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Sample records for experimental autoimmune uveitis

  1. Rodent Models of Experimental Autoimmune Uveitis

    PubMed Central

    Agarwal, Rajeev K.; Silver, Phyllis B.; Caspi, Rachel R.

    2013-01-01

    The model of experimental autoimmune uveitis (EAU) in mice and in rats is described. EAU targets immunologically privileged retinal antigens and serves as a model of autoimmune uveitis in humans as well as a model for autoimmunity in a more general sense. EAU is a well-characterized, robust, and reproducible model that is easily followed and quantitated. It is inducible with synthetic peptides derived from retinal autoantigens in commonly available strains of rats and mice. The ability to induce EAU in various gene-manipulated, including HLA-transgenic, mouse strains makes the EAU model suitable for the study of basic mechanisms as well as in clinically relevant interventions. PMID:22933083

  2. Low Dose Rapamycin Exacerbates Autoimmune Experimental Uveitis

    PubMed Central

    Zhang, Zili; Wu, Xiumei; Duan, Jie; Hinrichs, David; Wegmann, Keith; Zhang, Gary L.; Hall, Mark; Rosenbaum, James T.

    2012-01-01

    Background Rapamycin, a potent immune modulator, is used to treat transplant rejection and some autoimmune diseases. Uveitis is a potentially severe inflammatory eye disease, and 2 clinical trials of treating uveitis with rapamycin are under way. Unexpectedly, recent research has demonstrated that low dose rapamycin enhances the memory T cell population and function. However, it is unclear how low dose rapamycin influences the immune response in the setting of uveitis. Design and Methods B10.RIII mice were immunized to induce experimental autoimmune uveitis (EAU). Ocular inflammation of control and rapamycin-treated mice was compared based on histological change. ELISPOT and T cell proliferation assays were performed to assess splenocyte response to ocular antigen. In addition, we examined the effect of rapamycin on activation-induced cell death (AICD) using the MitoCapture assay and Annexin V staining. Results Administration of low dose rapamycin exacerbated EAU, whereas treating mice with high dose rapamycin attenuated ocular inflammation. The progression of EAU by low dose rapamycin coincided with the increased frequency of antigen-reactive lymphocytes. Lastly, fewer rapamycin-treated T cells underwent AICD, which might contribute to exaggerated ocular inflammation and the uveitogenic immune response. Conclusion These data reveal a paradoxical role for rapamycin in uveitis in a dose-dependent manner. This study has a potentially important clinical implication as rapamycin might cause unwanted consequences dependent on dosing and pharmacokinetics. Thus, more research is needed to further define the mechanism by which low dose rapamycin augments the immune response. PMID:22574188

  3. Cyclosporin a. Inhibition of experimental autoimmune uveitis in Lewis rats.

    PubMed Central

    Nussenblatt, R B; Rodrigues, M M; Wacker, W B; Cevario, S J; Salinas-Carmona, M C; Gery, I

    1981-01-01

    Cyclosporin A (CS-A), a selective inhibitor of T lymphocytes, is reported here to prevent S antigen (S-Ag) induced uveitis in Lewis rats. The S-Ag, found in all mammalian retinas, is uveitogenic under experimental conditions and patients with certain uveitic entities demonstrate cell mediated responses to this antigen. Daily treatment with CS-A (10 mg/kg) begun on the same day as S-Ag immunization totally inhibited the development of the uveitis in this experimental autoimmune model. Moreover a greater CS-A dose (40 mg/kg) efficiently prevented the disease process when therapy was started 7 d after S-Ag immunization. Anti-S-Ag antibody titers were observed to be similar in rats either protected or not protected with CS-A. Our data support strongly the need for T cell participation in this disease model. Since ocular inflammatory disease is an important cause of visual impairment, the data further suggest that CS-A may be useful in the treatment of patients with intractable uveitis. Images PMID:7204576

  4. IL-33 attenuates the development of experimental autoimmune uveitis

    PubMed Central

    Barbour, Mark; Allan, Debbie; Xu, Heping; Pei, Cheng; Chen, Mei; Niedbala, Wanda; Fukada, Sandra Y; Besnard, Anne-Galle; Alves-Filho, Jose C; Tong, Xiaoguang; Forrester, John V; Liew, Foo Yew; Jiang, Hui-Rong

    2014-01-01

    Interleukin-33 (IL-33) is associated with several important immune-mediated disorders. However, its role in uveitis, an important eye inflammatory disease, is unknown. Here, we investigated the function of IL-33 in the development of experimental autoimmune uveitis (EAU). IL-33 and IL-33 receptor (ST2) were expressed in murine retinal pigment epithelial (RPE) cells in culture, and IL-33 increased the expression of Il33 and Mcp1 mRNA in RPE cells. In situ, IL-33 was highly expressed in the inner nuclear cells of the retina of naïve mice, and its expression was elevated in EAU mice. ST2-deficient mice developed exacerbated EAU compared with WT mice, and administration of IL-33 to WT mice significantly reduced EAU severity. The attenuated EAU in IL-33-treated mice was accompanied by decreased frequency of IFN-γ+ and IL-17+ CD4+ T cells and reduced IFN-γ and IL-17 production but with increased frequency of IL-5+ and IL-4+ CD4 T cells and IL-5 production in the draining lymph node and spleen. Macrophages from the IL-33-treated mice show a significantly higher polarization toward an alternatively activated macrophage phenotype. Our results therefore demonstrate that the endogenous IL-33/ST2 pathway plays an important role in EAU, and suggest that IL-33 represents a potential option for treatment of uveitis. PMID:25116404

  5. Pathogenesis of innate immunity and adaptive immunity in the mouse model of experimental autoimmune uveitis.

    PubMed

    Bi, Hong-Sheng; Liu, Zheng-Feng; Cui, Yan

    2015-05-01

    Experimental autoimmune uveitis, a well-established model for human uveitis, is similar to human uveitis in many pathological features. Studies concerning the mechanisms of experimental autoimmune uveitis would cast a light on the pathogenesis of human uveitis as well as the search for more effective therapeutic agents. The cellular components of innate immunity include natural killer cells, gamma delta T lymphocytes, antigen-presenting dendritic cells, phagocytic macrophages, and granulocytes. It is believed that T cells are central in the generation of human uveitis. It has already become clear that CD4(+) effecter cells that predominantly produce interleukin-17 (the so-called Th17 cells) may play an important role in uveitis. In addition, the occurrence and recurrence of uveitis depends on a complex interplay between the elements of innate and adaptive immunity.

  6. [Effects of leflunomide on experimental autoimmune uveitis in Lewis rats].

    PubMed

    Fang, Chengbo; Zhou, Dexi; Zhan, Shuxiang; He, Yong; Lin, Zhen; Huang, Cheng; Li, Jun

    2015-10-01

    To investigate the protective efficacy of leflunomide on the Lewis rats with experimental autoimmune uveitis (EAU). Complete randomized controlled trials research. Lewis rats were immunized with interphotoreceptor retinoid-binding peptide (IRBP) in order to build the model of EAU. Rats were randomized assigned into four groups, that is control group as A, model group without leflunomide as B, model group with leflunomide administrations as C, and model group with cyclosporine A as D. Rats in group C received intragastric administration of three doses of leflunomide at 3mg/kg/d; 6mg/kg/d; 12mg/kg/d. Rats in group D received 10 mg/kg cyclosporin A were considered as a positive control. Each group has 6 to 8 rats. At the second day of immunization with IRBP, rats were intragastric administrated one time every day till day 13. Rats were investigated for EAU symptoms under slit lamp. Enucleated eyes were collected for sections with HE staining as histopathological evidences at the peak point of disease activity day 14. Treatment effectiveness was evaluated referred by Agarwal standard for clinical EAU and histopathological scoring. The expression of IL-17 in ocular sections was detected by immunohistochemistry (SP method). The expression levels of IL-17 and IFN-γ in the serum were quantified by ELISA. Intracellular expression of IL-17 in the activated CD4+T cells was assessed by flow cytometry. Ocular of rats were harvested and mRNA expression of IL-17 and IFN-γ were quantified through RT-PCR. Continuous variables were reported as mean ± SD. The comparison among groups was done by using analysis of students't test. Nonparametric test was used in Hierarchical data comparison and multiple comparison method was Bonferroni. The model of EAU disease was built successfully in Lewis rats. With giving IRBP for 14 days, the clinic EAU scores were lower in model rats than those without leflunomide. Moreover, the effects of leflunomide on the clinic EAU scores was dose

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

    PubMed

    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.

  8. The Complement Anaphylatoxin Receptors Are Not Required for the Development of Experimental Autoimmune Uveitis

    PubMed Central

    Read, Russell W.; Vogt, Susan D.; Barnum, Scott R.

    2013-01-01

    To determine if complement anaphylatoxin-mediated inflammation contributes to the development and progression of experimental autoimmune uveitis (EAU), we induced disease in wild type and complement anaphylatoxin receptor-deficient mice (C3a receptor−/−, C5a receptor−/− and C3aR−/−/C5aR−/−) and evaluated eyes three weeks post-induction. No differences in disease severity or in disease incidence were seen between wild type controls and anaphylatoxin receptor-deficient mice. Our data indicate that C3a and C5a-mediated functions are not critical to the development of EAU. PMID:24035596

  9. The complement anaphylatoxin receptors are not required for the development of experimental autoimmune uveitis.

    PubMed

    Read, Russell W; Vogt, Susan D; Barnum, Scott R

    2013-11-15

    To determine if complement anaphylatoxin-mediated inflammation contributes to the development and progression of experimental autoimmune uveitis (EAU), we induced disease in wild type and complement anaphylatoxin receptor-deficient mice (C3a receptor(-/-), C5a receptor(-/-) and C3aR(-/-)/C5aR(-/-)) and evaluated the eyes three weeks post-induction. No differences in disease severity or in disease incidence were seen between wild type controls and anaphylatoxin receptor-deficient mice. Our data indicate that C3a and C5a-mediated functions are not critical to the development of EAU.

  10. Inhibition of experimental auto-immune uveitis by the A3 adenosine receptor agonist CF101.

    PubMed

    Bar-Yehuda, Sara; Luger, Dror; Ochaion, Avivit; Cohen, Shira; Patokaa, Renana; Zozulya, Galina; Silver, Phyllis B; de Morales, Jose Maria Garcia Ruiz; Caspi, Rachel R; Fishman, Pnina

    2011-11-01

    Uveitis is an inflammation of the middle layer of the eye with a high risk of blindness. The Gi protein associated A3 adenosine receptor (A3AR) is highly expressed in inflammatory cells whereas low expression is found in normal cells. CF101 is a highly specific agonist at the A3AR known to induce a robust anti-inflammatory effect in different experimental animal models. The CF101 mechanism of action entails down-regulation of the NF-κB-TNF-α signaling pathway, resulting in inhibition of pro-inflammatory cytokine production and apoptosis of inflammatory cells. In this study the effect of CF101 on the development of retinal antigen interphotoreceptor retinoid-binding protein (IRBP)-induced experimental autoimmune uveitis (EAU) was assessed. Oral treatment with CF101 (10 µg/kg, twice daily), initiated upon disease onset, improved uveitis clinical score measured by fundoscopy and ameliorated the pathological manifestations of the disease. Shortly after treatment with CF101 A3AR expression levels were down-regulated in the lymph node and spleen cells pointing towards receptor activation. Downstream events included a decrease in PI3K and STAT-1 and proliferation inhibition of IRPB auto-reactive T cells ex vivo. Inhibition of interleukin-2, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) production and up-regulation of interleukin-10 was found in cultured splenocytes derived from CF101-treated animals. Overall, the present study data point towards a marked anti-inflammatory effect of CF101 in EAU and support further exploration of this small molecule drug for the treatment of uveitis.

  11. Notch signalling suppresses regulatory T-cell function in murine experimental autoimmune uveitis.

    PubMed

    Rong, Hua; Shen, Hongjie; Xu, Yueli; Yang, Hai

    2016-12-01

    Autoimmune uveitis is an intraocular inflammatory disorder in developed countries. Understanding the mechanisms underlying the development and modulation of immune reaction in uveitic eyes is critical for designing therapeutic interventions. Here we investigated the role of Notch signalling in regulatory T-cell (Treg cell) function during experimental autoimmune uveitis (EAU). Using the Foxp3-GFP reporter mouse strain, the significance of Notch signalling for the function of infiltrating Treg cells was characterized in an EAU model. We found that infiltrating Treg cells substantially expressed Notch-1, Notch-2, JAG1 and DLL1 in uveitic eyes. Activation of Notch signalling, represented by expression of HES1 and HES5, was enhanced in infiltrating Treg cells. Treatment with JAG1 and DLL1 down-regulated Foxp3 expression and immunosuppressive activity of isolated infiltrating Treg cells in vitro, whereas neutralizing antibodies against JAG1 and DLL1 diminished Notch ligand-mediated negative effects on Treg cells. To investigate the significance of Notch signalling for Treg cell function in vivo, lentivirus-derived Notch short hairpin RNAs were transduced into in vitro expanded Treg cells before adoptive transfer of Treg cells into EAU mice. Transfer of Notch-1-deficient Treg cells remarkably reduced pro-inflammatory cytokine production and inflammatory cell infiltration in uveitic eyes. Taken together, Notch signalling negatively modulates the immunosuppressive function of infiltrating Treg cells in mouse EAU.

  12. Immunosuppressive activity of a novel peptide analog of α-melanocyte stimulating hormone (α-MSH) in experimental autoimmune uveitis.

    PubMed

    Edling, Andrea E; Gomes, Danilo; Weeden, Timothy; Dzuris, John; Stefano, Jim; Pan, Clark; Williams, John; Kaplan, Johanne; Perricone, Michael A

    2011-07-01

    Autoimmune uveitis is an inflammatory disorder of the eye that can lead to pain and vision loss. Steroids and immunosuppressive drugs are currently the only therapeutics for uveitis and have serious ocular and systemic toxicities. Therefore, safer alternative therapeutics are desired. Alpha-melanocyte stimulating hormone (α-MSH) is a neuropeptide that suppresses effector T cell functions, induces regulatory T cells and has beneficial effects in certain autoimmune and transplant models. A novel d-amino acid peptide analog of native α-MSH (dRI-α-MSH) was produced that was protected from protease digestion and had increased selectivity for the melanocortin-1 receptor. Systemic delivery of the dRI-α-MSH analog dramatically suppressed disease progression and retained retinal architecture in the experimental autoimmune uveitis (EAU) model. Local delivery by periorbital injection was equally effective. Importantly, treatment with the novel dRI-α-MSH analog suppressed uveitis with a similar magnitude to the corticosteroid, dexamethasone. Data indicate that the novel dRI-α-MSH analogs show anti-inflammatory activities and have potential therapeutic use in uveitis and other autoimmune diseases.

  13. The Role of Interleukin-22 and Its Receptor in the Development and Pathogenesis of Experimental Autoimmune Uveitis

    PubMed Central

    Park, Yun Seong; Jeong, Eui Man; Lee, Dong-Sup; Kim, In-Gyu; Chung, Hum; Hwang, Young-il; Lee, Wang Jae; Yu, Hyeong Gon; Kang, Jae Seung

    2016-01-01

    IL-22 is a pro- and anti-inflammatory cytokine that is mainly produced by T cells and NK cells. Recent studies have reported the increased number of IL-22 producing T cells in patients with autoimmune noninfectious uveitis; however, the correlation between IL-22 and uveitis remains unclear. In this study, we aimed to determine the specific role of IL-22 and its receptor in the pathogenesis of uveitis. Serum concentration of IL-22 was significantly increased in uveitis patients. IL-22Rα was expressed in the retinal pigment epithelial cell line, ARPE-19. To examine the effect of IL-22, ARPE-19 was treated with recombinant IL-22. The proliferation of ARPE-19 and the production of monocyte chemoattractant protein (MCP)-1 from ARPE-19 were clearly elevated. IL-22 induced MCP-1 which facilitated the migration of inflammatory cells. Moreover, IL-22 increased the IL-22Rα expression in ARPE-19 through the activation of PI3K/Akt. Experimental animal models of uveitis induced by interphotoreceptor retinoid binding protein 1–20 (IRBP1-20) exhibited elevation of hyperplasia RPE and IL-22 production. When CD4+ T cells from the uveitis patients were stimulated with IRBP1-20, the production of IL-22 definitely increased. In addition, we examine the regulatory role of cysteamine, which has an anti-inflammatory role in the cornea, in uveitis through the down-regulation of IL-22Rα expression. Cysteamine effectively suppressed the IRBP1-20-induced IL-22Rα expression and prevented the development of IRBP1-20-induced uveitis in the experimental animal model. These finding suggest that IL-22 and its receptor have a crucial role in the development and pathogenesis of uveitis by facilitating inflammatory cell infiltration, and that cysteamine may be a useful therapeutic drug in treating uveitis by down-regulating IL-22Rα expression in RPE. PMID:27166675

  14. Immunotherapeutic strategies in autoimmune uveitis

    PubMed Central

    Papotto, Pedro Henrique; Marengo, Eliana Blini; Sardinha, Luiz Roberto; Goldberg, Anna Carla; Rizzo, Luiz Vicente

    2014-01-01

    Autoimmune uveitis is an organ-specific disorder characterized by irreversible lesions to the eye that predominantly affect people in their most productive years and is among the leading causes of visual deficit and blindness. Currently available therapies are effective in the treatment of a wide spectrum of uveitis, but are often associated with severe side effects. Here, we review ongoing research with promising immunomodulatory therapeutic strategies, describing their specific features, interactions and the responses triggered by the targeted immune molecules that aim to minimize clinical complications and the likelihood of disease relapse. We first review the main features of the disease, diagnostic tools, and traditional forms of therapy, as well as the animal models predominantly used to understand the pathogenesis and test the novel intervention approaches aiming to control the acute immune and inflammatory responses and to dampen chronic responses. Both exploratory research and clinical trials have targeted either the blockade of effector pathways or of their companion co-stimulatory molecules. Examples of targets are T cell receptors (CD3), their co-stimulatory receptors (CD28, CTLA-4) and corresponding ligands (B7-1 and B7-2, also known as CD80 and CD86), and cytokines like IL-2 and their receptors. Here, we summarize the available evidence on effectiveness of these treatments in human and experimental uveitis and highlight a novel CD28 antagonist monovalent Fab′ antibody, FR104, which has shown preclinical efficacy suppressing effector T cells while enhancing regulatory T cell function and immune tolerance in a humanized graft-versus-host disease (GVHD) mice model and is currently being tested in a mouse autoimmune uveitis model with encouraging results. PMID:24833504

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

    PubMed Central

    Zhao, Ronglan; Liang, Dongchun; Sun, Deming

    2016-01-01

    Various pathological conditions are accompanied by ATP release from the intracellular to the extracellular compartment. Extracellular ATP (eATP) functions as a signaling molecule by activating purinergic P2 purine receptors. The key P2 receptor involved in inflammation was identified as P2X7R. Recent studies have shown that P2X7R signaling is required to trigger the Th1/Th17 immune response, and oxidized ATP (oxATP) effectively blocks P2X7R activation. In this study we investigated the effect of oxATP on mouse experimental autoimmune uveitis (EAU). Our results demonstrated that induced EAU in B6 mice was almost completely abolished by the administration of small doses of oxATP, and the Th17 response, but not the Th1 response, was significantly weakened in the treated mice. Mechanistic studies showed that the therapeutic effects involve the functional change of a number of immune cells, including dendritic cells (DCs), T cells, and regulatory T cells. OxATP not only directly inhibits the T cell response; it also suppresses T cell activation by altering the function of DCs and Foxp3+ T cell. Our results demonstrated that inhibition of P2X7R activation effectively exempts excessive autoimmune inflammation, which may indicate a possible therapeutic use in the treatment of autoimmune diseases. PMID:27196432

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

    PubMed

    Zhao, Ronglan; Liang, Dongchun; Sun, Deming

    2016-01-01

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

  17. Fluctuation of lysosomal phospholipase A2 in experimental autoimmune uveitis in rats.

    PubMed

    Ohkawa, Ei; Hiraoka, Miki; Abe, Akira; Murata, Masaki; Ohguro, Hiroshi

    2016-08-01

    Intraocular inflammation leads to oxidative stress and may generate lipid oxidation products. The present study was conducted to elucidate the pathophysiological roles of the lysosomal phospholipase A2 (LPLA2), a phospholipid-degrading enzyme, and the production of oxidized phospholipids (oxPLs) in autoimmune uveitis using a rat model. Lewis rats were immunized with a bovine interphotoreceptor retinoid-binding protein (bIRBP) peptide with complete Freund's adjuvant (CFA) to induce experimental autoimmune uveitis (EAU). The aqueous humor (AH) and serum were collected every week for 4 weeks from the immunized rats. The LPLA2 activity of the AH and serum was detected using liposomes consisting of 1,2-dioleoylphosphatidylglycerol/N-acetylsphingosine as the substrate under acidic conditions. Immunohistochemical analysis was performed using antibodies against LPLA2 and oxPLs. The ocular inflammation was exacerbated at 2 weeks after immunization. The LPLA2 activity in the rat AH was increased by EAU induction, and was concomitant with the extent of inflammation in the anterior chamber (AC). In contrast, the LPLA2 activity in the rat serum was not influenced by EAU induction. At 2 weeks after immunization, immunoreactivity of LPLA2 was observed in infiltrated macrophages in the AC and vitreous cavity of the EAU rats. Furthermore, immunoreactivity of oxPLs was observed in the infiltrated macrophages of EAU rat eyes. These results demonstrated that the LPLA2 activity of the AH is augmented with the inflammation in the AC. The high expression of LPLA2 and production of oxPLs are found in the infiltrated macrophages in the acute inflammation of EAU rats. The present findings suggest the connection between LPLA2 activity and oxPL metabolism in the inflammation sites in the eye. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Complement anaphylatoxin receptors C3aR and C5aR are required in the pathogenesis of experimental autoimmune uveitis.

