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Sample records for experimental autoimmune uveitis

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

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

    2017-05-01

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

  2. 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.

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

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    Joo Youn Oh

    2014-01-01

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

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

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

    2009-09-01

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

  5. P2Y2R deficiency attenuates experimental autoimmune uveitis development.

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    Lia Judice M Relvas

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

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

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

    2013-12-01

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

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

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

    2014-12-16

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

  8. Comparative examination of two methods for modeling autoimmune uveitis

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    Svetlana V. Aksenova

    2017-09-01

    Full Text Available Introduction: Uveitis is a disease of the uveal tract, characterized by a variety of causes and clinical manifestations. The internal antigens prevail often in the pathogenesis of the disease and develop the so-called autoimmune reactions. The uveitis treatment has an important medico-social significance because of the high prevalence of uveitis, the significant rate of the disease in young people, and high disability. The article compares the efficiency of two methods for modeling autoimmune uveitis. Materials and Methods: The research was conducted on 6 rabbits of the Chinchilla breed (12 eyes. Two models of experimental uveitis were reproduced on rabbits using normal horse serum during the research. A clinical examination of the inflammatory process course in the eyes was carried out by biomicroscopy using a slit lamp, and a direct ophthalmoscope. Histological and immunological examinations were conducted by the authors of the article. Results: The faster-reproducing and vivid clinical picture of the disease was observed in the second group. The obvious changes in the immunological status of the animals were noted also: an increase in the number of leukocytes, neutrophils, HCT-active neutrophils, and activation of phagocytosis. Discussion and Conclusions: The research has showed that the second model of uveitis is the most convenient working variant, which is characterized by high activity and duration of the inflammatory process in the eye.

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

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    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

  10. CRALBP is a Highly Prevalent Autoantigen for Human Autoimmune Uveitis

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    Cornelia A. Deeg

    2007-01-01

    uveitis patient's sera was first evaluated in two-dimensional (2D Western blot analysis. Subsequent identification of the immunoreactive proteins by mass spectrometry resulted in the identification of CRALBP as a putative autoantigen. Additionally, sera from human uveitis and control patients were by Western blot using purified human recombinant CRALBP. Anti-CRALBP autoantibodies occur more frequently (P<.01 in human uveitis patients than in normal controls. Thirty out of 56 tested uveitis patient's sera contained autoantibodies reactive against CRALBP, compared to only four out of 23 normal control subjects. The presence of CRALBP autoantibodies in 54% of tested uveitis patients supports CRALBP as a possible autoantigen in human autoimmune uveitis.

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

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    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

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

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

    2015-11-01

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

  13. Targeting interleukin-6 in autoimmune uveitis.

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    Mesquida, Marina; Molins, Blanca; Llorenç, Víctor; de la Maza, Maite Sáinz; Adán, Alfredo

    2017-10-01

    Interleukin-6 (IL-6) is a key cytokine that is strongly up-regulated during infection and inflammation. Featuring pleiotropic activity, IL-6 is responsible for the induction of hepatic acute-phase proteins, trafficking of acute and chronic inflammatory cells, differentiation of adaptive T cell responses, homeostatic regulation, and tissue regeneration. Dysregulated IL-6 production has been associated with the development of a wide variety of systemic immune-mediated, chronic diseases, and even certain types of cancer. From the ocular perspective, significant elevation of IL-6 has been found in ocular fluids derived from diabetic macular edema, retinal vein occlusion, and refractory/chronic uveitis patients. During the last decade, tocilizumab, a neutralizing monoclonal antibody (mAb) that targets the IL-6 receptor (IL-6R), has been approved for the treatment of rheumatoid arthritis in >100 countries worldwide. Furthermore, it has been reported to be effective for the treatment of a number of autoimmune diseases including uveitis and its associated macular edema. Currently numerous candidate molecular strategies targeting the IL-6 signaling pathways are in progress through clinical trials in various disorders. Herein we discuss the basic biology of IL-6 and its pathological role in the development of immune-mediated conditions, particularly focusing on inflammatory eye diseases. It also provides an overview of the on-going clinical trials with the new anti-IL-6 mAbs and their potential use in the clinical practice. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Immunological and pathological investigations in equine experimental uveitis.

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    Simeonova, Galina P; Krastev, Svetozar Z; Simeonov, Radostin S

    2016-12-01

    The pathogenic mechanism of equine recurrent uveitis (ERU) is still poorly defined and many variations between experimental animal models and spontaneous disease exist. The aim of our study was to investigate if Th17 cell-mediated response plays role in the pathogenesis of the used experimental model in horses and to reveal its pathological findings. Experimental uveitis was induced in 6 healthy horses. The concentrations of retinal autoantigen CRALBP and IL-17 were measured using ELISA in aqueous humor and vitreous body of the 12 inflamed eyes as well as in 12 control non-inflamed eyes taken from 6 horses in slaughter house. After centrifugation of the two eye media, smears were prepared and cytological investigation was performed. Tissue specimens were taken from all eye globes and were submitted to histopathological investigation. CRALBP and IL-17 concentrations were significantly elevated in eye media of horses with experimental uveitis in comparison with controls. Cytological and histopathological findings corresponded to the changes characteristic of chronic immune-mediated inflammation with mononuclear cell infiltration of uvea, choroid, retina, and eye media as well as severe retinal destruction. Our study demonstrated the involvement of the retinal autoantigen CRALBP as well as IL-17 in the pathogenesis of experimental uveitis in horses. These findings suggests that this experimental uveitis in horses may serve as a suitable animal model for investigation of IL-17- mediated immune response during spontaneous autoimmune uveitis in horses as well as in humans.

  15. 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.

  16. Immunomodulation in human and experimental uveitis: Recent advances

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    Singh Vijay

    1999-01-01

    Full Text Available Experimental autoimmune uveitis (EAU is a T-cell mediated autoimmune disease that targets the neural retina and serves as a model of human uveitis. EAU can be induced against several retinal proteins in rats, mice, and subhuman primates. These include the S-antigen, a major protein in retinal photoreceptor cells; interphotoreceptor retinoid-binding protein (IRBP; and rhodopsin and other antigens of retinal origin. There are many similarities between clinical uveitis and EAU, but the latter differs in being self-limited, and needs adjuvant for disease induction. The experimental disease can be induced only in susceptible animal strains. Use of the EAU model has helped investigators understand the pathophysiology of the disease and to evaluate disease-modifying strategies, which could be applied in the clinic. There has been significant progress in this field during last decade, but much more understanding is needed before the knowledge can be transferred to clinical practice. A deeper understanding of the immune mechanisms involved in the EAU model may lead to the development of new therapeutic approaches targeted at various components of the immune response by immunomodulation to control uveitis. This review summarises the evidence from the EAU model, which could be of relevance to the clinical management of patients with uveitis.

  17. 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.

  18. Uveitis

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    ... Uveitis Focus On Pediatric Ophthalmology Education Center Oculofacial Plastic Surgery Center Laser Surgery Education Center Redmond Ethics Center ... Uveitis Focus On Pediatric Ophthalmology Education Center Oculofacial Plastic Surgery Center Laser Surgery Education Center Redmond Ethics Center ...

  19. Intraocular Implants for the Treatment of Autoimmune Uveitis

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    Darren J. Lee

    2015-07-01

    Full Text Available Uveitis is the third leading cause of blindness in developed countries. Currently, the most widely used treatment of non-infectious uveitis is corticosteroids. Posterior uveitis and macular edema can be treated with intraocular injection of corticosteroids, however, this is problematic in chronic cases because of the need for repeat injections. Another option is systemic immunosuppressive therapies that have their own undesirable side effects. These systemic therapies result in a widespread suppression of the entire immune system, leaving the patient susceptible to infection. Therefore, an effective localized treatment option is preferred. With the recent advances in bioengineering, biodegradable polymers that allow for a slow sustained-release of a medication. These advances have culminated in drug delivery implants that are food and drug administration (FDA approved for the treatment of non-infectious uveitis. In this review, we discuss the types of ocular implants available and some of the polymers used, implants used for the treatment of non-infectious uveitis, and bioengineered alternatives that are on the horizon.

  20. Predictors of Relapse after Discontinuing Systemic Treatment in Childhood Autoimmune Chronic Uveitis.

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    Simonini, Gabriele; Bracaglia, Claudia; Cattalini, Marco; Taddio, Andrea; Brambilla, Alice; De Libero, Cinzia; Pires Marafon, Denise; Caputo, Roberto; Cimaz, Rolando

    2017-06-01

    To identify clinical predictors of relapse in childhood autoimmune chronic uveitis after stopping systemic treatment. A retrospective, multicenter, cohort study. Ninety-four children in remission, receiving no treatments and with at least a 6-month followup, were enrolled. A higher probability of maintaining remission after discontinuing treatment was shown in idiopathic compared with juvenile idiopathic arthritis uveitis (Mantel-Cox chi-square = 23.21) if inactivity had been obtained within 6 months from starting systemic treatment (Mantel-Cox chi-square = 24.17) and by antitumor necrosis factor-α treatment (Mantel-Cox chi-square = 6.43). Type of disease, time, and type of systemic therapy to achieve inactivity predict different duration of uveitis remission after treatment withdrawal.

  1. Proteome Dynamics in Biobanked Horse Peripheral Blood Derived Lymphocytes (PBL) with Induced Autoimmune Uveitis.

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    Hauck, Stefanie M; Lepper, Marlen F; Hertl, Michael; Sekundo, Walter; Deeg, Cornelia A

    2017-10-01

    Equine recurrent uveitis is the only spontaneous model for recurrent autoimmune uveitis in humans, where T cells target retinal proteins. Differences between normal and autoaggressive lymphocytes were identified in this study by analyzing peripheral blood derived lymphocytes (PBL) proteomes from the same case with interphotoreceptor retinoid binding protein induced uveitis sampled before (Day 0), during (Day 15), and after uveitic attack (Day 23). Relative protein abundances of PBL were investigated in a quantitative, label-free differential proteome analysis in cells that were kept frozen for 14 years since the initial experiment. Quantitative data could be acquired for 2632 proteins at all three time points. Profound changes (≥2-fold change) in PBL protein abundance were observed when comparing Day 0 with 15, representing acute inflammation (1070 regulated proteins) and Day 0 with 23 (cessation; 1571 regulated). Significant differences applied to proteins with functions in integrin signaling during active uveitis, involving "Erk and pi-3 kinase are necessary for collagen binding in corneal epithelia," "integrins in angiogenesis," and "integrin-linked kinase signaling" pathways. In contrast, at cessation of uveitic attack, significantly changed proteins belonged to pathways of "nongenotropic androgen signaling," "classical complement pathway," and "Amb2 integrin signaling." Several members of respective pathways were earlier shown to be changed in naturally occurring uveitis, underscoring the significance of these findings here and proofing the value of the induced model in mimicking spontaneous autoimmune uveitis. All MS data have been deposited to the ProteomeXchange consortium via the PRIDE partner repository (dataset identifier PXD005580). © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Cytokines and Biologics in non-infectious autoimmune uveitis: Bench to Bedside

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    Rupesh Agrawal

    2014-01-01

    Full Text Available Intraocular inflammatory eye disease is one of the important causes of ocular morbidity. Even though the prevalence of uveitis is less common in relation to diabetic retinopathy, glaucoma or age related macular degeneration, the complexity and heterogeneity of the disease makes it more unique. Putative uveitogenic retinal antigens incite innate immunity by the process of antigen mimicry and have been shown to be associated in patients with intraocular inflammatory disease by numerous experimental studies. Laboratory diagnostic tools to aid the etiologic association in intraocular inflammatory disease have evolved over the last two decades and we are entering into an era of molecular diagnostic tests. Sophisticated novel technologies such as multiplex bead assays to assess biological signatures have revolutionized the management of complex refractory uveitis. Nevertheless, there is still a long way to go to establish the causal relationship between these biomarkers and specific uveitic entities. Experimental studies have shown the supreme role of infliximab in the management of Behcet′s disease. Despite significant experimental and case control studies, the deficiency of randomized clinical trials using these biologic agents has handicapped us in exploring them as a front line therapy in severe refractory uveitis. Studies still need to answer the safety of these potentially life threatening drugs in a selected group of patients and determine when to commence and for how long the treatment has to be given. This review article covers some basic concepts of cytokines in uveitis and their potential application for therapy in refractory uveitis.

  3. Dry eye disease and uveitis: A closer look at immune mechanisms in animal models of two ocular autoimmune diseases.

    Science.gov (United States)

    Bose, Tanima; Diedrichs-Möhring, Maria; Wildner, Gerhild

    2016-12-01

    Understanding the immunopathogenesis of autoimmune and inflammatory diseases is a prerequisite for specific and effective therapeutical intervention. This review focuses on animal models of two common ocular inflammatory diseases, dry eye disease (DED), affecting the ocular surface, and uveitis with inflammation of the inner eye. In both diseases autoimmunity plays an important role, in idiopathic uveitis immune reactivity to intraocular autoantigens is pivotal, while in dry eye disease autoimmunity seems to play a role in one subtype of disease, Sjögren' syndrome (SjS). Comparing the immune mechanisms underlying both eye diseases reveals similarities, and significant differences. Studies have shown genetic predispositions, T and B cell involvement, cytokine and chemokine signatures and signaling pathways as well as environmental influences in both DED and uveitis. Uveitis and DED are heterogeneous diseases and there is no single animal model, which adequately represents both diseases. However, there is evidence to suggest that certain T cell-targeting therapies can be used to treat both, dry eye disease and uveitis. Animal models are essential to autoimmunity research, from the basic understanding of immune mechanisms to the pre-clinical testing of potential new therapies. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. No Evidence of Association between Common Autoimmunity STAT4 and IL23R Risk Polymorphisms and Non-Anterior Uveitis

    Science.gov (United States)

    Cordero-Coma, Miguel; Gorroño-Echebarría, Marina Begoña; Fonollosa, Alejandro; Adán, Alfredo; Martínez-Berriotxoa, Agustín; Díaz Valle, David; Pato, Esperanza; Blanco, Ricardo; Cañal, Joaquín; Díaz-Llopis, Manuel; García Serrano, José Luis; de Ramón, Enrique; del Rio, María José; Martín-Villa, José Manuel; Molins, Blanca; Ortego-Centeno, Norberto; Martín, Javier

    2013-01-01

    Objective STAT4 and IL23R loci represent common susceptibility genetic factors in autoimmunity. We decided to investigate for the first time the possible role of different STAT4/IL23R autoimmune disease-associated polymorphisms on the susceptibility to develop non-anterior uveitis and its main clinical phenotypes. Methods Four functional polymorphisms (rs3821236, rs7574865, rs7574070, and rs897200) located within STAT4 gene as well as three independent polymorphisms (rs7517847, rs11209026, and rs1495965) located within IL23R were genotyped using TaqMan® allelic discrimination in a total of 206 patients with non-anterior uveitis and 1553 healthy controls from Spain. Results No statistically significant differences were found when allele and genotype distributions were compared between non-anterior uveitis patients and controls for any STAT4 (rs3821236: P=0.39, OR=1.12, CI 95%=0.87-1.43; rs7574865: P=0.59 OR=1.07, CI 95%=0.84-1.37; rs7574070: P=0.26, OR=0.89, CI 95%=0.72-1.10; rs897200: P=0.22, OR=0.88, CI 95%=0.71-1.08;) or IL23R polymorphisms (rs7517847: P=0.49, OR=1.08, CI 95%=0.87-1.33; rs11209026: P=0.26, OR=0.78, CI 95%=0.51-1.21; rs1495965: P=0.51, OR=0.93, CI 95%=0.76-1.15). Conclusion Our results do not support a relevant role, similar to that described for other autoimmune diseases, of IL23R and STAT4 polymorphisms in the non-anterior uveitis genetic predisposition. Further studies are needed to discard a possible weak effect of the studied variant. PMID:24312163

  5. Adalimumab Induced or Provoked MS in Patient with Autoimmune Uveitis: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Rana Alnasser Alsukhni

    2016-01-01

    Full Text Available Anti-tumor necrosis factor α (anti-TNF-α agents have been widely used in the field of autoimmune diseases and have proved decisive efficacy and relative safety. Data concerning their adverse effects has been lately describing central nervous system (CNS demyelination process at escalating basis. Case Presentation. A 23-year-old male with autoimmune uveitis and a family history of multiple sclerosis (MS developed two neurological attacks, after Adalimumab infusion, simultaneously with several cerebral lesions on magnetic resonance imaging (MRI. Hence the diagnosis of Adalimumab induced MS was suspected. Conclusion. This case is reported to tell physicians to be cautious when using anti-TNF-α in patients with family history of MS and to reconsider the risk of MS in patients with autoimmune diseases.

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

    DEFF Research Database (Denmark)

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

    2002-01-01

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

  7. Intravitreal implantation of the biodegradable cyclosporin A drug delivery system for experimental chronic uveitis.

    Science.gov (United States)

    Dong, Xiaoguang; Shi, Weiyun; Yuan, Gongqiang; Xie, Lixin; Wang, Shenguo; Lin, Ping

    2006-04-01

    The purpose was to evaluate the efficacy of the intravitreal implantation of the biodegradable cyclosporin A (CsA) drug delivery system (DDS) for experimental chronic uveitis. The DDS was prepared by formulating CsA into glycolide-co-lactide-co-caprolactone copolymer (PGLC). Right eyes of 30 New Zealand white rabbits were used to establish a model of uveitis and randomized into control, intravitreal non-medicated DDS, oral CsA (15 mg/kg daily), and intravitreal CsA-PGLC DDS (each containing 2 mg CsA) groups. The progress of ocular inflammation, results of electroretinography, and histopathological examination of ocular, renal, and hepatic functions were recorded. Intravitreal CsA levels were measured in another 13 rabbits receiving an implant of the CsA-PGLC DDS. Chronic uveitis was successfully induced in all 30 eyes. The inflammation in the eyes with no treatment, non-medicated implant, and oral CsA was more severe than those with the CsA-PGLC DDS at each timepoint. The electroretinography b-wave was depressed much less in the CsA-PGLC DDS group than in the other three groups (ptoxicity was detected. Intravitreal implantation of the biodegradable CsA-PGLC DDS may effectively reduce the intraocular inflammation in rabbits with no toxicity, which provides a potentially safe and convenient approach for the treatment of chronic uveitis.

  8. Intermediate uveitis.

    Science.gov (United States)

    Bonfioli, Adriana A; Damico, Francisco Max; Curi, Andre L L; Orefice, Fernando

    2005-01-01

    Intermediate uveitis is an intraocular inflammation involving the anterior vitreous, peripheral retina and pars plana. It usually affects patients from 5 to 30 years old, without gender or racial preferences. The etiology is unknown but there are several associated diseases: multiple sclerosis, idiopathic optic neuritis, autoimmune corneal endotheliopathy, sarcoidosis, thyroid diseases and inflammatory bowel diseases. Symptoms are blurry vision, floaters and distortion of central vision. The syndrome is bilateral in 80% of the patients and chronic with periods of exacerbation and remission. Clinical presentation includes: mild to moderate anterior chamber inflammation, thin keratic precipitates in the inferior portion of the cornea, autoimmune endotheliopathy, vitreitis, vasculitis in the peripheral retina, intravitreal "snowballs," retinal "snowbanking," optic neuritis and cystoid macular edema. Cataract and glaucoma are frequent complications. Treatment of intermediate uveitis is based on periocular and oral corticosteroids. Cryotherapy or laser photocoagulation of the peripheral retina are options in patients with snowbanking when there is an insufficient response to periocular or systemic corticosteroids. Imunosuppression may also be used when other therapies fail, and Cyclosporin A is the first drug of choice. Pars plana vitrectomy is indicated in patients with chronic significant inflammation, non-responsive cystoid macular edema, non-clearing vitreous hemorrhage, tractional retinal detachment and epiretinal membranes. The long-term prognosis of intermediate uveitis is usually good, particularly with strict control of inflammation and with proper management of complications. Patients can often maintain a vision of 20/50 or better.

  9. STAT3 Regulates Proliferation and Survival of CD8+ T Cells: Enhances Effector Responses to HSV-1 Infection, and Inhibits IL-10+ Regulatory CD8+ T Cells in Autoimmune Uveitis

    Directory of Open Access Journals (Sweden)

    Cheng-Rong Yu

    2013-01-01

    Full Text Available STAT3 regulates CD4+ T cell survival and differentiation. However, its effects on CD8+ T cells are not well understood. Here, we show that in comparison to WT CD8+ T cells, STAT3-deficient CD8+ T cells exhibit a preactivated memory-like phenotype, produce more IL-2, proliferate faster, and are more sensitive to activation-induced cell death (AICD. The enhanced proliferation and sensitivity to AICD correlated with downregulation of class-O forkhead transcription factors (FoxO1, FoxO3A, , , Bcl-2, OX-40, and upregulation of FasL, Bax, and Bad. We examined whether STAT3-deficient CD8+ T cells can mount effective response during herpes simplex virus (HSV-1 infection and experimental autoimmune uveitis (EAU. Compared to WT mice, HSV-1-infected STAT3-deficient mice (STAT3KO produced less IFN- and virus-specific KLRG-1+ CD8+ T cells. STAT3KO mice are also resistant to EAU and produced less IL-17-producing Tc17 cells. Resistance of STAT3KO to EAU correlated with marked expansion of IL-10-producing regulatory CD8+ T cells (CD8-Treg implicated in recovery from autoimmune encephalomyelitis. Thus, increases of IL-6-induced STAT3 activation observed during inflammation may inhibit expansion of CD8-Tregs, thereby impeding recovery from uveitis. These results suggest that STAT3 is a potential therapeutic target for upregulating CD8+ T cell-mediated responses to viruses and suggest the successful therapeutic targeting of STAT3 as treatment for uveitis, derived, in part, from promoting CD8-Treg expansion.

  10. Scleral plug of biodegradable polymers containing tacrolimus (FK506) for experimental uveitis.

    Science.gov (United States)

    Sakurai, Eiji; Nozaki, Miho; Okabe, Komei; Kunou, Noriyuki; Kimura, Hideya; Ogura, Yuichiro

    2003-11-01

    To evaluate the efficacy of a biodegradable polymeric scleral plug containing the immunosuppressive agent, FK506, in a rabbit model for experimental uveitis. The scleral plugs were prepared by dissolving poly(DL-lactide-co-glycolide; PLGA) and FK506 (weight, 8.5 mg; length, 5 mm; 1% FK506). The release of FK506 was evaluated in vitro by spectrophotometry on days 1, 3, 7, 14, 21, and 35. In vivo, FK506 concentrations of the vitreous were measured by high performance liquid chromatography 2 and 4 weeks after intravitreous plug implantation in pigmented rabbits. Sixteen pigmented rabbits were immunized twice subcutaneously with 10 mg of Mycobacterium tuberculosis H37Ra antigen. Twelve days later, the right eyes of all rabbits were challenged with an intravitreal injection of 50 micro g of antigen. After the first challenge, the 16 eyes of 16 pigmented rabbits were divided into two groups. Scleral plugs were implanted into the vitreous of the right eye of eight rabbits. Eight control rabbits received a sham device. The aqueous protein concentrations and cell counts were determined on postchallenge days 7, 14, and 28. To simulated chronic inflammation, the eyes were rechallenged with intravitreal antigen on day 14 and were observed for 1 month. Inflammation of the anterior chamber and the vitreous were graded clinically by two masked observers. Retinal function was evaluated by electroretinography (ERG) and histologic examination. Clinical scores (anterior chamber cells, flare, and vitreous opacity) showed that treated eyes had significantly less inflammation than untreated eyes (Ptoxicity was detected, histopathologically and electroretinographically. After antigen rechallenge, inflammation in experimental eyes was still less than in control eyes. Intravitreal sustained-release of FK506 from a biodegradable polymeric scleral plug was highly effective in suppressing the inflammation of experimental uveitis in a rabbit model for at least 6 weeks. This device may be

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

    Science.gov (United States)

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

    1995-01-15

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

  12. In Vivo Bioluminescence Imaging for Longitudinal Monitoring of Inflammation in Animal Models of Uveitis.

    Science.gov (United States)

    Gutowski, Michal B; Wilson, Leslie; Van Gelder, Russell N; Pepple, Kathryn L

    2017-03-01

    We develop a quantitative bioluminescence assay for in vivo longitudinal monitoring of inflammation in animal models of uveitis. Three models of experimental uveitis were induced in C57BL/6 albino mice: primed mycobacterial uveitis (PMU), endotoxin-induced uveitis (EIU), and experimental autoimmune uveitis (EAU). Intraperitoneal injection of luminol sodium salt, which emits light when oxidized, provided the bioluminescence substrate. Bioluminescence images were captured by a PerkinElmer In Vivo Imaging System (IVIS) Spectrum and total bioluminescence was analyzed using Living Image software. Bioluminescence on day zero was compared to bioluminescence on the day of peak inflammation for each model. Longitudinal bioluminescence imaging was performed in EIU and EAU. In the presence of luminol, intraocular inflammation generates detectable bioluminescence in three mouse models of uveitis. Peak bioluminescence in inflamed PMU eyes (1.46 × 105 photons/second [p/s]) was significantly increased over baseline (1.47 × 104 p/s, P = 0.01). Peak bioluminescence in inflamed EIU eyes (3.18 × 104 p/s) also was significantly increased over baseline (1.09 × 104 p/s, P = 0.04), and returned to near baseline levels by 48 hours. In EAU, there was a nonsignificant increase in bioluminescence at peak inflammation. In vivo bioluminescence may be used as a noninvasive, quantitative measure of intraocular inflammation in animal models of uveitis. Primed mycobacterial uveitis and EIU are both acute models with robust anterior inflammation and demonstrated significant changes in bioluminescence corresponding with peak inflammation. Experimental autoimmune uveitis is a more indolent posterior uveitis and generated a more modest bioluminescent signal. In vivo imaging system bioluminescence is a nonlethal, quantifiable assay that can be used for monitoring inflammation in animal models of uveitis.

