-12-01

    To review our current knowledge of the etiopathogenesis of Bell's palsy, including viral infection or autoimmunity, and to discuss disease pathogenesis with respect to pharmacotherapy. Relevant publications on the etiopathogenesis, clinical presentation, diagnosis and histopathology of Bell's palsy from 1975 to 2012 were analysed. Bell's palsy is an idiopathic peripheral nerve palsy involving the facial nerve. It accounts for 60 to 75% of all cases of unilateral facial paralysis. The annual incidence of Bell's palsy is 15 to 30 per 100,000 people. The peak incidence occurs between the second and fourth decades (15 to 45 years). The aetiology of Bell's palsy is unknown but viral infection or autoimmune disease has been postulated as possible pathomechanisms. Bell's palsy may be caused when latent herpes viruses (herpes simplex, herpes zoster) are reactivated from cranial nerve ganglia. A cell-mediated autoimmune mechanism against a myelin basic protein has been suggested for the pathogenesis of Bell's palsy. Bell's palsy may be an autoimmune demyelinating cranial neuritis, and in most cases, it is a mononeuritic variant of Guillain-Barré syndrome, a neurologic disorder with recognised cell-mediated immunity against peripheral nerve myelin antigens. In Bell's palsy and GBS, a viral infection or the reactivation of a latent virus may provoke an autoimmune reaction against peripheral nerve myelin components, leading to the demyelination of cranial nerves, especially the facial nerve. Given the safety profile of acyclovir, valacyclovir, and short-course oral corticosteroids, patients who present within three days of the onset of symptoms should be offered combination therapy. However it seems logical that in fact, steroids exert their beneficial effect via immunosuppressive action, as is the case in some other autoimmune disorders. It is to be hoped that (monoclonal) antibodies and/or T-cell immunotherapy might provide more specific treatment guidelines in the

  15. Adalimumab for orbital myositis in a patient with Crohn's disease who discontinued infliximab: a case report and review of the literature.

    Science.gov (United States)

    Verma, Sanam; Kroeker, Karen I; Fedorak, Richard N

    2013-04-04

    Orbital myositis is a rare extra-intestinal manifestation of inflammatory bowel disease. Seventeen cases of Crohn's disease associated orbital myositis and 3 cases of ulcerative colitis associated orbital myositis have been reported in the published literature since 1970. We report the use of adalimumab (Abbott, Canada, Inc.) for orbital myositis in a patient with Crohn's disease who discontinued infliximab (Janssen, Canada, Inc.) and review of the published literature. A 35 year-old male with a 7-year history of Crohn's disease was treated with an ileocolonic resection and re-anastomosis followed by infliximab which maintained full endoscopic and clinical remission for four years. After stopping the infliximab for infusion-related reactions he presented with 3-day history of severe right eye pain, pain with ocular movement, proptosis, and conjunctival injection. He had no intestinal symptoms and endoscopic assessment revealed no active luminal disease. CT of the orbit revealed an enlarged right medial rectus muscle with tendonous involvement and a diagnosis of orbital myositis was made. Treatment with 80 mg per day prednisone with tapering dose and adalimumab, induction and maintenance, resulted in rapid resolution of the orbital myositis and ocular symptoms with no recurrences on follow-up at 10 months. The current case demonstrates a rare extraintestinal manifestation of Crohn's disease, orbital myositis, and its temporal relationship to the discontinuance of infliximab therapy and its successful treatment, without recurrence with tapering prednisone and adalimumab.

  16. Preclinical Validation of 99mTc–Annexin A5–128 in Experimental Autoimmune Myocarditis and Infective Endocarditis: Comparison with 99mTc–HYNIC–Annexin A5

    Directory of Open Access Journals (Sweden)

    Khadija Benali

    2015-01-01

    Full Text Available Hydrazinonicotinamide–annexin A5 (HYNIC-Anx, a 99m technetium (99mTc-labeled agent targeting phosphatidylserine, proved to be sensitive for the detection of apoptosis and thrombosis but is no longer available for clinical use. A mutant of human annexin designed for direct 99mTc labeling (referred to as Anx A5–128 showed improved binding affinity to phosphatidylserine and is expected to be used in humans. We compared both radiotracers with regard to pharmacokinetics and diagnostic ability in animal models. Biodistribution studies were performed in normal rats. Radiolabeled Anx A5–128 and HYNIC-Anx were compared in cardiovascular settings involving phosphatidylserine expression: experimental autoimmune myocarditis and infective endocarditis. Initial blood clearance was faster for Anx A5–128 than for HYNIC-Anx, and tissue biodistribution was similar overall for both tracers. The diagnostic sensitivity of Anx A5–128 was excellent and comparable to that of HYNIC-Anx. Anx A5–128 showed biodistribution and diagnostic ability similar to those of the HYNIC-Anx derivative, supporting its translation to clinical use.

  17. The 2-min walk test is sufficient for evaluating walking abilities in sporadic inclusion body myositis.

    Science.gov (United States)

    Alfano, L N; Lowes, L P; Dvorchik, I; Yin, H; Maus, E G; Flanigan, K M; Mendell, J R

    2014-03-01

    Sporadic inclusion body myositis causes progressive functional loss due to declining muscle strength. Although the underlying cause is unknown, clinical trials are underway to improve strength and function. Selection of appropriate outcome measures is critical for the success of these trials. The 6-min walk test has been the de facto standard for assessing function in neuromuscular disease; however, the optimal walking test has not been determined in this disease. In this study, 67 individuals with sporadic inclusion body myositis completed a battery of quantitative strength and functional tests including timed walking tests, patient-reported outcomes, and other tasks. The 2-min and 6-min walk tests are highly correlated to each other (r=0.97, pwalk test, but 7% of subjects were unable to walk the full 6-min of the 6-min walk test due to fatigue. The 2-min walk test demonstrates similar correlation to all outcomes compared to the 6-min walk test, is less fatiguing and better tolerated. Results suggest that the 2-min walk test is a better alternative to tests of longer duration. Further research is needed to determine longitudinal changes on this outcome. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. [A rare complication of dysarthria in a patient with inclusion body myositis: a case report].

    Science.gov (United States)

    Isayama, Reina; Shiga, Kensuke; Tanaka, Eijirou; Itsukage, Masahiro; Tokuda, Takahiko; Nakagawa, Masanori

    2010-10-01

    We reported a 71-year-old man with inclusion body myositis with clinically overt dysarthria. He had been suffering from gradual progression of weakness in the hand muscles and lower extremities as well as dysarthria three years before admission. His neurological examination revealed muscle atrophy and weakness in the tongue, the forearm flexors, and the vastus medialis muscles. He had dysarthria to a moderate degree, while he denied any dysphasia. A biopsy from vastus lateralis muscle showed variation in fiber size, infiltration of mononucleated cells, and numerous fibers with rimmed vacuoles, leading to the diagnosis of definite inclusion body myositis. The EMG findings of the tongue demonstrated low amplitude motor unit potentials during voluntary contraction, abundant fibrillation potentials at rest, and preserved interference pattern at maximal contraction, implying myogenic changes. We surmised the dysarthria seen in this patient, an atypical clinical feature in IBM, presumably caused by muscle involvement in the tongue muscle. Dysphasia is common symptom in IBM patient and has been much reported previously. But dysarthria in IBM patient has not been aware, for this reason this report should be the rare case.

  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)/d