    PubMed

    Zhang, Lingjun; Bell, Brent A; Yu, Minzhong; Chan, Chi-Chao; Peachey, Neal S; Fung, John; Zhang, Xiaoming; Caspi, Rachel R; Lin, Feng

    2016-03-01

    Recent studies have suggested that reagents inhibiting complement activation could be effective in treating T cell mediated autoimmune diseases such as autoimmune uveitis. However, the precise role of the complement anaphylatoxin receptors (C3a and C5a receptors) in the pathogenesis of autoimmune uveitis remains elusive and controversial. We induced experimental autoimmune uveitis in mice deficient or sufficient in both C3a and C5a receptors and rigorously compared their retinal phenotype using various imaging techniques, including indirect ophthalmoscopy, confocal scanning laser ophthalmoscopy, spectral domain optical coherence tomography, topical endoscopic fundus imaging, and histopathological analysis. We also assessed retinal function using electroretinography. Moreover, we performed Ag-specific T cell recall assays and T cell adoptive transfer experiments to compare pathogenic T cell activity between wild-type and knockout mice with experimental autoimmune uveitis. These experiments showed that C3a receptor/C5a receptor-deficient mice developed much less severe uveitis than did control mice using all retinal examination methods and that these mice had reduced pathogenic T cell responses. Our data demonstrate that both complement anaphylatoxin receptors are important for the development of experimental autoimmune uveitis, suggesting that targeting these receptors could be a valid approach for treating patients with autoimmune uveitis.

  19. Upregulated IL-21 and IL-21 receptor expression is involved in experimental autoimmune uveitis (EAU).

    PubMed

    Liu, Lan; Xu, Yongfeng; Wang, Jianyong; Li, Huiyan

    2009-12-31

    Interleukin (IL)-21 has recently been shown to play a vital role in the development of many autoimmune diseases. Our study is designed to investigate the alteration and possible function of IL-21 in the development of an experimental autoimmune uveitis (EAU) model. EAU was induced in B10.RIII mice by subcutaneous injection of interphotoreceptor retinoid-binding protein (IRBP) 161-180 emulsified with complete Freund's adjuvant (CFA) and evaluated by clinical and histopathologic observation. IL-21 and IL-21R mRNA expressions in cells of draining lymph node (DLN) and spleen in EAU and control mice were determined by reverse transcription-PCR. The frequencies of interleukin-21 receptor positive cells were also examined using flow cytometry. IL-17 levels in the supernatant of the cell culture upon IL-21 stimulation were assayed by enzyme-linked immunosorbent assay. Results showed that EAU was successfully induced by IRBP161-180. Expression of IL-21 mRNA was significantly increased in cells of DLN and spleen in EAU compared with recovery phase mice and normal controls. IL-21R was also found upregulated in DLN and spleen cells of EAU mice by reverse transcription-PCR and flow cytometry. Cells in EAU cultured with IL-21 combined with transforming growth factor-beta induced increased production of IL-17. The findings revealed that increased IL-21 and IL-21R expression may be involved in the development of EAU, possibly by promoting IL-17 secretion.

  20. Experimental autoimmune anterior uveitis (EAAU): induction by melanin antigen and suppression by various treatments.

    PubMed

    Broekhuyse, R M; Kuhlmann, E D; Winkens, H J

    1993-02-01

    The uveitogenicity of melanin has been a controversial subject for a long time, presumably as a result of the use of ill-defined preparations in the experiments. We have developed procedures for the preparation of purified uveitogenic melanins from the retinal pigment epithelium and choroid that are free from pathogenic retinal photoreceptor proteins. The active melano-antigen is located at the surface of the melanin granules and is probably identical in both tissues. It retains its pathogenicity in hot polar detergent and during in vitro proteolysis, but it is inactivated by macrophage phagocytosis and hydrolysis in hot hydrochloric acid. Lewis rats immunized with microgram doses of bovine retinal pigment epithelial or choroidal melanin develop severe experimental autoimmune anterior uveitis (EAAU) about 10 days later. Retinitis and pinealitis are not observed. Skin melanin prepared in a similar way evokes EAAU as well, but it is only weakly pathogenic. EAAU cannot be transferred by serum, and its development can effectively be inhibited by antibodies to the inciting antigen and by cyclosporin. Vitamin E treatment of the animals causes a delay in its onset. The results indicate that cell-mediated immunity plays a dominant role in the pathogenesis of EAAU. This is the first time it has been shown that purified ocular and skin melanins are able to induce an autoimmune disease. The relevance of this finding for the study of melanin-related immunopathology in man is discussed.

  1. Spontaneously relapsing-remitting experimental autoimmune uveitis in rats allows successful therapeutic oral tolerance induction in ongoing disease.

    PubMed

    Huber, Andrea; Diedrichs-Möhring, Maria; Wildner, Gerhild

    2015-02-01

    Antigen-specific tolerance induction is a desired therapy for uveitis patients. Our relapsing-remitting rat model of experimental autoimmune uveitis (EAU) induced with IRBP peptide R14 enables us to test the effect of oral tolerance on the prevention of relapsing uveitis. We investigated several peptides overlapping the sequence of R14 for prevention and different doses of R14 for therapy to determine the tolerogenic epitope and the most effective therapeutic regimen for uveitis. Lewis rats were immunized with R14-CFA to induce EAU. Oral tolerance was induced prior to immunization (prevention) or after onset of EAU to prevent relapses (therapy). Therapeutic feeding was performed with high and/or low doses of oral antigen for clonal deletion of effector and induction of regulatory T cells. Uveitis was determined clinically and histologically; mesenteric lymph node (mLN) cells of tolerized rats were tested for surface markers, cytokines and Foxp3 expression. Preventive feeding of R14 and its major epitope R16, but none of the overlapping peptides significantly suppressed EAU and also prevented relapses, irrespective of their pathogenicity. Therapeutic feeding with R14 dramatically reduced relapses, while only the consecutive feeding of high and low-dose R14 had an ameliorating effect on the first course of disease. IL-10-producing T cells from mLN decreased after oral tolerization, and with R14-stimulation in vitro the TCRαβ+/Foxp3+ population increased in the low-dose fed group. No mLN population could be clearly assigned to successful oral tolerance induction during active autoimmune uveitis.

  2. Activation of Liver X Receptor Alleviates Ocular Inflammation in Experimental Autoimmune Uveitis

    PubMed Central

    Yang, Hongxia; Zheng, Shijie; Qiu, Yiguo; Yang, Yan; Wang, Chaokui; Yang, Peizeng; Li, Qiuhong; Lei, Bo

    2014-01-01

    Purpose. To investigate whether a synthetic LXR agonist TO901317 (TO90) ameliorates ocular inflammation in a mouse model of experimental autoimmune uveitis (EAU) and to explore its underlying mechanism. Methods. EAU was induced with subcutaneous injection of IRBP161–180 peptide (SGIPYIISYLHPGNTILHVD) in B10.RIII mice. TO90 (50 mg/kg/d) or vehicle was administrated orally for successive 16 days or 8 days as prevention or effector phase, respectively. The severity of EAU was evaluated with clinical and histological scores. The levels of LXRs, NF-κB subunit p65, and an LXR target gene ABCA1 in the retina were detected with real-time PCR and Western blotting. The expressions of proinflammatory genes, including TNF-α, IL-1β, IL-6, MCP-1, IFN-γ, and IL-17, were detected by real-time PCR. IRBP-specific lymphocyte proliferation was detected by MTT. Intracellular IFN-γ and IL-17 in CD4+ T cells were measured by flow cytometry. Results. We found both LXRα and LXRβ were expressed in mouse retina. After administering TO90 orally to B10.RIII mice, the expression of LXRα but not LXRβ was upregulated in the naïve mice. Compared with naïve mice, LXRα expression was increased in vehicle and TO90-treated EAU mice, but the LXRβ expression was unchanged. The protein level of ABCA1 was enhanced in TO90-treated naïve and EAU mice but was unchanged in vehicle-treated EAU mice, suggesting activation of LXRα by TO90 is ligand dependent. TO90-mediated activation of LXRα improved the clinical and morphological scores in EAU mice. Meanwhile, activation of LXRα decreased the expressions of proinflammatory cytokines, including TNF-α, IL-1β, IL-6, MCP-1, IFN-γ, and IL-17 in the retina. TO90 treatment inhibited IRBP-specific immune responses. The proportions of Th1 and Th17 expressing IFN-γ and IL-17 were reduced in TO90-treated EAU mice in both prevention and effector phases. Furthermore, TO90 significantly downregulated the expressions of an NF-κB subunit p65 at the

  3. Regulation of adenosine deaminase (ADA) on induced mouse experimental autoimmune uveitis (EAU) ‡

    PubMed Central

    Liang, Dongchun; Zuo, Aijun; Zhao, Ronglan; Shao, Hui; Kaplan, Henry J.; Sun, Deming

    2016-01-01

    Adenosine is an important regulator of the immune response and adenosine deaminase (ADA) inhibits this regulatory effect by converting adenosine into functionally inactive molecules. Studies have shown that adenosine receptor (AR) agonists can be either anti- or pro-inflammatory. Clarification of the mechanisms that cause these opposing effects should provide a better guide for therapeutic intervention. In this study, we investigated the effect of ADA on the development of experimental autoimmune uveitis (EAU) induced by immunizing EAU-prone mice with a known uveitogenic peptide, IRBP1–20. Our results showed that the effective time to administer a single dose of ADA to suppress induction of EAU was 8–14 days post-immunization, shortly before EAU expression, but ADA treatment at other time points exacerbated disease. ADA preferentially inhibited Th17 responses and this effect was γδ T cell-dependent. Our results demonstrated that the existing immune status strongly influences the anti- or proinflammatory effects of ADA. Our observations should help improve the design of ADA- and AR-targeted therapies. PMID:26856700

  4. Bromocriptine and low dose cyclosporine in the treatment of experimental autoimmune uveitis in the rat.

    PubMed Central

    Palestine, A G; Muellenberg-Coulombre, C G; Kim, M K; Gelato, M C; Nussenblatt, R B

    1987-01-01

    The immunologic effects of bromocriptine and low dose cyclosporine on experimental autoimmune uveitis (EAU) induced in Lewis rats by S-antigen immunization were studied. Rats treated with a sub-optimal dose (low dose) of cyclosporine (2 mg/kg per d), bromocriptine (1.8 mg/kg per d), or both drugs were compared with untreated rats in regard to the development of EAU, lymphocyte proliferative responses, and anti-S-antigen serum antibodies. Bromocriptine alone decreased the incidence of EAU only in female rats (P less than 0.01), did not effect the lymphocyte proliferative response, but did significantly decrease antibody titers in both males (P less than 0.004) and females (P less than 0.0005). Low dose cyclosporine also partially decreased the incidence of EAU in female rats, but did not decrease antibody titers or lymphocyte proliferative responses. Bromocriptine plus low-dose cyclosporine led to more marked decreases in the incidence of EAU and anti-S-antigen antibody titers as well as in the lymphocyte proliferative assay (P less than 0.01 for males, P less than 0.0005 for females). This study suggests that bromocriptine can enhance the immunosuppression of low dose cyclosporine. PMID:3494043

  5. P2Y2R Deficiency Attenuates Experimental Autoimmune Uveitis Development

    PubMed Central

    Relvas, Lia Judice M.; Makhoul, Maya; Dewispelaere, Remi; Caspers, Laure; Communi, Didier; Boeynaems, Jean-Marie; Robaye, Bernard; Bruyns, Catherine; Willermain, François

    2015-01-01

    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. PMID:25692550

  6. P2Y2R deficiency attenuates experimental autoimmune uveitis development.

    PubMed

    Relvas, Lia Judice M; Makhoul, Maya; Dewispelaere, Remi; Caspers, Laure; Communi, Didier; Boeynaems, Jean-Marie; Robaye, Bernard; Bruyns, Catherine; Willermain, François

    2015-01-01

    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.

  7. Imbalance Between Th17 Cells and Regulatory T Cells During Monophasic Experimental Autoimmune Uveitis.

    PubMed

    Zhang, Lian; Wan, Fangzhu; Song, Jike; Tang, Kai; Zheng, Fengming; Guo, Junguo; Guo, Dadong; Bi, Hongsheng

    2016-02-01

    The aim of this study is to explore the dynamic changes in IL-17-expressing T cells (Th17)/Treg expression in monophasic experimental autoimmune uveitis (mEAU). mEAU was induced in Lewis rats with IRBP1177-1191 peptide and evaluated clinically and pathologically on days 9, 13, 18, 23, 28, 35, and 48. Lymphocytes isolated from inguinal lymph nodes were subjected to flow cytometry to analyze the frequency of Th17/Treg cells. The levels of cytokines (IL-17, IL-6, IL-10, transforming growth factor (TGF)-β) in serum were detected by enzyme-linked immunosorbent assay (ELISA). Real-time quantitative PCR (RT-PCR) was used for measuring the levels of IL-17, IL-6, TGF-β, and Foxp3. Clinical and histopathologic assessment showed that mEAU began on day 9, peaked on day 13, and decreased to normal on day 18. The frequency of Th17 cells increased obviously on day 9, peaking on day 13, while the frequency of Treg cells increased on day 13, peaked on day 18, and remained at a high level until day 48. In the serum, the levels of IL-17 and IL-6 peaked on day 9 and gradually decreased to normal on day 28. The level of TGF-β increased on day 9, peaked on day 13, and decreased to normal on day 35. Meanwhile, the level of IL-10 increased on day 9 and stayed at a high level until day 48. Additionally, the above results were further confirmed by RT-PCR. The imbalance between Th17 and Treg cells contributes to the onset and progression of mEAU, and a compartmental imbalance of Treg over Th17 exists in the recovery phase of mEAU.

  8. Digoxin Inhibits Induction of Experimental Autoimmune Uveitis in Mice, but Causes Severe Retinal Degeneration

    PubMed Central

    Hinshaw, Samuel J. H.; Ogbeifun, Osato; Wandu, Wambui S.; Lyu, Cancan; Shi, Guangpu; Li, Yichao; Qian, Haohua; Gery, Igal

    2016-01-01

    Purpose Digoxin, a major medication for heart disease, was recently reported to have immunosuppressive capacity. Here, we determined the immunosuppressive capacity of digoxin on the development of experimental autoimmune uveitis (EAU) and on related immune responses. Methods The B10.A mice were immunized with interphotoreceptor retinoid-binding protein (IRBP) and were treated daily with digoxin or vehicle control. On postimmunization day 14, the mouse eyes were examined histologically, while spleen cells were tested for cytokine production in response to IRBP and purified protein derivative. The immunosuppressive activity of digoxin was also tested in vitro, by its capacity to inhibit development of Th1 or Th17 cells. To investigate the degenerative effect of digoxin on the retina, naïve (FVB/N × B10.BR)F1 mice were similarly treated with digoxin and tested histologically and by ERG. Results Treatment with digoxin inhibited the development of EAU, as well as the cellular response to IRBP. Unexpectedly, treatment with digoxin suppressed the production of interferon-γ to a larger extent than the production of interleukin 17. Importantly, digoxin treatment induced severe retinal degeneration, determined by histologic analysis with thinning across all layers of the retina. Digoxin treatment also induced dose-dependent vision loss monitored by ERG on naïve mice without induction of EAU. Conclusions Treatment of mice with digoxin inhibited the development of EAU and cellular immune response to IRBP. However, the treatment induced severe damage to the retina. Thus, the use of digoxin in humans should be avoided due to its toxicity to the retina. PMID:27028065

  9. Digoxin Inhibits Induction of Experimental Autoimmune Uveitis in Mice, but Causes Severe Retinal Degeneration.

    PubMed

    Hinshaw, Samuel J H; Ogbeifun, Osato; Wandu, Wambui S; Lyu, Cancan; Shi, Guangpu; Li, Yichao; Qian, Haohua; Gery, Igal

    2016-03-01

    Digoxin, a major medication for heart disease, was recently reported to have immunosuppressive capacity. Here, we determined the immunosuppressive capacity of digoxin on the development of experimental autoimmune uveitis (EAU) and on related immune responses. The B10.A mice were immunized with interphotoreceptor retinoid-binding protein (IRBP) and were treated daily with digoxin or vehicle control. On postimmunization day 14, the mouse eyes were examined histologically, while spleen cells were tested for cytokine production in response to IRBP and purified protein derivative. The immunosuppressive activity of digoxin was also tested in vitro, by its capacity to inhibit development of Th1 or Th17 cells. To investigate the degenerative effect of digoxin on the retina, naïve (FVB/N × B10.BR)F1 mice were similarly treated with digoxin and tested histologically and by ERG. Treatment with digoxin inhibited the development of EAU, as well as the cellular response to IRBP. Unexpectedly, treatment with digoxin suppressed the production of interferon-γ to a larger extent than the production of interleukin 17. Importantly, digoxin treatment induced severe retinal degeneration, determined by histologic analysis with thinning across all layers of the retina. Digoxin treatment also induced dose-dependent vision loss monitored by ERG on naïve mice without induction of EAU. Treatment of mice with digoxin inhibited the development of EAU and cellular immune response to IRBP. However, the treatment induced severe damage to the retina. Thus, the use of digoxin in humans should be avoided due to its toxicity to the retina.

  10. Complement Component C4 Regulates the Development of Experimental Autoimmune Uveitis through a T Cell-Intrinsic Mechanism

    PubMed Central

    Zhang, Lingjun; Bell, Brent A.; Li, Yan; Caspi, Rachel R.; Lin, Feng

    2017-01-01

    In addition to its conventional roles in the innate immune system, complement has been found to directly regulate T cells in the adaptive immune system. Complement components, including C3, C5, and factor D, are important in regulating T cell responses. However, whether complement component C4 is involved in regulating T cell responses remains unclear. In this study, we used a T cell-dependent model of autoimmunity, experimental autoimmune uveitis (EAU) to address this issue. We compared disease severity in wild-type (WT) and C4 knockout (KO) mice using indirect ophthalmoscopy, scanning laser ophthalmoscopy, spectral-domain optical coherence tomography, and histopathological analysis. We also explored the underlying mechanism by examining T cell responses in ex vivo antigen-specific recall assays and in in vitro T cell priming assays using bone marrow-derived dendritic cells, splenic dendritic cells, and T cells from WT or C4 KO mice. We found that C4 KO mice develop less severe retinal inflammation than WT mice in EAU and show reduced autoreactive T cell responses and decreased retinal T cell infiltration. We also found that T cells, but not dendritic cells, from C4 KO mice have impaired function. These results demonstrate a previously unknown role of C4 in regulating T cell responses, which affects the development of T cell-mediated autoimmunity, as exemplified by EAU. Our data could shed light on the pathogenesis of autoimmune uveitis in humans. PMID:28955337

  11. Characterization of microRNA expression profiling in peripheral blood lymphocytes in rats with experimental autoimmune uveitis.

    PubMed

    Guo, Dadong; Li, Jiao; Liu, Zhengfeng; Tang, Kai; Song, Huixin; Bi, Hongsheng

    2015-09-01

    We aimed to investigate the alterations of microRNA (miRNA) genomics in peripheral blood lymphocytes in experimental autoimmune uveitis (EAU) rats versus control samples. Six Lewis rats received interphotoreceptor retinoid-binding protein (IRBP) emulsion to induce EAU. On day 12, peripheral blood lymphocytes were isolated, and total RNAs were extracted. Using microarray analysis, we analyzed the aberrant miRNAs, validated the relevant expression of differentially expressed miRNAs, and predicted the possible miRNA targets and signaling pathways. The results indicated that 36 miRNAs were upregulated and 31 miRNAs were downregulated in EAU rats versus normal samples. Real-time quantitative PCR substantiated a high degree of confidence for the differentially expressed miRNAs, and miRNA analyses showed the differentially expressed miRNA targets were involved not only in the multicellular organismal process and developmental process, but also in T cell receptor signaling pathway, B cell receptor signaling pathway and so on. Our findings show that the differentially expressed miRNAs in EAU rats were closely associated with immune signaling pathways and may be applied in early prevention, prognosis and possible therapy in uveitis, indicating that miRNAs play an important role in the development of uveitis.

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

    PubMed Central

    Hsu, Sheng-Min; Yang, Chang-Hao; Shen, Fang-Hsiu; Chen, Shun-Hua; Lin, Chia-Jhen; Shieh, Chi-Chang

    2015-01-01

    Bortezomib is a proteasome inhibitor used for hematologic cancer treatment. Since it can suppress NF-κB activation, which is critical for the inflammatory process, bortezomib has been found to possess anti-inflammatory activity. In this study, we evaluated the effect of bortezomib on experimental autoimmune uveitis (EAU) in mice and investigated the potential mechanisms related to NF-κB inactivation. High-dose bortezomib (0.75 mg/kg), low-dose bortezomib (0.15 mg/kg), or phosphate buffered saline was given after EAU induction. We found that the EAU is ameliorated by high-dose bortezomib treatment when compared with low-dose bortezomib or PBS treatment. The DNA-binding activity of NF-κB was suppressed and expression of several key inflammatory mediators including TNF-α, IL-1α, IL-1β, IL-12, IL-17, and MCP-1 was lowered in the high-dose bortezomib-treated group. These results suggest that proteasome inhibition is a promising treatment strategy for autoimmune uveitis. PMID:25653480

  13. A murine model of experimental autoimmune lens-induced uveitis using Klebsiella O3 lipopolysaccharide as a potent immunological adjuvant.