  13. Therapeutic Potential of Shark Anti-ICOSL VNAR Domains is Exemplified in a Murine Model of Autoimmune Non-Infectious Uveitis

    Directory of Open Access Journals (Sweden)

    Marina Kovaleva

    2017-09-01

    Full Text Available Induced costimulatory ligand (ICOSL plays an important role in the activation of T cells through its interaction with the inducible costimulator, ICOS. Suppression of full T cell activation can be achieved by blocking this interaction and has been shown to be an effective means of ameliorating disease in models of autoimmunity and inflammation. In this study, we demonstrated the ability of a novel class of anti-ICOSL antigen-binding single domains derived from sharks (VNARs to effectively reduce inflammation in a murine model of non-infectious uveitis. In initial selections, specific VNARs that recognized human ICOSL were isolated from an immunized nurse shark phage display library and lead domains were identified following their performance in a series of antigen selectivity and in vitro bioassay screens. High potency in cell-based blocking assays suggested their potential as novel binders suitable for further therapeutic development. To test this hypothesis, surrogate anti-mouse ICOSL VNAR domains were isolated from the same phage display library and the lead VNAR clone selected via screening in binding and ICOS/ICOSL blocking experiments. The VNAR domain with the highest potency in cell-based blocking of ICOS/ICOSL interaction was fused to the Fc portion of human IgG1 and was tested in vivo in a mouse model of interphotoreceptor retinoid-binding protein-induced uveitis. The anti-mICOSL VNAR Fc, injected systemically, resulted in a marked reduction of inflammation in treated mice when compared with untreated control animals. This approach inhibited disease progression to an equivalent extent to that seen for the positive corticosteroid control, cyclosporin A, reducing both clinical and histopathological scores. These results represent the first demonstration of efficacy of a VNAR binding domain in a relevant clinical model of disease and highlight the potential of VNARs for the treatment of auto-inflammatory conditions.

  14. Label-free LC-MSMS analysis of vitreous from autoimmune uveitis reveals a significant decrease in secreted Wnt signalling inhibitors DKK3 and SFRP2.

    Science.gov (United States)

    Hauck, Stefanie M; Hofmaier, Florian; Dietter, Johannes; Swadzba, Margarete E; Blindert, Marcel; Amann, Barbara; Behler, Jennifer; Kremmer, Elisabeth; Ueffing, Marius; Deeg, Cornelia A

    2012-07-19

    Equine recurrent uveitis is a severe and frequent blinding disease in horses which presents with auto-reactive invading T-cells, resulting in the destruction of the inner eye. Infiltration of inflammatory cells into the retina and vitreous is driven by currently unknown guidance cues, however surgical removal of the vitreous (vitrectomy) has proven therapeutically successful. Therefore, proteomic analyses of vitrectomy samples are likely to result in detection of proteins contributing to disease pathogenesis. Vitreous from healthy and ERU diseased horses were directly compared by quantitative mass spectrometry based on label-free quantification of peak intensities across samples. We found a significant upregulation of complement and coagulation cascades and downregulation of negative paracrine regulators of canonical Wnt signalling including the Wnt signalling inhibitors DKK3 and SFRP2. Based on immunohistochemistry, both proteins are expressed in equine retina and suggest localisation to retinal Müller glial cells (RMG), which may be the source cells for these proteins. Furthermore, retinal expression levels and patterns of DKK3 change in response to ERU. Since many other regulated proteins identified here are associated with RMG cells, these cells qualify as the prime responders to autoimmune triggers. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Tuberculous uveitis

    OpenAIRE

    Oluleye TS

    2013-01-01

    Tunji Sunday OluleyeRetina and Vitreous Unit, Department of Ophthalmology, University College Hospital, Ibadan, NigeriaAbstract: Tuberculous uveitis is an underdiagnosed form of uveitis. Absence of pulmonary signs and symptoms does not rule out the disease. In an era of reduced immunity from human immunodeficiency virus and acquired immunodeficiency syndrome, the disease is becoming more prevalent. This review discusses the common manifestations of tuberculous uveitis, pointing out helpful di...

  16. 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...

  17. Uveitis and Gender: The Course of Uveitis in Pregnancy

    Directory of Open Access Journals (Sweden)

    Nathalie P. Y. Chiam

    2014-01-01

    Full Text Available The hormonal and immunological changes in pregnancy have a key role in maintaining maternal tolerance of the semiallogeneic foetus. These pregnancy-associated changes may also influence the course of maternal autoimmune diseases. Noninfectious uveitis tends to improve during pregnancy. Specifically, uveitis activity tends to ameliorate from the second trimester onwards, with the third trimester being associated with the lowest disease activity. The mechanism behind this phenomenon is likely to be multifactorial and complex. Possible mechanisms include Th1/Th2 immunomodulation, regulatory T-cell phenotype plasticity, and immunosuppressive cytokines. This clearly has management implications for patients with chronic sight threatening disease requiring systemic treatment, as most medications are not recommended during pregnancy due to lack of safety data or proven teratogenicity. Given that uveitis activity is expected to decrease in pregnancy, systemic immunosuppressants could be tapered during pregnancy in these patients, with flare-ups being managed with local corticosteroids till delivery. In the postpartum period, as uveitis activity is expected to rebound, patients should be reviewed closely and systemic medications recommenced, depending on uveitis activity and the patient’s breastfeeding status. This review highlights the current understanding of the course of uveitis in pregnancy and its management to help guide clinicians in managing their uveitis patients during this special time in life.

  18. Beneficial effects of blueberries in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

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

    2012-06-13

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

  19. Cyclosporine: A Historical Perspective on Its Role in the Treatment of Noninfectious Uveitis.

    Science.gov (United States)

    Smith, Wendy M

    2017-05-01

    The history of cyclosporine and uveitis is intertwined with the development of experimental autoimmune uveitis (EAU) animal models and the understanding that T lymphocytes play a major role in the pathogenesis of uveitis. The early studies of CsA in uveitis also demonstrated the power of collaborative efforts in translational research. Dr. Robert Nussenblatt and his colleagues were the first to show that CsA can inhibit EAU. Over many years after the initial CsA experiments, Dr. Nussenblatt's group as well as others continued to study CsA under experimental conditions as well as in clinical trials with human patients. The data and observations from these studies significantly advanced our knowledge of uveitis pathophysiology and demonstrated the value of well-designed masked, controlled treatment trials in uveitis. Dr. Nussenblatt and his collaborators delved into the most significant adverse effect of CsA, renal toxicity, and helped elucidate the pathophysiology of renal injury. They explored adjunctive treatments to improve the efficacy and decrease the toxicity of CsA and also studied other members of the cyclosporine family. Among the immunosuppressives used to treat ocular inflammation, CsA was the first, and remains the only medication comprehensively studied under both experimental and clinical conditions.

  20. Efficiency of Ozone Therapy in a Rat Model of Experimental Uveitis.

    Science.gov (United States)

    Kaya, Abdullah; Sonmez, Murat; Kar, Taner; Haholu, Aptullah; Yildirim, Yıldıray; Müftüoğlu, Tuba; Ünal, Melih Hamdi

    2017-10-01

    To investigate efficiency of ozone therapy in uveitis. A total of 24 albino Wistar rats were randomly assigned to four groups (n = 6); (a) control group; (b) sham group; (c) infliximab treatment group; (d) ozone therapy group. Vitreous haze scores of all groups were evaluated. Vitreous cytokine levels (TNF-α, IL-1, IL-6) measured by ELISA and eyes were enucleated for histopathologic examination. According to vitreous haze scores, there was statistically significant inflammation in Group (b) compared with Group (a), and there was less inflammation in infliximab and ozone groups compared with Group (b) (p 0.05). There was significantly less inflammation in histopathologic examination in treatment groups when compared with the sham group (p < 0.05). Clinical and histopathologic examination results indicate that systemic application of ozone may be efficient in the treatment of uveitis.

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

    Science.gov (United States)

    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.

  2. 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.

  3. Sodium butyrate regulates Th17/Treg cell balance to ameliorate uveitis via the Nrf2/HO-1 pathway.

    Science.gov (United States)

    Chen, Xiaoqing; Su, Wenru; Wan, Taoshang; Yu, Jianfeng; Zhu, Wenjie; Tang, Fen; Liu, Guangming; Olsen, Nancy; Liang, Dan; Zheng, Song Guo

    2017-10-15

    Autoimmune uveitis, a group of potentially blinding intraocular inflammatory diseases, remains a therapeutic challenge for ophthalmologists. Butyrates, which belong to the short-chain fatty acid family, possess immunomodulatory properties and therapeutic potential in several inflammatory disorders. However, the roles of butyrates in uveitis and their underlying immunomodulatory mechanisms remain elusive. Here, we report that treatment with sodium butyrate (NaB) significantly attenuated the ocular inflammatory response in mice with experimental autoimmune uveitis (EAU) at 14days after immunization, with significant decreases in inflammatory cell infiltration and inflammatory cytokine production in the retinas. Furthermore, NaB treatment decreased the frequency and number of Th17 cells and increased the frequency and number of T regulatory (Treg) cells in both draining lymph nodes and spleens of EAU mice. In vitro, NaB treatment directly converted the differentiation of naive T cells from Th17 cells toward Treg cells. Mechanistically, the NaB-mediated inhibition of Th17 cell differentiation may occur via inhibition of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1)/interleukin-6 receptor pathway. Moreover, the NaB-mediated inhibition on Th17 cell differentiation and uveitis were abrogated when an HO-1 inhibitor, SnPP, was used. These findings suggest that NaB inverts the differentiation of Th17 cells toward Treg cells and attenuates experimental autoimmune uveitis by modulating the Nrf2/HO-1 pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. 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.

  5. Diagnosis dan Penatalaksanaan Uveitis dalam Upaya Mencegah Kebutaan

    Directory of Open Access Journals (Sweden)

    Ratna Sitompul

    2016-06-01

    Treatment of Uveitis to Prevent Blindness Abstract Uveitis is an inflammation of the uvea which may result in blindness. Uveitis may be caused by limited inflamation of the uveal tract, manifestation of systemic diseases (autoimmune, infection, cancer, expansion of inflammation in the cornea and sclera, trauma or idiopathic. Anterior uveitis is an inflammation of the iris and cilliary body with symptoms of pain, red eye, photophobia, and decrease in visual acuity. Intermediate uveitis is the inflammation of the pars plana and frequently involves anterior vitreous and posterior uveitis. Clinical manifestation of intermediate uveitis is usually mild without red eye and pain, however vision may decrease due to macular edema and cell aggregation in vitreous. Posterior uveitis is an inflammation involving choroid layer, which is common in developing countries due to high prevalence of infectious diseases (toxoplasmosis, tuberculosis, HIV, syphilis. Patient may complain of blurry vision but not accompanied by pain, red eye, and photophobia. Complications of posterior uveitis are cataract, glaucoma, macular edema, keratopathy, turbidity of vitreous, retinal detachment, and optic nerve atrophy. The prognosis of posterior uveitis is worse than anterior uveitis. Panuveitis is an inflammation of the uvea and surrounding structures (retina, vitreous. Diagnosis is made based on anamnesis, ophthalmic examination, laboratory examination, and imaging. Treatment of uveitis is intended to reduce inflammation, minimize structural destruction, prevent blindness, reduce pain and photophobia. Corticosteroid and immunosuppresant are the drugs of choice to manage the inflammation, where NSAID is used to reduce pain and cyclopegic administration to prevent posterior synechiae. Antimicrobial is given if uveitis is caused by infection. Underlying diseases of uveitis must be treated comprehensively to prevent further progression, complications and blindness. Keywords: anterior uveitis, intermediate

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

    Science.gov (United States)

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

    2018-02-06

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

  7. [Effect of melatonin instillations on the clinical course of experimental uveitis and biochemical processes in tears and aqueous humor].

    Science.gov (United States)

    Chesnokova, N B; Beznos, O V; Lozinskaya, N A; Beyshenova, G A; Nesterova, T V

    2016-01-01

    Acute immunogenic uveitis was modeled in rabbits via the subcutaneous and intravitreal injections of normal horse serum. We studied the effect of instillations of 0.1% melatonin solution on the clinical course of uveitis and biochemical parameters of tear fluid and aqueous humor: antioxi-dant activity, protein concentration and α(2)-macroglobulin level. Melatonin instillations decreased clinical manifestations of uveitis. We found that the antioxidant activity in tears of the rabbits treated with melatonin was substantially higher and the α(2)-macroglobulin level lower than in untreated animals. Antioxidant activity in aqueous humor taken on day 10 of uveitis was also twice higher while protein and α(2)-macroglobulin levels were 1.5-2 times lower than in untreated animals. These data indicate that instillations of melatonin increase the local antioxidant activity and decrease the acuity of inflammation and permeability of hematoophthalmic barrier in uveitis.

  8. Clinical Trials in Noninfectious Uveitis

    Science.gov (United States)

    Kim, Jane S.; Knickelbein, Jared E.; Nussenblatt, Robert B.; Sen, H. Nida

    2015-01-01

    The treatment of noninfectious uveitis continues to remain a challenge for many ophthalmologists. Historically, clinical trials in uveitis have been sparse, and thus, most treatment decisions have largely been based on clinical experience and consensus guidelines. The current treatment paradigm favors initiation then tapering of corticosteroids with addition of steroid-sparing immunosuppressive agents for persistence or recurrence of disease. Unfortunately, in spite of a multitude of highly unfavorable systemic effects, corticosteroids are still regarded as the mainstay of treatment for many patients with chronic and refractory noninfectious uveitis. However, with the success of other conventional and biologic immunomodulatory agents in treating systemic inflammatory and autoimmune conditions, interest in targeted treatment strategies for uveitis has been renewed. Multiple clinical trials on steroid-sparing immunosuppressive agents, biologic agents, intraocular corticosteroid implants, and topical ophthalmic solutions have already been completed, and many more are ongoing. This review discusses the results and implications of these clinical trials investigating both alternative and novel treatment options for noninfectious uveitis. PMID:26035763

  9. Management of chronic anterior uveitis relapses: efficacy of oral phospholipidic curcumin treatment. Long-term follow-up

    Directory of Open Access Journals (Sweden)

    Pia Allegri

    2010-10-01

    Full Text Available Pia Allegri1, Antonio Mastromarino1, Piergiorgio Neri21Uveitis Center, Ophthalmological Department of Lavagna Hospital, Genova, Italy; 2Uveitis Unit, The Eye Clinic, Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Ancona, Ancona, ItalyAbstract: Curcumin has been successfully applied to treat inflammatory conditions in experimental research and in clinical trials. The purpose of our study is to evaluate the efficacy of an adjunctive-to-traditional treatment with Norflo tablets (curcumin-phosphatidylcholine complex; Meriva administered twice a day in recurrent anterior uveitis of different etiologies. The study group consisted of 106 patients who completed a 12-month follow-up therapeutic period. We divided the patients into three main groups of different uveitis origin: group 1 (autoimmune uveitis, group 2 (herpetic uveitis, and group 3 (different etiologies of uveitis. The primary end point of our work was the evaluation of relapses frequency in all treated patients, before and after Norflo treatment, followed by the number of relapse in the three etiological groups. Wilcoxon signed-rank test showed a P < 0.001 in all groups. The secondary end points were the evaluation of relapse severity and of the overall quality of life. The results showed that Norflo was well tolerated and could reduce eye discomfort symptoms and signs after a few weeks of treatment in more than 80% of patients. In conclusion, our study is the first to report the potential therapeutic role of curcumin and its efficacy in eye relapsing diseases, such as anterior uveitis, and points out other promising curcumin-related benefits in eye inflammatory and degenerative conditions, such as dry eye, maculopathy, glaucoma, and diabetic retinopathy.Keywords: curcumin, anterior recurrent uveitis, phosphatidylcholine-bound-curcumin (Meriva

  10. Advancements in the management of uveitis.

    Science.gov (United States)

    Schwartzman, Sergio

    2016-04-01

    Uveitis may exist as a clinical manifestation of an underlying systemic disease or may represent an idiopathic entity, sometimes with a very characteristic pattern. Different forms of uveitis have been defined on the basis of three important variables: chronicity, anatomic location, and underlying etiology. The evolving understanding of the immune system has resulted in a more targeted approach to manage patients with different forms of uveitis, although clearly this approach is at a very early stage. Altered patterns of cellular processing and different cytokine expression, including TNF, IL-1, IL-2, IL-6, and IL17, have been defined in uveitis, and this has laid the pathway for targeted therapy. Furthermore, approved biologic therapies for some of the more common autoimmune illnesses have now been tested in uveitis. Adalimumab and infliximab have been the best studied anti-TNF agents and indeed have now been recommended by an expert panel as the first line of treatment for ocular manifestations of Behçet's disease and the second line of treatment for other forms of uveitis. Adalimumab has been recently approved for intermediate uveitis, posterior uveitis, and panuveitis. Other biologic agents have been tested, including daclizumab, a monoclonal antibody directed against IL-2, anti-IL1, and anti-IL-6 receptor agents and therapies that block antigen-presenting cell and T-cell interaction, such as abatacept. In small case series, other biologics such as interferon and rituximab have also been evaluated. Although these biologic therapies have provided a larger armamentarium to treat uveitis, challenges remain. Uveitis is not a disease, but a manifestation of many potential systemic diseases that may have specific individual therapeutic targets. Identification and characterization of these underlying diseases are not always possible and, more importantly, the most effective therapies for each entity have not been defined. In this study, an approach to manage patients

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

    Directory of Open Access Journals (Sweden)

    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.

  12. [TATTOO-ASSOCIATED UVEITIS].

    Science.gov (United States)

    Klímová, A; Heissigerová, J; Říhová, E; Holan, P; Brichová, M; Svozílková, P

    2017-01-01

    The clinical case of tattoo-associated uveitis was first described by Lubeck and Epstein in 1952. Uveitis is accompanied by induration and hyperemia of tattoo skin, which can precede, follow or manifest simultaneously with uveitis. The diagnosis is determined on clinical grounds after exclusion of other causes. Uveitis is usually bilateral, chronic and vision impairment is variable. Tattoo-associated uveitis should be remembered in differential diagnosis due to the growing interest in tattoo.Key words: uveitis, tattoo, masquerade syndrome.

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

    Science.gov (United States)

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

    2017-01-01

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

  14. Experimental autoimmune encephalomyelitis from a tissue energy perspective.

    Science.gov (United States)

    Desai, Roshni A; Smith, Kenneth J

    2017-01-01

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

  15. Preventive Treatment with Methylprednisolone Paradoxically Exacerbates Experimental Autoimmune Encephalomyelitis

    Directory of Open Access Journals (Sweden)

    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.

  16. 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

  17. Lactobacillus helveticus SBT2171 Attenuates Experimental Autoimmune Encephalomyelitis in Mice

    Directory of Open Access Journals (Sweden)

    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.

  18. Cytoskeletal protein carbonylation and degradation in experimental autoimmune encephalomyelitis

    Science.gov (United States)

    Smerjac, Suzanne M.; Bizzozero, Oscar A.

    2013-01-01

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

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

    Science.gov (United States)

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

    2017-03-07

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

  20. Modulation of experimental autoimmune encephalomyelitis by endogenous Annexin A1

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    Flower Rod J

    2009-11-01

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

  1. 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...

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

    DEFF Research Database (Denmark)

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

    2013-01-01

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

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

    NARCIS (Netherlands)

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

    2005-01-01

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

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

    NARCIS (Netherlands)

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

    2012-01-01

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

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

    NARCIS (Netherlands)

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

    2012-01-01

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

  6. Beneficial role of rapamycin in experimental autoimmune myositis.

    Directory of Open Access Journals (Sweden)

    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.

  7. The Use of Biologic Therapies in Uveitis.

    Science.gov (United States)

    Schwartzman, Sergio; Schwartzman, Monica

    2015-12-01

    Therapy for autoimmune ophthalmic disease is currently evolving. The improved understanding of the abnormal immune response in the various forms of uveitis has resulted in targeted therapy. The aberrations of the immune system have been characterized by atypical cell populations, cytokine expression, and cell-cell interactions. Different patterns of cytokine expression have now been delineated in the abnormal uveal tract with exaggerated and/or abnormal expression of TNF, IL-1, IL-2, IL-6, and IL-17. The development of therapies for other conditions in which these cytokines play an important role has resulted in the availability of biological agents that have been adopted for use in the therapy for uveitis. Adalimumab and infliximab have been the best studied anti-TNF agents and indeed have now been recommended by an expert panel as first-line treatment of ocular manifestations of Behçet's disease and second-line treatment for other forms of uveitis (Levy-Clarke et al. (Ophthalmology, 2013). Other anti-TNF agents have been studied as well. Daclizumab, a monoclonal antibody directed against the IL-2 receptor, has also demonstrated utility in treating uveitis as have some of the anti-IL1 agents. Gevokizumab has been granted orphan drug designation for the treatment of resistant forms of uveitis. Therapies affecting IL-6, including tocilizumab are being studied, and available medications that block antigen presenting cell and T cell interaction such as abatacept have been reported to be effective in uveitis. Interferons as well as rituximab have also been evaluated in small studies. Although these biologic therapies have provided a larger armamentarium to treat uveitis, challenges remain. Uveitis is not a single illness; rather, it is a manifestation of many potential systemic diseases that may have very specific individual therapeutic targets. Identifying and characterizing these underlying diseases is not always achieved, and more importantly, the most effective

  8. Association of Cryptogenic Organizing Pneumonia in Bilateral Anterior Uveitis

    Directory of Open Access Journals (Sweden)

    Kaori Fujimoto

    2014-11-01

    Full Text Available Two female patients with histories of cancer who showed cryptogenic organizing pneumonia (COP complications and bilateral anterior uveitis with hypopyon were examined. Both patients had suffered from COP and received intermitted systemic corticosteroid administration (SCA. The first patient, a 65-year-old woman with a history of breast cancer, showed bilateral uveitis with hypopyon. The topical corticosteroid treatment was ineffective. After SCA for the treatment of COP was started, the hypopyon gradually dissipated. Upon termination of SCA, uveitis relapses were controlled by renewed SCA. The other patient, a 69-year-old woman with a history of ovarian cancer, showed bilateral anterior uveitis with hypopyon. Her intraocular outcome did not improve by the topical corticosteroid administration, but SCA that was applied to treat COP led to remission of uveitis. Imaging examinations, biochemical analysis, symptoms or HLA-B27 antigen screenings in either patient did not explain the development of uveitis. Bilateral anterior uveitis is commonly related to autoimmune disease or systemic syndrome. We report two cases with COP that developed bilateral anterior uveitis with hypopyon resistant to topical administration but responsive to systemic administration of corticosteroid. These findings suggest that COP can be associated with the etiology of anterior uveitis.

  9. Genetic dissection of experimental autoimmune neuroinflammatory diseases in rats

    OpenAIRE

    Dahlman, Ingrid

    1999-01-01

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

  10. 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.

  11. 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,...

  12. 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

  13. 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...

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

    DEFF Research Database (Denmark)

    Li, Lu; Itoh, Masahiro; Ablake, Maila

    2002-01-01

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

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

    DEFF Research Database (Denmark)

    Hasseldam, Henrik; Johansen, Flemming Fryd

    2010-01-01

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

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

    NARCIS (Netherlands)

    H.P.M. Brok (Herbert)

    2002-01-01

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

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

    DEFF Research Database (Denmark)

    Li, Lu; Itoh, Masahiro; Ablake, Maila

    2002-01-01

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

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

    DEFF Research Database (Denmark)

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

    2004-01-01

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

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

    NARCIS (Netherlands)

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

    2007-01-01

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

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

    OpenAIRE

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2012-11-01

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

  2. Drug-induced uveitis

    Science.gov (United States)

    2013-01-01

    A number of medications have been associated with uveitis. This review highlights both well-established and recently reported systemic, topical, intraocular, and vaccine-associated causes of drug-induced uveitis, and assigns a quantitative score to each medication based upon criteria originally described by Naranjo and associates. PMID:23522744

  3. The Role of M. leprae Hsp65 Protein and Peptides in the Pathogenesis of Uveitis

    Directory of Open Access Journals (Sweden)

    Alessandra Gonçalves Commodaro

    2012-01-01

    Full Text Available Experimental autoimmune uveitis (EAU is a well established model for immune-mediated organ-specific disease. Our group has recently shown that the M. leprae Hsp65 aggravated the uveitis in mice; in the present study, we evaluated the action of M. leprae  K409A mutant protein and the synthetic peptides Leader pep and K409A pep (covering amino acids residues 352–371 of WT and K409A proteins of M. leprae Hsp65, resp. on the pathogenesis of EAU. Mice received the 161–180 IRBP peptide and B. pertussis toxin followed by the intraperitoneal inoculation of K409A protein or the Leader pep or K409A pep. The Leader pep aggravated the disease, but mice receiving the K409A pep did not develop the disease and presented an increase in IL-10 levels by spleen cells and a decrease in the percentage of CD4+ IFN-γ+ T cells. Moreover, animals receiving the Leader pep presented the highest scores of the disease associated with increase percentage of CD4+ IFN-γ+ T cells. These results would contribute to understanding of the pathogenesis of EAU and support the concept that immune responses to Hsp are of potential importance in exacerbating, perpetuating, or even controlling organ-restricted autoimmune diseases, and it is discussed the irreversibility of autoimmune syndromes.

  4. Proteasome inhibitors as experimental therapeutics of autoimmune diseases

    NARCIS (Netherlands)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2007-07-01

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

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

    Science.gov (United States)

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

    2017-11-28

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

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

    Science.gov (United States)

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

    2009-01-01

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

  8. Pharmacotherapy for uveitis: current management and emerging therapy

    Science.gov (United States)

    Barry, Robert J; Nguyen, Quan Dong; Lee, Richard W; Murray, Philip I; Denniston, Alastair K

    2014-01-01

    Uveitis, a group of conditions characterized by intraocular inflammation, is a major cause of sight loss in the working population. Most uveitis seen in Western countries is noninfectious and appears to be autoimmune or autoinflammatory in nature, requiring treatment with immunosuppressive and/or anti-inflammatory drugs. In this educational review, we outline the ideal characteristics of drugs for uveitis and review the data to support the use of current and emerging therapies in this context. It is crucial that we continue to develop new therapies for use in uveitis that aim to suppress disease activity, prevent accumulation of damage, and preserve visual function for patients with the minimum possible side effects. PMID:25284976

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

    Science.gov (United States)

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

    2017-05-15

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

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Kalliopi Pitarokoili

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

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

    Science.gov (United States)

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

    2007-09-01

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

  13. A new era of uveitis: impact of polymerase chain reaction in intraocular inflammatory diseases.

    Science.gov (United States)

    Mochizuki, Manabu; Sugita, Sunao; Kamoi, Koju; Takase, Hiroshi

    2017-01-01

    Uveitis is a sight-threatening intraocular inflammatory disorder which may occur from both infectious and non-infectious or autoimmune causes. The frequency of infectious uveitis and autoimmune uveitis varies depending on countries and regions. According to a nationwide survey conducted by the Japanese Ocular Inflammation Society, infectious and non-infectious uveitis accounted for 16.4 and 50.1% of new patients, respectively while the remaining 33.5% of new uveitis cases were not classified or were idiopathic uveitis. Infectious uveitis is particularly important because it causes tissue damage to the eye and may result in blindness unless treated. However, it can be treated if the pathogenic microorganisms are identified promptly and accurately. Remarkable advancements in molecular and immunological technologies have been made in the last decade, and the diagnosis of infectious uveitis has been greatly improved by the application of molecular and immunological investigations, particularly polymerase chain reaction (PCR). PCR performed on a small amount of ocular samples provides a prompt, sensitive, and specific molecular diagnosis of pathogenic microorganisms in the eye. This technology has opened a new era in the diagnosis and treatment of uveitis, enabling physicians to establish new clinical entities of uveitis caused by infectious microorganisms, identify pathogens in the eyes of many patients with uveitis, and determine prompt diagnosis and appropriate therapy. Here we review the PCR process, new PCR tests specialized for ocular diseases, microorganisms detected by the PCR tests, diseases in the eye caused by these microorganisms, and the clinical characteristics, diagnosis, and therapy of uveitis.