    PubMed Central

    Yokochi, T.; Fujii, Y.; Nakashima, I.; Asai, J.; Kiuchi, M.; Kojima, K.; Kato, N.

    1993-01-01

    Experimental autoimmune uveitis and finally panophthalmitis could be produced in mice by repeated immunization of syngeneic eyeball extract mixed with Klebsiella O3 lipopolysaccharide (KO3 LPS) as a powerful immunological adjuvant. No ocular lesions were produced in mice given eyeball extract emulsified in complete Freund's adjuvant (CFA), KO3 LPS alone or eyeball extract alone. Histopathological changes in the ocular lesions at the early stage after the second or tertiary immunization were characterized by infiltration with inflammatory cells in the ciliary body and iris. The iridocyclitis was followed by extensive infiltration of polymorphonuclear leucocytes (PMN) into the cornea, lens and the surrounding tissues after repeated immunization. Finally, these areas were replaced by granulomatous tissues infiltrated with mononuclear cells. On the other hand, the structure of the retina and sclera was partially preserved. Those mice exhibited production of autoantibodies and development of the delayed-type hypersensitivity (DTH) to syngeneic eyeball extract. Moreover, ocular lesions could be produced in normal recipient mice by transfer of sensitized lymphocytes from hyperimmunized mice. Therefore, it was suggested that the ocular lesions produced by repeated immunization with the mixture of eyeball extract and KO3 LPS were due to the autoimmune mechanism. This might be useful to model immunological phenomena in the pathogenesis of human phacoantigenic uveitis. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:8292555

  14. Allograft-inflammatory factor-1 in rat experimental autoimmune encephalomyelitis, neuritis, and uveitis: expression by activated macrophages and microglial cells.

    PubMed

    Schluesener, H J; Seid, K; Kretzschmar, J; Meyermann, R

    1998-10-01

    Allograft inflammatory factor-1 (AIF-1) is a Ca2+ binding peptide expressed predominantly by activated monocytes. In order to investigate the role of AIF-1 in autoimmune lesions of the rat nervous system, we have used a synthetic gene to express AIF-1 in E. coli and have produced monoclonal antibodies against AIF-1. AIF-1 was localized to monocytes/macrophages with rather selective staining of a minor rat monocyte subpopulation of lymphoid tissue. We then investigated expression of AIF-1 in experimental autoimmune encephalomyelitis (EAE), neuritis (EAN), and uveitis (EAU). Within the local inflammatory lesions, infiltrating macrophages are prominently stained. In the diseased brain, AIF-1-positive microglial cells are not only found in the direct vicinity of the infiltrate, but widespread activation is seen in the parenchyma. This is the first demonstration that AIF-1 is present in autoimmune lesions. Immunostaining of microglial cells is noteworthy, as these cells are strategically placed regulatory elements of CNS immunosurveillance. Thus, AIF-1 might be a valuable marker to dissect the local monocyte heterogeneity in autoimmune disease.

  15. Preventive effect of chrysin on experimental autoimmune uveitis triggered by injection of human IRBP peptide 1-20 in mice.

    PubMed

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

    2016-03-21

    Uveitis is a common cause of blindness worldwide. Experimental autoimmune uveitis (EAU) is an animal model of noninfectious uveitis. Chrysin (5,7-dihydroxyflavone) is a member of the flavonoid family and has anti-inflammatory effects. We immunized C57BL/6J mice with human interphotoreceptor retinoid-binding protein peptide 1-20 to induce EAU. Chrysin was administered intragastrically at 25 mg/kg daily to the chrysin-treated mice from 3 days before immunization to 21 days after immunization. Vehicle was administered to the mice in the control group according to the same protocol. Lower clinical and histopathological scores, increased integrity of the blood-retinal barrier (BRB) and higher expression of tight junction proteins were observed in the chrysin-treated mice. Chrysin significantly decreased the proportions of Th1, Th17 and CD4(+)CD3(+)CD62L(+) Th0 cells, and increased the proportion of Treg cells. Both macrophage infiltration and the expression of inducible nitric oxide synthase in the retina were efficiently inhibited by chrysin treatment. In chrysin-treated mice, the expression of interferon-γ, interleukin (IL)-17A, IL-6, IL-1β and tumor necrosis factor-α was reduced in the retina, whereas higher levels of transforming growth factor-β were detected. Furthermore, NF-κBp65 was downregulated after chrysin treatment. In conclusion, as an anti-inflammatory molecule, chrysin exerts a preventive effect on EAU by modulating the balance among helper T-cell subsets and suppressing ocular inflammation, thereby maintaining the integrity of the BRB.Cellular & Molecular Immunology advance online publication, 21 March 2016; doi:10.1038/cmi.2015.107.

  16. MC5r and A2Ar Deficiencies During Experimental Autoimmune Uveitis Identifies Distinct T cell Polarization Programs and a Biphasic Regulatory Response

    PubMed Central

    Lee, Darren J.; Preble, Janine; Lee, Stacey; Foster, C. Stephen; Taylor, Andrew W.

    2016-01-01

    Autoantigen-specific regulatory immunity emerges in the spleen of mice recovering from experimental autoimmune uveitis (EAU), a murine model for human autoimmune uveoretinitis. This regulatory immunity provides induced tolerance to ocular autoantigen, and requires melanocortin 5 receptor (MC5r) expression on antigen presenting cells with adenosine 2 A receptor (A2Ar) expression on T cells. During EAU it is not well understood what roles MC5r and A2Ar have on promoting regulatory immunity. Cytokine profile analysis during EAU revealed MC5r and A2Ar each mediate distinct T cell responses, and are responsible for a functional regulatory immune response in the spleen. A2Ar stimulation at EAU onset did not augment this regulatory response, nor bypass the MC5r requirement to induce regulatory immunity. The importance of this pathway in human autoimmune uveitis was assayed. PBMC from uveitis patients were assayed for MC5r expression on monocytes and A2Ar on T cells, and comparison between uveitis patients and healthy controls had no significant difference. The importance for MC5r and A2Ar expression in EAU to promote the induction of protective regulatory immunity, and the expression of MC5r and A2Ar on human immune cells, suggests that it may be possible to utilize the melanocortin-adenosinergic pathways to induce protective immunity in uveitic patients. PMID:27886238

  17. MC5r and A2Ar Deficiencies During Experimental Autoimmune Uveitis Identifies Distinct T cell Polarization Programs and a Biphasic Regulatory Response.

    PubMed

    Lee, Darren J; Preble, Janine; Lee, Stacey; Foster, C Stephen; Taylor, Andrew W

    2016-11-25

    Autoantigen-specific regulatory immunity emerges in the spleen of mice recovering from experimental autoimmune uveitis (EAU), a murine model for human autoimmune uveoretinitis. This regulatory immunity provides induced tolerance to ocular autoantigen, and requires melanocortin 5 receptor (MC5r) expression on antigen presenting cells with adenosine 2 A receptor (A2Ar) expression on T cells. During EAU it is not well understood what roles MC5r and A2Ar have on promoting regulatory immunity. Cytokine profile analysis during EAU revealed MC5r and A2Ar each mediate distinct T cell responses, and are responsible for a functional regulatory immune response in the spleen. A2Ar stimulation at EAU onset did not augment this regulatory response, nor bypass the MC5r requirement to induce regulatory immunity. The importance of this pathway in human autoimmune uveitis was assayed. PBMC from uveitis patients were assayed for MC5r expression on monocytes and A2Ar on T cells, and comparison between uveitis patients and healthy controls had no significant difference. The importance for MC5r and A2Ar expression in EAU to promote the induction of protective regulatory immunity, and the expression of MC5r and A2Ar on human immune cells, suggests that it may be possible to utilize the melanocortin-adenosinergic pathways to induce protective immunity in uveitic patients.

  18. Long-Term Therapeutic Effects of Mesenchymal Stem Cells Compared to Dexamethasone on Recurrent Experimental Autoimmune Uveitis of Rats

    PubMed Central

    Zhang, Lingjun; Zheng, Hui; Shao, Hui; Nian, Hong; Zhang, Yan; Bai, Lingling; Su, Chang; Liu, Xun; Dong, Lijie; Li, Xiaorong; Zhang, Xiaomin

    2014-01-01

    Purpose. We tested the long-term effects of different regimens of mesenchymal stem cell (MSC) administration in a recurrent experimental autoimmune uveitis (rEAU) model in rats, and compared the efficacy of MSC to that of dexamethasone (DEX). Methods. One or two courses of MSC treatments were applied to R16-specific T cell–induced rEAU rats before or after disease onsets. The DEX injections were given for 7 or 50 days continuously after disease onsets. Clinical appearances were observed until the 50th day after transfer. On the 10th day, T cells from control and MSC groups were analyzed by flow cytometry. Supernatants from the proliferation assay and aqueous humor were collected for cytokine detection. Functions of T cells and APCs in spleens also were studied by lymphocyte proliferation assays. Results. One course of MSC therapy, administered after disease onset, led to a lasting therapeutic effect, with a decreased incidence, reduced mean clinical score, and reduced retinal impairment after 50 days of observation, while multiple courses of treatment did not improve the therapeutic benefit. Although DEX and MSCs equally reduced the severity of the first episode of rEAU, the effect of DEX was shorter lasting, and DEX therapy failed to control the disease even with long periods of treatment. The MSCs significantly decreased T helper 1 (Th1) and Th17 responses, suppressed the function of antigen-presenting cells, and upregulated T regulatory cells. Conclusions. These results suggested that MSCs might be new corticosteroid spring agents, while providing fewer side effects and longer lasting suppressive effects for recurrent uveitis. PMID:25125599

  19. Grouping annotations on the subcellular layered interactome demonstrates enhanced autophagy activity in a recurrent experimental autoimmune uveitis T cell line.

    PubMed

    Jia, Xiuzhi; Li, Jingbo; Shi, Dejing; Zhao, Yu; Dong, Yucui; Ju, Huanyu; Yang, Jinfeng; Sun, Jianhua; Li, Xia; Ren, Huan

    2014-01-01

    Human uveitis is a type of T cell-mediated autoimmune disease that often shows relapse-remitting courses affecting multiple biological processes. As a cytoplasmic process, autophagy has been seen as an adaptive response to cell death and survival, yet the link between autophagy and T cell-mediated autoimmunity is not certain. In this study, based on the differentially expressed genes (GSE19652) between the recurrent versus monophasic T cell lines, whose adoptive transfer to susceptible animals may result in respective recurrent or monophasic uveitis, we proposed grouping annotations on a subcellular layered interactome framework to analyze the specific bioprocesses that are linked to the recurrence of T cell autoimmunity. That is, the subcellular layered interactome was established by the Cytoscape and Cerebral plugin based on differential expression, global interactome, and subcellular localization information. Then, the layered interactomes were grouping annotated by the ClueGO plugin based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. The analysis showed that significant bioprocesses with autophagy were orchestrated in the cytoplasmic layered interactome and that mTOR may have a regulatory role in it. Furthermore, by setting up recurrent and monophasic uveitis in Lewis rats, we confirmed by transmission electron microscopy that, in comparison to the monophasic disease, recurrent uveitis in vivo showed significantly increased autophagy activity and extended lymphocyte infiltration to the affected retina. In summary, our framework methodology is a useful tool to disclose specific bioprocesses and molecular targets that can be attributed to a certain disease. Our results indicated that targeted inhibition of autophagy pathways may perturb the recurrence of uveitis.

  20. [Aspects of molecular immunology and immunogenetics in autoimmune uveitis].

    PubMed

    Istrate, Bogdan

    2012-01-01

    Generally speaking, the uveitis comprises a relative complex group of autoimmune diseases or other autoimmune associated illness. Until now, a little from molecular and cellular mechanisms are known in the autoimmunity of uveitis. The uveitis may cause a visual handicap as well, leading even to blindness. This paper tries to bring into focus some of the molecular mechanisms and immunogenetic features of the disease.

  1. Small Heat Shock Protein αA-Crystallin Prevents Photoreceptor Degeneration in Experimental Autoimmune Uveitis

    PubMed Central

    Rao, Narsing A.; Saraswathy, Sindhu; Pararajasegaram, Geeta; Bhat, Suraj P.

    2012-01-01

    The small heat shock protein, αA-crystallin null (αA−/−) mice are known to be more prone to retinal degeneration than the wild type mice in Experimental Autoimmune Uveoretinitis (EAU). In this report we demonstrate that intravenous administration of αA preserves retinal architecture and prevents photoreceptor damage in EAU. Interestingly, only αA and not αB-crystallin (αB), a closely related small heat shock protein works, pointing to molecular specificity in the observed retinal protection. The possible involvement of αA in retinal protection through immune modulation is corroborated by adaptive transfer experiments, (employing αA−/− and wild type mice with EAU as donors and Rag2−/− as the recipient mice), which indicate that αA protects against the autoimmune challenge by modulating the systemic B and T cell immunity. We show that αA administration causes marked reduction in Th1 cytokines (TNF-α, IL-12 and IFN-γ), both in the retina and in the spleen; notably, IL-17 was only reduced in the retina suggesting local intervention. Importantly, expression of Toll-like receptors and their associated adaptors is also inhibited suggesting that αA protection, against photoreceptor loss in EAU, is associated with systemic suppression of both the adaptive and innate immune responses. PMID:22479415

  2. SLAT/Def6 plays a critical role in the pathogenic process of experimental autoimmune uveitis (EAU)

    PubMed Central

    Vistica, Barbara P.; Shi, Guangpu; Nugent, Lindsey; Tan, Cuiyan; Altman, Amnon

    2012-01-01

    Purpose SWAP 70-like adaptor of T cells (SLAT; aka Def6) is a recently discovered guanine nucleotide exchange factor for Rho guanosine triphosphate (GTP)ases that has been previously shown to play a role in cluster of differentiation(CD)4+ T cell activation, T-helper (Th)1/Th2/Th17 differentiation and development of experimental autoimmune encephalomyelitis. Here, we investigated the role of SLAT/Def6 in the development of experimental autoimmune uveitis (EAU), an animal model for several uveitic conditions in humans. Methods SLAT/Def6 deficient (“KO”) mice and C57BL/6 controls were immunized with interphotoreceptor retinoid-binding protein (IRBP), along with pertussis toxin. The development of ocular inflammation was determined by both fundoscopy and histological examination. Lymphoid cells from draining lymph nodes were cultured with IRBP to measure lymphocyte proliferation and release of cytokines. Purified dendritic cells were tested for their capacity to present antigen to responding lymphocytes. In addition, the lymphoid cells were tested for the expression of forkhead box P3 (FoxP3), using conventional methods, and the activity of T-regulatory cells was determined by their capacity to inhibit in vitro proliferative responses. Serum anti -IRBP antibody levels were measured by enzyme-linked immonosorbant assay (ELISA). quantitative polymerase chain reaction (qPCR) was used to determine the transcript levels of cytokines in inflamed eyes. Results SLAT/Def6 KO mice had significantly reduced EAU compared to controls. Cells isolated from draining lymph nodes of SLAT/Def6 KO mice exhibited impaired proliferation and production of Th1 and Th17 signature cytokines (interferon [IFN]-γ and interleukin [IL]-17, respectively) when compared with cells isolated from control mice. qPCR of inflamed eyes detected similar levels of IFN-γ transcript in control and SLAT/Def6 KO mice, whereas the IL-17 transcript levels in eyes of the SLAT/Def6 KO mice were lower than in

  3. SLAT/Def6 plays a critical role in the pathogenic process of experimental autoimmune uveitis (EAU).

    PubMed

    Vistica, Barbara P; Shi, Guangpu; Nugent, Lindsey; Tan, Cuiyan; Altman, Amnon; Gery, Igal

    2012-01-01

    SWAP 70-like adaptor of T cells (SLAT; aka Def6) is a recently discovered guanine nucleotide exchange factor for Rho guanosine triphosphate (GTP)ases that has been previously shown to play a role in cluster of differentiation(CD)4+ T cell activation, T-helper (Th)1/Th2/Th17 differentiation and development of experimental autoimmune encephalomyelitis. Here, we investigated the role of SLAT/Def6 in the development of experimental autoimmune uveitis (EAU), an animal model for several uveitic conditions in humans. SLAT/Def6 deficient ("KO") mice and C57BL/6 controls were immunized with interphotoreceptor retinoid-binding protein (IRBP), along with pertussis toxin. The development of ocular inflammation was determined by both fundoscopy and histological examination. Lymphoid cells from draining lymph nodes were cultured with IRBP to measure lymphocyte proliferation and release of cytokines. Purified dendritic cells were tested for their capacity to present antigen to responding lymphocytes. In addition, the lymphoid cells were tested for the expression of forkhead box P3 (FoxP3), using conventional methods, and the activity of T-regulatory cells was determined by their capacity to inhibit in vitro proliferative responses. Serum anti -IRBP antibody levels were measured by enzyme-linked immunosorbant assay (ELISA). quantitative polymerase chain reaction (qPCR) was used to determine the transcript levels of cytokines in inflamed eyes. SLAT/Def6 KO mice had significantly reduced EAU compared to controls. Cells isolated from draining lymph nodes of SLAT/Def6 KO mice exhibited impaired proliferation and production of Th1 and Th17 signature cytokines (interferon [IFN]-γ and interleukin [IL]-17, respectively) when compared with cells isolated from control mice. qPCR of inflamed eyes detected similar levels of IFN-γ transcript in control and SLAT/Def6 KO mice, whereas the IL-17 transcript levels in eyes of the SLAT/Def6 KO mice were lower than in eyes of the controls. The SLAT

  4. An A2B Adenosine Receptor Agonist Promotes Th17 Autoimmune Responses in Experimental Autoimmune Uveitis (EAU) via Dendritic Cell Activation.

    PubMed

    Chen, Mingjiazi; Liang, Dongchun; Zuo, Aijun; Shao, Hui; Kaplan, Henry J; Sun, Deming

    2015-01-01

    We have recently reported that, although adenosine receptor (AR) agonists have a suppressive effect on Th1 autoreactive T cells, their effect on Th17 autoreactive T cells and γδ T cells is stimulatory and this effect is mainly mediated via A2A adenosine receptors (A2ARs). In this study, we further demonstrate that treatment of C57BL/6 (B6) mice with a selective A2B adenosine receptor (A2BR) agonist greatly enhanced the development of experimental autoimmune uveitis (EAU), whereas treatment with an A2BR antagonist significantly ameliorated severity of EAU. The A2BR agonist-treated mice showed augmented Th17, but not Th1, responses. Mechanistic studies showed that the A2BR agonist-induced enhancement of the Th17 response was significantly lower when TCR-δ-/- mice received the same treatment and that transfer of γδ T cells into TCR-δ-/- mice partially restored this effect. We also showed that dendritic cells (DCs) from A2BR agonist-treated mice showed a significantly increased ability to activate γδ T cells and Th17 autoreactive T cells. Thus, our previous studies have shown that, in EAU, activated γδ T cells possess greatly increased ability to enhance Th17 autoimmune responses. In the present study, we showed that exposure of DCs to A2BR agonist facilitated γδ T cell activation, leading to augmented Th17 responses and progressive EAU development. Our results further support our previous finding that AR agonists have distinct effects on Th1 and Th17 autoimmune responses.

  5. An A2B Adenosine Receptor Agonist Promotes Th17 Autoimmune Responses in Experimental Autoimmune Uveitis (EAU) via Dendritic Cell Activation

    PubMed Central

    Chen, Mingjiazi; Liang, Dongchun; Zuo, Aijun; Shao, Hui; Kaplan, Henry J.; Sun, Deming

    2015-01-01

    We have recently reported that, although adenosine receptor (AR) agonists have a suppressive effect on Th1 autoreactive T cells, their effect on Th17 autoreactive T cells and γδ T cells is stimulatory and this effect is mainly mediated via A2A adenosine receptors (A2ARs). In this study, we further demonstrate that treatment of C57BL/6 (B6) mice with a selective A2B adenosine receptor (A2BR) agonist greatly enhanced the development of experimental autoimmune uveitis (EAU), whereas treatment with an A2BR antagonist significantly ameliorated severity of EAU. The A2BR agonist-treated mice showed augmented Th17, but not Th1, responses. Mechanistic studies showed that the A2BR agonist-induced enhancement of the Th17 response was significantly lower when TCR-δ-/- mice received the same treatment and that transfer of γδ T cells into TCR-δ-/- mice partially restored this effect. We also showed that dendritic cells (DCs) from A2BR agonist-treated mice showed a significantly increased ability to activate γδ T cells and Th17 autoreactive T cells. Thus, our previous studies have shown that, in EAU, activated γδ T cells possess greatly increased ability to enhance Th17 autoimmune responses. In the present study, we showed that exposure of DCs to A2BR agonist facilitated γδ T cell activation, leading to augmented Th17 responses and progressive EAU development. Our results further support our previous finding that AR agonists have distinct effects on Th1 and Th17 autoimmune responses. PMID:26147733

  6. Modulating of ocular inflammation with macrophage migration inhibitory factor is associated with notch signalling in experimental autoimmune uveitis.

    PubMed

    Yang, H; Zheng, S; Mao, Y; Chen, Z; Zheng, C; Li, H; Sumners, C; Li, Q; Yang, P; Lei, B

    2016-02-01

    The aim of this study was to examine whether macrophage migration inhibitory factor (MIF) could exaggerate inflammatory response in a mouse model of experimental autoimmune uveitis (EAU) and to explore the underlying mechanism. Mutant serotype 8 adeno-associated virus (AAV8) (Y733F)-chicken β-actin (CBA)-MIF or AAV8 (Y733F)-CBA-enhanced green fluorescent protein (eGFP) vector was delivered subretinally into B10.RIII mice, respectively. Three weeks after vector delivery, EAU was induced with a subcutaneous injection of a mixture of interphotoreceptor retinoid binding protein (IRBP) peptide with CFA. The levels of proinflammatory cytokines were detected by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Retinal function was evaluated with electroretinography (ERG). We found that the expression of MIF and its two receptors CD74 and CD44 was increased in the EAU mouse retina. Compared to AAV8.CBA.eGFP-injected and untreated EAU mice, the level of proinflammatory cytokines, the expression of Notch1, Notch4, delta-like ligand 4 (Dll4), Notch receptor intracellular domain (NICD) and hairy enhancer of split-1 (Hes-1) increased, but the ERG a- and b-wave amplitudes decreased in AAV8.CBA.MIF-injected EAU mice. The Notch inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) reduced the expression of NICD, Hes-1 and proinflammatory cytokines. Further, a MIF antagonist ISO-1 attenuated intraocular inflammation, and inhibited the differentiation of T helper type 1 (Th1) and Th17 in EAU mice. We demonstrated that over-expression of MIF exaggerated ocular inflammation, which was associated with the activation of the Notch signalling. The expression of both MIF and its receptors are elevated in EAU mice. Over-expression of MIF exaggerates ocular inflammation, and this exaggerated inflammation is associated with the activation of the Notch signalling and Notch pathway. Our data suggest that the MIF-Notch axis

  7. The Role of TLR4 in Photoreceptor αA Crystallin Upregulation during Early Experimental Autoimmune Uveitis

    PubMed Central

    Saraswathy, Sindhu; Nguyen, Angeline M.

    2010-01-01

    Purpose. Previous studies indicate that the upregulation of αA crystallin prevents photoreceptor mitochondrial oxidative stress–mediated apoptosis in experimental autoimmune uveitis (EAU). In this study, the role of TLR4 was investigated in the upregulation of αA crystallin in the retinas of animals with EAU. Methods. TLR4−/−, iNOS−/−, TNF-α−/−, MyD88−/−, wild-type (WT) control (C57BL/6), and nude mice (B6.Cg-Foxn1nu) were immunized with IRBP mixed with complete Freund's adjuvant; eyes were enucleated on day 7 after immunization. Real-time polymerase chain reaction was first used to detect upregulated inflammatory cytokines and αA crystallin in retinas with EAU; confirmed with Western blot analysis, and the site of upregulation was localized by immunohistochemistry. Oxidative stress was localized using 8-OHdG, and TUNEL staining was used to detect apoptosis. Results. In early EAU, increased expression of TNF-α, iNOS, and αA crystallin genes were detected in the retinas of WT mice, whereas such upregulation was absent in TLR4-deficient mice (P < 0.001). αA Crystallin was not elevated in MyD88−/−, TNF-α−/−, and iNOS−/− mice with EAU. Immunostaining revealed TNF-α, iNOS, and αA crystallin localization in the photoreceptor inner segments and outer plexiform layer in the WT controls with EAU; but such staining was absent in TLR4-deficient mice with EAU. 8-OHdG staining showed oxidative stress in the photoreceptors in WT mice with EAU and there was no apoptosis. Conclusions. TLR4 plays an important role in the upregulation of αA crystallin through the interaction of MyD88 and the subsequent generation of TNF-α and iNOS in the EAU retina. Such crystallin upregulation may prevent oxidative stress–mediated apoptosis of photoreceptors in uveitis. PMID:20207969

  8. Gut Microbial Alterations Associated With Protection From Autoimmune Uveitis

    PubMed Central

    Nakamura, Yukiko K.; Metea, Christina; Karstens, Lisa; Asquith, Mark; Gruner, Henry; Moscibrocki, Cathleen; Lee, Iris; Brislawn, Colin J.; Jansson, Janet K.; Rosenbaum, James T.; Lin, Phoebe

    2016-01-01

    Purpose To investigate the contribution of the gut microbiota to the pathogenesis of uveitis. Methods Experimental autoimmune uveitis (EAU) in B10.RIII mice was induced using interphotoreceptor binding protein peptide. Mice were treated with oral or intraperitoneal (IP) antibiotics. Effector (Teff) and regulatory (Treg) T lymphocytes were identified using flow cytometry; 16S rRNA gene sequencing and qPCR were performed on gastrointestinal (GI) contents. Results Broad-spectrum (four antibiotics given simultaneously) oral, but not IP, antibiotics reduced mean uveitis clinical scores significantly compared with water-treated animals (0.5 vs. 3.0, P < 0.0001 for oral; 3.4 vs. 3.4, P > 0.99 for IP). Both oral metronidazole (P = 0.02) and vancomycin (P < 0.0001) alone decreased inflammation, whereas neomycin (P = 0.7) and ampicillin (P = 0.4) did not change mean uveitis scores. Oral broad-spectrum antibiotics increased Tregs in the GI lamina propria of EAU animals at 1 week, and in extraintestinal lymphoid tissues later, whereas Teff and inflammatory cytokines were reduced. 16S sequencing of GI contents revealed altered microbiota in immunized mice compared with nonimmunized mice, and microbial diversity clustering in EAU mice treated with uveitis-protective antibiotics. Experimental autoimmune uveitis mice also demonstrated gut microbial diversity clustering associated with clinical score severity. Conclusions Oral antibiotics modulate the severity of inducible EAU by increasing Tregs in the gut and extraintestinal tissues, as well as decreasing effector T cells and cytokines. 16S sequencing suggests that there may be protective and, conversely, potentially uveitogenic, gut microbiota. These findings may lead to a better understanding of how uveitis can be treated or prevented by modulating the gut microbiome. PMID:27415793

  9. Coordinated gene expression of Th17- and Treg-associated molecules correlated with resolution of the monophasic experimental autoimmune uveitis

    PubMed Central

    Jia, Xiuzhi; Hu, Minghui; Wang, Caihong; Wang, Chunyu; Zhang, Fengyun; Han, Qinglian; Zhao, Ruibo; Huang, Qi; Xu, Hongwei; Yuan, Huiping

    2011-01-01

    Purpose To investigate the role of T-cell-mediated immune response in a monophasic experimental autoimmune uveitis (EAU). Methods A monophasic EAU was induced in Lewis rats by immunization with interphotoreceptor retinoid-binding protein peptide. Optimized quantitative real-time RT–PCR was used for consecutive measurement of the relative expression of Th17-associated molecules, including interleukin 6 (IL-6), transforming growth factor-β (TGF-β), interleukin 23p19 (IL-23p19), interleukin 23p40 (IL-23p40), CD4, CD8, major histocompatibility complex I (MHC I), major histocompatibility complex II (MHC II), interleukin 17 (IL-17), interleukin 17F (IL-17F), interleukin 17 receptor A (IL-17RA), retinoic acid-related orphan receptor γt (RORγt) and Chemokine receptor 6 (CCR6), in addition to Treg-related forkhead box P3 (Foxp3), C-X-C chemokine receptor type 5 (CXCR5), and cluster of differentiation 25 (CD25) at the initiation, effector, and resolution phases of EAU and compared with those at 14 days post-immunization of control animals. Immunohistochemisty was used to examine IL-17 expression in retinas. Glial fibrillary acidic protein retinal astrocytes, Neuronal class III β-Tubulin(Tuj1+)retinal ganglion cells, and infiltrating CD11b+ microglia were analyzed by fluorescent microscopy in a kinetic manner. Results Our results indicated well organized T-cell activity, measured by relative expression of multiple T-cell-related factors at the mRNA level, synchronized with the initiation of autoimmune inflammation, and thereafter resolution of the monophasic EAU. Immune balance was achieved several times through coordinated expression of Th17- and Treg-related factors. The expression pattern of these factors and results from immunochemistry with an IL-17 antibody indicated that there may be intensive crosstalk between infiltrating immune cells and the resident neural cells, which were significantly activated during the course of disease. Conclusions T

  10. Regulation of experimental autoimmune uveitis in rats--separation of MHC and non-MHC gene effects.

    PubMed Central

    Hirose, S; Ogasawara, K; Natori, T; Sasamoto, Y; Ohno, S; Matsuda, H; Onoé, K

    1991-01-01

    Experimental autoimmune uveitis (EAU) is an organ-specific autoimmune disease and has served as a model of certain ocular inflammatory conditions in man. The present study was aimed at separating the effects of MHC and non-MHC genes on the development of EAU in the rat. EAU-susceptible LEW (RT1l), EAU-resistant WKAH (RT1k), and WKAH.1L (RT1l) MHC congenic strain of WKAH background rats were immunized with retinal soluble antigen (S-Ag) in Freund's complete adjuvant (FCA). LEW rats showed typical EAU, while neither WKAH nor WKAH.1L congenic rats developed EAU. However, when an additional i.v. injection of Bordetella pertussis was given, all rat strains developed EAU. Furthermore, when immunized with peptide M, an 18-mer synthetic peptide, which corresponds to amino acid positions 303-320 of bovine S-Ag, and given an additional i.v. injection of B. pertussis, LEW and WKAH.1L rats developed EAU, whereas WKAH did not. When ACI (RT1avl), BUF (RT1b), LEJ (RT1j), W (RT1k), F344 (RT1lvl), BN (RT1n), NIG-III (RT1q), TO (RT1t), and SDJ (RT1u) rats were immunized with peptide M or S-Ag and then B. pertussis, all strains developed EAU by immunization with S-Ag plus B. pertussis, but only F344 and NIG-III developed EAU by immunization with peptide M. These findings suggest that susceptibility to EAU in rats is controlled by both MHC and non-MHC genes; and that in the absence of B. pertussis adjuvant, the form of disease induced by native S-Ag in FCA is governed by non-MHC gene(s). However, this effect of non-MHC gene(s) could no longer be observed when the rats were also injected with B. pertussis adjuvant at sensitization. Images Fig. 1 PMID:1747950

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

    PubMed

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

    2017-07-18

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

  12. Autoimmune uveitis: clinical, pathogenetic, and therapeutic features.

    PubMed

    Prete, Marcella; Dammacco, Rosanna; Fatone, Maria Celeste; Racanelli, Vito

    2016-05-01

    Autoimmune uveitis (AU), an inflammatory non-infectious process of the vascular layer of the eye, can lead to visual impairment and, in the absence of a timely diagnosis and suitable therapy, can even result in total blindness. The majority of AU cases are idiopathic, whereas fewer than 20 % are associated with systemic diseases. The clinical severity of AU depends on whether the anterior, intermediate, or posterior part of the uvea is involved and may range from almost asymptomatic to rapidly sight-threatening forms. Race, genetic background, and environmental factors can also influence the clinical picture. The pathogenetic mechanism of AU is still poorly defined, given its remarkable heterogeneity and the many discrepancies between experimental and human uveitis. Even so, the onset of AU is thought to be related to an aberrant T cell-mediated immune response, triggered by inflammation and directed against retinal or cross-reactive antigens. B cells may also play a role in uveal antigen presentation and in the subsequent activation of T cells. The management of AU remains a challenge for clinicians, especially because of the paucity of randomized clinical trials that have systematically evaluated the effectiveness of different drugs. In addition to topical treatment, several different therapeutic options are available, although a standardized regimen is thus far lacking. Current guidelines recommend corticosteroids as the first-line therapy for patients with active AU. Immunosuppressive drugs may be subsequently required to treat steroid-resistant AU and for steroid-sparing purposes. The recent introduction of biological agents, such as those targeting tumor necrosis factor-α, is expected to remarkably increase the percentages of responders and to prevent irreversible sight impairment. This paper reviews the clinical features of AU and its crucial pathogenetic targets in relation to the current therapeutic perspectives. Also, the largest clinical trials

  13. The role of Th17-associated cytokines in the pathogenesis of experimental autoimmune uveitis (EAU).

    PubMed

    Sun, Deming; Liang, Dongchun; Kaplan, Henry J; Shao, Hui

    2015-07-01

    The proinflammatory and pathogenic function of Th17 cells in autoimmune diseases have been established but the mechanism by which such cells cause disease remains to be determined. Inflammatory cytokines produced by Th17 cells may either promote or inhibit disease development. The major cytokines produced by the uveitogenic T cells, such as IL-17 and IL-22, are not always pathogenic, and the disease-inducing ability of pathogenic T cells is not immediately correlated to the amount of cytokine they produce. Future studies identifying factors causing increased Th17 responses and determining the types of cells that regulating Th17 autoreactive T cells should facilitate our effort of understanding Th17-mediated disease pathogenesis. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    PubMed Central

    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

  15. Upregulation of DR3 expression in CD4+ T cells promotes secretion of IL-17 in experimental autoimmune uveitis

    PubMed Central

    2011-01-01

    Purpose This study investigated the role of death receptor 3 (DR3) in experimental autoimmune uveitis (EAU). Methods EAU was induced in B10.RIII mice by subcutaneous injection of interphotoreceptor retinoid-binding protein (IRBP) 161–180 emulsified with complete Freund’s adjuvant and evaluated with clinical and histopathologic observation. Total protein of draining lymph nodes (DLNs) was extracted from the control, EAU, or recovery phase mice. CD4+ T cells were separated from lymphocytes with magnetic-assisted cell sorting. At the same time, some of the CD4+ T cells were cultured with or without recombinant TL1A (rTL1A, the DR3 ligand) for three days, and the supernatants were collected for the interleukin-17 (IL-17) test. DR3 mRNA and protein levels in CD4+ T cells and the endogenous concentration of TL1A in mice DLNs were assessed with real-time PCR or western blotting. Levels of IL-17 in the supernatants were determined with enzyme-linked immunosorbent assay. Results Histopathological and clinical data revealed severe intraocular inflammation in the immunized mice. The inflammation reached its peak on day 14 in EAU and had resolved in the recovery phase (weeks 4–5 or more after IRBP immunization). CD4+ T cells obtained from EAU (day 7 or 14) had higher levels of DR3 mRNA and protein expression compared with the control group treated with complete Freund’s adjuvant alone and the recovery group. However, the DR3 mRNA and protein levels on day 21 in EAU were similar to those observed in the control and recovery groups. The endogenous levels of TL1A were upregulated in EAU, and decreased in the recovery phase mice. Adding rTL1A increased the production of IL-17 by CD4+ T cells isolated from mice DLNs. Moreover, the increased IL-17 levels in the culture supernatant of CD4+ T cells from EAU were much higher than those from the control and recovery phase mice. However, the effects on promoting IL-17 production in TL1A-stimulated CD4+ T cells were similar

  16. Novel CD28 antagonist mPEG PV1-Fab' mitigates experimental autoimmune uveitis by suppressing CD4+ T lymphocyte activation and IFN-γ production.

    PubMed

    Papotto, Pedro Henrique; Marengo, Eliana Blini; Sardinha, Luiz Roberto; Carvalho, Karina Inácio; de Carvalho, Ana Eduarda Zulim; Castillo-Mendez, Sheyla; Jank, Carina Calixto; Vanhove, Bernard; Goldberg, Anna Carla; Rizzo, Luiz Vicente

    2017-01-01

    Autoimmune Uveitis is an important chronic inflammatory disease and a leading cause of impaired vision and blindness. This ocular autoimmune disorder is mainly mediated by T CD4+ lymphocytes poising a TH1 phenotype. Costimulatory molecules are known to play an important role on T cell activation and therefore represent interesting therapeutical targets for autoimmune disorders. CD28 is the prototypical costimulatory molecule for T lymphocytes, and plays a crucial role in the initiation, and maintenance of immune responses. However, previous attempts to use this molecule in clinical practice achieved no success. Thus, we evaluated the efficacy of mPEG PV1-Fab' (PV1), a novel selective CD28 antagonist monovalent Fab fragment in the treatment of Experimental Autoimmune Uveitis (EAU). Here, we showed that PV1 treatment decreases both average disease score and incidence of EAU. A decrease in the activation profile of both T CD4+ and T CD8+ eye-infiltrating lymphocytes was evidenced. In the periphery, T CD4+ cells from PV1-treated mice also showed a decrease in their activation status, with reduced expression of CD69, CD25, and PD-1 molecules. This suppression was not dependent on Treg cells, as both their frequency and absolute number were lower in PV1-treated mice. In addition, frequency of CD4+IFN-γ+ T cells was significantly lower in PV1-treated group, but not of IL-17-producing T cells. Moreover, after specific restimulation, PV1 blockade selectively blocked IFN-γ production by CD4+ lymphocytes Taken together, our data suggest that mPEG PV1-Fab' acts mainly on IFN-γ-producing CD4+ T cells and emphasize that this specific CD28 blockade strategy is a potential specific and alternative tool for the treatment of autoimmune disorders in the eye.

  17. Novel CD28 antagonist mPEG PV1-Fab’ mitigates experimental autoimmune uveitis by suppressing CD4+ T lymphocyte activation and IFN-γ production

    PubMed Central

    Papotto, Pedro Henrique; Marengo, Eliana Blini; Sardinha, Luiz Roberto; Carvalho, Karina Inácio; de Carvalho, Ana Eduarda Zulim; Castillo-Mendez, Sheyla; Jank, Carina Calixto; Vanhove, Bernard; Goldberg, Anna Carla; Rizzo, Luiz Vicente

    2017-01-01

    Autoimmune Uveitis is an important chronic inflammatory disease and a leading cause of impaired vision and blindness. This ocular autoimmune disorder is mainly mediated by T CD4+ lymphocytes poising a TH1 phenotype. Costimulatory molecules are known to play an important role on T cell activation and therefore represent interesting therapeutical targets for autoimmune disorders. CD28 is the prototypical costimulatory molecule for T lymphocytes, and plays a crucial role in the initiation, and maintenance of immune responses. However, previous attempts to use this molecule in clinical practice achieved no success. Thus, we evaluated the efficacy of mPEG PV1-Fab’ (PV1), a novel selective CD28 antagonist monovalent Fab fragment in the treatment of Experimental Autoimmune Uveitis (EAU). Here, we showed that PV1 treatment decreases both average disease score and incidence of EAU. A decrease in the activation profile of both T CD4+ and T CD8+ eye-infiltrating lymphocytes was evidenced. In the periphery, T CD4+ cells from PV1-treated mice also showed a decrease in their activation status, with reduced expression of CD69, CD25, and PD-1 molecules. This suppression was not dependent on Treg cells, as both their frequency and absolute number were lower in PV1-treated mice. In addition, frequency of CD4+IFN-γ+ T cells was significantly lower in PV1-treated group, but not of IL-17-producing T cells. Moreover, after specific restimulation, PV1 blockade selectively blocked IFN-γ production by CD4+ lymphocytes Taken together, our data suggest that mPEG PV1-Fab’ acts mainly on IFN-γ-producing CD4+ T cells and emphasize that this specific CD28 blockade strategy is a potential specific and alternative tool for the treatment of autoimmune disorders in the eye. PMID:28248972

  18. Gut Microbial Alterations Associated With Protection From Autoimmune Uveitis

    DOE PAGES

    Nakamura, Yukiko K.; Metea, Christina; Karstens, Lisa; ...