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

    DEFF Research Database (Denmark)

    Penkowa, M; Hidalgo, J

    2001-01-01

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

  15. 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.

  16. Uveitis- a rare disease often associated with systemic diseases and infections- a systematic review of 2619 patients

    Directory of Open Access Journals (Sweden)

    Barisani-Asenbauer Talin

    2012-08-01

    Full Text Available Abstract Background Uveitis is an autoimmune disease of the eye that refers to any of a number of intraocular inflammatory conditions. Because it is a rare disease, uveitis is often overlooked, and the possible associations between uveitis and extra-ocular disease manifestations are not well known. The aim of this study was to characterize uveitis in a large sample of patients and to evaluate the relationship between uveitis and systemic diseases. Methods The present study is a cross-sectional study of a cohort of patients with uveitis. Records from consecutive uveitis patients who were seen by the Uveitis Service in the Department of Ophthalmology at the Medical University of Vienna between 1995 and 2009 were selected from the clinical databases. The cases were classified according to the Standardization of Uveitis Nomenclature Study Group criteria for Uveitis. Results Data were available for 2619 patients, of whom 59.9% suffered from anterior, 14.8% from intermediate, 18.3% from posterior and 7.0% from panuveitis. 37.2% of all cases showed an association between uveitis and extra-organ diseases; diseases with primarily arthritic manifestations were seen in 10.1% of all cases, non-infectious systemic diseases (i.e., Behçet´s disease, sarcoidosis or multiple sclerosis in 8.4% and infectious uveitis in 18.7%. 49.4% of subjects suffering from anterior uveitis tested positively for the HLA-B27 antigen. In posterior uveitis cases 29% were caused by ocular toxoplasmosis and 17.7% by multifocal choroiditis. Conclusion Ophthalmologists, rheumatologists, infectiologists, neurologists and general practitioners should be familiar with the differential diagnosis of uveitis. A better interdisciplinary approach could help in tailoring of the work-up, earlier diagnosis of co-existing diseases and management of uveitis patients.

  17. 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.

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

    OpenAIRE

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

    2013-01-01

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

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

    DEFF Research Database (Denmark)

    Kaneko, Tetsushi; Itoh, Masahiro; Nakamura, Yoichi

    2003-01-01

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

  20. 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....

  1. Uveitis in children.

    Science.gov (United States)

    Angeles-Han, Sheila T; Rabinovich, Consuelo Egla

    2016-09-01

    The review provides updates on novel risk markers for the development of pediatric inflammatory uveitis and a severe disease course, on treatment of refractory disease, and on the measurement of visual outcomes. There are several new genetic markers, biomarkers, and clinical factors that may influence a child's uveitis disease course. It is important to identify children at risk for poor visual outcomes and who are refractory to traditional therapy. Racial disparities have recently been reported. We describe agents of potential benefit. In addition, we discuss the importance of patient reported outcomes in this population. Uveitis can lead to vision-threatening complications. Timely and aggressive treatment of children identified to be at risk for a severe uveitis course may lead to improved outcomes.

  2. Management of pediatric uveitis

    Science.gov (United States)

    Wentworth, Bailey A.; Freitas-Neto, Clovis A.

    2014-01-01

    Pediatric uveitis is a topic of special interest not only because of the unique diagnostic and therapeutic challenges but also because of the lifetime burden of vision loss if the problem is not adequately treated, as well as the economic and psychological toll on the family. Often, uveitis in children is discovered as part of a routine eye exam; this silent, insidious inflammation can be difficult to treat and can lead to further complications if not handled skillfully. Corticosteroids have long been the mainstay of therapy; however, the significant associated side effects mandate a corticosteroid-sparing therapeutic regimen in pursuit of remission. In this review, we cover the therapeutic options for pediatric uveitis, specifically focusing on the most common non-infectious varieties, juvenile idiopathic arthritis-associated uveitis and pars planitis. PMID:24991418

  3. Infectious uveitis in Virginia

    Directory of Open Access Journals (Sweden)

    Engelhard SB

    2015-08-01

    Full Text Available Stephanie B Engelhard,1 Zeina Haddad,1 Asima Bajwa,1 James Patrie,2 Wenjun Xin,2 Ashvini K Reddy1 1Department of Ophthalmology, 2Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA Purpose: To report the causes, clinical features, and outcomes of infectious uveitis in patients managed in a mid-Atlantic tertiary care center.Methods: Retrospective, observational study of infectious uveitis patients seen at the University of Virginia from 1984 to 2014.Results: Seventy-seven of 491 patients (15.7% were diagnosed with infectious uveitis (mean age 58 years, 71.4% female, 76.6% Caucasian. The mean follow-up was 5 years. Anterior uveitis was the most common anatomic classification (39 patients, 50.6% followed by panuveitis (20 patients, 26.0% and posterior uveitis (18 patients, 23.4%. The most common infectious etiology was herpetic anterior uveitis (37 patients, 48.1% followed by toxoplasma uveitis (14 patients, 18.2%. The most prevalent viral pathogen was varicella-zoster virus (21 patients, 27.3% followed by herpes simplex virus (20 patients, 26.0%. Acute retinal necrosis (ARN was diagnosed in 14 patients (18.2%. Aqueous humor yielded an etiologic diagnosis in seven (50% of ARN patients, four of whom tested positive for cytomegalovirus and three for varicella-zoster virus. On presentation, 43 patients (55.8% had a visual acuity (VA better than 20/40 and 17 (22.1% had a VA worse than 20/200. VA at the final follow-up was better than 20/40 in 39 patients (50.6% and worse than 20/200 in 22 patients (28.6%. In all, 16 (20.8% and 10 (13.0% patients required cataract and vitrectomy surgery, respectively. A total of 14 patients (18.2% were on glaucoma topical treatment and four (5.2% required glaucoma surgery.Conclusion: The most common type of infectious uveitis seen over the study period was herpetic anterior uveitis secondary to varicella-zoster virus or herpes simplex virus, found to be most prevalent in patients

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

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    Rosetta Pedotti

    2012-11-01

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

  5. 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.

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

    Science.gov (United States)

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

    2016-11-30

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

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

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    Ward J. van den Hoogen

    2017-09-01

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

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

    DEFF Research Database (Denmark)

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

    2000-01-01

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

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

    Science.gov (United States)

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

    2015-06-01

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

  10. Brimonidine Induced Anterior Uveitis.

    Science.gov (United States)

    Beltz, Jacqueline; Zamir, Ehud

    2016-01-01

    To present the largest series reported so far of brimonidine induced granulomatous anterior uveitis. Retrospective chart review of patients with chronic glaucoma on treatment with brimonidine presenting with anterior uveitis. 19 eyes of 12 patients with chronic glaucoma developed anterior uveitis with granulomatous keratic precipitates after being treated with brimonidine for periods of 7 days to 5 years (mean 19.7 months, +18.6 months). One patient had a gap of 1 year between onset in one eye and onset in the other. Ten eyes (52.6%) had concurrent granulomatous conjunctivitis; 16 eyes were pseudophakic. Stopping brimonidine led to complete, rapid resolution of uveitis in all patients, in most cases (11 eyes, 58%) without topical corticosteroids. No recurrences have occurred after withdrawal of brimonidine, over a follow-up period of 12-52 months (mean 27.9 months, +13.8 months). Ophthalmologists should be aware of this easily reversible uveitis syndrome that is induced by a common glaucoma medication. Familiarity with this entity is essential in making the correct diagnosis and avoiding unnecessary investigations and interventions.

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

    Science.gov (United States)

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

    2014-08-01

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

  12. 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.

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

    Directory of Open Access Journals (Sweden)

    Garth E. Ringheim

    2013-10-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Stojkov Danijela

    2006-01-01

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

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

    DEFF Research Database (Denmark)

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

    2004-01-01

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

  17. 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...

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

    OpenAIRE

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

    2016-01-01

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

  19. 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.

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

    Science.gov (United States)

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

    2004-01-01

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

  1. 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

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

    Directory of Open Access Journals (Sweden)

    Johanna Prinz

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

  3. 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.

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

    Science.gov (United States)

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

    2011-03-01

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

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

    Science.gov (United States)

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

    2012-07-05

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

  6. Interleukin-35 induces regulatory B cells that suppress autoimmune disease.

    Science.gov (United States)

    Wang, Ren-Xi; Yu, Cheng-Rong; Dambuza, Ivy M; Mahdi, Rashid M; Dolinska, Monika B; Sergeev, Yuri V; Wingfield, Paul T; Kim, Sung-Hye; Egwuagu, Charles E

    2014-06-01

    Interleukin-10 (IL-10)-producing regulatory B (Breg) cells suppress autoimmune disease, and increased numbers of Breg cells prevent host defense to infection and promote tumor growth and metastasis by converting resting CD4(+) T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of Breg cells remain unclear. Here we show that IL-35 induces Breg cells and promotes their conversion to a Breg subset that produces IL-35 as well as IL-10. Treatment of mice with IL-35 conferred protection from experimental autoimmune uveitis (EAU), and mice lacking IL-35 (p35 knockout (KO) mice) or defective in IL-35 signaling (IL-12Rβ2 KO mice) produced less Breg cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of Breg cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 (TH17) and TH1 cells while promoting Treg cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12Rβ2 and IL-27Rα subunits. As IL-35 also induced the conversion of human B cells into Breg cells, these findings suggest that IL-35 may be used to induce autologous Breg and IL-35(+) Breg cells and treat autoimmune and inflammatory disease.

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

    NARCIS (Netherlands)

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

    2016-01-01

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

  8. 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.

  9. The treatment of refractory uveitis with intravenous immunoglobulin.

    Science.gov (United States)

    Rosenbaum, J T; George, R K; Gordon, C

    1999-05-01

    To study the treatment of uveitis that has not responded to immunosuppressive medication. Intravenous immunoglobulin (IVIg) effectively treats a variety of autoimmune diseases, but it has not been adequately studied in the treatment of uveitis. The trial included patients who satisfied criteria that included noninfectious uveitis, active inflammatory disease, and a failure to respond adequately to immunosuppressive medication. We treated two patients with IVIg (0.5 gm/day, 3 days/mo initial dosage) as a pilot study and then treated an additional eight patients with a similar dosage as part of a formal but uncontrolled protocol. Patients on the protocol have been followed for a median of 11 months and have received a median of 7.5 treatment cycles. Five of 10 patients have had a clinically important and sustained improvement in visual acuity, and two of eight protocol patients have markedly reduced their immunosuppressive medication. Intravenous immunoglobulin can benefit some patients with uveitis that is otherwise refractory to immunosuppressive therapy. Although our preliminary experience is encouraging, the use of IVIg for uveitis should be limited because of cost, toxicity, the requirement for repeated administration, and the absence of controlled trials that demonstrate efficacy.

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

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    Justin D Glenn

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

  11. 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.

  12. 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.

  13. 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.

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

    Science.gov (United States)

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

    2016-01-01

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

  15. 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.

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

    Science.gov (United States)

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

    2014-09-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

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    Muzhou Wu

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

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

    Science.gov (United States)

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

    2014-02-01

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

  20. 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.

  1. 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.

  2. 5-Androstenediol Ameliorates Pleurisy, Septic Shock, and Experimental Autoimmune Encephalomyelitis in Mice

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    Ferdinando Nicoletti

    2010-01-01

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

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

    Science.gov (United States)

    Pierson, Emily R; Goverman, Joan M

    2017-04-06

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

  4. Emerging Role of Antioxidants in the Protection of Uveitis Complications

    Science.gov (United States)

    Yadav, Umesh C S; Kalariya, Nilesh M; Ramana, Kota V

    2011-01-01

    Current understanding of the role of oxidative stress in ocular inflammatory diseases indicates that antioxidant therapy may be important to optimize the treatment. Recently investigated antioxidant therapies for ocular inflammatory diseases include various vitamins, plant products and reactive oxygen species scavengers. Oxidative stress plays a causative role in both non-infectious and infectious uveitis complications, and novel strategies to diminish tissue damage and dysfunction with antioxidant therapy may ameliorate visual complications. Preclinical studies with experimental animals and cell culture demonstrate significance of anti-inflammatory effects of a number of promising antioxidant agents. Many of these antioxidants are under clinical trial for various inflammatory diseases other than uveitis such as cardiovascular, rheumatoid arthritis and cancer. Well planned interventional clinical studies of the ocular inflammation will be necessary to sufficiently investigate the potential medical benefits of antioxidant therapies for uveitis. This review summarizes the recent investigation of novel antioxidant agents for ocular inflammation, with selected studies focused on uveitis. PMID:21182473

  5. [Less frequent etiology in uveitis].

    Science.gov (United States)

    Ignat, F; Preda, M; Perovic, I

    2001-01-01

    This material intends to present three clinical observations regarding the uveitis etiology, that is represented by the association of some etiological factors less known: Toxoplasma gondii, Listeria monocytogenes, Leptospira icterohaemorrhagiae. The uveitis described here have been severe in the fast evolution and with trends of reappearence. This work demonstrates that the strict etiological antibacteria and antiparasite therapy is not enough and only corticotherapy is able to fight against the accentuated inflammatory phenomena that go along with type of uveitis.

  6. Basic and clinical immunology in uveitis.

    Science.gov (United States)

    Nussenblatt, R B

    1987-01-01

    Understanding the basic immune mechanisms and how they relate to the eye are becoming obtainable goals with far reaching implications. Attempts are made to classically divide the immune responses noted into Type I-IgE mediated, Type II-Antibody mediated killing, Type III-Immune complex mediation, and Type IV-Cell mediated. Though several mechanisms are surely working simultaneously, it remains an helpful method of analysis. Until recently, Type III hypersensitivity reactions were thought to be the basic underlying cause of most ocular inflammatory disease, but recent evidence would suggest that cell mediated mechanisms are more important for sight threatening ocular disease (uveitis). The S-antigen and IRBP induced experimental models for uveitis have provided us with invaluable information concerning the potential mechanisms underpinning uveitis, while the diseases themselves manifest many aspects of that seen in human disease. Additionally, it has permitted us to investigate the way in which immune cells may "home" to a target organ, this in part due to the expression of HLA antigens on non-immune tissues in the eye. The observation that T-cell mechanisms appear of major import in uveitis permitted a new approach to therapy, the use of the anti-T-cell drug cyclosporine. Its use in severe sight threatening disease has shown it to be effective, thereby confirming the notion of the importance of T-cell mediation of these diseases. Perhaps most notable is this agent's efficacy in the treatment of Behçet uveitis. The problem of renal toxicity has been addressed by using cyclosporine in combination with other agents, including those not directly affecting the immune system.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. [Tubulointerstitial nephritis syndrome and uveitis].

    Science.gov (United States)

    Isnardi, Carolina A; Vilela, Andrés; Kuschner, Pablo; Salvo, Carolina; Vanzetti, Cecilia; Zelechower, Hugo; Arpa, Adriana

    Intermediate uveitis is described as inflammation in the anterior vitreous, ciliary body and the peripheral retina. It is a subset of uveitis where the vitreous is the major site of damage. It has been reported to be associated with many local and systemic inflammatory and infectious diseases. An infrequent cause is the tubulointerstitial nephritis and uveitis syndrome. We report a case of an acute visual acuity loss related with renal failure in a 64 years old woman with Hashimoto disease. It was an acute tubulointerstitial nephritis and uveitis syndrome case.

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

    DEFF Research Database (Denmark)

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

    1997-01-01

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

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

    DEFF Research Database (Denmark)

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

    2010-01-01

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

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

    DEFF Research Database (Denmark)

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

    2010-01-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Science.gov (United States)

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

    2012-12-01

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

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

    DEFF Research Database (Denmark)

    Teige, Ingrid; Treschow, Alexandra; Teige, Anna

    2003-01-01

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

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

    Science.gov (United States)

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

    2011-02-16

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

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

    Directory of Open Access Journals (Sweden)

    Nancy L Monson

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

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

    Science.gov (United States)

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

    2016-01-01

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

  17. 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

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

    Science.gov (United States)

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

    2017-01-01

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

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

    DEFF Research Database (Denmark)

    Penkowa, Milena; Hidalgo, Juan

    2003-01-01

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

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

    DEFF Research Database (Denmark)

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

    2001-01-01

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

  1. 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...

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

    Directory of Open Access Journals (Sweden)

    Suzana Stanisavljevic

    2016-12-01

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

  3. 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

  4. High Levels of Serum Ubiquitin and Proteasome in a Case of HLA-B27 Uveitis

    Directory of Open Access Journals (Sweden)

    Settimio Rossi

    2017-02-01

    Full Text Available In this paper, the authors describe a case of high serum levels of ubiquitin and proteasome in a woman under an acute attack of autoimmune uveitis. The woman was 52 years old, diagnosed as positive for the Human leukocyte antigen-B27 gene, and came to our observation in January 2013 claiming a severe uveitis attack that involved the right eye. During the acute attack of uveitis, this woman had normal serum biochemical parameters but higher levels of serum ubiquitin and proteasome 20S subunit, with respect to a healthy volunteer matched for age and sex. These levels correlated well with the clinical score attributed to uveitis. After the patient was admitted to therapy, she received oral prednisone in a de-escalation protocol (doses from 50 to 5 mg/day for four weeks. Following this therapy, she had an expected reduction of clinical signs and score for uveitis, but concomitantly she had a reduction of the serum levels of ubiquitin, poliubiquitinated proteins (MAb-FK1 and proteasome 20S activity. Therefore, a role for ubiquitin and proteasome in the development of human autoimmune uveitis has been hypothesized.

  5. High Levels of Serum Ubiquitin and Proteasome in a Case of HLA-B27 Uveitis.

    Science.gov (United States)

    Rossi, Settimio; Gesualdo, Carlo; Maisto, Rosa; Trotta, Maria Consiglia; Di Carluccio, Nadia; Brigida, Annalisa; Di Iorio, Valentina; Testa, Francesco; Simonelli, Francesca; D'Amico, Michele; Di Filippo, Clara

    2017-02-26

    In this paper, the authors describe a case of high serum levels of ubiquitin and proteasome in a woman under an acute attack of autoimmune uveitis. The woman was 52 years old, diagnosed as positive for the Human leukocyte antigen-B27 gene, and came to our observation in January 2013 claiming a severe uveitis attack that involved the right eye. During the acute attack of uveitis, this woman had normal serum biochemical parameters but higher levels of serum ubiquitin and proteasome 20S subunit, with respect to a healthy volunteer matched for age and sex. These levels correlated well with the clinical score attributed to uveitis. After the patient was admitted to therapy, she received oral prednisone in a de-escalation protocol (doses from 50 to 5 mg/day) for four weeks. Following this therapy, she had an expected reduction of clinical signs and score for uveitis, but concomitantly she had a reduction of the serum levels of ubiquitin, poliubiquitinated proteins (MAb-FK1) and proteasome 20S activity. Therefore, a role for ubiquitin and proteasome in the development of human autoimmune uveitis has been hypothesized.

  6. Preparation and evaluation of sinomenine hydrochloride in situ gel for uveitis treatment.

    Science.gov (United States)

    Song, Jike; Bi, Hongsheng; Xie, Xiaofeng; Guo, Junguo; Wang, Xingrong; Liu, Damei

    2013-09-01

    The aim of the present study was to develop and optimize sinomenine hydrochloride (SIN) in situ gel for uveitis treatment. Carbopol 940 was used as the gelling agent in combination with hydroxypropyl methylcellulose (HPMC), which acts as a viscosity enhancer. The formulations were prepared using various concentrations of Carbopol 940 and HPMC. The prepared in situ gels were evaluated for gellation, drug release, ocular irritation, elimination time and pharmacokinetic studies. Furthermore, the effect of SIN on the development of experimental autoimmune anterior uveitis (EAAU) was assessed. The optimum concentration of Carbopol was 0.1% (w/v), and that for HPMC was 0.4% (w/v). Which showed a significant enhancement in gel strength in the physiological condition while free flowing at non-physiological condition. Optimum formula F(2-3) consisting of 0.5% SIN was prepared and kept as gel group, and 0.5% SIN solution was prepared and kept as control group. Gel group provided sustained release of the drug over a period of 480 min. No evidence of overt toxicity and irritation was observed in any study. The elimination time of control group and gel group was completed within 10 min and 25 min, respectively. The area under the aqueous humor concentration vs. time curve (AUC(0-t)) and maximum concentration (C(max)) values of gel group was 2.70-fold and 1.79-fold higher than that of control group. Additionally, clinical examination showed that SIN suppressed inflammation in EAAU. These results support the potential applications of SIN in situ gel for uveitis treatment. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. 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.

  10. Association Between Thyroid Disease and Uveitis: Results From the Pacific Ocular Inflammation Study.

    Science.gov (United States)

    Borkar, Durga S; Homayounfar, Gelareh; Tham, Vivien M; Ray, Kathryn J; Vinoya, Aleli C; Uchida, Aileen; Acharya, Nisha R

    2017-06-01

    Common pathophysiological mechanisms may be responsible for immune dysregulation in both thyroid disease and uveitis. Studies investigating a possible association are limited. To determine the association between thyroid disease and uveitis. A retrospective, population-based case-control study was conducted from January 1, 2006, to December 31, 2007, among 217 061 members of the Kaiser Permanente Hawaii health system during the study period. A clinical diagnosis of uveitis was determined through a query of the electronic medical record followed by individual medical record review for confirmation by a uveitis specialist. Thyroid disease was determined based on International Classification of Diseases, Ninth Revision, coding. Two control groups were chosen at a 4:1 ratio for comparison with patients with uveitis. A logistic regression analysis was performed with uveitis as the main outcome variable and thyroid disease as the main predictor variable, while adjusting for age, sex, race, smoking status, and history of autoimmune disease. Data analysis was conducted between 2014 and 2016. A diagnosis of thyroid disease among patients with uveitis and respective controls. Of the 224 patients with uveitis (127 women and 97 men; mean [SD] age, 54.1 [17.8] years) identified during the study period, 29 (12.9%) had a diagnosis of thyroid disease, compared with 62 of 896 patients (6.9%) in the control group (P = .01) and 78 of 896 patients (8.7%) in the ophthalmology clinic control group (P = .06). Using the general Kaiser Permanente Hawaii population control group, patients who had thyroid disease had a 1.7-fold (95% CI, 1.03-2.80; P = .04) higher odds of having uveitis compared with patients who did not have thyroid disease when controlling for age, sex, race, smoking status, and autoimmune disease. A similar association was found using the ophthalmology clinic control group (odds ratio, 1.8; 95% CI, 1.1-2.9; P = .02) while adjusting for these factors

  11. Uveitis in childhood : clinical and fundamental developments

    NARCIS (Netherlands)

    Kalinina Ayuso, V.|info:eu-repo/dai/nl/33793259X

    2013-01-01

    This thesis aimed to gain new insights regarding the course and prognosis of uveitis in childhood, the pathogenesis of JIA-uveitis and the treatment of uveitis in children. The role of baseline prognostic factors in JIA-uveitis was studied by a retrospective analysis of 117 affected eyes of 65

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

    Science.gov (United States)

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

    2010-12-01

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

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

    Science.gov (United States)

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

    2014-07-01

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

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

    DEFF Research Database (Denmark)

    Kuhlmann, Tanja; Remington, Leah; Cognet, Isabelle

    2006-01-01

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

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

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    Hiroyuki Hirakawa

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

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

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    Henry Kaminski

    2016-11-01

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

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

    Science.gov (United States)

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

    2014-07-01

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

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

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

    2015-01-01

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

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

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    Violetta Zujovic

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

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

    Science.gov (United States)

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

    2012-01-01

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

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

    Science.gov (United States)

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

    2014-12-01

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

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

    Science.gov (United States)

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

    2012-04-01

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

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

    DEFF Research Database (Denmark)

    Mustafa, M; Vingsbo, C; Olsson, T

    1994-01-01

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

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

    Science.gov (United States)

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

    2006-09-20

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

  5. 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

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

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    Wijmenga Sybren S

    2011-06-01

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

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

    Science.gov (United States)

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

    2012-01-01

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

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

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    De-Carvalho M.C.A.

    1999-01-01

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

  9. 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.

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

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    Yifat Amir-Levy

    2014-01-01

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

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

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    Fernanda Chiuso-Minicucci

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

  12. 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

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

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    Itay Raphael

    2017-07-01

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

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

    Science.gov (United States)

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

    2017-04-27

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

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

    Science.gov (United States)

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

    2015-09-18

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

  16. Magnetic resonance imaging of uveitis

    Energy Technology Data Exchange (ETDEWEB)

    Li, Charles Q.; Mafee, Mahmood F. [University of California, San Diego, Department of Radiology, San Diego, CA (United States); Cho, Aaron A. [Naval Medical Center, San Diego, CA (United States); Edward, Neeraj J. [University of Cincinnati, Department of Anesthesiology, Cincinnati, OH (United States); Edward, Deepak P. [King Khaled Eye Specialist Hospital, Riyadh (Saudi Arabia); Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, MD (United States); Fajardo, Roman G. [University of California, San Diego, Shiley Eye Center, La Jolla, CA (United States)

    2015-08-15

    Uveitis is a term used to describe inflammation of the choroid, iris, or ciliary body, which make up the uveal tract. It can be idiopathic or associated with a systemic disease which may be infectious or noninfectious. With the exception of B-scan ultrasonography, current imaging methods for diagnosing and monitoring uveitis are predominately non-radiologic. Although MRI has been anecdotally shown to detect various inflammatory conditions of the globe, such as posterior scleritis, endophthalmitis, and posterior uveitis secondary to Vogt-Koyanagi-Harada disease, a more comprehensive review of the MRI findings in uveitis of various etiologies is presented here. The MRI and CT studies of seven patients with uveitis and the clinical history of three of them (not available in four patients) were reviewed. Etiologies included ankylosing spondylitis, relapsing polychondritis, Vogt-Koyanagi-Harada disease, sarcoidosis, and tuberculosis. Increased gadolinium enhancement of the uveal tract, which is visualized as the enhancing layer immediately deep to the low-signal sclera, was seen on all six MRI studies. Diffusion-weighted imaging of a case with posterior uveitis and subretinal effusions revealed restriction within the uvea and effusions. Two patients had inflammatory nodules adherent to the uvea, two patients had vitreous humor abnormalities, and one patient exhibited proximal perineural and perimuscular spread of enhancement. Uveoscleral thickening and enhancement with a posterior calcification were observed in the patient with chronic uveitis imaged with CT. Increased uveal tract enhancement is a common finding in patients with uveitis, regardless of anatomic distribution and etiology. MRI can also further evaluate complications of uveitis and help differentiate it from masquerade syndromes. (orig.)