    2016-07-01

    The bacteria that live normally in our intestinal tract, or the gut microbiota contribute to the pathogenesis of extra intestinal autoimmune disease via their ability to dynamically educate the immune system. For example, in a mouse model of relapsing, remitting multiple sclerosis (MS), experimental autoimmune encephalomyelitis or EAE, several studies demonstrated that commensal microorganisms are essential in causing clinical disease activity. Interestingly, MS patients have a distinct gut microbiota to healthy controls. Several studies have also illustrated the importance of the gut microbiome in the development of other diseases, including Type 1 diabetes, metabolic syndrome, rheumatoid arthritis, and ankylosing spondylitis.more » Furthermore, HLA=B27 transgenic rats, which develop spontaneous spondyloarthropathy analogous to patients who have ankylosing spondylitis, associated with uveitis in humans, do not develop intestinal or peripheral join inflammation when raised in a germ-free environment. Our group has shown that HLA-B27 transgenic rats have an altered intestinal microbiota compared to healthy control rats. Given the similarities between the central nervous system (CNS) and the retina, as well as co-expression of potentially immunogenic self-antigens from the CNS and joint in the eye, we hypothesized that modulating the gut microbiome can result in amelioration of autoimmune uveitis. Although uveitis is a heterogeneous collection of diseases, in general immune-mediated, non-infectious, uveitis is thought to be due to a combination of genetic and environmental factors. It arises from an imbalance between the regulatory and effector arms of the immune system, result in an inappropriate immune reaction at an otherwise immune-privileged tissue site, the eye. Th1 and Th17 T lymphocytes are examples of effector immune cell subsets that my contribute to inflammatory disease of the eye, whereas regulatory T cells (Tregs) are an example of a regulatory immune

  19. Gut Microbial Alterations Associated With Protection From Autoimmune Uveitis

    SciTech Connect

    Nakamura, Yukiko K.; Metea, Christina; Karstens, Lisa; Asquith, Mark; Gruner, Henry; Moscibrocki, Cathleen; Lee, Iris; Brislawn, Colin J.; Jansson, Janet K.; Rosenbaum, James T.; Lin, Phoebe

    2016-07-01

    The bacteria that live normally in our intestinal tract, or the gut microbiota contribute to the pathogenesis of extra intestinal autoimmune disease via their ability to dynamically educate the immune system. For example, in a mouse model of relapsing, remitting multiple sclerosis (MS), experimental autoimmune encephalomyelitis or EAE, several studies demonstrated that commensal microorganisms are essential in causing clinical disease activity. Interestingly, MS patients have a distinct gut microbiota to healthy controls. Several studies have also illustrated the importance of the gut microbiome in the development of other diseases, including Type 1 diabetes, metabolic syndrome, rheumatoid arthritis, and ankylosing spondylitis. Furthermore, HLA=B27 transgenic rats, which develop spontaneous spondyloarthropathy analogous to patients who have ankylosing spondylitis, associated with uveitis in humans, do not develop intestinal or peripheral join inflammation when raised in a germ-free environment. Our group has shown that HLA-B27 transgenic rats have an altered intestinal microbiota compared to healthy control rats. Given the similarities between the central nervous system (CNS) and the retina, as well as co-expression of potentially immunogenic self-antigens from the CNS and joint in the eye, we hypothesized that modulating the gut microbiome can result in amelioration of autoimmune uveitis. Although uveitis is a heterogeneous collection of diseases, in general immune-mediated, non-infectious, uveitis is thought to be due to a combination of genetic and environmental factors. It arises from an imbalance between the regulatory and effector arms of the immune system, result in an inappropriate immune reaction at an otherwise immune-privileged tissue site, the eye. Th1 and Th17 T lymphocytes are examples of effector immune cell subsets that my contribute to inflammatory disease of the eye, whereas regulatory T cells (Tregs) are an example of a regulatory immune cell

  20. AAV8-Mediated Angiotensin-Converting Enzyme 2 Gene Delivery Prevents Experimental Autoimmune Uveitis by Regulating MAPK, NF-κB and STAT3 Pathways

    PubMed Central

    Qiu, Yiguo; Tao, Lifei; Zheng, Shijie; Lin, Ru; Fu, Xinyu; Chen, Zihe; Lei, Chunyan; Wang, Jiaming; Li, Hongwei; Li, Qiuhong; Lei, Bo

    2016-01-01

    Renin angiotensin system (RAS) is a key hormonal system which regulates the cardiovascular function and is implicated in several autoimmune diseases. With the discovery of the angiotensin-converting enzyme 2 (ACE2), a protective axis of RAS namely ACE2/Ang-(1–7)/Mas that counteracts the deleterious ACE/AngII/AT1R axis has been established. This axis is emerging as a novel target to attenuate ocular inflammation. However, the underlying molecular mechanisms remain unclear. We investigated the hypothesis that enhancing the activity of the protective axis of RAS by subretinal delivery of an AAV8 (Y733F)-ACE2 vector would protect against the ocular inflammation in experimental autoimmune uveitis (EAU) mice through regulating the local immune responses. Our studies demonstrated that increased ACE2 expression exerts protective effects on inflammation in EAU mouse by modulating ocular immune responses, including the differentiation of Th1/Th17 cells and the polarization of M1/M2 macrophages; whereas the systemic immune responses appeared not affected. These effects were mediated by activating the Ang-(1–7)/Mas and inhibiting the MAPK, NF-κB and STAT3 signaling pathways. This proof-of-concept study suggests that activation of ocular ACE2/Ang-(1–7)/Mas axis with AAV gene transfer modulates local immune responses and may be a promising, long-lasting therapeutic strategy for refractory and recurrent uveitis, as well as other inflammatory eye diseases. PMID:27558087

  1. Dynamics of Intraocular IFN-γ, IL-17 and IL-10-Producing Cell Populations during Relapsing and Monophasic Rat Experimental Autoimmune Uveitis

    PubMed Central

    Kaufmann, Ulrike; Diedrichs-Möhring, Maria; Wildner, Gerhild

    2012-01-01

    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 with strongly

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

    PubMed

    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

  3. Both MC5r and A2Ar are required for protective regulatory immunity in the spleen of post-experimental autoimmune uveitis in mice

    PubMed Central

    Lee, Darren J.; Taylor, Andrew W.

    2013-01-01

    The ocular microenvironment uses a poorly defined melanocortin 5 receptor (MC5r)-dependent pathway to recover immune tolerance following intraocular inflammation. This dependency is seen in experimental autoimmune uveoretinitis (EAU), a mouse model of endogenous human autoimmune uveitis, with the emergence of autoantigen-specific regulatory immunity in the spleen that protects the mice from recurrence of EAU. In this new study, it was found that the MC5r-dependent regulatory immunity was an increase of CD11b+ F4/80+ Ly-6Clow Ly-6G+ CD39+ CD73+ APC in the spleen of post-EAU mice. These MC5r-dependent APC require adenosine 2A receptor (A2Ar) expression on T cells to activate EAU-suppressing CD25+ CD4+ FoxP3+ Treg cells. Therefore, in the recovery from autoimmune disease the ocular microenvironment induces tolerance through a melanocortin mediated expansion of Ly-6G+ regulatory APC in the spleen that utilize the adenosinergic pathway to promote activation of autoantigen-specific Treg cells. PMID:24043903

  4. Comparative Analysis of Induced vs. Spontaneous Models of Autoimmune Uveitis Targeting the Interphotoreceptor Retinoid Binding Protein

    PubMed Central

    Chen, Jun; Qian, Haohua; Horai, Reiko; Chan, Chi-Chao; Falick, Yishay; Caspi, Rachel R.

    2013-01-01

    Animal models of autoimmunity to the retina mimic specific features of human uveitis, but no model by itself reproduces the full spectrum of human disease. We compared three mouse models of uveitis that target the interphotoreceptor retinoid binding protein (IRBP): (i) the “classical” model of experimental autoimmune uveitis (EAU) induced by immunization with IRBP; (ii) spontaneous uveitis in IRBP T cell receptor transgenic mice (R161H) and (iii) spontaneous uveitis in Autoimmune Regulator (AIRE)−/− mice. Disease course and severity, pathology and changes in visual function were studied using fundus imaging and histological examinations, optical coherence tomography and electroretinography. All models were on the B10.RIII background. Unlike previously reported, IRBP-induced EAU in B10.RIII mice exhibited two distinct patterns of disease depending on clinical scores developed after onset: severe monophasic with extensive destruction of the retina and rapid loss of visual signal, or lower grade with a prolonged chronic phase culminating after several months in retinal degeneration and loss of vision. R161H and AIRE−/− mice spontaneously developed chronic progressive inflammation; visual function declined gradually as retinal degeneration developed. Spontaneous uveitis in R161H mice was characterized by persistent cellular infiltrates and lymphoid aggregation, whereas AIRE−/− mice characteristically developed multi-focal infiltrates and severe choroidal inflammation. These data demonstrate variability and unique distinguishing features in the different models of uveitis, suggesting that each one can represent distinct aspects of uveitis in humans. PMID:24015215

  5. Ex-vivo tolerogenic F4/80+ antigen-presenting cells (APC) induce efferent CD8+ regulatory T cell-dependent suppression of experimental autoimmune uveitis

    PubMed Central

    Hsu, S-M; Mathew, R; Taylor, A W; Stein-Streilein, J

    2014-01-01

    It is known that inoculation of antigen into the anterior chamber (a.c.) of a mouse eye induces a.c.-associated immune deviation (ACAID), which is mediated in part by antigen-specific local and peripheral tolerance to the inciting antigen. ACAID can also be induced in vivo by intravenous (i.v.) inoculation of ex-vivo-generated tolerogenic antigen-presenting cells (TolAPC). The purpose of this study was to test if in-vitro-generated retinal antigen-pulsed TolAPC suppressed established experimental autoimmune uveitis (EAU). Retinal antigen-pulsed TolAPC were injected i.v. into mice 7 days post-induction of EAU. We observed that retinal antigen-pulsed TolAPC suppressed the incidence and severity of the clinical expression of EAU and reduced the expression of associated inflammatory cytokines. Moreover, extract of whole retina efficiently replaced interphotoreceptor retinoid-binding protein (IRBP) in the preparation of TolAPC used to induce tolerance in EAU mice. Finally, the suppression of EAU could be transferred to a new set of EAU mice with CD8+ but not with CD4+regulatory T cells (Treg). Retinal antigen-pulsed TolAPC suppressed ongoing EAU by inducing CD8+ Treg cells that, in turn, suppressed the effector activity of the IRBP-specific T cells and altered the clinical symptoms of autoimmune inflammation in the eye. The ability to use retinal extract for the antigen raises the possibility that retinal extract could be used to produce autologous TolAPC and then used as therapy in human uveitis. PMID:24266626

  6. Leucine-Rich Repeat Kinase 2 (Lrrk2) Deficiency Diminishes the Development of Experimental Autoimmune Uveitis (EAU) and the Adaptive Immune Response.

    PubMed

    Wandu, Wambui S; Tan, Cuiyan; Ogbeifun, Osato; Vistica, Barbara P; Shi, Guangpu; Hinshaw, Samuel J H; Xie, Chengsong; Chen, Xi; Klinman, Dennis M; Cai, Huaibin; Gery, Igal

    2015-01-01

    Mutations in LRRK2 are related to certain forms of Parkinson's disease and, possibly, to the pathogenesis of Crohn's disease. In both these diseases inflammatory processes participate in the pathogenic process. LRRK2 is expressed in lymphoid cells and, interestingly, Lrrk2 (-/-) mice were reported to develop more severe experimental colitis than their wild type (WT) controls. Here, we examined the possible involvement of LRRK2 in the pathogenesis of experimental autoimmune uveitis (EAU), an animal model for human uveitis, by testing Lrrk2 (-/-) mice for their capacity to develop this experimental eye disease and related immune responses. Lrrk2 (-/-) mice and their WT controls (C57Bl/6) were immunized with interphotoreceptor retinoid-binding protein (IRBP) and compared for their development of EAU, delayed type hypersensitivity (DTH) by skin tests, production of cytokines in culture, and expression of interferon (IFN)-γ, interleukin (IL)-17 and FoxP3 by spleen cells, using flow cytometry. Peritoneal macrophages were examined for their production of cytokines/chemokines in culture following stimulation with LPS or the oligodeoxynucleotide CpG. The Lrrk2 (-/-) and WT mice were also compared for their response to bovine serum albumin (BSA). The Lrrk2 (-/-) mice developed lower levels of EAU, DTH responses and cytokine production by lymphocytes than did their WT controls. Intracellular expression of IFN-γ and IL-17, by spleen cells, and secretion of cytokines/chemokines by activated peritoneal macrophages of Lrrk2 (-/-) mice trended toward diminished levels, although variabilities were noted. The expression levels of FoxP3 by Lrrk2 (-/-) spleen cells, however, were similar to those seen in WT controls. Consistent with their low response to IRBP, Lrrk2 (-/-) mice responded to BSA less vigorously than their WT controls. Lrrk2 deficiency in mice diminished the development of EAU and the related adaptive immune responses to IRBP as compared to the WT controls.

  7. Leucine-Rich Repeat Kinase 2 (Lrrk2) Deficiency Diminishes the Development of Experimental Autoimmune Uveitis (EAU) and the Adaptive Immune Response

    PubMed Central

    Vistica, Barbara P.; Shi, Guangpu; Hinshaw, Samuel J. H.; Xie, Chengsong; Chen, Xi; Klinman, Dennis M.; Cai, Huaibin; Gery, Igal

    2015-01-01

    Background Mutations in LRRK2 are related to certain forms of Parkinson’s disease and, possibly, to the pathogenesis of Crohn’s disease. In both these diseases inflammatory processes participate in the pathogenic process. LRRK2 is expressed in lymphoid cells and, interestingly, Lrrk2 (-/-) mice were reported to develop more severe experimental colitis than their wild type (WT) controls. Here, we examined the possible involvement of LRRK2 in the pathogenesis of experimental autoimmune uveitis (EAU), an animal model for human uveitis, by testing Lrrk2 (-/-) mice for their capacity to develop this experimental eye disease and related immune responses. Methods Lrrk2 (-/-) mice and their WT controls (C57Bl/6) were immunized with interphotoreceptor retinoid-binding protein (IRBP) and compared for their development of EAU, delayed type hypersensitivity (DTH) by skin tests, production of cytokines in culture, and expression of interferon (IFN)-γ, interleukin (IL)-17 and FoxP3 by spleen cells, using flow cytometry. Peritoneal macrophages were examined for their production of cytokines/chemokines in culture following stimulation with LPS or the oligodeoxynucleotide CpG. The Lrrk2 (-/-) and WT mice were also compared for their response to bovine serum albumin (BSA). Results The Lrrk2 (-/-) mice developed lower levels of EAU, DTH responses and cytokine production by lymphocytes than did their WT controls. Intracellular expression of IFN-γ and IL-17, by spleen cells, and secretion of cytokines/chemokines by activated peritoneal macrophages of Lrrk2 (-/-) mice trended toward diminished levels, although variabilities were noted. The expression levels of FoxP3 by Lrrk2 (-/-) spleen cells, however, were similar to those seen in WT controls. Consistent with their low response to IRBP, Lrrk2 (-/-) mice responded to BSA less vigorously than their WT controls. Conclusions Lrrk2 deficiency in mice diminished the development of EAU and the related adaptive immune responses to IRBP

  8. Uveitis in autoimmune hepatitis: A case report

    PubMed Central

    Romanelli, Roberto Giulio; Villa, Giorgio La; Almerigogna, Fabio; Vizzutti, Francesco; Pietro, Elena Di; Fedi, Valentina; Gentilini, Paolo; Laffi, Giacomo

    2006-01-01

    In this case report we describe for the first time an association between autoimmune hepatitis (AIH) and uveitis, without any doubts about other possible etiologies, such as HCV, since all the old reports describe the association of AIH with iridocyclitis before tests for HCV-related hepatitis could be available. A 38-year-old businessman with abnormal liver function tests and hyperemia of the bulbar conjunctiva was admitted to the hospital. Six years before admission, the patient presented with persistent fever, arthralgias, conjunctival hyperemia, leukocytosis and increased ESR, referred to acute rheumatic fever. The presence of systemic diseases, most commonly associated with uveitis, was investigated without results and the patient was then treated with topical corticosteroids. His symptoms resolved. A test for anti-nuclear antibodies was positive, at a titre of 1:320, with a speckled and nucleolar staining pattern. Liver ultrasound showed mild hepatomegaly with an increased echostructure of the liver. Percutaneous liver biopsy was performed under ultrasound assistance. Histological examination showed necroinflammation over the portal, periportal and lobular areas, fibrotic portal tracts, with periportal fibrosis and occasional portal-to-portal bridgings, but intact hepatic architecture. Some hepatocytes showed barely discernible granules of hemosiderin in the lobular area. Bile ductules had not any significant morphological alterations. METAVIR score was A2-F3, according to the modified HAI grading/fibrosis staging. The patient was diagnosed to have AIH with mild activity and fibrosis and was discharged on 25 mg prednisone, entering clinical and biochemical remission, further confirming diagnosis. After discharge the patient continued to have treatment with corticosteroids as an outpatient at a dose of 5 mg. On January 2002 the patient was readmitted to the hospital. A test for anti-nuclear antibodies was positive, at a titre of 1:320, with a speckled and

  9. The HMGB1–CXCL12 Complex Promotes Inflammatory Cell Infiltration in Uveitogenic T Cell-Induced Chronic Experimental Autoimmune Uveitis

    PubMed Central

    Yun, Juan; Jiang, Guomin; Wang, Yunsong; Xiao, Tong; Zhao, Yuan; Sun, Deming; Kaplan, Henry J.; Shao, Hui

    2017-01-01

    It is largely unknown how invading autoreactive T cells initiate the pathogenic process inside the diseased organ in organ-specific autoimmune diseases. In experimental autoimmune uveitis (EAU) induced by uveitogenic, interphotoreceptor retinoid-binding protein (IRBP)-specific T cells (tEAU) in mice, we have previously reported that high mobility group box 1 (HMGB1) released as a consequence of the direct interaction between IRBP-specific T cells and retinal parenchymal cells is an early and critical mediator in induction of intraocular inflammation. Our present study explored the roles of HMGB1 in intraocular inflammation, focusing on its role in recruiting inflammatory cells into the eye. Our results showed that supernatants from retinal explants either stimulated with HMGB1 or cocultured with IRBP-specific T cells attracted leukocytes. Notably, HMGB1 antagonists blocked supernatant-induced chemoattraction when present from the start of coculture, but not when added to the culture supernatants after coculture, indicating that molecules released by HMGB1-treated retinal cells are chemoattractive. Moreover, CXCL12 levels in the coculture supernatants were dependent on HMGB1, since they were increased in the cocultures and reduced when HMGB1 antagonists were added at the beginning of the coculture. When either anti-CXCL12 Ab was added to the supernatants after coculture or the responding lymphocytes were pretreated with Ab against CXCL12 specific receptor, CXCR4, chemoattraction by the coculture supernatants was decreased. Finally, induction of tEAU was significantly inhibited by a CXCR4 antagonist, AMD3100, at the time of autoreactive T cell transfer. Our study demonstrates that, at a very early stage of intraocular inflammation initiated by uveitogenic autoreactive T cells, synergism between HMGB1 and CXCL12 is crucial for the infiltration of inflammatory cells. PMID:28261206

  10. Immunological and pathological investigations in equine experimental uveitis.

    PubMed

    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.

  11. Lipid peroxidation in experimental uveitis: sequential studies.

    PubMed

    Goto, H; Wu, G S; Chen, F; Kristeva, M; Sevanian, A; Rao, N A

    1992-06-01

    Previously we have detected the occurrence of retinal lipid peroxidation initiated by phagocyte-derived oxygen radicals in experimental autoimmune uveitis (EAU). In the current studies, the confirmation of inflammation-mediated lipid peroxidation was proceeded further to include measurement of multiple parameters, including conjugated dienes, ketodienes, thiobarbituric acid reactive substances and fluorescent chromolipids. The assay for myeloperoxidase, a measure for the number of polymorphonuclear leukocytes in the inflammatory sites was also carried out. The levels of all these parameters were followed through the course of EAU development. The sequential evaluation of histologic changes using both light and electron microscopy was also carried out and the results were correlated with lipid peroxidation indices. These data suggest that the retinal lipid peroxidation plays a causative role in the subsequent retinal degeneration.

  12. [Histopathologic studies in experimental uveitis].

    PubMed

    Misiuk-Hojło, Marta; Woźniak, Zdzisław; Szymaniec, Stanisław; Lugowski, Czesław; Agopsowicz, Karolina

    2004-01-01

    Experimental uveitis is one of the main models in the diseases of autoimmunological background. The purpose of this paper was to analyze the quantitative histological changes in the experimental uveitis, induced by different types of homogenous endotoxin salts of Havnia alvei. We studied 74 eyes of Lewis rats (males) divided into 4 groups. Each group received a homogenous salt of Havnia alvei in a single subcutaneous injection. In the 1 group-LPS Ca++, in 2 group-LPS Na++, in 3 group-LPS 981, in 4 group physiological salt (control group). The histologic and immunocitochemical examinations were performed after 24, 48 hours, and after 4 and 7 days following the injection. The histologic changes were analyzed (he intensity of inflammatory reaction) using a Highly Optimazed Microscope Enviroment system. The most intensive inflammation was observed in experimental group after 24 hours (n the LPS 981D group in 5 rats out of 6, in LPS Ca++ group in 3 rats out of 6). After 48 hours the intensity of inflammatory reaction visibly decreased. On the fourth day the inflammation revealed a minimal intensity and after 7 days was practically absent. In the control group minimal inflammation was observed only in a few rats. Cilliary body hypermia was present for 48 hours in most of the experimental rats. Only a few of them had hyperemia on the fourth day. In the posterior segment minimal inflammation was noted at the end of the first day (I and II-nd group after 24 hours); this process continued until the fourth day, on the 7th day disappeared. The most intensive inflammation of the anterior and posterior choroidal segment is caused by homogenous salts of Havnia alvei 981.

  13. Upregulation of DR3 expression in CD4⁺ T cells promotes secretion of IL-17 in experimental autoimmune uveitis.

    PubMed

    Qin, Tingyu

    2011-01-01

    This study investigated the role of death receptor 3 (DR3) in experimental autoimmune uveitis (EAU). EAU was induced in B10.RIII mice by subcutaneous injection of interphotoreceptor retinoid-binding protein (IRBP) 161-180 emulsified with complete Freund's adjuvant and evaluated with clinical and histopathologic observation. Total protein of draining lymph nodes (DLNs) was extracted from the control, EAU, or recovery phase mice. CD4⁺ T cells were separated from lymphocytes with magnetic-assisted cell sorting. At the same time, some of the CD4⁺ T cells were cultured with or without recombinant TL1A (rTL1A, the DR3 ligand) for three days, and the supernatants were collected for the interleukin-17 (IL-17) test. DR3 mRNA and protein levels in CD4⁺ T cells and the endogenous concentration of TL1A in mice DLNs were assessed with real-time PCR or western blotting. Levels of IL-17 in the supernatants were determined with enzyme-linked immunosorbent assay. Histopathological and clinical data revealed severe intraocular inflammation in the immunized mice. The inflammation reached its peak on day 14 in EAU and had resolved in the recovery phase (weeks 4-5 or more after IRBP immunization). CD4⁺ T cells obtained from EAU (day 7 or 14) had higher levels of DR3 mRNA and protein expression compared with the control group treated with complete Freund's adjuvant alone and the recovery group. However, the DR3 mRNA and protein levels on day 21 in EAU were similar to those observed in the control and recovery groups. The endogenous levels of TL1A were upregulated in EAU, and decreased in the recovery phase mice. Adding rTL1A increased the production of IL-17 by CD4⁺ T cells isolated from mice DLNs. Moreover, the increased IL-17 levels in the culture supernatant of CD4⁺ T cells from EAU were much higher than those from the control and recovery phase mice. However, the effects on promoting IL-17 production in TL1A-stimulated CD4⁺ T cells were similar between the controland

  14. Proteolytic Cleavage of Type I Collagen Generates an Autoantigen in Autoimmune Uveitis*

    PubMed Central

    Jha, Purushottam; Manickam, Balasubramanian; Matta, Bharati; Bora, Puran S.; Bora, Nalini S.