  17. Tubulointerstitial nephritis and uveitis.

    Science.gov (United States)

    Pakzad-Vaezi, Kaivon; Pepple, Kathryn L

    2017-11-01

    Tubulointerstitial nephritis and uveitis (TINU) is an important yet underrecognized ocular inflammatory syndrome. This review summarizes key historical publications that identified and defined the syndrome, and more recent literature that reveal the importance of urinary β2-microglobulin testing and kidney biopsy in the diagnostic evaluation of patients with TINU. Additionally, research studies providing new insights into disease pathogenesis are highlighted. In contrast with initial reports of TINU manifesting exclusively as an anterior uveitis in pediatric patients, more recent reports have identified TINU in patients of all ages with a wide range of ocular manifestations. Urinary β2-microglobulin has emerged as a sensitive and specific laboratory screening test, and the role of kidney biopsy in differentiating TINU from sarcoidosis continues to evolve. Genetic studies have identified HLA-DQA101, HLA-DQB105, and HLA-DRB101 as high-risk alleles and the identification of antimonomeric C-reactive protein antibodies suggests a role for humoral immunity in disease pathogenesis. Management strategies have evolved to include systemic anti-inflammatory treatment as a result of important outcome studies in patients with significant renal and ocular disease. With greater recognition, understanding, and treatment of this syndrome, both ocular inflammation and renal disease can be better addressed.

  18. 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...

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

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

    DEFF Research Database (Denmark)

    Donia, M; Mangano, K; Quattrocchi, C

    2010-01-01

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

  1. Oral voclosporin: novel calcineurin inhibitor for treatment of noninfectious uveitis

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    Roesel M

    2011-09-01

    Full Text Available Martin Roesel1, Christoph Tappeiner2, Arnd Heiligenhaus1,3, Carsten Heinz1,31Department of Ophthalmology, St Franziskus-Hospital, Muenster, Germany; 2Department of Ophthalmology, Inselspital, University of Bern, Switzerland; 3University Duisburg-Essen, GermanyAbstract: Voclosporin, a novel immunomodulatory drug inhibiting the calcineurin enzyme, was developed to prevent organ graft rejection and to treat autoimmune diseases. The chemical structure of voclosporin is similar to that of cyclosporine A, with a difference in one amino acid, leading to superior calcineurin inhibition and less variability in plasma concentration. Compared with placebo, voclosporin may significantly reduce inflammation and prevent recurrences of inflammation in patients with noninfectious uveitis. Future studies have to show if these advantages are accompanied by greater clinical efficacy and fewer side effects compared with the classic calcineurin inhibitors.Keywords: uveitis, immunosuppression, voclosporin

  2. 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.

  3. Causes of Red Eye-Uveitis

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    Selçuk Sızmaz

    2012-12-01

    Full Text Available Uveitis, being an important cause of ocular morbidity, must be taken into consideration in the differential diagnosis and the management of patients with red eye. Uveitis entities can demonstrate variable clinical features. Patients presenting with uveitis must undergo careful systemic evaluation for exact diagnosis and treatment. Studies for standardization of uveitis with variable clinical pictures are emerging. Acute anterior uveitis and panuveitis can cause red eye. The purpose of this current study is to summarize the clinical features and laboratory investigations that could help the differential diagnosis of acute anterior uveitis and panuveitis cases. (Turk J Ophthalmol 2012; 42: Supplement 57-62

  4. Pediatric Uveitis: Experience in Colombia.

    Science.gov (United States)

    Lonngi, Marcela; Aguilar, María Camila; Ríos, Hernán Andrés; Aristizábal-Duque, Cristhian H; Rodríguez, Francisco José; de-la-Torre, Alejandra

    2016-08-01

    To describe the clinical features of uveitis in children treated at two ophthalmologic centers in Bogotá, Colombia, in a 13 year-period. Retrospective observational clinical record review of pediatric children with diagnosis of uveitis. In total, 310 children were evaluated, 51.9% were female, mean age of 10.1 years. Posterior uveitis was the most common location (58.7%), of insidious onset (87.4%) and chronic course (78.1%). The most common etiology was infection (58.4%) caused by toxoplasmosis (76.8%). There was a statistically significant difference in visual acuity between anterior (20/68) and intermediate uveitis (20/70), compared with posterior uveitis (20/434) (puveitis in Colombia, where infectious etiologies are the leading cause. It will improve awareness and knowledge of pediatric uveitis in developing countries, and contribute to the development of public health policies of pediatric visual health. Received 12 September 2015; revised 23 February 2016; accepted 25 February 2016; published online 18 May 2016.

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

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    Sofia Fernanda Gonçalves Zorzella

    2007-12-01

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

  6. 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.

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

    Science.gov (United States)

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

    2016-01-01

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

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

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    Norbert W Lutz

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

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

    Science.gov (United States)

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

    2015-10-01

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

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

    Science.gov (United States)

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

    2016-11-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

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

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    Ilan Vaknin

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

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

    Science.gov (United States)

    Teitelbaum, Dvora; Arnon, Ruth; Sela, Michael

    1999-03-01

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

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

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    Fen Hu

    2016-05-01

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

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

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    Lu Jianning

    2012-10-01

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

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

    Science.gov (United States)

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

    2003-10-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

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

    2012-11-01

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

  19. 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

    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...

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

    Science.gov (United States)

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

    2014-01-01

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

  1. 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.

  2. Analysis of the impact of allergy and atopy on new onset of uveitis.

    Science.gov (United States)

    Grajewski, Rafael S; Barahmand Pour, Niusha; Burian, Katja; Caramoy, Albert; Kirchhof, Bernd; Cursiefen, Claus; Heindl, Ludwig M

    2017-05-01

    The inappropriate immune response to harmless foreign and self-antigens is a common feature of allergy, atopy and autoimmune disease. The influence of environmental factors in the initiation of autoimmunity is not well understood. It is conceivable that immune responses to allergens may also serve as a trigger of bystander immune reactions, including autoimmunity such as uveitis. Therefore, we wanted to investigate the prevalence of allergies and atopy in patients with different types of uveitis in comparison to a control cohort. In total, 530 consecutive patients with new-onset anterior, intermediate, posterior and panuveitis were compared to a non-uveitis control cohort consisting of 1.060 consecutive new-referral patients who attended our specialized outpatient clinics for other reasons than uveitis. Allergy and atopy status as well as demographic data (age, gender and ethnicity) were obtained by standardized interviewer-assisted questionnaires. Uveitis case cohort and control cohort did not differ significantly in the allergy status (p = 0.910), such as the history of pollen allergy (p = 0.671), history of drug allergy (p = 0.920), history of food allergy (p = 0.941), history of house dust mite allergy (p = 0.197) or history of other allergens (p = 0.593), nor in the atopy status (p = 0.802), such as the history of atopic dermatitis (p = 0.365), history of asthma (p = 0.430) or history of allergic rhinitis (p = 0.115). Our results argue against a substantial influence of allergies and atopy on the onset of uveitis. © 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  3. Pembrolizumab-triggered Uveitis: An Additional Surrogate Marker for Responders in Melanoma Immunotherapy?

    Science.gov (United States)

    Diem, Stefan; Keller, Fabienne; Rüesch, Reinhard; Maillard, Samia A; Speiser, Daniel E; Dummer, Reinhard; Siano, Marco; Urner-Bloch, Ursula; Goldinger, Simone M; Flatz, Lukas

    Immunotherapy leads to significantly prolonged survival of patients with metastatic melanoma. Autoimmune side effects including colitis, dermatitis, and endocrine abnormalities are common in patients treated with ipilimumab [anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4)]. Antibodies such as pembrolizumab that interfere with the PD-1 (programmed cell death 1)/PD-L1 pathway show greater efficacy and less toxicity than ipilimumab. Here we report 2 cases of pembrolizumab-induced uveitis associated with complete or partial tumor response. We suggest that uveitis may serve as a surrogate marker for a tumor response to therapy with pembrolizumab.

  4. Vitrectomia en la uveitis

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    Alvaro Rodríguez

    1989-09-01

    Full Text Available

    La vitrectomía es una alternativa de tratamiento de la inflamación en casos seleccionados de uveítis activas anteriores, posteriores e intermedias que por diversos motivos no ceden adecuadamente al tratamiento médico, o para etapas cicatriciales más tardías en las que la vitrectomía ayuda a resolver complicaciones y secuelas propias de esta enfermedad. Las posibilidades de éxito son menores en los casos severamente avanzados de éste último grupo.

    Se recalca sobre la etiología de los procesos uveíticos que condujeron a la vitrectomía y, en especial, las enfermedades parasitarias como toxocariasis, toxoplasmosis y cisticercosis. También se recalca sobre la catarata que acompaña a procesos de uveítis. Se presentan los hallazgos clínicos, algunos detalles sobre la técnica de la vitrectomía, sus complicaciones y finalmente los resultados funcionales.

    Se realizaron 61 vitrectomías en uveítis; 24 de ellas para la endoftalmitis de la toxocariasis ocular. En esta última luego de la vitrectomía, los resultados visuales fueron: mejoría en 670/0; visión ígual a la preoperatoria en 13% y peor en 20%, que también fueron fracasos anatómicos. Nos parece recomendable la realización de vitrectomías precoces en casos seleccionados de uveítis por los mejores resultados obtenidos y antes de que su evolución natural conduzca a estados irreversíbles. La vitrectomía y su seguimiento deben ser cuídados por los peligros naturales de esta cirugía.


    Summary
    Vitrectomy is an alternative in the management of inflammation in cases of active anterior, posterior and intermediate uveitis which, because of several reasons, have not responded well to medical treatmento Also, it is indicated in moderately advanced stages of uveítis to treat their frequent complications and secuela although with less possibilíties of success in the very advanced cases. This study presents the etiologies of diseases

  5. 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...

  6. 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

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

    Science.gov (United States)

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

    2017-01-01

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

  8. 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

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

    Science.gov (United States)

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

    2016-01-01

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

  10. The association between multiple sclerosis and uveitis

    DEFF Research Database (Denmark)

    Olsen, Tine Gadegaard; Frederiksen, Jette

    2016-01-01

    The association between multiple sclerosis (MS) and uveitis has been questioned. Nerve tissue and eye tissue develop from the same embryonic cells; thus, MS and uveitis could be etiologically associated. In published studies, the prevalence of MS in patients with uveitis differe from 0.7% to 30...

  11. 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.

  12. 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.

  13. 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.

  14. Higher risk of incident ankylosing spondylitis in patients with uveitis: a secondary cohort analysis of a nationwide, population-based health claims database.

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    Lu, M-C; Hsu, B-B; Koo, M; Lai, N-S

    2017-11-01

    Ankylosing spondylitis (AS) is a progressive, systemic, inflammatory autoimmune disease that typically affects young adults. Uveitis is a common extra-articular manifestation of AS. Nevertheless, the magnitude of the risk of AS among patients with uveitis is not clear. The aim of this secondary retrospective cohort study was to investigate the risk of incident AS in patients with uveitis using data from a nationwide, population-based health claims research database. Using Taiwan's National Health Insurance Research Database, we identified 6637 patients with uveitis between 2000 and 2012. A comparison cohort was assembled, which consisted of five patients without uveitis, based on frequency matching for gender, 10 year age interval, and index year, for each patient with uveitis. Both groups were followed until diagnosis of AS or the end of the follow-up period. A Poisson regression model was used to calculate the incidence rate ratio for AS between the uveitis cohort and the comparison cohort. Patients with uveitis exhibited a significantly higher incidence of AS than the comparison cohort (adjusted incidence rate ratio = 2.57, p < 0.001). Subgroup analysis with stratification by the interval between the diagnosis of uveitis and AS indicated that the adjusted incidence rates were significantly higher in the uveitis cohort with an interval of up to 7.9 years. A significant increased risk in AS among patients with uveitis was observed, with a time lag of up to 7.9 years between the diagnosis of uveitis and subsequent diagnosis of AS.

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

    Science.gov (United States)

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

    2013-01-01

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

  16. Clinical manifestations in uveitis patients with and without rheumatic disease in a Chinese population in Taiwan

    Directory of Open Access Journals (Sweden)

    Shi-Ting Tseng

    2017-12-01

    Full Text Available Background/Purpose: Uveitis can be a local eye disease or a manifestation of systemic rheumatologic disorders. However, the differences of clinical manifestations between uveitis patients with or without systemic rheumatologic disease have been seldom described in literature. We investigated the clinical features and complications of rheumatic disease-related uveitis, and compared the characteristics in patients with and without rheumatic disease in a Chinese population in Taiwan. Methods: A retrospective review was performed for all patients who had been diagnosed with uveitis between January 2009 and June 2014 at the Department of Ophthalmology, Chang Gung Memorial Hospital, Taoyuan, Taiwan. Results: A total of 823 uveitis patients were enrolled in the study, including 123 patients with rheumatic diseases. The most frequent rheumatic diseases included ankylosing spondylitis (5.8%, followed by Behçet's disease (2.8%, sarcoidosis (1.4%, psoriasis (1.1%, and juvenile idiopathic arthritis (1.1%. Compared with patients without rheumatic disease, those with rheumatic disease-related uveitis had a lower mean age at onset (35.1 ± 15.8 years vs. 44.0 ± 17.5 years, a longer follow-up period (27.1 ± 25.3 months vs. 22.2 ± 23.0 months, a higher incidence of anterior uveitis (69.0% vs. 46.3%, less frequent posterior uveitis (4.9% vs. 21.4%, a higher incidence of recurrence (26.8% vs. 14.1%, more frequent bilateral involvement (53.7% vs. 38.8%, and more frequent posterior synechiae (17.2% vs. 9.4%. Conclusion: The disease course and clinical manifestations of rheumatic disease-related uveitis were different from those unrelated. Patients with rheumatic disease-related uveitis had a higher recurrent rate and more frequent posterior synechiae than patients without rheumatic diseases. Keywords: autoimmune disease, epidemiology, rheumatic disease, uveitis

  17. Uveitis is predominantly of infectious origin in a high HIV and TB prevalence setting in rural South Africa.

    Science.gov (United States)

    Schaftenaar, Erik; Meenken, Christina; Baarsma, G Seerp; Khosa, N Sellina; Luijendijk, Ad; McIntyre, James A; Osterhaus, Albert D M E; Verjans, Georges M G M; Peters, Remco P H

    2016-10-01

    To determine the burden of disease in a unique sample of patients with uveitis from a rural South African setting. Data in this cross-sectional study were collected from patients presenting with uveitis (n=103) at the ophthalmology outpatient department of three hospitals in rural South Africa. Demographic and clinical data were collected, and laboratory analysis of aqueous humour, serological evaluation and routine diagnostics for tuberculosis (TB) were performed. Sixty-six (64%) participants were HIV infected. Uveitis was predominantly of infectious origin (72%) followed by idiopathic (16%) and autoimmune (12%). Infectious uveitis was attributed to herpes virus (51%), Mycobacterium tuberculosis (24%) and Treponema pallidum (7%) infection. HIV-infected individuals were more likely to have infectious aetiology of uveitis compared with HIV-uninfected individuals (83% vs 51%; p=0.001). Microbial aetiology of uveitis is common in areas where HIV and TB are endemic. In these settings, a high index of suspicion for infectious origin of uveitis is warranted. 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/

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

    Science.gov (United States)

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

    2017-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Qiang Liu

    2017-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Rui Li

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    DEFF Research Database (Denmark)

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

    1997-01-01

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

  3. Uveitis--manifestation af syfilis

    DEFF Research Database (Denmark)

    Andersen, Ellen Sloth; Kofoed, Kristian; Andersen, Mads Varis Nis

    2007-01-01

    We describe two cases of neurosyphilis whose diagnosis was based on ocular symptoms. Both patients were treated in the Eye Department for bilateral uveitis, and they were tested serologically positive for syphilis. The diagnoses of neurosyphilis were confirmed by demonstration of CSF pleocytosis...... and specific intrathecal antibody production. Both patients were treated with 21 million units of penicillin IV daily for 15 days. Ocular syphilis is an unusual manifestation of the disease but should be considered in patients with uveitis of uncertain origin, especially if the patient has a rash and...

  4. The association between multiple sclerosis and uveitis.

    Science.gov (United States)

    Olsen, Tine Gadegaard; Frederiksen, Jette

    The association between multiple sclerosis (MS) and uveitis has been questioned. Nerve tissue and eye tissue develop from the same embryonic cells; thus, MS and uveitis could be etiologically associated. In published studies, the prevalence of MS in patients with uveitis differe from 0.7% to 30.4%, whereas the prevalence of uveitis in patients with MS differe from 0.65% to 36.7%. Based on the largest retrospective studies, the prevalence of uveitis among MS patients is ∼1%, and the prevalence of MS among patients with uveitis is ∼1%. This is considerably higher than in the general population; thus, more research on this topic is needed to further understand the relationship between MS and uveitis. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. DIAGNOSTICS, TREATMENT AND FOLLOW-UP OF AN ADULT PATIENT WITH INTERMEDIATE UVEITIS

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    Saša Počkar

    2016-07-01

    Full Text Available Intermediate uveitis is a chronic inflammatory eye disease where the vitreous is the major site of the inflammation. It mostly affects younger patients. The inflammation can be idiopathic or related to either infectious or autoimmune systemic disease. The leading cause of visual deterioration in intermediate uveitis is cystoid macular edema and cataract is the most common complication.Criteria for treating intermediate uveitis depend on the cause of the disease. We consider the presence of cystoid macular edema, vitreous haze 2+ or more, retinal neovascularization or vasculitis. We decide to treat the patient early, because it is easier to preserve visual function and ocular structures. The basic approach to treatment is a »step approach«. We start the treatment  with periocular, intraocular or systemic corticosteroids. If the treatment is ineffective we use immunosuppressants/immunomodulators. Prognosis is improved with  early control of inflammation and early treatment of the complications.

  6. Rabbit hunter uveitis: case report of tularemia uveitis.

    Science.gov (United States)

    Terrada, Céline; Azza, Said; Bodaghi, Bahram; Le Hoang, Phuc; Drancourt, Michel

    2016-09-01

    Literature reports on ophthalmological manifestations related to tularemia, a zoonose caused by the bacterium Francisella tularensis, largely refer to Parinaud's oculoglandular syndrome, which consists of the association of conjunctivitis with preauricular lymphadenitis. In this paper, we report a case of intraocular inflammation during tularemia infection. A 52-year-old Caucasian man was diagnosed with unilateral uveitis. The uveitis was posterior, with a 2+ vitritis and a large yellowish lesion involving the macula with an overlying sub-retinal detachment, extending inferiorly, and subretinal hemorrhages. Fluorescein angiography showed a late hyperfluorescence with focal vascular leakage. Ultrasound biomicroscopy confirmed the presence of a 3.8 mm parietal granuloma with a few calcifications in the left eye. While extensive work-up eliminated any other infectious and non-infectious etiology, tularemia was diagnosed by advanced serology consisting of two-dimensional Western-immunoblotting. The patient, a hunter, recalled having killed rabbits in the days before the symptoms appeared. Uveitis was rapidly controlled following treatment with doxycycline, yet three years after initiation of the treatment, the patient still complained of loss of vision in the left eye with a central scotoma. Posterior uveitis may be an infrequent manifestation of tularemia infection, and therefore this infection should be considered in the differential diagnosis of intraocular inflammation in areas where F. tularensis is endemic.

  7. Peran Pencitraan dalam Diagnosis Uveitis

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    Ratna Sitompul

    2016-09-01

    Full Text Available Uveitis merupakan penyakit inflamasi yang dapat melibatkan berbagai bagian mata seperti iris, badansiliar, pars plana, vitreus, koroid dan retina. Penyakit tersebut dapat disebabkan oleh inflamasi lokal di mataatau merupakan bagian dari penyakit inflamasi sistemik akibat autoimun, infeksi dan keganasan. Uveitisdapat menimbulkan gejala nyeri, fotofobia, penurunan tajam penglihatan hingga kebutaan. Oleh karenaitu, diagnosis harus segera ditegakkan agar tata laksana uveitis dapat dilakukan dengan cepat dan tepat.Diagnosis uveitis dapat ditetapkan berdasarkan anamnesis, pemeriksaan mata secara klinis, pemeriksaanlaboratorium dan pemeriksaan penunjang yaitu pencitraan. Slitlamp dan fotografi umum adalah teknikpencitraan sederhana yang dapat membantu menegakkan diagnosis uveitis. Pemeriksaan tersebut dapatdigunakan untuk melihat tanda inflamasi di bagian luar mata hingga ke bilik mata depan. Untuk menilai derajatinflamasi secara kuantitatif dapat digunakan laser flare photometry (LFP dan fotografi fundus berwarna dapatdigunakan untuk melihat bagian posterior bola mata. fundus fluorescein angiography (FFA, indocyaninegreen angiography (ICG, dan fundus autofluorescence (FAF bermanfaat untuk mengevaluasi integritasvaskular retina dan koroid. USG, optical coherence tomography (OCT, dan pencitraan multimodal merupakanteknik pencitraan non-kontak dan non-invasif yang dapat memperlihatkan gambaran retina, koroid, sarafoptik dan lapisan serat saraf retina dengan baik. Magnetic resonance imaging (MRI dapat digunakan untukmengevaluasi kondisi inflamasi di mata. Berbagai teknik pencitraan tersebut dapat membantu dokter dalammenegakkan diagnosis uveitis serta memantau perjalanan penyakit dan keberhasilan terapi. Kata kunci: uveitis, slit lamp, fotografi fundus, LFP, FFA, ICG, FAF, USG, OCT, MRI   The Role of Imaging in Uveitis Diagnosis Abstract Uveitis is an inflammatory disease affecting iris, ciliary body, pars plana, vitreous, choroid and retina

  8. Tumour necrosis factor-mediated macrophage activation in the target organ is critical for clinical manifestation of uveitis

    Science.gov (United States)

    Khera, T K; Copland, D A; Boldison, J; Lait, P J P; Szymkowski, D E; Dick, A D; Nicholson, L B

    2012-01-01

    Clinically available anti-tumour necrosis factor (TNF) biologics, which inhibit both soluble (sTNF) and transmembrane forms (tmTNF) of TNF, eliminating all TNF signalling, have successfully treated autoimmune diseases including uveitis. These have potentially serious side effects such as reactivation of latent Mycobacterium tuberculosis and, therefore, more specific inhibition of TNF signalling pathways may maintain clinical efficacy while reducing adverse effects. To determine the effects of specific pharmacological inhibition of sTNF on macrophage activation and migration, we used a mouse model of uveitis (experimental autoimmune uveoretinitis; EAU). We show that selective inhibition of sTNF is sufficient to suppress EAU by limiting inflammatory CD11b+ macrophages and CD4+ T cell migration into the eye. However, inhibition of both sTNF and tmTNF is required to inhibit interferon-γ-induced chemokine receptor 2, CD40, major histocompatibility complex class II and nitric oxide (NO) up-regulation, and signalling via tmTNF is sufficient to mediate tissue damage. In confirmation, intravitreal inhibition of sTNF alone did not suppress disease, and inflammatory cells that migrated into the eye were activated, generating NO, thus causing structural damage to the retina. In contrast, intravitreal inhibition of both sTNF and tmTNF suppressed macrophage activation and therefore disease. We conclude that sTNF is required for inflammatory cell infiltration into target tissue, but at the tissue site inhibition of both sTNF and tmTNF is required to inhibit macrophage activation and to protect from tissue damage. PMID:22471277

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

    DEFF Research Database (Denmark)

    Taupin, V; Renno, T; Bourbonnière, L

    1997-01-01

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

  10. UVEITIS INA RHEUMATOLOGISTS PRACTICE: A ROLE OF TUMOR NECROSIS FACTOR-а INHIBITORS

    Directory of Open Access Journals (Sweden)

    Sergey Valentinovich Moiseyev

    2009-01-01

    Full Text Available Uveitis frequently develops in patients with ankylosing spondylitis (AS and other autoimmune diseases. It is occasionally characterized by a severe recurrent course and untreatable with systemic glucocorticoids (GC and standard immunosuppressive agents. The results of (mainly small clinical trials, as well as some observations suggest that therapy with tumor necrosis factor-а (TNF-а inhibitors is effective in such patients. There is the strongest evidence that they are beneficial in treating recurrent uveitis in patients with AS, infliximab having some efficacy advantages over etanercept and adalimumab. Accordingly, chronic uveitis in AS can be considered as an additional argument in favor of the use of TNF-а inhibitors. Furthermore, treatment with drugs of this group is warranted in severe uveitis refractory to GC and immunosuppressants. It is conceivable that in some forms of uveitis, for example, in patients with Behcet's disease, treatment with TNF-а inhibitors should be initiated at an earlier stage as the efficacy of standard immunosuppressants is generally limited

  11. PERIPHERAL RETINOSCHISIS IN INTERMEDIATE UVEITIS.

    Science.gov (United States)

    Pichi, Francesco; Srivastava, Sunil K; Nucci, Paolo; Baynes, Kimberly; Neri, Piergiorgio; Lowder, Careen Y

    2017-11-01

    To examine cases of intermediate uveitis complicated by retinoschisis and review the pathogenetic hypothesis. A retrospective chart review of patients with intermediate uveitis. Data were collected at three uveitis referral centers on sex, age, best-corrected visual acuity, degree of vitritis, extent and location of snowbanking, presence of hard exudates, neovascularization, vitreous hemorrhage, and extent and nature of retinal elevations. A series of 23 eyes of 20 patients were examined; patient's age ranged from 10 years to 70 years and follow-up period from 8 months to 6 years. Twenty-two eyes had retinoschisis (95.6%), and 1 had retinoschisis associated with serous retinal detachment (4.3%). Extensive inferior pars plana exudates with snowbanking were present in 12 eyes (52.2%), whereas 3 eyes had inferior snowballs over the elevated retina. Neovascularization of the vitreous base accompanied by vitreous hemorrhage occurred in one eye. There was no coexisting macular pathology in 16 eyes, whereas 4 eyes had cystoid macular edema. The appearance of peripheral retinoschisis in this series of uncontrolled intermediate uveitis patients seems to be secondary to a complex balance between the persistent fluorescein leakage, a subclinical peripheral ischemia, and the constant low-grade vitreous inflammation that causes vitreous shrinkage and traction. The results of this study suggest that the absence of macroscopic changes in the retina does not preclude ischemic peripheral abnormalities, and the detection of a peripheral retinoschisis in an intermediate uveitis patient with active fluorescein leakage must suggest the need for a more aggressive form of treatment despite the good visual acuity.