    2009-01-01

    This study was initiated to induce experimental autoimmune anterior uveitis (EAAU) in Lewis rats by melanin-associated antigen (MAA; 22-kDa fragment of type I collagen α2 chain) derived from rat iris and ciliary body (CB), to localize MAA within the eye, and to investigate the possible mechanism of MAA generation in vivo. The EAAU model replicates idiopathic human anterior uveitis. Lewis rats sensitized to rat MAA developed anterior uveitis, and EAAU induced by rat MAA can be adoptively transferred to naive syngenic rats by MAA-primed T cells. Animals immunized with rat MAA developed cellular immunity to the antigen. MAA was detected only in the iris and CB of the eye. Iris and CB were the major source of matrix metalloproteinase-1 (MMP-1) in the naive eye, and ocular expression of MMP-1 was up-regulated, whereas expression of tissue inhibitor of metalloproteinase 1 decreased before the onset of EAAU. These results demonstrated that EAAU can be induced by autologous MAA. Uveitogenic antigen is present only in the iris and CB of the eye, and the imbalance between MMP-1 and tissue inhibitor of metalloproteinase 1 may play a role in the generation of MAA in vivo. Collectively, the evidence presented here suggests that MAA is an autoantigen in EAAU. These observations may extend to idiopathic human anterior uveitis and facilitate the development of antigen-specific therapy. PMID:19755419

  15. Therapeutic Effect of Melatonin in Experimental Uveitis

    PubMed Central

    Sande, Pablo Horacio; Fernandez, Diego Carlos; Aldana Marcos, Hernán Javier; Chianelli, Mónica Silvia; Aisemberg, Julieta; Silberman, Dafne Magalí; Sáenz, Daniel Alberto; Rosenstein, Ruth Estela

    2008-01-01

    Uveitis is a common ophthalmic disorder that can be induced in hamsters by a single intravitreal injection of bacterial lipopolysaccharide (LPS). To examine the therapeutic effects of melatonin on uveitis, a pellet of melatonin was implanted subcutaneously 2 hours before the intravitreal injection of either vehicle or LPS. Both 24 hours and 8 days after the injection, inflammatory responses were evaluated in terms of i) the integrity of the blood-ocular barrier, ii) clinical signs, iii) histopathological studies, and iv) retinal function. Melatonin reduced the leakage of proteins and cells in the anterior segment of LPS-injected eyes, decreased clinical signs such as dilation of the iris and conjunctival vessels, and flare in the anterior chamber, and protected the ultrastructure of the blood-ocular barrier. A remarkable disorganization of rod outer segment membranous disks was observed in animals injected with LPS, whereas no morphological changes in photoreceptor outer segments were observed in animals treated with melatonin. Furthermore, melatonin prevented a decrease in LPS-induced electroretinographic activity. In addition, melatonin significantly abrogated the LPS-induced increase in retinal nitric-oxide synthase activity, tumor necrosis factor-α, and nuclear factor κB p50 and p65 subunit levels. These results indicate that melatonin prevents the clinical, biochemical, histological, ultrastructural, and functional consequences of experimental uveitis, likely through a nuclear factor κB-dependent mechanism, and support the use of melatonin as a new therapeutic strategy for the treatment of uveitis. PMID:19008374

  16. Histochemical analysis of experimental granulomatous uveitis.

    PubMed

    Kristeva, M; Biswas, J; Pararajasegaram, G; Sevanian, A; Rao, N A

    1991-01-01

    We have previously demonstrated the effects of various inhibitors of arachidonic acid metabolism on experimental lens-induced granulomatous uveitis. In the present study, we investigated the effect of these same inhibitors on the expression of lysosomal enzymes at different stages of choroidal inflammation in experimental lens-induced granulomatous uveitis and compared this to the inflammation observed at each stage examined. Lysosomal enzymes such as acid phosphatase, beta-glucuronidase and succinate dehydrogenase are known to be liberated during the maturation of mononuclear phagocytes to epithelioid cell granulomas. Although animals treated with nordihydroguaiaretic acid showed less severe inflammation than did indomethacin-treated or control animals, none of these agents appeared to affect the expression of acid phosphatase and beta-glucuronidase, as determined histochemically. Succinate dehydrogenase could not be detected in any of the eyes examined, even though sections of liver and kidney from these same animals were positive for this enzyme.

  17. Oral Echinacea purpurea extract in low-grade, steroid-dependent, autoimmune idiopathic uveitis: a pilot study.

    PubMed

    Neri, Pier Giorgio; Stagni, Edoardo; Filippello, Massimo; Camillieri, Giovanni; Giovannini, Alfonso; Leggio, Gian Marco; Drago, Filippo

    2006-12-01

    The aim of to test efficacy and safety of Echinacea purpurea (echinacea) extract in the control of low-grade uveitis. Fifty-one (51) patients with low-grade, steroid dependent, autoimmune uveitis were recruited; posterior uveitis was excluded. The start therapy was represented by topical desamethazone for anterior uveitis and oral prednisone, rapidly tapered, for anterior uveitis with inflammatory scores equal to +2 and in all cases of intermediate uveitis. Best-corrected visual acuity (BCVA) decrease or improvement was defined as a reduction or increase of 2 or more letters seen from the initial BCVA; ETDRS chart was used. Thirty-two (32) patients (21 with anterior uveitis and 11 with intermediate uveitis) received Echinacea (150 mg twice/day) as add-on therapy, whereas 20 patients (10 with anterior uveitis and 9 with intermediate uveitis) were treated with the conventional steroid therapy alone. Thirty-one (31) patients showed anterior uveitis and 20 intermediate uveitis. The follow-up duration was 9 months. At the last follow-up, 19/21 patients with anterior uveitis and 9/11 with intermediate uveitis treated with echinacea presented uveitis settled, with a steroid-off time of 209 and 146 days, respectively. BCVA was stable or improved in 19/21 of anterior uveitis and 9/11 of intermediate uveitis. No adverse reactions supposed to be resulting from commercial-grade echinacea were recorded. Patients who did not receive echinacea required a longer treatment period with steroids with a steroid-off time of 121 and 87 days. Systemic echinacea appears safe and effective in the control of low-grade autoimmune idiopathic uveitis.

  18. Intraocular Implants for the Treatment of Autoimmune Uveitis

    PubMed Central

    Lee, Darren J.

    2015-01-01

    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. PMID:26264035

  19. Multiple etiologies of equine recurrent uveitis--A natural model for human autoimmune uveitis: A brief review.

    PubMed

    Witkowski, Lucjan; Cywinska, Anna; Paschalis-Trela, Katarzyna; Crisman, Mark; Kita, Jerzy

    2016-02-01

    Equine recurrent uveitis (ERU) has various etiologies, with Leptospira infection and genetic predisposition being the leading risk factors. Regardless of etiology, expression of ocular proteins associated with maintenance of the blood-ocular barrier is impaired in ERU. The recurring-remitting cycle of ERU repeatedly disrupts the blood-ocular barrier, allowing the previously immune-privileged ocular environment to become the site of a progressive local autoimmune pathology that ultimately results in tissue destruction and vision loss. The immune-mediated process involves humoral and cellular mechanisms. Intraocular antibodies either produced in the eye or that leak through the blood-ocular barrier, are often present at higher levels than in serum and react with antigens in ocular tissue of horses with ERU. Ocular infiltration of auto-aggressive lymphocytes occurs with each uveitis episode and is the most crucial contributor to inflammation and eye damage. Recurring uveitis episodes may be initiated when epitopes of an ocular antigen become visible to the immune system (intramolecular spreading) or another autoantigen (intermolecular spreading), resulting in a new inflammatory reaction. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Uveitis.

    PubMed

    Dunn, James P

    2015-09-01

    Multidisciplinary management in the diagnosis and management of patients with ocular inflammatory disease is often critical. The workup of uveitis or scleritis may reveal an underlying systemic disease. Recognition of inflammation by the primary care physician can facilitate prompt referral to a uveitis specialist and improve patient outcomes. The primary care physician can assist the ophthalmologist in monitoring for potential side effects of corticosteroids and immunosuppressive drugs, including the newer biologic agents. The ophthalmologist in turn can assist the primary care physician in recognizing that active uveitis may suggest incomplete control of preexisting conditions.

  1. Systematic review on the effectiveness of immunosuppressants and biological therapies in the treatment of autoimmune posterior uveitis.

    PubMed

    Pato, Esperanza; Muñoz-Fernández, Santiago; Francisco, Félix; Abad, Miguel A; Maese, Jesús; Ortiz, Ana; Carmona, Loreto

    2011-02-01

    To analyze the effectiveness of immunosuppressants and biological therapies in autoimmune posterior uveitis, chronic anterior uveitis associated with juvenile idiopathic arthritis, and macular edema. Systematic review. We conducted a sensitive literature search in Medline (from 1961) and EMBASE (from 1980) until October 2007. Selection criteria were as follows: (1) population: autoimmune posterior uveitis, chronic anterior uveitis in juvenile idiopathic arthritis, and macular edema; (2) intervention: immunosuppressive and biologic therapies; (3) outcomes: visual acuity, Tyndall, vitreous haze, macular edema, pars planitis, and retinal vasculitis. There were no limitations regarding study design. The quality of each study was evaluated using the Jadad's scale and Oxford Levels of Evidence. Two hundred sixty-five articles were selected for detailed review of the 4235 found in the initial search: 128 records were on immunosuppressants, 105 on biological therapies, and 32 on macular edema. Overall, both the immunosuppressive and the biologic therapies appeared effective in the treatment of autoimmune posterior uveitis, except for daclizumab in uveitis related to Behçet's disease, and for etanercept in any uveitis. In the treatment of macular edema, the drugs tested were also effective. Based on the evidence collated, immunosuppressants and biological therapies (except for daclizumab in Behçet and etanercept) may be effective in autoimmune uveitis and macular edema. No superiority may be inferred from this review. Copyright © 2011 Elsevier Inc. All rights reserved.

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

    PubMed

    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.

  3. Aldose Reductase Deficiency Protects from Autoimmune- and Endotoxin-Induced Uveitis in Mice

    PubMed Central

    Yadav, Umesh C. S.; Shoeb, Mohammed; Srivastava, Satish K.

    2011-01-01

    Purpose. To investigate the effect of aldose reductase (AR) deficiency in protecting the chronic experimental autoimmune (EAU) and acute endotoxin-induced uveitis (EIU) in c57BL/6 mice. Methods. The WT and AR-null (ARKO) mice were immunized with human interphotoreceptor retinoid-binding peptide (hIRPB-1–20), to induce EAU, or were injected subcutaneously with lipopolysaccharide (LPS; 100 μg) to induce EIU. The mice were killed on day 21 for EAU and at 24 hours for EIU, when the disease was at its peak, and the eyes were immediately enucleated for histologic and biochemical studies. Spleen-derived T-lymphocytes were used to study the antigen-specific immune response in vitro and in vivo. Results. In WT-EAU mice, severe damage to the retinal wall, especially to the photoreceptor layer was observed, corresponding to a pathologic score of ∼2, which was significantly prevented in the ARKO or AR inhibitor–treated mice. The levels of cytokines and chemokines increased markedly in the whole-eye homogenates of WT-EAU mice, but not in ARKO-EAU mice. Further, expression of inflammatory marker proteins such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, and vascular cell adhesion molecule (VCAM)-1 was increased in the WT-EIU mouse eyes but not in the ARKO-EIU eyes. The T cells proliferated vigorously when exposed to the hIRPB antigen in vitro and secreted various cytokines and chemokines, which were significantly inhibited in the T cells isolated from the ARKO mice. Conclusions. These findings suggest that AR-deficiency/inhibition protects against acute as well as chronic forms of ocular inflammatory complications such as uveitis. PMID:21911582

  4. Serum PEDF levels are decreased in a spontaneous animal model for human autoimmune uveitis.

    PubMed

    Zipplies, Johanna K; Hauck, Stefanie M; Schoeffmann, Stephanie; Amann, Barbara; Stangassinger, Manfred; Ueffing, Marius; Deeg, Cornelia A

    2009-02-01

    Identification of biomarkers is of critical relevance toward improving diagnosis and therapy of autoimmune disorders. Serum markers are a desirable choice as sera are easily accessible and the development of assays for routine clinical detection prompts feasible. Autoimmune uveitis, a recurrent disease affecting the eye, is characterized by returning inflammatory attacks of the inner eye followed by variable periods of quiescent stages. Spontaneous equine recurrent uveitis (ERU) is the equine equivalent and serves as a model for the human disease. To identify potential biomarker candidates, we first systematically compared the proteomes of individual ERU cases with healthy controls by proteomic profiling using 2-D difference-gel-electrophoresis (2-D DIGE) followed by tandem mass spectrometry. A total of seven differentially expressed proteins were identified. Besides the upregulation of IgG and the significant lower expression of albumin, Antithrombin III, and Vitamin D binding protein, we found complement components C1q and C4, to be downregulated in uveitic state. Interestingly, Pigment epithelium-derived factor (PEDF), a marker already detected by 2DE differential proteome analysis in ERU target tissues, vitreous and retina, was found to be also significantly downregulated in sera. The lower expression of PEDF in sera of horses with uveitis could be verified in a cohort of 116 ERU cases and 115 healthy controls. Our findings of a significant lower PEDF expression in ERU cases also in the periphery of the eye proves PEDF as a promising uveitis biomarker.

  5. Roscovitine suppresses CD4+ T cells and T cell-mediated experimental uveitis.

    PubMed

    Zhang, Zili; Liu, Qi; Leskov, Konstantin S; Wu, Xiumei; Duan, Jie; Zhang, Gary L; Hall, Mark; Rosenbaum, James T

    2013-01-01

    T cells are essential for the development of uveitis and other autoimmune diseases. After initial activation, CD4+ lymphocytes express the co-stimulatory molecule OX40 that plays an important role in T cell proliferation. Cyclin dependent kinase 2 (CdK2) plays a pivotal role in the cell cycle transition from G1 to S phase. In addition, recent research has implicated CdK2 in T cell activation. Thus, we sought to test the immunosuppressive effect of roscovitine, a potent CdK2 inhibitor, on CD4+ T cell activation, proliferation, and function. Mouse CD4+ T cells were activated by anti-CD3 and anti-CD28 antibodies. The expression of OX40, CD44, and CdK2 were analyzed by flow cytometry. In addition, cell cycle progression and apoptosis of control and roscovitine-treated T lymphocytes were measured by BrdU incorporation and annexin V assay, respectively. Furthermore, the immunoregulatory effect of roscovitine was evaluated in both ovalbumin-induced uveitis and experimental autoimmune uveitis (EAU) models. In this study, we found that T cell activation induced OX40 expression. Cell cycle analysis showed that more CD4+OX40+ cells entered S phase than OX40- T cells. Concurrently, CD4+OX40+ cells had a higher level of CdK2 expression. Roscovitine treatment blocked activated CD4+ cells from entering S phase. In addition, roscovitine not only reduced the viability of CD4+ lymphocytes but also suppressed T cell activation and cytokine production. Finally, roscovitine significantly attenuated the severity of T cell-dependent, OX40-enhanced uveitis. These results implicate CdK2 in OX40-augmented T cell response and expansion. Furthermore, this study suggests that roscovitine is a novel, promising, therapeutic agent for treating T cell-mediated diseases such as uveitis.

  6. Roscovitine Suppresses CD4+ T Cells and T Cell-Mediated Experimental Uveitis

    PubMed Central

    Zhang, Zili; Liu, Qi; Leskov, Konstantin S.; Wu, Xiumei; Duan, Jie; Zhang, Gary L.; Hall, Mark; Rosenbaum, James T.

    2013-01-01

    Background T cells are essential for the development of uveitis and other autoimmune diseases. After initial activation, CD4+ lymphocytes express the co-stimulatory molecule OX40 that plays an important role in T cell proliferation. Cyclin dependent kinase 2 (CdK2) plays a pivotal role in the cell cycle transition from G1 to S phase. In addition, recent research has implicated CdK2 in T cell activation. Thus, we sought to test the immunosuppressive effect of roscovitine, a potent CdK2 inhibitor, on CD4+ T cell activation, proliferation, and function. Design and Methods Mouse CD4+ T cells were activated by anti-CD3 and anti-CD28 antibodies. The expression of OX40, CD44, and CdK2 were analyzed by flow cytometry. In addition, cell cycle progression and apoptosis of control and roscovitine-treated T lymphocytes were measured by BrdU incorporation and annexin V assay, respectively. Furthermore, the immunoregulatory effect of roscovitine was evaluated in both ovalbumin-induced uveitis and experimental autoimmune uveitis (EAU) models. Results In this study, we found that T cell activation induced OX40 expression. Cell cycle analysis showed that more CD4+OX40+ cells entered S phase than OX40- T cells. Concurrently, CD4+OX40+ cells had a higher level of CdK2 expression. Roscovitine treatment blocked activated CD4+ cells from entering S phase. In addition, roscovitine not only reduced the viability of CD4+ lymphocytes but also suppressed T cell activation and cytokine production. Finally, roscovitine significantly attenuated the severity of T cell-dependent, OX40-enhanced uveitis. Conclusion These results implicate CdK2 in OX40-augmented T cell response and expansion. Furthermore, this study suggests that roscovitine is a novel, promising, therapeutic agent for treating T cell-mediated diseases such as uveitis. PMID:24260551

  7. Epitope recognition and T cell receptors in recurrent autoimmune anterior uveitis in Lewis rats immunized with myelin basic protein.

    PubMed

    Adamus, G; Manczak, M; Sugden, B; Arendt, A; Hargrave, P A; Offner, H

    2000-08-01

    Lewis rats immunized with myelin basic protein (MBP) develop experimental autoimmune encephalomyelitis (EAE) and associated anterior uveitis (AU). Rats recover and become resistant to further reinduction of EAE. We investigated whether the resistance to reinduction of EAE was associated with the resistance to AU in LEW rats reinjected with MBP. We demonstrated that while rats remained resistant to EAE, they become susceptible to uveitis after recovery, and suffered a second episode of disease. The susceptibility to reinduced disease was associated with the recognition of new MBP epitopes. In contrast to the initial episode of AU, TCR Vbeta8.2 predominance was not observed in the iris/ciliary body. Our results suggest that T cells specific for MBP, which are rapidly reactivated when re-exposed to antigen, are sufficient to induce clinical uveitis in LEW rats. This process may involve a shifting of T cell specificity from the major encephalitogenic peptide utilizing the Vbeta8.2 receptor to a more diverse cell repertoire.

  8. Expression changes and novel interaction partners of talin 1 in effector cells of autoimmune uveitis.

    PubMed

    Degroote, Roxane L; Hauck, Stefanie M; Treutlein, Gudrun; Amann, Barbara; Fröhlich, Kristina J H; Kremmer, Elisabeth; Merl, Juliane; Stangassinger, Manfred; Ueffing, Marius; Deeg, Cornelia A

    2013-12-06

    Autoimmune uveitis is characterized by crossing of blood-retinal barrier (BRB) by autoaggressive immune cells. Equine recurrent uveitis (ERU) is a valuable spontaneous model for autoimmune uveitis and analyses of differentially expressed proteins in ERU unraveled changed protein clusters in target tissues and immune system. Healthy eyes are devoid of leukocytes. In ERU, however, leukocytes enter the inner eye and subsequently destroy it. Molecular mechanisms enabling cell migration through BRB still remain elusive. Previously, we detected decreased talin 1 expression in blood-derived granulocytes of ERU cases, linking the innate immune system to ERU. Because changes in leukocyte protein expression pattern may play a role in pathological abnormalities leading to migration ability, we aimed at identifying interactors of talin 1 in leukocytes with immunoprecipitation, followed by LC-MS/MS for candidate identification. This enabled us to identify CD90 (Thy1) as novel interactor of talin 1 besides several other interactors. In blood-derived granulocytes from healthy individuals, CD90 was highly abundant and significantly reduced in ERU, especially in effector cells. Connection between talin 1 and CD90 and their expression differences in inflammation is an interesting novel finding allowing deeper insight into immune response of innate immune system and granulocyte migration ability in this organ-specific autoimmune disease.

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

    PubMed Central

    Agrawal, Rupesh; Iyer, Jayant; Connolly, John; Iwata, Daiju; Teoh, Stephen

    2014-01-01

    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. PMID:24492505

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

    PubMed

    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.

  11. Use of Optical Coherence Tomography and Electroretinography to Evaluate Retinal Pathology in a Mouse Model of Autoimmune Uveitis

    PubMed Central

    Chen, Jun; Qian, Haohua; Horai, Reiko; Chan, Chi-Chao; Caspi, Rachel R.

    2013-01-01

    Experimental autoimmune uveoretinitis (EAU) in mice is a model for human autoimmune uveitis. Longitudinal follow-up is only possible by non-invasive techniques, but the information obtained by visual fundus examination can be limited. We therefore evaluated the efficacy of optical coherence tomography (OCT) and electroretinography (ERG) to monitor pathological and functional changes of the retina in vivo. OCT imaging and ERG recording as a measure of visual function were compared with visual fundoscopic imaging and histology findings in the same mouse. Our results showed that OCT imaging of the retina was well correlated with clinical and histological observations in mice during EAU. However, OCT imaging was more sensitive than fundoscopic imaging in detecting the cell infiltrates at the early phase of disease onset. Furthermore, by allowing multi-layer cross- and horizontal-sectional visualizations of retinal lesions longitudinally in a noninvasive fashion, OCT added information that could not be obtained by fundoscopic and histological examinations. Lastly, retinal thickness obtained by OCT imaging provided a key indicator reflecting disease activity, which showed a close association with visual dysfunction as measured by ERG recordings in EAU mice. Thus, our findings demonstrate that OCT is a highly sensitive and reliable technique, and a valuable method for the semi-quantitative evaluation of retinal inflammation in vivo in the mouse. PMID:23691112

  12. Dual Function of the IRF8 Transcription Factor in Autoimmune Uveitis: Loss of IRF8 in T Cells Exacerbates Uveitis, Whereas Irf8 Deletion in the Retina Confers Protection.