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

    Science.gov (United States)

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

    2009-04-28

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

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

    Directory of Open Access Journals (Sweden)

    Shafagh Jasmine

    2009-04-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

  15. 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.

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

    Science.gov (United States)

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

    2009-09-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

    2015-01-01

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

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

    Science.gov (United States)

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

    2001-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Thomas B Thornley

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

  1. Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China

    NARCIS (Netherlands)

    Yang, P.; Zhang, Z.; Zhou, H.; Li, B.; Huang, X.; Gao, Y.; Zhu, L.; Ren, Y.; Klooster, J.; Kijlstra, A.

    2005-01-01

    Purpose: To address the clinical pattern and characteristics of uveitis in a tertiary center for uveitis in China and compare the similarity and difference in the distribution of uveitis entities between China and other countries. Methods: A retrospective study was performed on the patients with

  2. Effects of the immunomodulator, VGX-1027, in endotoxin-induced uveitis in Lewis rats

    DEFF Research Database (Denmark)

    Mangano, K; Sardesai, N Y; Quattrocchi, C

    2008-01-01

    VGX-1027 is a novel, low molecular weight, immunomodulatory compound that has shown efficacy against a variety of immuno-inflammatory disease models in animals including autoimmune diabetes in NOD mice, collagen-induced arthritis and chemically induced inflammatory colitis. Here, we have studied ...... the effects of VGX-1027 on the development of endotoxin-induced uveitis (EIU) in male Lewis rats, as a model of inflammatory ocular diseases in humans....

  3. Pembrolizumab-triggered uveitis: an additional surrogate marker for responders in melanoma immunotherapy?

    OpenAIRE

    Diem, Stefan; Keller, Fabienne; Rüesch, Reinhard; Maillard, Samia A; Speiser, Daniel E.; Dummer, Reinhard; Siano, Marco; Urner-Bloch, Ursula; Goldinger, Simone M.; Flatz, Lukas

    2016-01-01

    Immunotherapy leads to significantly prolonged survival of patients with metastatic melanoma. Autoimmune side effects including colitis, dermatitis, and endocrine abnormalities are common in patients treated with ipilimumab [anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4)]. Antibodies such as pembrolizumab that interfere with the PD-1 (programmed cell death 1)/PD-L1 pathway show greater efficacy and less toxicity than ipilimumab. Here we report 2 cases of pembrolizumab-induced uveiti...

  4. Pembrolizumab-triggered Uveitis: An Additional Surrogate Marker for Responders in Melanoma Immunotherapy?

    OpenAIRE

    Stefan Diem; Fabienne Keller; Reinhard Rüesch; Samia Maillard; Daniel Speiser; Reinhard Dummer; Marco Siano; Simone Goldinger; Ursula Urner-Bloch; Lukas Flatz

    2016-01-01

    Immunotherapy leads to significantly prolonged survival of patients with metastatic melanoma. Autoimmune side effects including colitis dermatitis and endocrine abnormalities are common in patients treated with ipilimumab [anti CTLA4 (cytotoxic T lymphocyte associated protein 4)]. Antibodies such as pembrolizumab that interfere with the PD 1 (programmed cell death 1)/PD L1 pathway show greater efficacy and less toxicity than ipilimumab. Here we report 2 cases of pembrolizumab induced uveitis ...

  5. 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.

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

    Science.gov (United States)

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

    2015-03-15

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

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

    Directory of Open Access Journals (Sweden)

    Annelies Vanheel

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2014-02-18

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

  11. Enhanced Vitreous Imaging in Uveitis.

    Science.gov (United States)

    Mahendradas, Padmamalini; Madhu, Sumukh; Kawali, Ankush; Sinha Roy, Abhijit; Vala, Ruchi; Vinekar, Anand; Shetty, Rohit

    2017-10-16

    To study the structural visibility of the posterior vitreous cavity and vitreoretinal interface using Spectral Domain-Optical Coherence Tomography in patients with uveitis using conventional, Enhanced Depth Imaging (EDI), Combined Depth Imaging (CDI), and Enhanced Vitreous Imaging (EVI) techniques. It was an observational cross-sectional study of 59 eyes of 33 patients between age group 12-72 years (Median 43) diagnosed as uveitis with posterior segment manifestations underwent OCT using conventional, EDI, CDI, and EVI techniques. The visibility of posterior vitreous was graded in all the techniques. A statistically significant difference was seen in posterior vitreous visibility on comparing all four techniques. EVI showed better visibility of posterior vitreous cavity compared to all other techniques (P vitreous compared to conventional, EDI, and CDI techniques.

  12. Diagnostic vitrectomy for infectious uveitis

    Science.gov (United States)

    Jeroudi, Abdallah; Yeh, Steven

    2014-01-01

    The identification of an infectious or noninfectious uveitis syndrome is important to determine the range of therapeutic and prognostic implications of that disease entity. Diagnostic dilemmas arise with atypical history, atypical clinical presentations, inconclusive diagnostic workup, and persistent or worsened inflammation despite appropriate immunosuppression. More invasive intraocular testing is indicated in these situations particularly in infectious uveitis where a delay in treatment may result in worsening of the patient’s disease and a poor visual outcome. Laboratory analysis of vitreous fluid via diagnostic pars plana vitrectomy is an important technique in the diagnostic armamentarium, but the most important aspects of sample collection include rapid processing, close coordination with an ophthalmic pathology laboratory, and directed testing on this limited collected sample. Culture and staining has utility in bacterial, fungal, and nocardial infection. Polymerase chain reaction (PCR) analysis has shown promising results for bacterial endophthalmitis and infection with mycobacterium tuberculosis whereas PCR testing for viral retinitides and ocular toxoplasmosis has a more established role. Antibody testing is appropriate for toxoplasmosis and toxocariasis, and may be complementary to PCR for viral retinitis. Masquerade syndromes represent neoplastic conditions that clinically appear as infectious or inflammatory conditions and should be considered as part of the differential diagnosis. Diagnostic vitrectomy and chorioretinal biopsy are thus critical tools for the management of patients in whom an infectious etiology of uveitis is suspected. PMID:24613892

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

    DEFF Research Database (Denmark)

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

    2006-01-01

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

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

    DEFF Research Database (Denmark)

    Vowinckel, E; Reutens, D; Becher, B

    1997-01-01

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

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

    NARCIS (Netherlands)

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

    2013-01-01

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

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

    Science.gov (United States)

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

    2014-09-01

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

  17. 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.

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

    Science.gov (United States)

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

    2017-07-01

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

  19. 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.

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

    Science.gov (United States)

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

    2016-01-01

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

  1. A review and update on orphan drugs for the treatment of noninfectious uveitis

    Directory of Open Access Journals (Sweden)

    You C

    2017-01-01

    Full Text Available Caiyun You,1–3 Haitham F Sahawneh,1,2 Lina Ma,1,2 Buraa Kubaisi,1,2 Alexander Schmidt,1,2 C Stephen Foster1,2,4 1Massachusetts Eye Research and Surgery Institution (MERSI, Waltham, 2Ocular Immunology and Uveitis Foundation, Weston, MA, USA; 3Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 4Harvard Medical School, Boston, MA, USA Introduction: Uveitis, a leading cause of preventable blindness around the world, is a critically underserved disease in regard to the medications approved for use. Multiple immunomodulatory therapy (IMT drugs are appropriate for uveitis therapy but are still off-label. These IMT agents, including antimetabolites, calcineurin inhibitors, alkylating agents, and biologic agents, have been designated as “orphan drugs” and are widely used for systemic autoimmune diseases or organ transplantation.Area covered: The purpose of this paper is to comprehensively review and summarize the approved orphan drugs and biologics that are being used to treat systemic diseases and to discuss drugs that have not yet received approval as an “orphan drug for treating uveitis” by the US Food and Drug Administration (FDA.Our perspective: IMT, as a steroid-sparing agent for uveitis patients, has shown promising clinical results. Refractory and recurrent uveitis requires combination IMT agents. IMT is continued for a period of 2 years while the patient is in remission before considering tapering medication. Our current goals include developing further assessments regarding the efficacy, optimal dose, and safety in efforts to achieve FDA approval for “on-label” use of current IMT agents and biologics more quickly and to facilitate insurance coverage and expand access to the products for this orphan disease. Keywords: immunomodulatory, orphan drug, steroid sparing, uveitis

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

    Science.gov (United States)

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

    2012-01-01

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

  3. Perspectives for uveitis treatment in rheumatic diseases

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    Alla Aleksandrovna Godzenko

    2011-01-01

    Full Text Available The paper describes current approaches to treating uveitis in rheumatic diseases and theoretical backgrounds for using tumor necrosis factor-α (TNF-α inhibitors. The data available in the literature suggest that anti-TNF-α therapy is highly effective in relieving and preventing uveitis attacks.

  4. Effects of carprofen administered by different routes to control experimental uveitis in dogs Efeitos do carprofeno, aplicado por diferentes vias, no controle de uveítes experimentais em cães

    Directory of Open Access Journals (Sweden)

    A.P. Ribeiro

    2010-04-01

    Full Text Available Efficacy of carprofen, administered by different routes, was studied in experimental uveitis in dogs. Anterior chamber paracenteses was accomplished at two different moments (M0 and M1, with a five hour interval between them. At M0 and M1, 0.2mL of aqueous humor was collected and quantitation of total protein and prostaglandin E2 (PGE2 were determined. Four groups were formed (n=8, which received carprofen at the end of M0, by the following routes: subcutaneous (GIm, subconjunctival (GII, and topical (GIII. A fourth group that received no treatment was instituted (Control. Conjunctival histopathology of the GII animals was performed. In all groups, values of protein and PGE2 significantly enhanced at M1; however, they did not significantly change among groups at M1. Inflammatory exudate of acute character and mild hemorrhage were seen at histopathology after carprofen administration. Carprofen was unable to inhibit PGE2 synthesis and the protein influx to the anterior chamber by any of the tested routes. However, the reduction of 44% in protein levels (topical suggests that the agent can be used by this route as an adjuvant to control uveitis in dogs.Estudaram-se os efeitos do carprofeno, aplicado por diferentes vias, em uveítes experimentais em cães. Realizou-se paracentese de câmara anterior em dois momentos (M0 e M1, com intervalo de cinco horas entre si. Em M0 e M1, colheram-se 0,2mL de humor aquoso e determinaram-se as concentrações de proteína total e de prostaglandina E2 (PGE2. Constituíram-se quatro grupos (n = 8, que receberam carprofeno ao final de M0 pelas vias subcutânea (GI, subconjuntival (GII e tópica (GIII. Um quarto grupo não recebeu tratamento (controle. Procedeu-se à avaliação histopatológica nos indivíduos do GII. Em todos os grupos, encontrou-se aumento significativo dos níveis proteicos e de PGE2 em M1. Não se observou diferença significativa, em M1, entre os grupos para nenhum dos parâmetros estudados

  5. Antinuclear antibodies in arthritic and nonarthritic children with uveitis.

    Science.gov (United States)

    Rosenberg, A M; Romanchuk, K G

    1990-01-01

    We determined whether a positive test for antinuclear antibodies correlated with uveitis only in children with juvenile rheumatoid arthritis (JRA) or whether they also represented a serologic marker for isolated idiopathic chronic uveitis in children. We conclude that the immunopathogenesis of uveitis associated with JRA is different from that of idiopathic chronic uveitis.

  6. Association of Psoriatic Disease With Uveitis

    DEFF Research Database (Denmark)

    Egeberg, Alexander; Khalid, Usman; Gislason, Gunnar Hilmar

    2015-01-01

    IMPORTANCE: Psoriasis, psoriatic arthritis, and uveitis are inflammatory disorders with significant overlap in their inflammatory pathways. Limited evidence is available about the relationship between psoriatic disease and uveitis. OBJECTIVE: To investigate the potential bidirectional relationship...... between psoriatic disease, including psoriasis and psoriatic arthritis, and uveitis. DESIGN, SETTING, AND PARTICIPANTS: We performed a nationwide cohort study of the Danish population from January 1, 1997, through December 31, 2011. We included 74,129 Danish patients with psoriasis who were 18 years...... association between psoriatic disease and uveitis. Increased focus on eye symptoms in patients with psoriasis and psoriatic arthritis and on skin and joint symptoms in patients with prior or current uveitis may be appropriate....

  7. Pediatric uveitis: new and future treatments

    Science.gov (United States)

    Mehta, Preema J.; Alexander, Janet L.; Sen, H. Nida

    2017-01-01

    Purpose of review Pediatric uveitis is relatively uncommon, accounting for only 5–10% of all patients with uveitis. However, owing to high prevalence of complications and devastating outcomes, its lifetime burden can be significant. Recent findings Immunomodulatory therapy has been associated with better outcomes in noninfectious pediatric uveitis. However, effective treatments are limited by medication-related complications, including multiorgan toxicities and systemic side effects. Summary We review the current therapies available to treat pediatric uveitis, discuss novel and future therapies, and provide clinical recommendations utilizing these new agents. The consideration for treatment regimens in noninfectious pediatric uveitis is multifactorial. Understanding past, present, and future technology will aid in treatment of a complex and refractory disease. PMID:23872814

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

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    Su Zhang

    2013-01-01

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

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

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    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.

  10. Etiology research on different types of uveitis

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    Zhe Yang

    2016-05-01

    Full Text Available AIM:To analysis and discuss etiology of different types of uveitis. METHODS:We selected 60 patients(120 eyeswith uveitis treated in our hospital from June 2012 to June 2015. All patients examined by the same uveitis specialist with unified standards. According to international standards, uveitis was customized into:anterior uveitis(AU, intermediate uveitis(IU, posterior uveitis(PU, panuveitis(PanU. Age, gender, type of uveitis and causes of the disease were analyzed. RESULTS:Through the analysis of the etiology and clinical types of patients, the main types were idiopathic(26 cases, 21.7%, VKH syndrome(18 cases, 15.0%, HLA-B27 related(14 cases, 11.7%, viral(12 cases, 10.0%, Fuchs syndrome(8 cases, 6.7%, Behcet's disease(8 eyes, 6.7%, diabetes(6 eyes, 5.0%, syphilis(6 eyes, 5.0%, Posner-Schlossman syndrome(6 eyes, 5.0%, juvenile chronic arthritis(4 eyes, 3.3%, sympathetic ophthalmia(4 eyes,3.3%, traumatic(2 eyes, 1.7%, sarcoid(2 eyes, 1.7%, endophthalmitis(2 eyes, 1.7%and others(2 eyes, 1.7%. By the observation for different types uveitis, the main cause of AU was idiopathic, followed by HLA-B27-related and viral; for PanU, it was VKH syndrome, idiopathic ones and Behcet's disease; for PU, it was idiopathic, then viral; for IU, it was idiopathic. CONCLUSION:Through observation and analysis for clinical patients, male patients were more than female; idiopathic, caused by VKH syndrome, viral and Behcet's disease are the common types of uveitis.

  11. A review and update on orphan drugs for the treatment of noninfectious uveitis

    Science.gov (United States)

    You, Caiyun; Sahawneh, Haitham F; Ma, Lina; Kubaisi, Buraa; Schmidt, Alexander; Foster, C Stephen

    2017-01-01

    Introduction Uveitis, a leading cause of preventable blindness around the world, is a critically underserved disease in regard to the medications approved for use. Multiple immunomodulatory therapy (IMT) drugs are appropriate for uveitis therapy but are still off-label. These IMT agents, including antimetabolites, calcineurin inhibitors, alkylating agents, and biologic agents, have been designated as “orphan drugs” and are widely used for systemic autoimmune diseases or organ transplantation. Area covered The purpose of this paper is to comprehensively review and summarize the approved orphan drugs and biologics that are being used to treat systemic diseases and to discuss drugs that have not yet received approval as an “orphan drug for treating uveitis” by the US Food and Drug Administration (FDA). Our perspective IMT, as a steroid-sparing agent for uveitis patients, has shown promising clinical results. Refractory and recurrent uveitis requires combination IMT agents. IMT is continued for a period of 2 years while the patient is in remission before considering tapering medication. Our current goals include developing further assessments regarding the efficacy, optimal dose, and safety in efforts to achieve FDA approval for “on-label” use of current IMT agents and biologics more quickly and to facilitate insurance coverage and expand access to the products for this orphan disease. PMID:28203051

  12. Evaluating the presence of Toxoplasma gondii in peripheral blood of patients with diverse forms of uveitis.

    Science.gov (United States)

    Belfort, Rubens N; Isenberg, Jordan; Fernandes, Bruno F; Di Cesare, Sebastian; Belfort, Rubens; Burnier, Miguel N

    2017-02-01

    The purpose of this study was to evaluate the presence of Toxoplasmosis gondii in samples of peripheral blood from patients with varying etiologies of uveitis. Whole blood from patients with different forms of uveitis was tested for the presence of T. gondii using real-time PCR targeting the well-characterized 529 bp fragment. Extracted DNA was both frozen. Thirty-one patients were included in the current study and grouped as follows: acute toxoplasmosis (n = 10); toxoplasmic retinal scars (n = 9); non-infectious etiologies of uveitis (n = 6); and IgG negative for toxoplasmosis (n = 6). In total, only two patients were shown to have circulating T. gondii in peripheral blood; both of these patients were IgG positive for toxoplasmosis, were receiving immunosuppressive therapy for autoimmune uveitis, and had no clinical features of toxoplasmosis. T. gondii was identified in peripheral blood of some immunosuppressed patients. No other patients, including those with acute toxoplasmosis, had circulating parasites in peripheral blood.

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

    OpenAIRE

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

    2012-01-01

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

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

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    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.

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

    Science.gov (United States)

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

    2017-02-01

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

  16. Autoimmune Diseases

    Science.gov (United States)

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

  17. Psoriasis and uveitis: a literature review*

    Science.gov (United States)

    Fraga, Naiara Abreu de Azevedo; de Oliveira, Maria de Fátima Paim; Follador, Ivonise; Rocha, Bruno de Oliveira; Rêgo, Vitória Regina

    2012-01-01

    Psoriasis is a systemic, chronic, immunologically mediated disease, with significant genetic and environmental influences. It affects from 1 to 3% of the world population. Recently, the relation between psoriasis and different comorbidities, particularly metabolic syndrome, has become extremely relevant. Uveitis is characterized by a process of intraocular inflammation resulting from various causes. Considering psoriasis and uveitis as immune-mediated diseases, this study aims to evaluate the possible association of psoriasis and/or psoriatic arthritis with uveitis and its subtypes. Few studies have evaluated the association of uveitis and psoriasis without joint involvement. It seems that psoriasis without arthropathy is not a risk factor for the development of uveitis. Uveitis tends to develop more frequently in patients with arthropathy or pustular psoriasis than in patients with other forms of psoriasis. Ophthalmic examination should be performed periodically in patients with psoriasis and uveitis. If ophthalmopathy is diagnosed, the patient should receive adequate treatment with anti-inflammatory drugs or immunomodulators to prevent vision loss. PMID:23197207

  18. Metals and kidney autoimmunity.

    Science.gov (United States)

    Bigazzi, P E

    1999-10-01

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

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

    Science.gov (United States)

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

    2009-01-01

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

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

    Science.gov (United States)

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

    2014-11-07

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-04-09

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

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

    Directory of Open Access Journals (Sweden)

    Yan Zhou

    2016-01-01

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

  3. 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.

  4. 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.

  5. 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.

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

    Science.gov (United States)

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

    2010-12-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    DEFF Research Database (Denmark)

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

    2001-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Francois Feron

    2012-08-01

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

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

    Directory of Open Access Journals (Sweden)

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

    Science.gov (United States)

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

    2007-10-01

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

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

    DEFF Research Database (Denmark)

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

    2015-01-01

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

  13. The Association of Race with Childhood Uveitis

    Science.gov (United States)

    Angeles-Han, Sheila T; McCracken, Courtney; Yeh, Steven; Jenkins, Kirsten; Stryker, Daneka; Travers, Curtis; Rouster-Stevens, Kelly; Vogler, Larry B.; Lambert, Scott R.; Drews-Botsch, Carolyn; Prahalad, Sampath

    2015-01-01

    Purpose To identify risk factors for a severe uveitis course among children with non-infectious uveitis. Design Retrospective cohort study Method This was a retrospective analysis of a prospectively collected database. Records of 94 children with uveitis were reviewed at enrollment and every 3-6 months (2011-2015). Severe uveitis was defined as a history of ocular complications or a visual acuity (VA) of ≤20/200. Children were compared by disease, VA, complications and race. Regression models were used to model risk factors for severe disease. When examining race, we focused on non-Hispanic African American and non-Hispanic White children only. Results Of 85 children with uveitis and complete ocular examinations, 27 (32%) had a history of a VA of ≤20/200. A subanalysis of non-Hispanic African American and White children showed an increased prevalence of VA ≤20/200 in non-Hispanic African Americans (18/25 (72%) vs. 4/43 (9%)). Non-Hispanic African Americans were more likely to be diagnosed at an older age (p=0.030), have intermediate uveitis (p=0.026), bilateral disease (p=0.032), a history of VA ≤20/50 (p=0.002), VA ≤20/200 (puveitis duration. Non-Hispanic African Americans also developed 2.2 times more unique complications per year of disease than non-Hispanic Whites when controlling for uveitis type and duration. Conclusions There appear to be racial differences in the outcomes of children with uveitis. Non-Hispanic African American children with non-juvenile idiopathic arthritis associated uveitis may have worse visual outcomes with increased vision loss and ocular complications. These findings highlight the need for future studies in minority populations. PMID:26255577

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

    Science.gov (United States)

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

    2015-10-31

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

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

    Science.gov (United States)

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

    2017-01-01

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

  16. Algorithmic approach in the diagnosis of uveitis

    Science.gov (United States)

    Rathinam, S R; Babu, Manohar

    2013-01-01

    Uveitis is caused by disorders of diverse etiologies including wide spectrum of infectious and non-infectious causes. Often clinical signs are less specific and shared by different diseases. On several occasions, uveitis represents diseases that are developing elsewhere in the body and ocular signs may be the first evidence of such systemic diseases. Uveitis specialists need to have a thorough knowledge of all entities and their work up has to be systematic and complete including systemic and ocular examinations. Creating an algorithmic approach on critical steps to be taken would help the ophthalmologist in arriving at the etiological diagnosis. PMID:23803476

  17. The association between genetic polymorphisms of the interleukin-23 receptor gene and susceptibility to uveitis: a meta-analysis.

    Science.gov (United States)

    Jung, Jae Hyun; Song, Gwan Gyu; Kim, Jae-Hoon; Seo, Young Ho; Choi, Sung Jae

    2017-05-30

    Uveitis is an eye inflammatory disease, which is sometimes associated with underlying systemic disease. Interleukin-23 plays an important role in autoimmune disease. The aim of this meta-analysis was to evaluate the association between the interleukin-23 receptor (IL-23R) and susceptibility to uveitis. Published literature from PUBMED and EMBASE were retrieved. Seven studies were included in this meta-analysis, covering a total of 1309 cases of uveitis and 2400 controls. Meta-analyses were conducted on the associations between uveitisand rs7517847, rs17375018, and rs11209032 polymorphisms in the IL-23R gene. There were no significant associations between IL-23R polymorphisms and uveitis with regard to the following alleles: for G allele vs. T allele of rs7517847, OR 1.01, 95% CI 0.92-1.12, P = 0.83; for A allele vs. G allele of rs17375018, OR 0.68, 95% CI 0.47-0.99, P = 0.05; rs11209032 OR 1.12, 95% CI 0.84-1.51, P = 0.43. In contrast, there were significant associations between the AA + AG gene versus GG gene of rs17375018 and the AA gene versus AG + GG gene of rs11209032 polymorphism with uveitis (OR 0.59, 95% CI 0.35-0.99, P = 0.04; OR 1.32, 95% CI 1.10-1.59, P = 0.003). This meta-analysis suggests that each allele of IL-23R, including rs7519847, rs17375018 and rs11209032 was negatively associated with uveitis. However, homozygote models, including the rs17375018 GG genotype and rs11209032 AA genotype, were significantly associated with uveitis.

  18. 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.

  19. Small molecules as therapy for uveitis: a selected perspective of new and developing agents.

    Science.gov (United States)

    Pleyer, Uwe; Algharably, Engi Abdel-Hady; Feist, Eugen; Kreutz, Reinhold

    2017-09-01

    Intraocular inflammation (uveitis) remains a significant burden of legal blindness. Because of its immune mediated and chronic recurrent nature, common therapy includes corticosteroids, disease-modifying anti-rheumatic drugs and more recently biologics as immune modulatory agents. The purpose of this article is to identify the role of new treatment approaches focusing on small molecules as therapeutic option in uveitis. Areas covered: A MEDLINE database search was conducted through February 2017 using the terms 'uveitis' and 'small molecule'. To provide ongoing and future perspectives in treatment options, also clinical trials as registered at ClinicalTrials.gov were included. Both, results from experimental as well as clinical research in this field were included. Since this field is rapidly evolving, a selection of promising agents had to be made. Expert opinion: Small molecules may interfere at different steps of the inflammatory cascade and appear as an interesting option in the treatment algorithm of uveitis. Because of their highly targeted molecular effects and their favorable bioavailability with the potential of topical application small molecules hold great promise. Nevertheless, a careful evaluation of these agents has to be made, since current experience is almost exclusively based on experimental uveitis models and few registered trials.

  20. 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

  1. 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

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Cintia S De Paiva

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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    OpenAIRE

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

    2012-01-01

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

  6. Characteristics of syphilitic uveitis in northern China.

    Science.gov (United States)

    Zhang, Xiaomin; Du, Qian; Ma, Feifei; Lu, Yinglong; Wang, Meiyan; Li, Xiaorong

    2017-06-19

    To describe the characteristics of patients with syphilitic uveitis in northern China. A case series of 21 patients (33 eyes) diagnosed with syphilitic uveitis from 2011 to 2016 at a tertiary center in northern China was retrospectively analyzed. Twenty-one patients (33 eyes) were diagnosed as syphilitic uveitis. Posterior segment involvement was found in 32 eyes (97.0%). Vitreous haze, neuroretinitis, and posterior placoid chorioretinitis were mainly found in patients with a relatively short duration of the disease, while diffuse chorioretinitis, pseudoretinitis pigmentosa, cystoid macular edema, and epiretinal membrane were found in patients with relatively long duration of ocular involvement. A low best-corrected visual acuity (P = 0.022) and a delay of syphilis treatment (P uveitis should be included in the differential diagnosis of any form of posterior ocular inflammation. The pattern of ocular involvement may change with the disease progression.

  7. Causes of visual loss in uveitis

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    Stanković Zora

    2009-01-01

    Full Text Available Background/Aim. Epidemiological studies of blindness in a working age population require a precise definition of the true connection of uveitis and visual damage. Since most patients with more severe types of uveitis are hospitalized in tertiary referral uveitis service, our aim was to determine whether age, sex and age of onset of uveitis, as well as duration of visual loss and its causes influence the degree of visual damage in patients with different types of uveitis. Methods. The data were collected from medical records of 237 patients at the Department for Uveitis of the Institute for Eye Diseases in Belgrade over a three-year period (March 2005 to March 2008. Results. Visual acuity reduction (≤ 0.3 was found in 161/237 (67.9% patients, 85 of whom had visual acuity of ≤ 0.1 later. Working age patients (up to 60 years of age most often suffered from uveitis (173/237; 73%. The highest number of patients with visual loss was in the group suffering from panuveitis (77/94; 81.91%. The age of onset of uveitis and sex have no statistically significant influence on visual loss. The most common causes of visual loss (34/161; 21.1% were cystoid macular oedema (CMO (43/161; 26.7%, cataract (28/161; 17.39% and combination of CMO and cataract. Conclusion. The risk factors for severe visual loss (≤ 0.1 are panuveitis, bilateral inflammation, prolonged visual reduction and a significant number of relapses. The main causes of visual loss in 65.2% of our patients were CMO and cataract.

  8. Quality of life Metrics in Pediatric Uveitis

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    Angeles-Han, Sheila T.

    2015-01-01

    Uveitis can lead to vision loss and blindness in children. It can significantly impact a child’s vision related quality of life and daily function. Outcome studies in pediatric uveitis focus on the clinical ocular exam and general measures of quality of life whereas in adults, measures of visual function are incorporated. Adequate vision can affect a child’s daily activities and is crucial for daily function in the home and school. A comprehensive approach that incorporates all aspects of dis...

  9. Postirradiation periocular granuloma faciale associated with uveitis.

    Science.gov (United States)

    Nayak, Natasha V; Frohman, Larry P; Lambert, William C; Langer, Paul D

    2014-01-01

    Granuloma faciale is a rare dermatopathologic condition that presents as brown-red plaques, nodules, or papules primarily on the face, with the potential for extrafacial and mucous membrane involvement. A case of an 83-year-old woman with periocular granuloma faciale accompanied by a marked anterior uveitis is presented; an association of periocular granuloma faciale with anterior uveitis has not been previously reported.

  10. Optic neuritis and acute anterior uveitis associated with influenza A infection: a case report

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    Nakagawa H

    2017-01-01

    Full Text Available Hayate Nakagawa, Hidetaka Noma, Osamu Kotake, Ryosuke Motohashi, Kanako Yasuda, Masahiko Shimura Department of Ophthalmology, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan Background: A few reports have described ocular complications of influenza A infection, such as impaired ocular movement, parasympathetic ocular nerve, keratitis, macular lesion, and frosted branch angiitis. We encountered a rare case of acute anterior uveitis and optic neuritis associated with influenza A infection. Case presentation: A 70-year-old man presented with symptoms of upper respiratory tract infection. A rapid diagnostic test showed a positive result for influenza A. At the same time, he developed ocular symptoms including blurred vision with optic disk edema and hemorrhage in the left eye, and bilateral red eyes. Multiplex polymerase chain reaction performed on aqueous humor sample detected no viral infection. Visual field testing with a Goldmann perimeter showed central and paracentral scotomas in the left eye. In addition to antiviral agent (oseltamivir phosphate 75 mg, the patient was prescribed topical prednisolone acetate ophthalmic suspension eye drops every 5 hours and high-dose intravenous methylprednisolone 1,000 mg daily for 3 days. Two months later, his best-corrected visual acuity improved to 20/50 with regression of visual field defects in his left eye. Conclusion: We report a case of bilateral acute anterior uveitis and unilateral optic neuritis concomitant with influenza A infection. Topical and systemic corticosteroids were effective to resolve acute anterior uveitis and neuritis. Analysis of aqueous humor sample suggested that acute anterior uveitis and optic neuritis in this case were not caused by influenza A virus infection per se but by autoimmune mechanism. Keywords: optic neuritis, anterior uveitis, influenza virus, multiplex polymerase chain reaction

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

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    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

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

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

    2016-12-01

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

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

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

    2017-01-01

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

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

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    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.)

  15. 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.

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

    Science.gov (United States)

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

    2013-10-01

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

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

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    Alan D Curtis

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

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

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    Rafael C Dutra

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

  19. 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.

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

    Science.gov (United States)

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

    2017-08-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

  2. 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.

  3. Uveitis

    Science.gov (United States)

    ... EA, eds. Duane's Ophthalmology 2013 ed . Philadelphia, PA: Lippincott Williams & Wilkins; 2013:vol 4, chap 60. Goldstein ... EA, eds. Duane's Ophthalmology 2013 ed . Philadelphia, PA: Lippincott Williams & Wilkins; 2013:vol 4, chap 32. Jap ...

  4. Hypotony in patients with uveitis: The Multicenter Uveitis Steroid Treatment (MUST) Trial.

    Science.gov (United States)

    Sen, H Nida; Drye, Lea T; Goldstein, Debra A; Larson, Theresa A; Merrill, Pauline T; Pavan, Peter R; Sheppard, John D; Burke, Alyce; Srivastava, Sunil K; Jabs, Douglas A

    2012-04-01

    To assess the prevalence of hypotony in patients with severe forms of uveitis. The Multicenter Uveitis Steroid Treatment (MUST) Trial, a randomized study, enrolled 255 patients. Patients with hypotony at the baseline visit were identified. Twenty (8.3%) of 240 patients with sufficient data had hypotony. Hypotony was more common in patients with uveitis ≥5 years duration (odds ratio [OR] = 5.0; p 51 years vs. <51 years, OR = 0.1; p = .02), in Caucasian patients (OR = 0.1; p < .01) compared to African American patients. Hypotonous eyes were more likely to have visual impairment (OR = 22.9; p < .01). Hypotony is an important complication of uveitis and more commonly affects African-American patients, those with uveitis onset at a younger age, and those with longer disease duration. It is associated with visual impairment.

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

    Science.gov (United States)

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

    2016-09-14

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

  6. 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

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

    Science.gov (United States)

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

    2014-10-01

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

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

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    Furong Yuan

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

  9. Cystoid macular edema in uveitis : More than meets the eye

    NARCIS (Netherlands)

    Kooij, Bram Wouter van

    2006-01-01

    Cystoid macular edema (CME) is a major complication of uveitis, which has an especially severe course in elderly patients. CME was noted in 33% of all uveitis patients, of whom 44% had low vision (visual acuity equal to or less than 20/60) in at least one eye. Of all uveitis patients with low

  10. Eosinophils in Autoimmune Diseases

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    Daniela Čiháková

    2017-04-01

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

  11. 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.

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

    Science.gov (United States)

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

    2017-08-01

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

  13. New Immunosuppressive Therapies in Uveitis Treatment

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    Salvador Mérida

    2015-08-01

    Full Text Available Uveitis is an inflammatory process that initially starts in the uvea, but can also affect other adjacent eye structures, and is currently the fourth cause of blindness in developed countries. Corticoids are probably the most widespread treatment, but resorting to other immunosuppressive treatments is a frequent practice. Since the implication of different cytokines in uveitis has been well demonstrated, the majority of recent treatments for this disease include inhibitors or antibodies against these. Nevertheless, adequate treatment for each uveitis type entails a difficult therapeutic decision as no clear recommendations are found in the literature, despite the few protocolized clinical assays and many case-control studies done. This review aims to present, in order, the mechanisms and main indications of the most modern immunosuppressive drugs against cytokines.

  14. New Immunosuppressive Therapies in Uveitis Treatment

    Science.gov (United States)

    Mérida, Salvador; Palacios, Elena; Navea, Amparo; Bosch-Morell, Francisco

    2015-01-01

    Uveitis is an inflammatory process that initially starts in the uvea, but can also affect other adjacent eye structures, and is currently the fourth cause of blindness in developed countries. Corticoids are probably the most widespread treatment, but resorting to other immunosuppressive treatments is a frequent practice. Since the implication of different cytokines in uveitis has been well demonstrated, the majority of recent treatments for this disease include inhibitors or antibodies against these. Nevertheless, adequate treatment for each uveitis type entails a difficult therapeutic decision as no clear recommendations are found in the literature, despite the few protocolized clinical assays and many case-control studies done. This review aims to present, in order, the mechanisms and main indications of the most modern immunosuppressive drugs against cytokines. PMID:26270662

  15. 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.

  16. 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.

  17. A Systematic Approach to Emergencies in Uveitis

    Science.gov (United States)

    Al-Dhibi, Hassan A.; Al-Mahmood, Ammar M.; Arevalo, J. Fernando

    2014-01-01

    Uveitis is a common cause of preventable blindness although it is consider a sight-threatening condition particularly in cases with posterior segment inflammation. To deal with emergency conditions in uveitis, we must aware of the essential signs and symptoms that reflect a true uveitic emergency. Failure to recognize these essential signs and symptoms of a true uveitic emergency may result in a devastating visual outcome. This review provides general ophthalmologists and residents, clinical guidelines for the main uveitic entities that require immediate recognition and urgent intervention in the emergency room to prevent severe permanent visual loss. PMID:25100911

  18. Uveitis in adults: What do rheumatologists need to know?

    Science.gov (United States)

    Sève, Pascal; Kodjikian, Laurent; Adélaïde, Léopold; Jamilloux, Yvan

    2015-10-01

    Rheumatologists may need to establish the etiological diagnosis and handle the therapeutic management of adults with uveitis. To date, no diagnostic strategy for uveitis has been validated by prospective studies. Investigations are selected based on the clinical features and on the anatomic location of the ocular abnormalities. Infections such as syphilis, Lyme disease, tuberculosis, and Whipple's disease may cause uveitis, with concomitant joint inflammation in a few cases. In patients with a known history of chronic inflammatory joint disease, causes of uveitis include bisphosphonate therapy and immunodepression-related infections (e.g., due to Toxoplasma or a herpes virus). Sarcoidosis is an underestimated cause of uveitis, which occurs in 15% of cases, with a predilection for middle-aged women. In spondyloarthritis, uveitis is almost always acute, unilateral, and anterior. Among patients with uveitis and spondyloarthritis, about two thirds have their joint disease diagnosed during an evaluation for uveitis. Therefore, patients with inflammatory or noninflammatory back pain should be routinely evaluated for spondyloarthritis, which is the leading cause of uveitis in western countries. The risk of blindness is extremely low, and the main complication is recurrent uveitis, seen in 50% to 60% of cases. Sulfasalazine decreases the frequency, duration, and severity of uveitis and can be used prophylactically. Copyright © 2015. Published by Elsevier SAS.

  19. Autoimmune disorders

    Science.gov (United States)

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

  20. Autoimmune Hepatitis

    Science.gov (United States)

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

  1. Supramolecular nanofibers of triamcinolone acetonide for uveitis therapy

    Science.gov (United States)

    Li, Xingyi; Wang, Yuqin; Yang, Chengbiao; Shi, Shuai; Jin, Ling; Luo, Zichao; Yu, Jing; Zhang, Zhaoliang; Yang, Zhimou; Chen, Hao

    2014-11-01

    Supramolecular nanofibers of prodrugs hold advantages for drug release due to their high drug payload, sustained and constant drug release behavior, and stimuli responsiveness. In this study, we report on a supramolecular hydrogel mainly formed by a clinically used drug triamcinolone acetonide (TA). Such a hydrogel could only be prepared via an ester bond hydrolysis process from its prodrug of succinated triamcinolone acetonide (STA). The resulting hydrogel could constantly release TA in the in vitro release experiment. The TA hydrogel possessed an excellent transscleral penetration ability, as evaluated by the in vitro transscleral transport study. The developed TA hydrogel also exhibited a great ocular compatibility in rats, as indicated by the optical coherence tomography (OCT) images, HE observation, and glial fibrillary acidic protein (GFAP) and vimentin immuno-staining assays of the retinas. Our TA hydrogel showed a decreased efficacy to inhibit ocular inflammation in the rat's experiment autoimmune uveitis (EAU) model compared to the commercial TA suspension (Transton®), but without causing complications such as high intraocular pressure and cataracts. These promising properties of the hydrogel indicated its great potential for the treatment of eye diseases.Supramolecular nanofibers of prodrugs hold advantages for drug release due to their high drug payload, sustained and constant drug release behavior, and stimuli responsiveness. In this study, we report on a supramolecular hydrogel mainly formed by a clinically used drug triamcinolone acetonide (TA). Such a hydrogel could only be prepared via an ester bond hydrolysis process from its prodrug of succinated triamcinolone acetonide (STA). The resulting hydrogel could constantly release TA in the in vitro release experiment. The TA hydrogel possessed an excellent transscleral penetration ability, as evaluated by the in vitro transscleral transport study. The developed TA hydrogel also exhibited a great ocular

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

    Science.gov (United States)

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

    2017-07-01

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

  3. Autoimmune pancreatitis

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    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

  4. Evaluation of the IL2/IL21, IL2RA and IL2RB genetic variants influence on the endogenous non-anterior uveitis genetic predisposition.

    Science.gov (United States)

    Cénit, María Carmen; Márquez, Ana; Cordero-Coma, Miguel; Fonollosa, Alejandro; Adán, Alfredo; Martínez-Berriotxoa, Agustín; Llorenç, Victor; Díaz Valle, David; Blanco, Ricardo; Cañal, Joaquín; Díaz-Llopis, Manuel; García Serrano, José Luis; de Ramón, Enrique; del Rio, María José; Begoña Gorroño-Echebarría, Marina; Martín-Villa, José Manuel; Ortego-Centeno, Norberto; Martín, Javier

    2013-05-15

    Recently, different genetic variants located within the IL2/IL21 genetic region as well as within both IL2RA and IL2RB loci have been associated to multiple autoimmune disorders. We aimed to investigate for the first time the potential influence of the IL2/IL21, IL2RA and IL2RB most associated polymorphisms with autoimmunity on the endogenous non-anterior uveitis genetic predisposition. A total of 196 patients with endogenous non-anterior uveitis and 760 healthy controls, all of them from Caucasian population, were included in the current study. The IL2/IL21 (rs2069762, rs6822844 and rs907715), IL2RA (2104286, rs11594656 and rs12722495) and IL2RB (rs743777) genetic variants were genotyped using TaqMan® allelic discrimination assays. A statistically significant difference was found for the rs6822844 (IL2/IL21 region) minor allele frequency in the group of uveitis patients compared with controls (P(-value)=0.02, OR=0.64 CI 95%=0.43-0.94) although the significance was lost after multiple testing correction. Furthermore, no evidence of association with uveitis was detected for the analyzed genetic variants of the IL2RA or IL2RB loci. Our results indicate that analyzed IL2/IL21, IL2RA and IL2RB polymorphisms do not seem to play a significant role on the non-anterior uveitis genetic predisposition although further studies are needed in order to clear up the influence of these loci on the non-anterior uveitis susceptibility.

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

    Science.gov (United States)

    Yang, Xue; Yan, Jun; Feng, Juan

    2016-01-15

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

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

    Science.gov (United States)

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

    2017-06-01

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

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

    OpenAIRE

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

    2002-01-01

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

  8. THERAPY OF FIBRINOUS PLASTIC ANTERIOR UVEITIS

    Directory of Open Access Journals (Sweden)

    A. L. Onishchenko

    2015-01-01

    Full Text Available Aim. To analyze the efficacy of modified pupillary massage technique using cycloplegic agent Appamide Plus in the treatment of anterior uveitis. Patients and methods. 45 patients (25 men and 20 women aged 21‑69 with endogenous uveitis (51 eyes were enrolled in the study. Etiology of uveitis was identified in 57.7 % of cases: herpes simplex virus (22.2 %; systemic disorders — rheumatoid arthritis, Reiter syndrome, Bechterew’s disease, psoriasis (17.7 %; local infection — purulent periodontitis or sinusitis (11 %. Patients were divided into two groups. Group I received basic therapy in combination with traditional pupillary massage. Group II received basic therapy in combination with modified pupillary massage using Appamide Plus (muscarinic receptor antagonist and alpha adrenergic agonist and plasma exchange with cell mass ozonation. Results. Inflammation of the uveal tract was prevented in all patients. In group I (traditional pupil massage, posterior synechiae persisted in 26 % of cases. In group II (pupil massage using Appamide Plus, anterior chamber humor was transparent, posterior synechiae were broken, normal pupillary response was re-established. Additionally, inflammatory exudate in the anterior chamber and endothelial precipitates resolved by 3.3 days earlier than in group I (р < 0.05. Visual outcomes were also better in Appamide Plus group. T cell-mediated immunity study revealed initial CD3+ cell and T cell subpopulation deficiency. Relative and absolute references of T cells and their subpopulations tended to decrease even when uveitis signs reduced. Conclusions. T cell-mediated immunity depression is probably due to pharmacotherapy. Appamide Plus eye drops are highly effective for therapeutic mydriasis and pupillary massage in the course of anterior uveitis treatment to prevent synechiae formation in enlarged or small pupil.

  9. 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.

  10. Autoimmune encephalopathies

    Science.gov (United States)

    Leypoldt, Frank; Armangue, Thaís; Dalmau, Josep

    2014-01-01

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

  11. Vitiligo: A part of a systemic autoimmune process

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    Gopal KVT

    2007-01-01

    Full Text Available Background : Recent clinical and animal experimental studies postulate that the pathogenetic mechanisms of vitiligo could be of systemic origin as vitiligo is associated with ocular and auditory abnormalities as well as other autoimmune disorders.Hence, we studied genetic factors, systemic associations, ocular and auditory abnormalities of vitiligo. Methods: The study group included 150 new cases of various types of vitiligo. One hundred age- and sex-matched nonvitiligo cases were included as controls in the study. A complete family history was taken for all patients. Examination was carried out taking note of the type of vitiligo and approximate percentage of body surface involved. All relevant laboratory investigations, a thorough audiological examination including pure tone audiometry and a complete ophthalmologic examination were carried out in all patients and controls. Statistical analysis was done using the Chi square test. Results: Fifty-four vitiligo patients (36% had a family history of vitiligo. Anemia was present in 30 (20% vitiligo patients but only in five (5% controls, a difference that was statistically significant (c2 = 15.8, P < 0.001. Diabetes mellitus was present in 24 (16% vitiligo patients and only 2 (2% of controls (Chi square, c2 = 12.4, P < 0.001. Hypothyroidism and alopecia areata were present in 18 (12% and 11 (7.4% vitiligo patients respectively and none of the controls. Hypoacusis was seen in 30 (20% vitiligo patients and two (2% controls (c2 = 8.19, P < 0.005. Twenty-four vitiligo patients (16% and five controls (5% had specific ocular abnormalities like uveitis, iris and retinal pigmentary abnormalities (c2 = 7.39, P < 0.001. Conclusion: This study demonstrates statistically significant clinical evidence confirming that vitiligo is a part of systemic autoimmune process.

  12. Sex and Reproduction in the Transmission of Infectious Uveitis

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    Janet L. Davis

    2014-01-01

    Full Text Available Current data permit only speculations regarding sex differences in the prevalence of infectious uveitis between women and men because uveitis case surveys do not uniformly report gender data. Differences in prevalence that are reported in the literature could relate to simple differences in the number of women and men at risk for infection or to biological differences between men and women. Compared to other types of uveitis, infectious uveitis may be directly related to occupational exposures or sexual behaviors, which differ between women and men, and may mask actual biological differences in susceptibility to ocular manifestations of the infection and its prognosis. In infectious uveitis for which there is no element of sexual transmission and data is available, prevalence of ocular disease is roughly equal between women and men. Women also have a unique relationship with infectious uveitis in their role as mothers. Vertical transmission of infections such as herpes simplex, toxoplasmosis, and cytomegalovirus can produce severe chorioretinitis in neonates.

  13. Two functional variants of IRF5 influence the development of macular edema in patients with non-anterior uveitis.

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    Ana Márquez

    Full Text Available OBJECTIVE: Interferon (IFN signaling plays a crucial role in autoimmunity. Genetic variation in interferon regulatory factor 5 (IRF5, a major regulator of the type I interferon induction, has been associated with risk of developing several autoimmune diseases. In the current study we aimed to evaluate whether three sets of correlated IRF5 genetic variants, independently associated with SLE and with different functional roles, are involved in uveitis susceptibility and its clinical subphenotypes. METHODS: Three IRF5 polymorphisms, rs2004640, rs2070197 and rs10954213, representative of each group, were genotyped using TaqMan® allelic discrimination assays in a total of 263 non-anterior uveitis patients and 724 healthy controls of Spanish origin. RESULTS: A clear association between two of the three analyzed genetic variants, rs2004640 and rs10954213, and the absence of macular edema was observed in the case/control analysis (P FDR =5.07E-03, OR=1.48, CI 95%=1.14-1.92 and P FDR =3.37E-03, OR=1.54, CI 95%=1.19-2.01, respectively. Consistently, the subphenotype analysis accordingly with the presence/absence of this clinical condition also reached statistical significance (rs2004640: P=0.037, OR=0.69, CI 95%=0.48-0.98; rs10954213: P=0.030, OR=0.67, CI 95%=0.47-0.96, thus suggesting that both IRF5 genetic variants are specifically associated with the lack of macular edema in uveitis patients. CONCLUSION: Our results clearly showed for the first time that two functional genetic variants of IRF5 may play a role in the development of macular edema in non-anterior uveitis patients. Identifying genetic markers for macular edema could lead to the possibility of developing novel treatments or preventive therapies.

  14. Two Functional Variants of IRF5 Influence the Development of Macular Edema in Patients with Non-Anterior Uveitis

    Science.gov (United States)

    Cordero-Coma, Miguel; Ortego-Centeno, Norberto; Adán, Alfredo; Fonollosa, Alejandro; Díaz Valle, David; Pato, Esperanza; Blanco, Ricardo; Cañal, Joaquín; Díaz-Llopis, Manuel; de Ramón, Enrique; del Rio, María José; García Serrano, José Luis; Artaraz, Joseba; Martín-Villa, José Manuel; Llorenç, Víctor; Gorroño-Echebarría, Marina Begoña; Martín, Javier

    2013-01-01

    Objective Interferon (IFN) signaling plays a crucial role in autoimmunity. Genetic variation in interferon regulatory factor 5 (IRF5), a major regulator of the type I interferon induction, has been associated with risk of developing several autoimmune diseases. In the current study we aimed to evaluate whether three sets of correlated IRF5 genetic variants, independently associated with SLE and with different functional roles, are involved in uveitis susceptibility and its clinical subphenotypes. Methods Three IRF5 polymorphisms, rs2004640, rs2070197 and rs10954213, representative of each group, were genotyped using TaqMan® allelic discrimination assays in a total of 263 non-anterior uveitis patients and 724 healthy controls of Spanish origin. Results A clear association between two of the three analyzed genetic variants, rs2004640 and rs10954213, and the absence of macular edema was observed in the case/control analysis (PFDR=5.07E-03, OR=1.48, CI 95%=1.14-1.92 and PFDR=3.37E-03, OR=1.54, CI 95%=1.19-2.01, respectively). Consistently, the subphenotype analysis accordingly with the presence/absence of this clinical condition also reached statistical significance (rs2004640: P=0.037, OR=0.69, CI 95%=0.48-0.98; rs10954213: P=0.030, OR=0.67, CI 95%=0.47-0.96), thus suggesting that both IRF5 genetic variants are specifically associated with the lack of macular edema in uveitis patients. Conclusion Our results clearly showed for the first time that two functional genetic variants of IRF5 may play a role in the development of macular edema in non-anterior uveitis patients. Identifying genetic markers for macular edema could lead to the possibility of developing novel treatments or preventive therapies. PMID:24116155

  15. Topical Ganciclovir in Cytomegalovirus Anterior Uveitis.

    Science.gov (United States)

    Antoun, Joelle; Willermain, François; Makhoul, Dorine; Motulsky, Elie; Caspers, Laure; Relvas, Lia Judice

    2017-05-01

    To study the effects of topical ganciclovir 0.15% gel on cytomegalovirus (CMV) anterior uveitis in a tertiary uveitis referral center in Brussels, Belgium. A retrospective study of patients with a clinical diagnosis of CMV anterior uveitis/endotheliitis demonstrated by a positive polymerase chain reaction and/or Goldmann-Witmer coefficient (GWc). We report a series of 15 patients presenting clinical characteristics of CMV anterior uveitis. Patients had a pretreatment follow-up of 13.00 ± 12.78 months and a posttreatment follow-up of 42.64 ± 31.23 months. The 14 non-Asian patients (93.3%) had clinical characteristics of Posner-Schlossman syndrome, and the only Asian patient (6.7%) had keratic precipitates like Fuchs heterochromic iridocyclitis. At presentation, uveitis was unilateral in all patients, visual acuity (VA) was 0.91 ± 0.25, and all patients had an increased intraocular pressure (IOP), with a mean IOP of 41.40 ± 10.35 mmHg. At the end of the follow-up, 5 patients (33.3%) had glaucoma, 2 needed glaucoma surgery (13.3%). The mean final VA was 0.93 ± 0.11; 13 patients (86.5%) reached a final VA of 0.7 to 1. Patients had a significantly lower number of recurrences/year posttreatment (0.76 ± 0.57) than in the pretreatment period (3.76 ± 2.44) (P = 0.001). The mean time to recurrence increased from 4.03 months before treatment to 12.58 months after treatment (P = 0.003). Our results suggest that patients treated with 0.15% topical ganciclovir have a decreased frequency of CMV anterior uveitis recurrences, most preserve a relatively good central vision over time. However, glaucoma is a frequent and severe complication.