    PubMed

    Kim, Sung-Hye; Burton, Jenna; Yu, Cheng-Rong; Sun, Lin; He, Chang; Wang, Hongsheng; Morse, Herbert C; Egwuagu, Charles E

    2015-08-15

    IFN regulatory factor 8 (IRF8) is constitutively expressed in monocytes and B cells and plays a critical role in the functional maturation of microglia cells. It is induced in T cells following Ag stimulation, but its functions are less well understood. However, recent studies in mice with T cell-specific Irf8 disruption under direction of the Lck promoter (LCK-IRF8KO) suggest that IRF8 directs a silencing program for Th17 differentiation, and IL-17 production is markedly increased in IRF8-deficient T cells. Paradoxically, loss of IRF8 in T cells has no effect on the development or severity of experimental autoimmune encephalomyelitis (EAE), although exacerbating colitis in a mouse colitis model. In contrast, mice with a macrophage/microglia-specific Irf8 disruption are resistant to EAE, further confounding our understanding of the roles of IRF8 in host immunity and autoimmunity. To clarify the role of IRF8 in autoimmune diseases, we have generated two mouse strains with targeted deletion of Irf8 in retinal cells, including microglial cells and a third mouse strain with targeted Irf8 deletion in T cells under direction of the nonpromiscuous, CD4 promoter (CD4-IRF8KO). In contrast to the report that IRF8 deletion in T cells has no effect on EAE, experimental autoimmune uveitis is exacerbated in CD4-IRF8KO mice and disease enhancement correlates with significant expansion of Th17 cells and a reduction in T regulatory cells. In contrast to CD4-IRF8KO mice, Irf8 deletion in retinal cells confers protection from uveitis, underscoring divergent and tissue-specific roles of IRF8 in host immunity. These results raise a cautionary note in the context of therapeutic targeting of IRF8.

  13. Formin like 1 expression is increased on CD4+ T lymphocytes in spontaneous autoimmune uveitis.

    PubMed

    Degroote, Roxane L; Uhl, Patrizia B; Amann, Barbara; Krackhardt, Angela M; Ueffing, Marius; Hauck, Stefanie M; Deeg, Cornelia A

    2017-02-10

    The membrane protein expression repertoire of cells changes in course of activation. In equine recurrent uveitis (ERU), a spontaneous autoimmune disease in horses with relapsing and ultimately blinding inner eye inflammation, CD4+ T lymphocytes are the crucial pathogenic cells activated in the periphery directly prior to an inflammatory episode. In order to find relevant changes in the membrane proteome associated to disease, we sorted CD4+ lymphocytes and compared protein abundance from the generated proteome datasets of both healthy horses and ERU cases. We detected formin like 1, a key player in actin dependent cellular processes such as phagocytosis, cell adhesion and cell migration, with significantly higher abundance in the CD4+ cell membrane proteome of horses with ERU. In transmigration experiments, we demonstrated higher migration rate of cells originating from diseased animals connecting formin like 1 to the migratory ability of cells. These findings are the first description of formin like 1 in association to processes involved in migration of inflammatory CD4+ T cells across the blood-retinal barrier in a spontaneous ocular autoimmune disease and suggest formin like 1 to play a role in the molecular mechanisms of ERU disease pathogenesis. Data are available via ProteomeXchange with identifier PXD005384.

  14. Experimental posterior uveitis. I: A clinical, angiographic, and pathological study.

    PubMed Central

    Stanford, M R; Brown, E C; Kasp, E; Graham, E M; Sanders, M D; Dumonde, D C

    1987-01-01

    The clinical, angiographic, and histopathological features of experimental posterior uveitis in the black hooded Lister rat are described. This mild form of experimental allergic uveoretinitis (EAU) is induced by sensitisation with retinal S antigen in Freund's complete adjuvant, and the inflammation produced is confined to the posterior segment of the eye. This allows for the first time precise photographic and angiographic documentation of the evolution of clinical signs, because there is minimal clouding of the vitreous by inflammatory cells. Clinically the disease is characterised by the appearance of disc oedema and periphlebitis, followed by focal infiltrates in the deep retinal layers, with eventual atrophy of the pigment epithelium. Histologically, retinal vasculitis is associated with focal mononuclear cell infiltration and necrosis of the photoreceptor layers. This model closely resembles the clinical features of idiopathic retinal vasculitis seen in man. Images PMID:3651374

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

    PubMed Central

    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

  16. Maturation-Resistant Dendritic Cells Ameliorate Experimental Autoimmune Uveoretinitis

    PubMed Central

    Oh, Keunhee; Kim, Yon Su

    2011-01-01

    Background Endogenous uveitis is a chronic inflammatory eye disease of human, which frequently leads to blindness. Experimental autoimmune uveoretinitis (EAU) is an animal disease model of human endogenous uveitis and can be induced in susceptible animals by immunization with retinal antigens. EAU resembles the key immunological characteristics of human disease in that both are CD4+ T-cell mediated diseases. Dendritic cells (DCs) are specialized antigen-presenting cells that are uniquely capable of activating naïve T cells. Regulation of immune responses through modulation of DCs has thus been tried extensively. Recently our group reported that donor strain-derived immature DC pretreatment successfully controlled the adverse immune response during allogeneic transplantation. Methods EAU was induced by immunization with human interphotoreceptor retinoid-binding protein (IRBP) peptide1-20. Dendritic cells were differentiated from bone marrow in the presence of recombinant GM-CSF. Results In this study, we used paraformaldehyde-fixed bone marrow-derived DCs to maintain them in an immature state. Pretreatment with fixed immature DCs, but not fixed mature DCs, ameliorated the disease progression of EAU by inhibiting uveitogenic CD4+ T cell activation and differentiation. Conclusion Application of iBMDC prepared according to the protocol of this study would provide an important treatment modality for the autoimmune diseases and transplantation rejection. PMID:22346781

  17. Altered expression of talin 1 in peripheral immune cells points to a significant role of the innate immune system in spontaneous autoimmune uveitis.

    PubMed

    Degroote, Roxane L; Hauck, Stefanie M; Kremmer, Elisabeth; Amann, Barbara; Ueffing, Marius; Deeg, Cornelia A

    2012-07-19

    The molecular mechanism which enables activated immune cells to cross the blood-retinal barrier in spontaneous autoimmune uveitis is yet to be unraveled. Equine recurrent uveitis is the only spontaneous animal model allowing us to investigate the autoimmune mediated transformation of leukocytes in the course of this sight threatening disease. Hypothesizing that peripheral blood immune cells change their protein expression pattern in spontaneous autoimmune uveitis, we used DIGE to detect proteins with altered abundance comparing peripheral immune cells of healthy and ERU diseased horses. Among others, we found a significant downregulation of talin 1 in peripheral blood granulocytes of ERU specimen, pointing to changes in β integrin activation and indicating a significant role of the innate immune system in spontaneous autoimmune diseases.

  18. Retinal Mueller glial cells trigger the hallmark inflammatory process in autoimmune uveitis.

    PubMed

    Hauck, Stefanie M; Schoeffmann, Stephanie; Amann, Barbara; Stangassinger, Manfred; Gerhards, Hartmut; Ueffing, Marius; Deeg, Cornelia A

    2007-06-01

    Spontaneous equine recurrent uveitis (ERU) is an incurable autoimmune disease affecting the eye. Although retinal-autoantigen specific T-helper 1 cells have been demonstrated to trigger disease progression and relapses, the molecular processes leading to retinal degeneration and consequent blindness remain unknown. To elucidate such processes, we studied changes in the total retinal proteome of ERU-diseased horses compared to healthy controls. Severe changes in the retinal proteome were found for several markers for blood-retinal barrier breakdown and whose emergence depended upon disease severity. Additionally, uveitic changes in the retina were accompanied by upregulation of aldose 1-epimerase, selenium-binding protein 1, alpha crystallin A chain, phosphatase 2A inhibitor (SET), and glial fibrillary acidic protein (GFAP), the latter indicating an involvement of retinal Mueller glial cells (RMG) in disease process. To confirm this, we screened for additional RMG-specific markers and could demonstrate that, in uveitic retinas, RMG concomitantly upregulate vimentin and GFAP and downregulate glutamine synthetase. These expression patterns suggest for an activated state of RMG, which further downregulate the expression of pigment epithelium-derived factor (PEDF) and begin expressing interferon-gamma, a pro-inflammatory cytokine typical for T-helper 1 cells. We thus propose that RMG may play a fatal role in uveitic disease progression by directly triggering inflammatory processes through the expression and secretion of interferon-gamma.

  19. [Effect of bacteriophage on the lipid peroxidation process and antioxidant protective enzymes in experimental uveitis].

    PubMed

    Karimova, M Kh; Bakhritdinova, F A

    2002-01-01

    Experimental uveitis features distinct hyperlipoperoxidation in damaged eye tissues, blood serum and the liver. The activity of antioxidant defense (AOD) enzymes decreases in tissues and blood of experimental animals whereas catalase compensatorily activates in hepatic tissue. Experimental therapy of uveitis with gentamycin and bacteriophage results in reducing hyperlipoperoxidation, increased activity of AOD enzymes but no complete normalization is observed. This manifested in preservation of inflammations to a certain degree.

  20. [Translational research with experimental autoimmune uveoretinitis (EAU)].

    PubMed

    Usui, Masahiko

    2007-03-01

    Experimental autoimmune uveoretinitis (EAU) induced by immunization with retinal antigen (Santigen or interphotoreceptor retinoid-binding protein; IRBP) serves as an animal model of human uveoretinitis. As the first stage, we demonstrated the similarities between EAU and ocular inflammation in Behçet's disease by investigating anti-retinal antibodies, leukocyte migration inhibition by retinal antigen, immunogenic antigens, aberrant functions of neutrophils, and dominant Th1 lymphocyte reaction. From these findings, we verified that EAU, which is not associated with the systemic disorders observed in Behçet's disease, is an appropriate model for translational research targeting ocular inflammation. In the second stage, we set 3 therapeutic strategies for uveitis in Behçet's disease to be conducted in the translational research: (1) intraocular administration of an immunosuppressive drug; (2) inhibition of Th1 lymphocytes; and (3) activation of immunoregulatory cells. In strategy 1, our studies indicated that intravitreal injection of 10 microg of tacrolimus (FK 506) was not harmful to the retina and was predominantly effective in suppressing ongoing EAU in rats. In strategy 2, two approaches were adopted to prevent differentiation of Thl cells. One is anti-cytokine antibody therapy using anti-IL-12 monoclonal antibodies(mAb). The other is blockade of co-stimulatory signals, especially the ICOS-B7RP-1 pathway. Administration of anti-IL-12 mAb at the time of IRBP immunization completely inhibited development of EAU, and antagonistic anti B7RP-1 mAb suppressed the severity of EAU even when administered after development of EAU. In strategy 3, adoptive transfer of antigen presenting cells treated with a neuropeptide (vasoactive intestinal peptide or calcitonin gene-related peptide) or CD 4+ CD 25+ regulatory T cells suppressed EAU. We look forward to the day when therapies that are being developed in our translational research using EAU will become available for

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

    PubMed Central

    Jriekh, Ziena; Aboras, Yasmin

    2016-01-01

    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. PMID:27840642

  2. Roles of interleukin-17 in uveitis.

    PubMed

    Guedes, Marta Catarina Esteves; Borrego, Luis Miguel; Proença, Rui Daniel

    2016-09-01

    Th17 cells, a CD4+ T-cell subset, produce interleukin (IL)-17, a pro-inflammatory cytokine that has been shown to be involved in several forms of infectious and noninfectious uveitis. Here, we explore the roles of this IL in uveitic disorders as well as in experimental autoimmune uveitis, the possible pathogenic implications of several cytokines associated with IL-17 and analyze the current outcomes and goals for drugs aiming for the IL-17 pathway.

  3. Roles of interleukin-17 in uveitis

    PubMed Central

    Guedes, Marta Catarina Esteves; Borrego, Luis Miguel; Proença, Rui Daniel

    2016-01-01

    Th17 cells, a CD4+ T-cell subset, produce interleukin (IL)-17, a pro-inflammatory cytokine that has been shown to be involved in several forms of infectious and noninfectious uveitis. Here, we explore the roles of this IL in uveitic disorders as well as in experimental autoimmune uveitis, the possible pathogenic implications of several cytokines associated with IL-17 and analyze the current outcomes and goals for drugs aiming for the IL-17 pathway. PMID:27853008

  4. Experimental Autoimmune Encephalomyelitis in Marmosets.

    PubMed

    Jagessar, S Anwar; Dijkman, Karin; Dunham, Jordon; 't Hart, Bert A; Kap, Yolanda S

    2016-01-01

    Experimental autoimmune encephalomyelitis (EAE) in the common marmoset, a small-bodied Neotropical primate, is a well-known and validated animal model for multiple sclerosis (MS). This model can be used for exploratory research, i.e., investigating the pathogenic mechanisms involved in MS, and applied research, testing the efficacy of new potential drugs.In this chapter, we will describe a method to induce EAE in the marmoset. In addition, we will explain the most common immunological techniques involved in the marmoset EAE research, namely isolation of mononuclear cells (MNC) from peripheral blood and lymphoid tissue, assaying T cell proliferation by thymidine incorporation, MNC phenotyping by flow cytometry, antibody measurement by ELISA, generation of B cell lines and antigen-specific T cell lines, and assaying cytotoxic T cells.

  5. Osteopontin and fibronectin levels are decreased in vitreous of autoimmune uveitis and retinal expression of both proteins indicates ECM re-modeling.

    PubMed

    Deeg, Cornelia A; Eberhardt, Christina; Hofmaier, Florian; Amann, Barbara; Hauck, Stefanie M

    2011-01-01

    Autoimmune uveitis is an intraocular inflammation that arises through autoreactive T-cells attacking the inner eye, eventually leading to blindness. However, the contributing molecular pathomechanisms within the affected tissues remain as yet elusive. The extracellular matrix (ECM) is a highly dynamic structure that varies tremendously and influences the encompassing tissue. In order to assess ECM re-modeling in autoimmune uveitis, we investigated the expression of ECM molecules fibronectin and osteopontin in vitreous and retina samples. This was carried out in the only spontaneous animal model for human autoimmue uveitis, namely equine recurrent uveitis (ERU) that resembles the human disease in clinical as well as in immunopathological aspects. ERU is a naturally occurring autoimmune disease in horses that develops frequently and has already proved its value to study disease-related pathomechanisms. Western blot analysis of fibronectin and osteopontin in healthy and uveitic vitreous revealed significant reduction of both proteins in uveitis. Immunohistochemical expression of fibronectin in healthy retinas was restricted to the inner limiting membrane abutting vimentin positive Müller cell endfeet, while in uveitic sections, a disintegration of the ILM was observed changing the fibronectin expression to a dispersed pattern extending toward the vitreous. Retinal expression of osteopontin in control tissue was found in a characteristic Müller cell pattern illustrated by co-localization with vimentin. In uveitic retinas, the immunoreactivity of osteopontin in gliotic Müller cells was almost absent. The ability of Müller cells to express fibronectin and osteopontin was additionally shown by immunocytochemistry of primary cultured equine Müller cells and the equine Müller cell line eqMC-7. In conclusion, severe ECM re-modeling in autoimmune uveitis reported here, might affect the adhesive function of fibronectin and thus the anchoring of Müller cell endfeet to

  6. Osteopontin and Fibronectin Levels Are Decreased in Vitreous of Autoimmune Uveitis and Retinal Expression of Both Proteins Indicates ECM Re-Modeling

    PubMed Central

    Deeg, Cornelia A.; Eberhardt, Christina; Hofmaier, Florian; Amann, Barbara; Hauck, Stefanie M.

    2011-01-01

    Autoimmune uveitis is an intraocular inflammation that arises through autoreactive T-cells attacking the inner eye, eventually leading to blindness. However, the contributing molecular pathomechanisms within the affected tissues remain as yet elusive. The extracellular matrix (ECM) is a highly dynamic structure that varies tremendously and influences the encompassing tissue. In order to assess ECM re-modeling in autoimmune uveitis, we investigated the expression of ECM molecules fibronectin and osteopontin in vitreous and retina samples. This was carried out in the only spontaneous animal model for human autoimmue uveitis, namely equine recurrent uveitis (ERU) that resembles the human disease in clinical as well as in immunopathological aspects. ERU is a naturally occurring autoimmune disease in horses that develops frequently and has already proved its value to study disease-related pathomechanisms. Western blot analysis of fibronectin and osteopontin in healthy and uveitic vitreous revealed significant reduction of both proteins in uveitis. Immunohistochemical expression of fibronectin in healthy retinas was restricted to the inner limiting membrane abutting vimentin positive Müller cell endfeet, while in uveitic sections, a disintegration of the ILM was observed changing the fibronectin expression to a dispersed pattern extending toward the vitreous. Retinal expression of osteopontin in control tissue was found in a characteristic Müller cell pattern illustrated by co-localization with vimentin. In uveitic retinas, the immunoreactivity of osteopontin in gliotic Müller cells was almost absent. The ability of Müller cells to express fibronectin and osteopontin was additionally shown by immunocytochemistry of primary cultured equine Müller cells and the equine Müller cell line eqMC-7. In conclusion, severe ECM re-modeling in autoimmune uveitis reported here, might affect the adhesive function of fibronectin and thus the anchoring of Müller cell endfeet to

  7. Opsin-induced experimental autoimmune retinitis in rats.

    PubMed

    Broekhuyse, R M; Winkens, H J; Kuhlmann, E D; van Vugt, A H

    1984-12-01

    Experimental autoimmune retinitis has been induced in Lewis rats by injection of opsin in mycobacterial adjuvant and Hemophilus pertussis adjuvant. Clinical, histopathological and immunological parameters of the disease are reported. Two types of opsin were prepared from purified bovine retina outer segments, one type in Triton X-100 and the other in lithium dodecyl sulfate. Both preparations were free from S-antigen. Dodecyl sulfate-denaturated-opsin displayed lower antigenicity and pathogenicity than Triton-opsin. Triton-opsin (250 micrograms) induced moderate to severe non-granulomatous uveitis (predominantly retinitis) in 70% of the Lewis rats at the end of the second week after injection. The photoreceptor cell layer was destructed within a few days. This group displayed high responses to opsin in the lymphocyte transformation test. In view of observed histological features, the possible early involvement of vasoactive factors is discussed. Low opsin doses (50 or 100 micrograms) seldomly induced severe retinitis, while the incidence of mild pathology was low. Lewis rats appeared to be more susceptible for the development of experimental autoimmune retinitis than Wistar rats.

  8. Precipitation of experimental autoallergic uveoretinitis by cyclosporin A withdrawal: an experimental model of uveitis relapse.

    PubMed Central

    Atkinson, E G; Dinning, W J; Kasp, E; Graham, E M; Dumonde, D C

    1989-01-01

    This study set out to determine whether withdrawal of cyclosporin A (CyA) in Lewis rats sensitized to retinal S antigen would precipitate experimental autoallergic uveoretinitis (EAU), and whether challenge of such animals with S antigen or an unrelated stimulus would accelerate EAU onset after drug withdrawal. Rats were sensitized with 50 micrograms S antigen in Freund's complete adjuvant (FCA) and EAU onset was suppressed by 18 days of treatment with CyA at doses ranging from 3 to 10 mg/kg daily. Without challenge, seven out of 11 animals developed EAU with a median onset of 78 days. This was reduced to 68 days in rats challenged on day 32 with FCA alone, to 48 days with 10 micrograms S antigen in FCA, and to 41 days with 50 micrograms S antigen in FCA. The incidence, onset and severity of anterior uveitis and extent of photoreceptor destruction were related to both CyA dose and nature of challenge. The extent of photoreceptor destruction ran parallel with severity of anterior uveitis; and delayed-type hypersensitivity reactivity on day 43 was related to both severity of anterior uveitis (P less than 0.001) and photoreceptor damage (P less than 0.002). At the highest dose, CyA also delayed the appearance of antibody to S antigen; however, subsequent antibody levels were unrelated to EAU severity or to nature of challenge. The results indicate that CyA-induced suppression of the immunological response to S antigen can recover spontaneously after drug withdrawal, that challenge with either S antigen or FCA alone can accelerate the subsequent onset of EAU, and that these phenomena may provide a basis for investigating mechanisms underlying relapse of human uveoretinitis. Images Fig. 5 PMID:2805414

  9. Equine recurrent uveitis--a spontaneous horse model of uveitis.

    PubMed

    Deeg, Cornelia A; Hauck, Stefanie M; Amann, Barbara; Pompetzki, Dirk; Altmann, Frank; Raith, Albert; Schmalzl, Thomas; Stangassinger, Manfred; Ueffing, Marius

    2008-01-01

    Equine recurrent uveitis (ERU) is an autoimmune disease that occurs with a high prevalence (10%) in horses. ERU represents the only reliable spontaneous model for human autoimmune uveitis. We already identified and characterized novel autoantigens (malate dehydrogenase, recoverin, CRALBP) by analyzing the autoantibody-binding pattern of horses affected by spontaneous recurrent uveitis (ERU) to the retinal proteome. CRALBP also seems to be relevant to human autoimmune uveitis. Proteomic screening of vitreous and retinal samples from ERU diseased cases in comparison to healthy controls has led to the identification of a series of differentially regulated proteins, which are functionally linked to the immune system and the maintenance of the blood-retinal barrier.