  16. Causes of uveitis in dogs: 102 cases (1989-2000).

    Science.gov (United States)

    Massa, Kathleen L; Gilger, Brian C; Miller, Tammy L; Davidson, Michael G

    2002-06-01

    Uveitis is one of the most common ocular diseases and one of the most common causes of blindness in dogs. The purpose of this retrospective study was to correlate the signalment, history, clinical signs and ophthalmic findings of dogs with uveitis with the underlying etiology. We conducted a retrospective study of 102 dogs presented to the NCSU-VTH from 1989 to 2000 with clinical signs of uveitis. Medical records of dogs presented for uveitis were reviewed. Dogs were included in the study only if a complete diagnostic work-up database was collected, if sufficient follow-up was documented, and if the uveitis was not secondary to trauma or a hypermature cataract. The mean age +/- SD of all dogs in this study was 6.2 +/- 3.6 years. There were 33 intact and 16 castrated males, and 14 intact and 27 neutered females. Fourteen breeds were represented, with the Golden Retriever (n = 14) most common. Fifty-nine dogs (58%) were diagnosed with idiopathic/immune-mediated uveitis, neoplasia was diagnosed in 25 dogs (24.5%) and 18 dogs (17.6%) were diagnosed with infectious causes of uveitis. Aqueous flare was the most common clinical sign, occurring in 88 dogs (86%). The most common infectious organisms associated with uveitis in the dogs of this study were Ehrlichia canis (n = 7). Lymphosarcoma (n = 17) was the most common neoplasm. In approximately 60% of dogs presenting for uveitis an underlying cause was not found, and a diagnosis of immune-mediated or idiopathic uveitis was made. However, approximately 25% of dogs had ocular and/or systemic neoplasia (with 17% of cases having lymphosarcoma) and 18% with an underlying infectious cause for uveitis. Because of the high percentage of systemic disease associated with uveitis in dogs, extensive diagnostic testing is recommended before instituting symptomatic anti-inflammatory therapy.

  17. Use of Immunomodulatory Drugs at a Uveitis Clinic.

    Science.gov (United States)

    Millán-Longo, Claudia; Peiteado, Diana; Schlincker, Armelle; Hidalgo, Ventura; Pieren, Amara; Balsa, Alejandro; de Miguel, Eugenio

    2017-11-10

    The treatment of noninfectious uveitis includes steroids and immunomodulatory drugs, the use of which has increased in the last few years, and the options have been enriched with the development of new treatments. However, clear therapeutic guidelines and protocols have not been developed. The purpose is to analyze the response to the drugs used and the characteristics of the patients treated at a multidisciplinary uveitis clinic. Observational and retrospective study of the patients attended to from January 2012 to December 2015. Infectious, posttraumatic and postoperative uveitis, as well as masquerade syndrome, were excluded. Two hundred six patients were included. Overall, 58.80% had uveitis without association of systemic disease, mostly idiopathic uveitis, and 35.65% had uveitis with systemic involvement, mainly related to spondyloarthritis. Uveitis without systemic association and anterior uveitis achieved disease control with local treatment more frequently than others (p=.002 and p <.001, respectively). In all, 49.76% of the patients required systemic treatment. Among those treated with immunomodulators, 53.26% needed a second drug and 31.52% needed a third drug. Women required immunomodulators more often than men (P=.042). Methotrexate was the most widely used immunomodulator. Posterior uveitis responded less favorably to the second immunomodulator than anterior uveitis (p=.006). Almost half of the patients needed an immunomodulatory drug and some of them required successive drug changes. Intermediate uveitis was the most treatment-refractory uveitis. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  18. 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

  19. 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...

  20. Ipsilateral uveitis and optic neuritis in multiple sclerosis.

    Science.gov (United States)

    Thouvenot, Eric; Mura, Frédéric; De Verdal, Marie; Carlander, Bertrand; Charif, Mahmoud; Schneider, Christelle; Navarre, Sophie; Camu, William

    2012-01-01

    Background. Uveitis is 20 times more frequent in multiple sclerosis (MS) patients than in the general population. Methods. A retrospective study of local multiple sclerosis (n = 700) and uveitis cohorts (n = 450) described the ophthalmological and neurological characteristics of patients with multiple sclerosis and uveitis. Results. Uveitis and multiple sclerosis were associated in seven patients. The time intervals between diagnoses of MS and uveitis ranged from 6 months to 15 years. Analysis of the patients' characteristics revealed that multiple sclerosis was associated with an older age of onset than usually expected, that is, 39 years. Uveitis was bilateral in three cases and mainly posterior (5/10). Five patients presented with acute optic neuritis (two in one eye and three in both eyes). All eyes presenting with acute optic neuritis were also affected by uveitis (P = 0.02), though not simultaneously. Conclusion. The ipsilateral association between optic neuritis and uveitis in this series of patients with multiple sclerosis may suggest a reciprocal potentiation between optic neuritis and uveitis in multiple sclerosis.

  1. Ipsilateral Uveitis and Optic Neuritis in Multiple Sclerosis

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    Eric Thouvenot

    2012-01-01

    Full Text Available Background. Uveitis is 20 times more frequent in multiple sclerosis (MS patients than in the general population. Methods. A retrospective study of local multiple sclerosis (n=700 and uveitis cohorts (n=450 described the ophthalmological and neurological characteristics of patients with multiple sclerosis and uveitis. Results. Uveitis and multiple sclerosis were associated in seven patients. The time intervals between diagnoses of MS and uveitis ranged from 6 months to 15 years. Analysis of the patients’ characteristics revealed that multiple sclerosis was associated with an older age of onset than usually expected, that is, 39 years. Uveitis was bilateral in three cases and mainly posterior (5/10. Five patients presented with acute optic neuritis (two in one eye and three in both eyes. All eyes presenting with acute optic neuritis were also affected by uveitis (P=0.02, though not simultaneously. Conclusion. The ipsilateral association between optic neuritis and uveitis in this series of patients with multiple sclerosis may suggest a reciprocal potentiation between optic neuritis and uveitis in multiple sclerosis.

  2. Efficacy of cataract surgery in patients with uveitis

    Science.gov (United States)

    Zhang, Yinglei; Zhu, Xiangjia; He, Wenwen; Jiang, Yongxiang; Lu, Yi

    2017-01-01

    Abstract To evaluate the visual outcomes of cataract surgery in patients with uveitis, and to determine risk factors for the recurrence of uveitis and postoperative complications. Eighty patients with uveitis who underwent phacoemulsification with intraocular lens (IOL) implantation were included in this retrospective study. We analyzed the following data: patient characteristics, medications used, visual acuity, and complications of cataract surgery. The mean ± standard deviation time from cataract surgery to the last visit was 20.8 ± 10.4 months. Best-corrected visual acuity improved significantly after surgery (P uveitis. Gender (P = .018) and IOL type (P = .020) were significantly associated with recurrent uveitis after surgery. The incidence of recurrent inflammation was not significantly different between patients who did or did not receive systemic therapy (P = .43). Perioperative systemic therapies (P = .011) and recurrent uveitis within 3 months of surgery (P = .043) were associated with posterior capsular opacification. Perioperative systemic therapies (P = .026) and recurrent uveitis after surgery (P = .006) were also significantly associated with cystoid macular edema. Patients with uveitis could benefit from cataract surgery. Patients with Behçet disease had worse postoperative prognosis than patients with other etiologies of uveitis. A heparin-surface-modified IOL may reduce the incidence of recurrent inflammation. PMID:28746181

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

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    Zaidoon Al-Jaderi

    2015-11-01

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

  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...... and its CCR5 receptor in the induction of EAE by immunizing C57BL / 6 mice deficient in either MIP-1alpha or CCR5 with myelin oligodendrocyte glycoprotein (MOG). We found that MIP-1alpha-deficient mice were fully susceptible to MOG-induced EAE. These knockout animals were indistinguishable from wild-type...... mice in Th1 cytokine gene expression, the kinetics and severity of disease, and infiltration of the central nervous system by lymphocytes, macrophages and granulocytes. RNase protection assays showed comparable accumulation of mRNA for the chemokines interferon-inducible protein-10, RANTES, macrophage...

  5. 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.

  6. 1,25-Dihydroxyvitamin D3 inhibits the differentiation and migration of T(H17 cells to protect against experimental autoimmune encephalomyelitis.

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    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.

  7. Pseudomonas aeruginosa endophthalmitis masquerading as chronic uveitis

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    Kalpana Badami Nagaraj

    2013-01-01

    Full Text Available A 65-year-old male presented with decreased vision in the left eye of 15-day duration after having undergone an uneventful cataract surgery 10 months back. He had been previously treated with systemic steroids for recurrent uveitis postoperatively on three occasions in the same eye. B-scan ultrasonography showed multiple clumplike echoes suggestive of vitreous inflammation. Aqueous tap revealed Pseudomonas aeruginosa sensitive to ciprofloxacin. The patient was treated with intravitreal ciprofloxacin and vancomycin along with systemic ciprofloxacin with good clinical response. Even a virulent organism such as P.aeruginosa can present as a chronic uveitis, which, if missed, can lead to a delay in accurate diagnosis and appropriate management.

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

    Science.gov (United States)

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

    2017-09-01

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

  9. Clinical Characteristics of Patients with Intermediate Uveitis

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    Sirel Gür Güngör

    2014-01-01

    Full Text Available Objectives: To analyze the clinical characteristics and findings in patients with intermediate uveitis. Materials and Methods: The records of the 35 patients diagnosed as intermediate uveitis in our clinic between years 1996 and 2011 were reviewed retrospectively. Best-corrected visual acuity, intraocular pressure, slit lamp examination, dilated fundus examination, fundus fluorescein angiography, and systemic examination results of the patients were noted. Results: The mean follow-up time was 6.2 years (2-16 years. The mean age at diagnosis of intermediate uveitis was 32.4 years (8-68 years. 17.1% of patients were under 18 years old. 65.7% of patients were women, 34.2% were men, and both eyes were affected in 54.3% of patients. The most frequent findings were vitritis (100%, snowball opacities (97.1%, retinal vasculitis (65.7%, and snowbanking (45.7%. Concurrent iridocyclitis was determined in 71.4% of patients. Systemic association was found in 40.1% of patients, with disease being multiple sclerosis (22.9%, sarcoidosis (11.4%, tuberculosis (2.9%, or Lyme disease (2.9%. The most common complication that developed during the follow-up period included secondary glaucoma (22.9%, cataract formation (17.1%, and cystoid macular edema (17.1%. The visual acuity of 3 patients was less than 0.5 due to the optic atrophy, macular hole, and cystoid macular edema sequel, respectively. The mean final visual acuity of the remaining patients was 0.9±0.2. Conclusion: When the inflammation and complications are treated effectively in intermediate uveitis, the visual prognosis is fairly good. Detailed clinical evaluation of such cases may reveal systemic diseases at the initial examinations or follow-up visits. (Turk J Ophthalmol 2014; 44: 27-30

  10. American uveitis society meeting october 31, 1994 san francisco, california.

    Science.gov (United States)

    Lowder, C Y; Meisler, D M

    1995-01-01

    1 Ophthalmic manifestations of presumed rifabutin-related uveitis. Arevalo JF, Freeman WR, La Jolla, CA, USA. 2 Diagnosis of toxoplasmosis acute anterior uveitis by PCR. Cano J, Diaz M, Navee A, Maldonado M, Barcelona, Spain. 3 Neuroretinits in patients with AIDS. Berger B, Austin TX, USA. 4 Presumed varicella zoster retinitis in a pediatric patient with AIDS. El Baba F, Nachman S, Stony Brook, NY, USA. 5 ARN with hypopyon caused by EVB and herpes type VI viruses. Cano J, Diaz M, Navea A, Maldonado MJ, Barcelona, Spain. 6 CD8(+) T-lymphocytes and ocular infections in HIV(+) patients. Lowder CY, Butler CP, Dodds EM, Recillas-Gispert C, Cleveland, OH, USA. 7 Intravitreal foscanet for persistent CMV. Lieberman RM, Orellana J, New York, NY, USA. 8 Perfluorocarbon liquid versus air-fluid exchange during surgical repair of retinal detachment caused by cytomegalovirus retinitis in patients with AIDS. Sery T, Gomes J, Sando R, Dua H, Donoso L, Vrabec T, Philadelphia, PA, USA. 9 Endogenous ophthalmitis simulating retinoblastoma: a report of six cases. Shields J, Shields C, Eagle R, Barrett J, DePotter P, Philadelphia, PA, USA. 10 Ocular lymphoma resembling chronic postoperative endophthalmitis. Fox G, Chan CC, Whitcup SM, Nussenblatt R, Bethesda, MD, USA. 11 A phase II trial of combination chemotherapy for primary central nervous system lymphoma. Whitcup SM, Stark-Vanes V, Nussenblatt RB, Heiss H, Witte R, Bethesda, MD, USA. 12 Cancer-induced autoimmune retinopathy. Thirkill C, Sacramento, CA, USA. 13 Leukocytoclastic vasculitis. Tessler H. Chicago, IL, USA. 14 Bilateral choroidal neovascular membranes after Candida albicans chorioretinitis. Dodds E, Townsend-Pico W, Lowder CY, Lewis H, Cleveland, OH, USA. 15 An unusual complications of Toxoplasma retinochoroiditis. Gormley PD, Flaxel CJ, Pavesio CE, Conrad DK, Lightman S, London, UK. 16 Surgical removal of a choroidal neovascular membrane in sympahtetic ophthalmia. Conrad DK, McCluskey PJ, Schwartz S, Gregor Z. Lightman S

  11. Management of cataract in uveitis patients.

    Science.gov (United States)

    Conway, Mandi D; Stern, Ethan; Enfield, David B; Peyman, Gholam A

    2018-01-01

    This review is timely because the outcomes of surgical invention in uveitic eyes with cataract can be optimized with adherence to strict anti-inflammatory principles. All eyes should be free of any cell/ flare for a minimum of 3 months preoperatively. Another helpful maneuver is to place dexamethasone in the infusion fluid or triamcinolone intracamerally at the end of surgery. Recent reports about the choice of intraocular lens material or lens design are germane to the best surgical outcome. Integrating these findings will promote better visual outcomes and allow advancement in research to further refine these surgical interventions in high-risk uveitic eyes. Control of inflammation has been shown to greatly improve postoperative outcomes in patients with uveitis. Despite better outcomes, more scientific research needs to be done regarding lens placement and materials and further research needs to adhere to the standardized reporting of uveitis nomenclature. Future studies should improve postoperative outcomes in eyes with uveitis so that they approach those of eyes undergoing routine cataract procedures.

  12. PEMBROLIZUMAB ADMINISTRATION ASSOCIATED WITH POSTERIOR UVEITIS.

    Science.gov (United States)

    Aaberg, Michael T; Aaberg, Thomas M

    2017-01-01

    To describe the development of uveitis and retinal vasculitis in association with pembrolizumab treatment for metastatic uveal melanoma. A case report and a brief review of the literature are presented. Information collected and reported include the patient's clinical course, physical examination findings, fluorescein angiogram images, retinal photographs, and her response to treatment. A 54-year-old woman was diagnosed with a large choroidal malignant melanoma and had the affected eye enucleated. Pathology confirmed a mixed cell choroidal melanoma, and gene expression profiling was Class 2. Seventeen months after enucleation, the patient was diagnosed with metastatic uveal melanoma to the liver. Disease progression was observed during ipilimumab treatment. Pembrolizumab treatment was initiated, and after four infusions, she presented to clinic complaining of floaters and blurred vision. Examination revealed a nongranulomatous panuveitis characterized by perivascular retinal pigment epithelium pigmentary changes, retinal venous sheathing, 1+ anterior chamber and vitreous cellular reaction, 2+ vitreous haze, and optic disk edema. A dexamethasone sustained-release implant was administered and the uveitis regressed. A relapse in symptoms occurred but quickly subsided with a repeat injection. Pembrolizumab may induce a uveitic reaction. There is mounting evidence that patients using prembrolizumab should be educated and monitored for signs of uveitis.

  13. Autoimmun pankreatitis

    DEFF Research Database (Denmark)

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

    2015-01-01

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

  14. PROGRESSION AND OUTCOMES OF UVEITIS IN PATIENTS WITH ANKYLOSING SPONDILITIS

    Directory of Open Access Journals (Sweden)

    A. A. Godzenko

    2014-01-01

    Full Text Available Uveitis is a common extraskeletal manifestation of ankylosing spondylitis (AS occurring in 20–40% of patients. Mostauthors underline a favorable prognosis for AS-associated uveitis.Objective: to study features of clinical picture and progression of AS-associated uveitis and to estimate the occurrence of its complications.Subjects and methods. Across-sectional study of 140 patients (98 males and 42 females with AS, who had at least one uveitis attack over the period of disease and was followed up at V.A. Nasonova Research Institute of Rheumatology during 2008–2012. In addition to standard rheumatologic examination all patients were examined by ophthalmologist. Biomicroscopy, ophthalmoscopy, tonometry, computer-assisted perimetry, ultrasonography (B-scanning of eyes and, if needed, fluorescein angiography and electrophysiological examination of retina were performed. Localization of uveitis, presence of complications affecting vision, total number of uveitis attacks by the moment of examination, mean number of uveitis attacks per year, correlation between the frequency of attacks and complications, presence of other extraskeletal manifestations and peripheral arthritis were assessed. The total number of uveitis attacks was defined from patients' interviews and respective medical documentation. Mean number of uveitis attacks was calculated as ratio of total number of uveitis attacks to the duration of disease for each patient. In the case of more than two attacks per year uveitis progression was consideredrefractory.Results.Mean duration of the disease was 17.7±11.03 years. In 19 patients (14% AS manifested before and in 121 (86% – after the age of 16 years. HLA-B27 was revealed in 135 (96% patients, peripheral arthritis – in 43 (30%, whereas other extraskeletal manifestations – in 46 (32%. Early onset of uveitis in first 10 years of the disease was recorded in 81 (58% patients, after10 years – in 21 (15%. Uveitis was the

  15. 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

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

    Science.gov (United States)

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

    2017-01-01

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

  17. 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.

  18. Evaluations of therapeutic efficacy of intravitreal injected polylactic-glycolic acid microspheres loaded with triamcinolone acetonide on a rabbit model of uveitis.

    Science.gov (United States)

    Li, Wenchang; He, Bing; Dai, Wenbing; Zhang, Qiang; Liu, Yuling

    2014-06-01

    Conventional treatments of uveitis are not ideal because of the short period of therapeutic efficacy. In the present study, biodegradable polylactic-glycolic acid microspheres loaded with triamcinolone acetonide (TA) were prepared to achieve sustained drug release and their therapeutic efficacy was investigated on a rabbit model of uveitis. TA-loaded microspheres (TA-MS) were prepared by the solvent evaporation method and characterized for encapsulation efficiency, particle size, morphology and in vitro release. The therapeutic efficacy was studied on the rabbit experimental uveitis model based on scoring of the inflammation, aqueous leukocyte counting, aqueous protein determination and histological examination. The TA-MS exhibited smooth and intact surfaces with an average diameter of 50.87 μm. The drug-loading coefficient and encapsulation efficiency were 15.2 ± 0.6 % and 91.24 ± 3.77 %, respectively. The drug release from TA-MS lasted up to 87 days, but only 46 days for TA suspension. The change in surface morphology also showed sustained drug release from TA-MS. TA-MS exhibited improved therapeutic efficacy in lipopolysaccharide -induced uveitis compared to TA suspension, especially in regard to the inhibition of inflammation. The TA-MS had a longer-term therapeutic effect on intraocular inflammation in LPS-induced uveitis in rabbits compared to TA suspension. The results suggested that TA-MS can be developed as a potential sustained-release system for the treatment of uveitis.

  19. Therapeutic and toxicological evaluations of cyclosporine a microspheres as a treatment vehicle for uveitis in rabbits.

    Science.gov (United States)

    He, Yuan; Wang, Jian-Cheng; Liu, Yu-Ling; Ma, Zhi-Zhong; Zhu, Xiu-An; Zhang, Qiang

    2006-04-01

    This study was undertaken to investigate the therapeutic efficacy and the toxicity of the intravitreal biodegradable poly(dl-lactide-co-glycolide)co-polymer microspheres containing cyclosporin A (CsA-PLGA-MS) on experimental uveitis in rabbits. CsA-PLGA-MS that had been prepared by a solvent evaporation approach were characterized for morphology, particle size, entrapment efficiency, and in vitro release profile of CsA-PLGA-MS. Therapeutic efficacy of the CsA-PLGA-MS was evaluated by scoring of the inflammation, aqueous leukocyte counting, aqueous protein determination, and histological examination in the experimental rabbits with artificial uveitis induced by the injection of lipopolysaccharide. The toxicity was investigated by slit-lamp examination, indirect ophthalmoscopy, and electroretinography (ERG) in the noninflamed rabbit eye. The CsA-PLGA-MS were spherical in shape, with an average particle size of nearly 50 microm and an entrapment efficiency of more than 80%. The compositions of the formulation that was most effective in the in vivo studies included CsA, PLGA, and 3% Pluronic F68. In vitro released cyclosporine A from the optimized microspheres was approximately 25% during the 60-day incubation at 37 degrees C. It was demonstrated that the intravitreal injection of the optimized CsA-PLGA-MS decreased significantly the severity of the inflammatory signs, cellular infiltrate, aqueous leukocyte counts, and protein levels in the eyes of experimental rabbits with uveitis, compared to other formulations. Also, the preparation did not cause obvious toxicity in the noninflamed eyes of rabbits, except that the ERG b-wave amplitude for the test eyes was reversibly depressed, compared to those of the control eyes at 2 weeks, which almost recovered at the end of 6 weeks. The CsA-PLGA-MS preparation might be useful in the treatment of patients with severe chronic posterior uveitis who cannot tolerate systemic or periocular therapy.

  20. Usher syndrome associated with Fuchs’ heterochromic uveitis: a case report

    Directory of Open Access Journals (Sweden)

    Turan-Vural E

    2011-04-01

    Full Text Available Ece Turan-Vural, Banu Torun-Acar, Nejla Tükenmez, M Şahin Sevim, Bulent Buttanri, Suphi AcarOphthalmology Clinic, Haydarpasa Numune Education and Research Hospital, Istanbul, TurkeyAbstract: We report a case of Usher syndrome in association with unilateral Fuchs' heterochromic uveitis.Keywords: Fuchs’ heterochromic uveitis, Usher syndrome, deafness, blindness

  1. Rubella virus-associated uveitis in a nonvaccinated child

    NARCIS (Netherlands)

    Siemerink, Martin J.; Sijssens, Karen M.; de Groot-Mijnes, Jolanda D. F.; de Boer, Joke H.

    2007-01-01

    PURPOSE: To report presumed Fuchs heterochromic uveitis (FHU) associated with Rubella virus (RV)-specific intraocular antibody production in a child who was not vaccinated against rubella. DESIGN: Observational case report. METHODS: We examined a 13-year-old boy with chronic anterior uveitis

  2. Risk factors for uveitis in sarcoidosis | Kaye | South African Medical ...

    African Journals Online (AJOL)

    Uveitis is a potentially sight-threatening complication of sarcoidosis. The object of this study was to determine which patients with sarcoidosis are at greater risk of developing uveitis. We retrospectively assessed 136 patients with clinical, radiological and histological features of sarcoidosis. Of the 48 patients (35,3%) with ...

  3. Impact of juvenile idiopathic arthritis associated uveitis in early adulthood

    NARCIS (Netherlands)

    Haasnoot, A.-M.J.W. (Anne-Mieke J. W.); Vernie, L.A. (Lenneke A.); A. Rothová (Aniki); Doe, P.V.D. (Patricia V. D.); L.I. Los (Leonoor I.); N.E. Schalij-Delfos (Nicoline); J.H. de Boer (Joke)

    2016-01-01

    textabstractBackground: Typically juvenile idiopathic arthritis (JIA)-associated uveitis (further referred as 'JIA-uveitis') has its onset in childhood, but some patients suffer its, sometimes visual threatening, complications or ongoing disease activity in adulthood. The objective of this study was

  4. Impact of Juvenile Idiopathic Arthritis Associated Uveitis in Early Adulthood

    NARCIS (Netherlands)

    Haasnoot, AJW; Vernie, Lenneke A; Rothova, Aniki; V D Doe, Patricia; Los, Leonoor I; Schalij-Delfos, Nicoline E; de Boer, Joke H

    2016-01-01

    BACKGROUND: Typically juvenile idiopathic arthritis (JIA)-associated uveitis (further referred as 'JIA-uveitis') has its onset in childhood, but some patients suffer its, sometimes visual threatening, complications or ongoing disease activity in adulthood. The objective of this study was to analyze

  5. Impact of Juvenile Idiopathic Arthritis Associated Uveitis in Early Adulthood

    NARCIS (Netherlands)

    Haasnoot, Anne-Mieke J. W.; Vernie, Lenneke A.; Rothova, Aniki; van der Doe, Patricia; Los, Leonoor I.; Schalij-Delfos, Nicoline E.; de Boer, Joke H.

    2016-01-01

    Background Typically juvenile idiopathic arthritis (JIA)-associated uveitis (further referred as 'JIA-uveitis') has its onset in childhood, but some patients suffer its, sometimes visual threatening, complications or ongoing disease activity in adulthood. The objective of this study was to analyze

  6. Adalimumab for the treatment of refractory noninfectious paediatric uveitis.

    Science.gov (United States)

    Muñoz-Gallego, Alicia; Barral, Estefanía; Enríquez, Eugenia; Tejada, Pilar; Barceló, Ana; de Inocencio, Jaime

    2017-06-01

    To report the experience of our center with the use of adalimumab (ADA) for the treatment of severe refractory noninfectious paediatric uveitis. The study is a retrospective case series of all paediatric patients with refractory uveitis who were treated with ADA at the Paediatric Uveitis Unit of our center from 2008 to 2015. We present 12 patients (6 Juvenile idiopathic arthritis-associated uveitis, 4 idiopathic panuveitis, 1 early-onset sarcoidosis-associated panuveitis, and 1 intermediate uveitis), with uveitis in 19/24 eyes. Once ADA therapy was started, all the patients presented improved activity according to Standardization of Uveitis Nomenclature (SUN) criteria. Nine out of the 12 patients had structural damage before ADA could be started: cataract (n = 4), glaucoma (n = 2), cystic macular edema (n = 1), exudative retinal detachment (n = 1), and optic disk edema (n = 5). Visual acuity improved or maintained stable in 17/19 affected eyes, and only 2 eyes decreased its visual acuity because of structural damage, which was already present before ADA therapy. In our experience, ADA presents a good safety profile and is efficacious in the treatment of paediatric patients with different forms of refractory noninfectious uveitis.

  7. Infectious uveitis. New developments in etiology and pathogenesis

    NARCIS (Netherlands)

    de Visser, L.

    2009-01-01

    Uveitis is an inflammation of the inner-eye and is initiated by various infectious and noninfectious causes. In a large portion of patients the etiology is unknown and might be associated with until now undiagnosed infections.The identification of infectious uveitis is of crucial importance since

  8. Risk Factors for Secondary Glaucoma in Herpetic Anterior Uveitis

    NARCIS (Netherlands)

    Hoeksema, Lisette; Jansonius, Nomdo M.; Los, Leonoor I.

    PURPOSE: To determine the incidence of elevated intraocular pressure (TOP) and secondary glaucoma in herpetic anterior uveitis (AU), owing to either herpes simplex or varicella zoster virus, by using the Standardization of Uveitis Nomenclature (SUN) criteria, and to identify risk factors for the

  9. Impact of Juvenile Idiopathic Arthritis Associated Uveitis in Early Adulthood.

    Directory of Open Access Journals (Sweden)

    Anne-Mieke J W Haasnoot

    Full Text Available Typically juvenile idiopathic arthritis (JIA-associated uveitis (further referred as 'JIA-uveitis' has its onset in childhood, but some patients suffer its, sometimes visual threatening, complications or ongoing disease activity in adulthood. The objective of this study was to analyze uveitis activity, complications and visual prognosis in adulthood.In this multicenter study, 67 adult patients (129 affected eyes with JIA-uveitis were retrospectively studied for best corrected visual acuity, visual fields, uveitis activity, topical/systemic treatments, ocular complications, and ocular surgeries during their 18th, 22nd and 30th year of life. Because treatment strategies changed after the year 1990, outcomes were stratified for onset of uveitis before and after 1990.Sixty-two of all 67 included patients (93% had bilateral uveitis. During their 18th life year, 4/52 patients (8% had complete remission, 28/52 (54% had uveitis activity and 37/51 patients (73% were on systemic immunomodulatory treatment. Bilateral visual impairment or legal blindness occurred in 2/51 patients (4%; unilateral visual impairment or legal blindness occurred in 17/51 patients (33% aged 18 years. The visual prognosis appeared to be slightly better for patients with uveitis onset after the year 1990 (for uveitis onset before 1990 (n = 7 four patients (58% and for uveitis onset after 1990 (n = 44 13 patients (30% were either visual impaired or blind. At least one ocular surgery was performed in 10/24 patients (42% between their 18th and 22nd year of life.Bilateral visual outcome in early adulthood in patients with JIA-uveitis appears to be fairly good, although one third of the patients developed one visually impaired or blind eye. However, a fair amount of the patients suffered from ongoing uveitis activity and needed ongoing treatment as well as surgical interventions. Awareness of these findings is important for ophthalmologists and rheumatologists treating patients with JIA-uveitis

  10. Recent advances in uveitis of juvenile idiopathic arthritis.

    Science.gov (United States)

    Kotaniemi, Kaisu; Savolainen, Anneli; Karma, Anni; Aho, Kimmo

    2003-01-01

    Chronic scarring-type uveitis is a frequent extra-articular manifestation of juvenile idiopathic arthritis. It occurs in about 20% of children with this disease, commencing typically within a few years from its onset. The risk of uveitis is greatest in antinuclear antibody-positive girls with early onset oligoarthritis. The classic clinical picture is chronic bilateral anterior uveitis, usually asymptomatic until substantial damage to intraocular structures occurs. In view of the asymptomatic nature of the condition, routine screening of juvenile idiopathic arthritis patients 2-4 times a year is crucial to prevent complications. The treatment consists of topical corticosteroids and mydriatics, in severe cases with immunosuppressive agents, and surgical management of complications. Although the prognosis of uveitis is improving, there are cases refractory to standard regimens. Patients in whom uveitis commences prior to the onset of arthritis present a special problem.

  11. 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

  12. 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

  13. A critical role for interleukin-1β in the progression of autoimmune diseases.

    Science.gov (United States)

    Zhao, Ruijuan; Zhou, Hongyan; Su, Shao Bo

    2013-11-01

    Interleukin-1β (IL-1β) belongs to IL-1 family and is a potent pro-inflammatory cytokine. It is known to be also involved in a variety of cellular activities, including cell proliferation, differentiation and apoptosis. In addition to its pathophysiologic role in host protection, IL-1β promotes the progression of a number of autoimmune diseases. Most of such diseases can be controlled by anti-IL-1β treatment. This review discusses the contribution of IL-1β to the course of autoimmune diseases, such as rheumatic diseases, uveitis, autoimmune thyroid diseases (AITD), insulin-dependent diabetes mellitus (IDDM), autoimmune inner ear disease (AIED), multiple sclerosis (MS), myocarditis, hepatitis and kidney diseases. The critical involvement of IL-1β in the pathogenesis of autoimmune diseases provides targets for developing therapeutic treatment. © 2013. Published by Elsevier B.V. All rights reserved.

  14. Iris autofluorescence in Fuchs' heterochromic uveitis.

    Science.gov (United States)

    Liu, Qian; Jia, Yading; Zhang, Suhua; Xie, Juan; Chang, Xin; Hou, Jia; Li, Gaiyun; Koch, Douglas D; Wang, Li

    2016-10-01

    To explore the characteristic autofluorescence patterns of iris depigmentation in eyes diagnosed with Fuchs' heterochromic uveitis (FHU). Near-infrared autofluorescence images and colour images of iris were taken in 21 eyes of 21 patients with FHU, 30 eyes of 15 normal subjects, 30 eyes of 15 normal age-related iris atrophy and 33 eyes of 20 patients with uveitis other than FHU. The confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph 2, HRA2) was used for melanin-related autofluorescence imaging. The indocyanine green angiography mode of HRA2 was applied for near-infrared laser imaging, and the wavelength of the excitation laser was 795 nm. Iris colour images were also taken with the slit lamp. In normal iris, moderately intense autofluorescence was noted for the pigment ruff at the pupillary border, the crests in the pupillary zone and the collarette; and there was mild autofluorescence in the ciliary zone. In eyes with age-related iris atrophy and uveitis, much less autofluorescence was seen than the healthy normal irides. In eyes with FHU, there was moderate but discontinuous autofluorescence in the pigment ruff, a petaloid pattern of autofluorescence in the pupillary zone, moderate autofluorescence in the collarette and reticular pattern of autofluorescence in the ciliary zone. Characteristic autofluorescence patterns appeared in eyes diagnosed with FHU. Near-infrared autofluorescence is a promising objective technique to document the iris changes in FHU. 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/

  15. Autoimmune liver disease panel

    Science.gov (United States)

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

  16. Traumatic uveitis in the mid-Atlantic United States

    Directory of Open Access Journals (Sweden)

    Engelhard SB

    2015-10-01

    Full Text Available Stephanie B Engelhard,1 James Patrie,2 John Prenshaw,1 Asima Bajwa,1 Rose Monahan,1 Ashvini K Reddy1 1Department of Ophthalmology, 2Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA Purpose: The purpose of this study was to conduct an in-depth analysis of traumatic uveitis in patients managed in a mid-Atlantic tertiary care center with the goal of better characterizing the clinical features and outcomes of this large and important subset of uveitis patients.Methods: This was a retrospective, observational study comparing traumatic uveitis patients with nontraumatic uveitis patients seen at the University of Virginia, Charlottesville, VA, USA, from 1984 to 2014.Results: Fifty-four traumatic uveitis patients (55 eyes were identified. The patient population was 70.4% male, 57.4% Caucasian, and 37.0% African American. Mean age at diagnosis was 31.2 years; mean duration of follow-up was 5.4 years; and mean number of visits to the clinic was 4. The most common treatment modality was local steroids (77.8%. Glaucoma was medically managed in eight patients (14.8%. Cataract surgery was performed in five patients (9.3%. Mean best-corrected visual acuity at baseline for traumatic uveitis patients was 0.33 logMAR (SD 0.42 at the initial visit and 0.16 logMAR (SD 0.33 at the final visit. Mean baseline intraocular pressure (IOP in the traumatic uveitis group was 15.5 mmHg (SD 7.4 at the initial visit and 14.6 mmHg (SD 4.0 at the final visit. Patients in the traumatic uveitis cohort tended to have better visual outcomes than those in the nontraumatic uveitis cohort.Conclusion: In our series, traumatic uveitis patients tended to be young and male and present with unilateral disease, all findings consistent with other reports. Despite relatively good visual outcomes, the traumatic uveitis patients still experienced a high burden of disease, measured both in the number of clinic visits and duration of follow-up. Due to the

  17. Surgical management in patient with uveitis

    Directory of Open Access Journals (Sweden)

    Somasheila I Murthy

    2013-01-01

    Full Text Available Surgery in the management of uveitis can be divided based on indication: either for therapeutic or can be for diagnostic purposes or to manage complications. The commonest indications include: Visual rehabilitation: surgery for removal of cataract, band keratopathy, corneal scars, pupillary membranes, removal of dense vitreous membranes, management of complications: anti-glaucoma surgery, vitreous hemorrhage, retinal detachment and chronic hypotony and diagnostic: aqueous tap, vitreous biopsy, tissue biopsy (iris, choroid. In this review, we shall describe the surgical technique for visual rehabilitation and for management of complications.

  18. [Autoimmune pancreatitis].

    Science.gov (United States)

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

    2013-11-01

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

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

    DEFF Research Database (Denmark)

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

    1994-01-01

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

  20. 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.

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

    Science.gov (United States)

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

    2009-05-01

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

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

    Science.gov (United States)

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

    2013-10-01

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

  3. 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.

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

    Science.gov (United States)

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

    2014-11-15

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

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

    Science.gov (United States)

    Sun, Li; Weng, Huan; Li, Zhenxin

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Laura Oliveira

    2015-01-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Thomas Secher

    2017-09-01

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

  10. 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.

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

    Science.gov (United States)

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

    2017-12-29

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

  12. 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.

  13. Vitreomacular Interface Disorders in Behçet’s Uveitis

    Directory of Open Access Journals (Sweden)

    Hilal Eser Öztürk

    2017-12-01

    Full Text Available Objectives: To determine the prevalence of vitreomacular interface (VMI disorders in patients with Behçet’s uveitis and assess the relationship between VMI disorders and clinical characteristics. Materials and Methods: The macular optical coherence tomography (OCT images of 160 eyes of 96 patients with Behçet’s uveitis who were being followed in the Uvea-Behçet’s clinic were assessed retrospectively for VMI disorders including posterior vitreous detachment (PVD, epiretinal membrane (ERM, vitreomacular adhesion (VMA, vitreomacular traction (VMT, full-thickness macular hole (FTMH, lamellar hole (LH and pseudohole. Results: Twenty-four patients (25% with unilateral and 72 patients with bilateral uveitis were included in the study. Six (30% of 20 eyes with anterior uveitis and 57 (40.7% of 140 eyes with posterior uveitis, in total 63 (39.4% eyes of 160 eyes had at least one VMI disorder. PVD was detected in 4 eyes (2.5%, ERM in 48 eyes (30%, VMA in 12 eyes (7.5%, and LH in 1 eye (0.6%. None of the eyes had VMT, FTMH, or pseudohole. ERM was detected in 13 eyes (8.1% on fundus examination and 48 (30% eyes by OCT (p=0.001. VMI was detected in 12 (50% of 24 eyes with prior intraocular surgery and 51 (37.5% of 136 eyes without. The mean duration of uveitis was 7.3±5.8 years in patients with VMI disorders and 5.8±7.7 years in patients without (p=0.04. There was no relation between VMI disorders and anatomic location of uveitis, history of past ocular surgery, number of ocular/periocular steroid injections, or visual acuity. Conclusion: VMI disorders are common in patients with Behçet’s uveitis. Their frequency increases with the duration of uveitis. OCT is more sensitive than fundus examination in the detection of VMI disorders.

  14. 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.

  15. 1,25-Dihydroxyvitamin D3 suppresses TLR8 expression and TLR8-mediated inflammatory responses in monocytes in vitro and experimental autoimmune encephalomyelitis in vivo.

    Directory of Open Access Journals (Sweden)

    Bo Li

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

  16. 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

  17. 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

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

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    Sofia Sisay

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

  19. Fibrinous anterior uveitis following laser in situ keratomileusis

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    Parmar Pragya

    2009-01-01

    Full Text Available A 29-year-old woman who underwent laser in situ keratomileusis (LASIK for myopic astigmatism in both eyes presented with severe pain, photophobia and decreased visual acuity in the left eye eight days after surgery. Examination revealed severe anterior uveitis with fibrinous exudates in the anterior chamber, flap edema and epithelial bullae. Laboratory investigations for uveitis were negative and the patient required systemic and intensive topical steroids with cycloplegics to control the inflammation. This case demonstrates that severe anterior uveitis may develop after LASIK and needs prompt and vigorous management for resolution.

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

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    Pernilla Stridh

    2014-03-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

  2. Seronegative autoimmune diseases.

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

    2009-09-01

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

  3. Cytomegalovirus as a cause of anterior uveitis in immunocompetent patients

    NARCIS (Netherlands)

    van Boxtel, Lonneke A. A.; van der Lelij, Allegonda; van der Meer, Johannes; Los, Leonoor I.

    Purpose: To describe 7 cases of unilateral, chronic and/or recurrent anterior uveitis caused by cytomegalovirus (CMV) in immunocompetent patients; to identify specific ophthalmologic characteristics; and to evaluate the clinical effect of valganciclovir treatment. Design: Retrospective observational

  4. Increased CD40 ligand in patients with acute anterior uveitis

    DEFF Research Database (Denmark)

    Øgard, Carsten; Sørensen, Torben Lykke; Krogh, Erik

    2005-01-01

    The inflammatory response in acute anterior uveitis (AU) is believed to be primarily mediated by autoreactive T-cells. We wanted to evaluate whether the T-cell activation marker CD40 ligand is involved in the AU immunopathogenesis.......The inflammatory response in acute anterior uveitis (AU) is believed to be primarily mediated by autoreactive T-cells. We wanted to evaluate whether the T-cell activation marker CD40 ligand is involved in the AU immunopathogenesis....

  5. An unusual case of bilateral anterior uveitis related to moxifloxacin: the first report in Latin America

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    Rangel, Carlos M.

    2017-07-01

    Full Text Available Objective: To report a case of bilateral anterior uveitis secondary to oral moxifloxacin.Methods: Case report.Results: A 54-year-old female presented bilateral anterior uveitis following a 10-day course of oral moxifloxacin. She developed a bilateral anterior uveitis associated with pigment dispersion syndrome and iris transillumination.Conclusions: Drug-induced uveitis is one of the causes of anterior uveitis. Uveitis related to fluoroquinolones is a rare entity, there are few cases reported in the literature, this is the first case reported in Latin America.

  6. 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.

  7. Autoimmune pancreatitis.

    Science.gov (United States)

    Pannala, Rahul; Chari, Suresh T

    2008-09-01

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

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

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    Nuruddeen D Lewis

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

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

    Science.gov (United States)

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

    2014-01-01

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

  10. 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.

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

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    Carolyn J MacMillan

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

  12. 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.

  13. 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

  14. 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.

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

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    Grzegorz Sulkowski

    2013-01-01

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

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

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    Rie Yamamoto

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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

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

    2013-07-01

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

  19. 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.

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

    Science.gov (United States)

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

    2013-09-01

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

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

    Science.gov (United States)

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

    2017-12-01

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

  2. Evaluation of a prednisolone acetate-loaded subconjunctival implant for the treatment of recurrent uveitis in a rabbit model.

    Directory of Open Access Journals (Sweden)

    Marcus Ang

    Full Text Available AIM: To assess the efficacy of a biodegradable, prednisolone acetate implant in a rabbit uveitis model. METHODS: Randomized, controlled study of biodegradable microfilms preloaded with prednisolone acetate (PA in a rabbit uveitis model. Experimental uveitis was induced by unilateral intravitreal injection of Mycobacterium tuberculosis H37Ra antigen (50 ug; 1 ug/uL in preimmunized rabbits. PA-loaded poly[d,l-lactide-co-ε-caprolactone] (PLC microfilms (n = 10 and blank microfilms (n = 6 were implanted subconjunctivally. An estimate of PA release in vivo was calculated from measured residual PA amounts in microfilms after the rabbits were sacrificed. The eyes were clinically monitored for ocular inflammation for 28 days. Histopathological examination of the enucleated eyes was performed at the end of the study period. RESULTS: In vitro studies revealed that sandwich PA-loaded microfilm formulations exhibited higher release kinetic compared to homogenous PA-loaded microfilms. The 60-40-60% microfilm released an average of 0.034 mg/day of PA over the period of 60 days in vitro; and we found that approximately 0.12 mg/day PA was released in vivo. Animals implanted with the PA-loaded microfilms exhibited significantly lowered median inflammatory scores when compared against the control group in this model for recurrent uveitis (P<0.001. The implants were clinically well tolerated by all the animals. Histology results showed no significant scarring or inflammation around the PA-loaded microfilms. CONCLUSION: Our pilot study demonstrated that a subconjunctival PA-loaded implant is effective in suppressing inflammation in the rabbit model of uveitis, by providing therapeutic levels of PA that attenuated the inflammatory response even after a rechallenge. Longer term studies are now needed to establish the therapeutic potential of such a delivery system for treatment of ocular inflammation.

  3. Anti-inflammatory and ultrastructural effects of Turkish propolis in a rat model of endotoxin-induced uveitis.

    Science.gov (United States)

    Ertürküner, Salime Pelin; Yaprak Saraç, Elif; Göçmez, Semil Selcen; Ekmekçi, Hakan; Öztürk, Zeynep Banu; Seçkin, İsmail; Sever, Özkan; Keskinbora, Kadircan

    2016-01-01

    Experimental animal models of acute uveitis, an inflammatory eye disease, can be established via endotoxin-induced inflammation. Propolis, a natural substance collected by honeybees from buds and tree exudates, has antioxidant, antibacterial, antiviral, and anti-inflammatory effects. We investigated the effects of propolis, obtained from the Sakarya province of Turkey, on endotoxin-induced uveitis using immunohistochemical, ultrastructural, and biochemical approaches. Male Wistar albino rats (n = 6/group) received intraperitoneal (ip) lipopolysaccharide (LPS) endotoxin (150 μg/kg) followed by aqueous extract of propolis (50 mg/kg ip) or vehicle; two additional groups received either saline (control) or propolis only. After 24 h, aqueous humor (AH) was collected from both eyes of each animal for analysis of tumor necrosis factor-α (TNF-α) and hypoxia-inducible factor-1α (HIF-1α). Right eyeballs were paraffin-embedded for immunohistochemical staining of nuclear factor κB (NF-κB)/p65 and left eyeballs were araldite-embedded for ultrastructural analysis. Treatment of LPS-induced uveitis with propolis significantly reduced ciliary body NF-κB/p65 immunoreactivity and AH levels of HIF-1α and TNF-α. Ultrastructural analysis showed fewer vacuoles and reduced mitochondrial degeneration in the retinal pigment epithelium, as compared to the uveitis group. The intercellular spaces of the inner nuclear layer and outer limiting membrane were comparable with those of the control group; no polymorphonuclear cells or stasis was observed in intravascular or extravascular spaces. This is the first report demonstrating an anti-inflammatory effect of Turkish propolis in a rat model of LPS-induced acute uveitis, suggesting a therapeutic potential of propolis for the treatment of inflammatory ophthalmic diseases.

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

    Directory of Open Access Journals (Sweden)

    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.

  5. 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.

  6. Tumornekrosefaktor alpha-haemning som led i behandling af uveitis hos børn

    DEFF Research Database (Denmark)

    Fledelius, Hans Callø; Nielsen, Susan M; Nissen, Kamilla Rothe

    2007-01-01

    To present our experience with anti-TNFalpha treatment of juvenile idiopatic arthritis (JIA) associated uveitis.......To present our experience with anti-TNFalpha treatment of juvenile idiopatic arthritis (JIA) associated uveitis....

  7. HLA-B27-ASSOCIATED UVEITIS: EPIDEMIOLOGY, CLINICAL PICTURE, AND COMPLICATIONS

    Directory of Open Access Journals (Sweden)

    T. V. Dubinina

    2014-01-01

    Full Text Available Anterior uveitis is the most common form of intraocular inflammation. Among them, HLA-B27-associated uveitis occupies one of the leading places, which may be an independent disease or one of the manifestations of spondy- loarthritis (SA. The paper considers the general issues of the nomenclature and classification of uveitis, by using the classification criteria of the International Uveitis Study Group and the Standardization of Uveitis Nomenclature Workshop. The epidemiological aspects of uveitis are described. Emphasis is laid on a difference in the detection rate of uveitis in different countries, in men and women, as well as in different forms of SA. The clinical features of SA- associated uveitis and its complications are discussed. 

  8. Infiltration of Plasma Cells in the Iris of Children With ANA-Positive Anterior Uveitis

    NARCIS (Netherlands)

    Kalinina Ayuso, Viera; van Dijk, Marijke R; de Boer, Joke H

    2015-01-01

    PURPOSE: We investigated inflammatory cell infiltrates in iris biopsies in uveitis associated with juvenile idiopathic arthritis (JIA) in comparison with other pediatric uveitis entities and noninflammatory pediatric controls. METHODS: Iridectomy specimens were obtained during elective

  9. Treatment of noninfectious posterior uveitis with dexamethasone intravitreal implant

    Directory of Open Access Journals (Sweden)

    Jane S Myung

    2010-12-01

    Full Text Available Jane S Myung, Grant D Aaker, Szilárd KissDepartment of Ophthalmology, Weill Cornell Medical Center, New York, NY, USAPurpose: To report our experience with dexamethasone 0.7 mg sustained-release intravitreal implant (Ozurdex®; Allergan, Inc, Irvine, CA in noninfectious posterior uveitis.Methods: A retrospective chart review of patients with noninfectious uveitis treated with sustained-release dexamethasone 0.7 mg intravitreal implant was performed. Complete ophthalmic examination including signs of inflammatory activity, visual acuity, fundus photography, fluorescein angiography, optical coherence tomography, and tolerability of the implant were assessed.Results: Six eyes of 4 consecutive patients treated with a total of 8 dexamethasone 0.7 mg sustained-release intravitreal implants for posterior noninfectious uveitis were included. Two patients presented with unilateral idiopathic posterior uveitis; 2 patients had bilateral posterior uveitis, one secondary to sarcoidosis and the other to Vogt-Koyanagi-Harada syndrome. All eyes showed clinical and angiographic evidence of decreased inflammation following implant placement. Mean follow-up time post-injection was 5.25 months. Four eyes received 1 and 2 eyes received 2 Ozurdex implants during the follow-up period. The duration of effect of the implant was 3 to 4 months. No serious ocular or systemic adverse events were noted during the follow-up period.Conclusions: In patients with noninfectious posterior uveitis, sustained-release dexamethasone 0.7 mg intravitreal implant may be an effective treatment option for controlling intraocular inflammation.Keywords: corticosteroids, dexamethasone implant, Ozurdex, uveitis

  10. Management of uveitis in pediatric patients: special considerations.

    Science.gov (United States)

    Smith, Justine R

    2002-01-01

    Uveitis refers to inflammation involving the uvea or middle coat of the eye. This condition occurs uncommonly, particularly in persons aged uveitis deserves special consideration for reasons that include the relatively poor prognosis, unique systemic associations, and various age-related treatment considerations. Accurate diagnosis requires history from both patient and parents, a complete ophthalmic examination that may require general anesthesia, and carefully selected investigations. Infections and masquerade syndromes, such as leukemia and retinoblastoma, must be excluded before treatment is commenced with immunosuppressive agents. Noninfectious anterior uveitis generally responds to topical corticosteroid and mydriatic therapy. Although used frequently in adults with posterior uveitis, periocular corticosteroid injections may require a general anesthetic, and systemic corticosteroids may cause serious adverse effects, including growth retardation, in pediatric patients. Consequently, in children, one or more corticosteroid-sparing immunosuppressive drugs are usually employed for vision-threatening noninfectious posterior eye inflammation. Methotrexate is the most commonly used systemic immunosuppressive agent for pediatric uveitis. It is effective in small retrospective clinical series, generally well tolerated, easy to administer, and inexpensive. Cyclosporin has also been used successfully in children with uveitis, being associated with a low risk of renal toxicity when used at standard doses. Although prescribed for severe ocular inflammation in adults, alkylating agents are generally contraindicated in children owing to risks including secondary malignancy, sterility and bone marrow suppression. Drugs that inhibit tumor necrosis factor-alpha have recently been used successfully to treat children with uveitis; however, in some patients there may be a risk of potentiating the ocular inflammation. Randomized clinical trials would provide valuable information

  11. American Autoimmune Related Diseases Association

    Science.gov (United States)

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

  12. 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

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

    Science.gov (United States)

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

    2014-09-04

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

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

    Science.gov (United States)

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

    2013-01-01

    Several animal studies and few pilot clinical trials have tested the therapeutic potential of mesenchymal stem cells (MSC) in experimental autoimmune encephalomyelitis (EAE) and in multiple sclerosis (MS). In almost all of the preclinical studies, healthy animals (or humans) served as donors of the MSCs. This setting does not accurately simulate the clinical situation of autologous transplantation in patients with MS. In the current research we used MSC isolated from mice with EAE in order to mimic human autologous transplantation and to test if the inflammatory process affects the functional properties of MSC. MSC(EAE) were found to retain their mesodermal features (as evidenced by the expression of surface cell markers and their ability to differentiate toward cells of the mesodermal lineage). Moreover, MSC(EAE) were able to support neurite outgrowth in the N2A cell line and to suppress the proliferation of lymphocytes induced by the mitogen phytohaemagglutinin