  10. Regulatory T cells in experimental autoimmune disease.

    PubMed

    Suri-Payer, Elisabeth; Fritzsching, Benedikt

    2006-08-01

    During the past 10 years, CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) have been extensively studied for their function in autoimmune disease. This review summarizes the evidence for a role of Treg in suppression of innate and adaptive immune responses in experimental models of autoimmunity including arthritis, colitis, diabetes, autoimmune encephalomyelitis, lupus, gastritis, oophoritis, prostatitis, and thyroiditis. Antigen-specific activation of Treg, but antigen-independent suppressive function, emerges as a common paradigm derived from several disease models. Treg suppress conventional T cells (Tcon) by direct cell contact in vitro. However, downmodulation of dendritic cell function and secretion of inhibitory cytokines such as IL-10 and TGF-beta might underlie Treg function in vivo. The final outcome of autoimmunity vs tolerance depends on the balance between stimulatory signals (Toll-like receptor engagement, costimulation, and antigen dose) and inhibitory signals from Treg. Whereas most experimental settings analyze the capacity of Treg to prevent onset of autoimmune disease, more recent efforts indicate successful treatment of ongoing disease. Thus, Treg are on the verge of moving from experimental animal models into clinical applications in humans.

  11. [Epidemiology of uveitis].

    PubMed

    Guex-Crosier, Y

    1999-11-15

    Uveitis are a large group of inflammatory diseases involving the iris, the ciliary body and the uvea. Multiple causes can be responsible for ocular inflammation that can result either from infectious or autoimmune disease. The incidence varies from 14 to 28/100,000 habitants. According to the anatomical classification, about 30-60% (average 47%) are related to anterior uveitis. 6-30% average 21%) are posterior uveitis, 7-15% (average 12%) are intermediate uveitis and 7-69% (average 20%) are panuveitis. A specific diagnostic can be established in more than 70% in most series. The most frequently diagnosed entities are HLA-B27 related uveitis, acute anterior uveitis in herpes zoster disease, toxoplasmosis, sarcoidosis and pars planitis.

  12. Caffeic acid phenethyl ester lessens disease symptoms in an experimental autoimmune uveoretinitis mouse model.

    PubMed

    Choi, Jae-Hyeog; Roh, Kug-Hwan; Oh, Hana; Park, Sol-Ji; Ha, Sung-Min; Kang, Mi Seon; Lee, Ji-Hyun; Jung, So Young; Song, Hyunkeun; Yang, Jae Wook; Park, SaeGwang

    2015-05-01

    Experimental autoimmune uveoretinitis (EAU) is an autoimmune disease that models human uveitis. Caffeic acid phenethyl ester (CAPE), a phenolic compound isolated from propolis, possesses anti-inflammatory and immunomodulatory properties. CAPE demonstrates therapeutic potential in several animal disease models through its ability to inhibit NF-κB activity. To evaluate these therapeutic effects in EAU, we administered CAPE in a model of EAU that develops after immunization with interphotoreceptor retinal-binding protein (IRBP) in B10.RIII and C57BL/6 mice. Importantly, we found that CAPE lessened the severity of EAU symptoms in both mouse strains. Notably, treated mice exhibited a decrease in the ocular infiltration of immune cell populations into the retina; reduced TNF-α, IL-6, and IFN-γ serum levels: and inhibited TNF-α mRNA expression in retinal tissues. Although CAPE failed to inhibit IRBP-specific T cell proliferation, it was sufficient to suppress cytokine, chemokine, and IRBP-specific antibody production. In addition, retinal tissues isolated from CAPE-treated EAU mice revealed a decrease in NF-κB p65 and phospho-IκBα. The data identify CAPE as a potential therapeutic agent for autoimmune uveitis that acts by inhibiting cellular infiltration into the retina, reducing the levels of pro-inflammatory cytokines, chemokine, and IRBP-specific antibody and blocking NF-κB pathway activation.

  13. Lymphoplasmacytic endotheliitis and anterior uveitis in sheep infected experimentally with rift valley fever virus.

    PubMed

    Galindo-Cardiel, I; Busquets, N; Velarde, R; Abad, F X; Solanes, D; Rivas, R; Valle, R; Brun, A; Domingo, M

    2012-01-01

    Lymphoplasmacytic endotheliitis and anterior uveitis was diagnosed in four lambs infected experimentally with field isolates of Rift Valley fever virus (RVFV). Formalin-fixed and paraffin wax-embedded tissue from these animals was investigated by histopathology and quantitative real time reverse transcriptase polymerase chain reaction. To our knowledge, this is the first pathological description of this ocular manifestation of RVFV infection in ruminants, although these lesions have been described in man.

  14. SOCS1 Mimetic Peptide Suppresses Chronic Intraocular Inflammatory Disease (Uveitis)

    PubMed Central

    He, Chang; Yu, Cheng-Rong; Mattapallil, Mary J.; Sun, Lin

    2016-01-01

    Uveitis is a potentially sight-threatening disease characterized by repeated cycles of remission and recurrent inflammation. The JAK/STAT pathway regulates the differentiation of pathogenic Th1 and Th17 cells that mediate uveitis. A SOCS1 mimetic peptide (SOCS1-KIR) that inhibits JAK2/STAT1 pathways has recently been shown to suppress experimental autoimmune uveitis (EAU). However, it is not clear whether SOCS1-KIR ameliorated uveitis by targeting JAK/STAT pathways of pathogenic lymphocytes or via inhibition of macrophages and antigen-presenting cells that also enter the retina during EAU. To further investigate mechanisms that mediate SOCS1-KIR effects and evaluate the efficacy of SOCS1-KIR as an investigational drug for chronic uveitis, we induced EAU in rats by adoptive transfer of uveitogenic T-cells and monitored disease progression and severity by slit-lamp microscopy, histology, and optical coherence tomography. Topical administration of SOCS1-KIR ameliorated acute and chronic posterior uveitis by inhibiting Th17 cells and the recruitment of inflammatory cells into retina while promoting expansion of IL-10-producing Tregs. We further show that SOCS1-KIR conferred protection of resident retinal cells that play critical role in vision from cytotoxic effects of inflammatory cytokines by downregulating proapoptotic genes. Thus, SOCS1-KIR suppresses uveitis and confers neuroprotective effects and might be exploited as a noninvasive treatment for chronic uveitis. PMID:27703302

  15. Treatment of experimental autoimmune uveoretinitis with different natural compounds

    PubMed Central

    LI, MAN; CHEN, XIAOMING; LIU, JUANJUAN; WANG, DONGMEI; GAN, LU; LV, XIN; QIAO, YU

    2016-01-01

    Uveitis is an important eye disease that potentially causes loss of sight. Although extensive studies have been conducted on uveitis, the exact pathogenesis remains to be determined. The effects of treatment with natural compounds on an experimental autoimmune uveoretinitis (EAU) rat model were examined in the present study. A total of 25 rats were divided into 5 groups: Alkaloids (n=5), saponins (n=5), flavonoids (n=5), phenols (n=5), and the normal saline group (n=5). The rats in each group were treated with an intraperitoneal injection of proper alkaloids (berberine hydrochloride), saponins (steroidal saponins), flavonoids (baicalein), or phenols (chlorogenic acid) or physiological saline, respectively. The rats' aqueous humour and crystalline lens was then observed under the slit lamp periodically, looking for signs of inflammation. After 2 weeks, the rats were sacrificed and the degree of pathological changes on their eyeballs under different treatment methods were determined using an optical microscope. The expression of the interleukin (IL)-17 gene in the ocular tissues of the rats was assessed via RT-PCR and western blot analysis. Apoptosis on the rats' retinal tissues was detected using flow cytometry. The results showed that rats injected with phenols (chlorogenic acid) had serious ocular vascular dilatation, iris hemorrhage and purulent exudation; those injected with alkaloids (berberine hydrochloride) and flavonoids (baicalein) had a more mild form of inflammation; and those administered saponins (steroidal saponins) had only mild inflammation signs. Following detection of IL-17 mRNA and protein expression levels in the ocular tissues of rats of the five groups, it was found that their expression was lowest in the saponin-treated group and the other differences in expression were all statistically significant (P<0.05). A comparison with other groups revealed that cell apoptosis in the eyes of rats in the saponin group was the most prominent, reflecting

  16. Endotoxin-induced uveitis in rodents.

    PubMed

    Yadav, Umesh C S; Ramana, Kota V

    2013-01-01

    Uveitis is a common cause of vision loss, accounting for 10-15 % of all cases of blindness worldwide and affects individuals of all ages, genders, and races. Uveitis represents a broad range of intraocular inflammatory conditions due to complications of autoimmune diseases, bacterial infections, viral infections, and chemical and metabolic injuries. Endotoxin-induced uveitis (EIU) in rodents is an efficient experimental model to investigate the pathological mechanism and pharmacological efficacy of potential drug agents. EIU is characterized by clinically relevant classical signs of inflammation, including inflammatory exudates and cells in the anterior and vitreous chambers. EIU in small animal models such as rats, mice, and rabbits is a short-lived uveal inflammation that can be developed subsequent to administration of bacterial endotoxin, such as lipopolysaccharide. Here, we present a reproducible, reliable, and simplified protocol to induce EIU in mice. This method could be used with similar efficacy for EIU induction in other small animals as well.

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

    PubMed

    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.

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

    PubMed Central

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

    2017-01-01

    Purpose We develop a quantitative bioluminescence assay for in vivo longitudinal monitoring of inflammation in animal models of uveitis. Methods 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. Results 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. Conclusions 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. PMID:28278321

  19. Anti-inflammatory effects of vitamin E on experimental lens-induced uveitis.

    PubMed

    Cid, L; Pararajasegaram, G; Sevanian, A; Gauderman, W; Romero, J L; Marak, G E; Rao, N A

    1992-01-01

    The anti-phlogistic effect of dietary vitamin E supplementation on the acute inflammation observed in experimental lens-induced uveitis in Brown Norway rats was studied. The effects of vitamin E were examined using histopathologic parameters as well as by measuring the levels of arachidonic acid metabolites. Histologic examination of the eyes revealed that the vitamin E-deficient animals had the most severe destruction of the retina, while those animals receiving the vitamin E-supplemented diet exhibited the best preservation of the retinal architecture. Levels of arachidonic acid metabolites, as determined by radioimmunoassay, were significantly higher in vitamin E deficient rats as compared with rats on a normal diet.

  20. Treatment with melatonin after onset of experimental uveitis attenuates ocular inflammation

    PubMed Central

    Sande, P H; Dorfman, D; Fernandez, D C; Chianelli, M; Domínguez Rubio, A P; Franchi, A M; Silberman, D M; Rosenstein, R E; Sáenz, D A

    2014-01-01

    Background and Purpose Uveitis is a prevalent intraocular inflammatory disease and one of the most damaging ocular conditions. Pretreatment with melatonin prevented ocular inflammation induced by an intravitreal injection of bacterial LPS in the Syrian hamster. Here, we have assessed the anti-inflammatory effects of melatonin administered after the onset of ocular inflammation. Experimental Approach The eyes of male Syrian hamsters were intravitreally injected with vehicle or LPS. Melatonin was injected i.p. every 24 h, starting 12 or 24 h after the LPS injection. A clinical evaluation (with a score index based on clinical symptoms), the number of infiltrating cells, protein concentration and PGE2 and PGF2α levels in the aqueous humour, as well as retinal NOS activity, lipid peroxidation and TNF-α levels were assessed. Retinal function was assessed by scotopic electroretinography, and light microscopy and immunohistochemistry were used to evaluate the state of the retinal structure. Key Results Both treatment regimens with melatonin decreased clinical symptoms, reduced the leakage of cells and proteins, and decreased PG levels in aqueous humour from eyes injected with LPS. In addition, melatonin treatment blocked the decrease in scotopic electroretinogram a- and b-wave amplitude, protected the retinal structure and reduced the increase in NOS activity, lipid peroxidation and TNF-α levels, induced by LPS. Conclusions and Implications These results indicate that treatment with melatonin, starting after the onset of uveitis, attenuated ocular inflammation induced by LPS in the Syrian hamster and support the use of melatonin as a therapeutic resource for uveitis treatment. PMID:25131343

  1. Forced-exercise attenuates experimental autoimmune neuritis.

    PubMed

    Calik, Michael W; Shankarappa, Sahadev A; Stubbs, Evan B

    2012-07-01

    Physical inactivity in combination with a sedentary lifestyle is strongly associated with an increased risk of development of inflammatory-mediated diseases, including autoimmune disorders. Recent studies suggest that anti-inflammatory effects of physical exercise may be of therapeutic value in some affected individuals. In this study, we determined the effects of forced-exercise (treadmill running) on the development and progression of experimental autoimmune neuritis (EAN), an established animal model of Guillain-Barré syndrome. Adult male Lewis rats were subjected to sedentary (control) or forced-exercise (1.2 km per day, 5 days a week) for three weeks prior to induction of EAN. P2 (53-78)-immunized sedentary control rats developed a monophasic course of EAN beginning on post-injection day 12.33 ± 0.59 (n = 18) and reaching peak severity on day 15.83 ± 0.35 (n = 18). At near peak of disease, ankle- and sciatic notch-evoked compound muscle action potential (CMAP) amplitudes in sedentary control rats were reduced (~50%) while motor nerve conduction velocity (MNCV) was slowed (~30%) compared with pre-induction evoked responses. In marked contrast, rats undergoing forced-exercise exhibited a significantly less severe clinical course of EAN beginning on post-injection day 12.63 ± 0.53 (n = 16) and reaching peaking severity on day 14.69 ± 0.73 (n = 16). At near peak of disease, ankle- and sciatic-notch-evoked CMAP amplitudes in forced-exercised rats were preserved while EAN-associated slowing of MNCV was modestly attenuated by exercise. Three weeks of forced-exercise reduced by 46% total plasma corticosterone content while elevating the levels of corticosteroid binding globulin. We conclude from this study that forced-exercise administered prior to and during development of EAN affords a novel measure of protection against autoimmune-associated deficits in peripheral nerve evoked responses independent of steroid-induced immune suppression.

  2. Amelioration of Experimental Autoimmune Uveoretinitis by Aldose Reductase Inhibition in Lewis Rats

    PubMed Central

    Yadav, Umesh C. S.; Shoeb, Mohammad; Srivastava, Satish K.

    2011-01-01

    Purpose. Recently, the authors showed that the inhibition of aldose reductase (AR) prevents bacterial endotoxin-induced uveitis in rats. They have now investigated the efficacy of AR inhibitors in the prevention of experimental autoimmune-induced uveitis (EAU) in rats. Methods. Lewis rats were immunized with bovine interphotoreceptor retinoid-binding peptide (IRBP) to develop EAU. Two or 8 days after immunization, the rats started receiving the AR inhibitor fidarestat (7 mg/kg/d; intraperitoneally). They were killed when the disease was at its peak; aqueous humor (AqH) was collected from one eye, and the other eye of each rat was used for histologic studies. The protein concentration and the levels of inflammatory markers were determined in AqH. Immunohistochemical analysis of eye sections was performed to determine the expression of inflammatory markers. The effect of AR inhibition on immune response was investigated in isolated T lymphocytes. Results. Immunization of rats by IRBP peptide resulted in a significant infiltration of leukocytes in the posterior and the anterior chambers of the eye. Further, EAU caused an increase in the concentration of proteins, inflammatory cytokines, and chemokines in AqH, and the expression of inflammatory markers such as inducible-nitric oxide synthase and cycloxygenase-2 in the rat eye ciliary bodies and retina. Treatment with fidarestat significantly prevented the EAU-induced ocular inflammatory changes. AR inhibition also prevented the proliferation of spleen-derived T cells isolated from EAU rats in response to the IRBP antigen. Conclusions. These results suggest that AR could be a novel mediator of bovine IRBP-induced uveitis in rats. PMID:21900376

  3. Ninjurin1 deficiency attenuates susceptibility of experimental autoimmune encephalomyelitis in mice.

    PubMed

    Ahn, Bum Ju; Le, Hoang; Shin, Min Wook; Bae, Sung-Jin; Lee, Eun Ji; Wee, Hee-Jun; Cha, Jong-Ho; Lee, Hyo-Jong; Lee, Hye Shin; Kim, Jeong Hun; Kim, Chang-Yeon; Seo, Ji Hae; Lo, Eng H; Jeon, Sejin; Lee, Mi-Ni; Oh, Goo Taeg; Yin, Guo Nan; Ryu, Ji-Kan; Suh, Jun-Kyu; Kim, Kyu-Won

    2014-02-07

    Ninjurin1 is a homotypic adhesion molecule that contributes to leukocyte trafficking in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. However, in vivo gene deficiency animal studies have not yet been done. Here, we constructed Ninjurin1 knock-out (KO) mice and investigated the role of Ninjurin1 on leukocyte trafficking under inflammation conditions such as EAE and endotoxin-induced uveitis. Ninjurin1 KO mice attenuated EAE susceptibility by reducing leukocyte recruitment into the injury regions of the spinal cord and showed less adhesion of leukocytes on inflamed retinal vessels in endotoxin-induced uveitis mice. Moreover, the administration of a custom-made antibody (Ab26-37) targeting the Ninjurin1 binding domain ameliorated the EAE symptoms, showing the contribution of its adhesion activity to leukocyte trafficking. In addition, we addressed the transendothelial migration (TEM) activity of bone marrow-derived macrophages and Raw264.7 cells according to the expression level of Ninjurin1. TEM activity was decreased in Ninjurin1 KO bone marrow-derived macrophages and siNinj1 Raw264.7 cells. Consistent with this, GFP-tagged mNinj1-overexpressing Raw264.7 cells increased their TEM activity. Taken together, we have clarified the contribution of Ninjurin1 to leukocyte trafficking in vivo and delineated its direct functions to TEM, emphasizing Ninjurin1 as a beneficial therapeutic target against inflammatory diseases such as multiple sclerosis.

  4. Primed Mycobacterial Uveitis (PMU): Histologic and Cytokine Characterization of a Model of Uveitis in Rats

    PubMed Central

    Pepple, Kathryn L.; Rotkis, Lauren; Van Grol, Jennifer; Wilson, Leslie; Sandt, Angela; Lam, Deborah L.; Carlson, Eric; Van Gelder, Russell N.

    2015-01-01

    Purpose The purpose of this study was to compare the histologic features and cytokine profiles of experimental autoimmune uveitis (EAU) and a primed mycobacterial uveitis (PMU) model in rats. Methods In Lewis rats, EAU was induced by immunization with interphotoreceptor binding protein peptide, and PMU was induced by immunization with a killed mycobacterial extract followed by intravitreal injection of the same extract. Clinical course, histology, and the cytokine profiles of the aqueous and vitreous were compared using multiplex bead fluorescence immunoassays. Results Primed mycobacterial uveitis generates inflammation 2 days after intravitreal injection and resolves spontaneously 14 days later. CD68+ lymphocytes are the predominant infiltrating cells and are found in the anterior chamber, surrounding the ciliary body and in the vitreous. In contrast to EAU, no choroidal infiltration or retinal destruction is noted. At the day of peak inflammation, C-X-C motif ligand 10 (CXCL10), IL-1β, IL-18, and leptin were induced in the aqueous of both models. Interleukin-6 was induced 2-fold in the aqueous of PMU but not EAU. Cytokines elevated in the aqueous of EAU exclusively include regulated on activation, normal T cell expressed and secreted (RANTES), lipopolysaccharide-induced CXC chemokine (LIX), growth-related oncogene/keratinocyte chemokine (GRO/KC), VEGF, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), and IL-17A. In the vitreous, CXCL10, GRO/KC, RANTES, and MIP-1α were elevated in both models. Interleukin-17A and IL-18 were elevated exclusively in EAU. Conclusions Primed mycobacterial uveitis generates an acute anterior and intermediate uveitis without retinal involvement. Primed mycobacterial uveitis has a distinct proinflammatory cytokine profile compared with EAU, suggesting PMU is a good complementary model for study of immune-mediated uveitis. CXCL10, a proinflammatory cytokine, was increased in the aqueous and

  5. Taenia crassiceps infection abrogates experimental autoimmune encephalomyelitis.

    PubMed

    Reyes, José L; Espinoza-Jiménez, Arlett F; González, Marisol I; Verdin, Leticia; Terrazas, Luis I

    2011-01-01

    Helminth infections induce strong immunoregulation that can modulate subsequent pathogenic challenges. Taenia crassiceps causes a chronic infection that induces a Th2-biased response and modulates the host cellular immune response, including reduced lymphoproliferation in response to mitogens, impaired antigen presentation and the recruitment of suppressive alternatively activated macrophages (AAMФ). In this study, we aimed to evaluate the ability of T. crassiceps to reduce the severity of experimental autoimmune encephalomyelitis (EAE). Only 50% of T. crassiceps-infected mice displayed EAE symptoms, which were significantly less severe than uninfected mice. This effect was associated with both decreased MOG-specific splenocyte proliferation and IL-17 production and limited leukocyte infiltration into the spinal cord. Infection with T. crassiceps induced an anti-inflammatory cytokine microenvironment, including decreased TNF-α production and high MOG-specific production of IL-4 and IL-10. While the mRNA expression of TNF-α and iNOS was lower in the brain of T. crassiceps-infected mice with EAE, markers for AAMФ were highly expressed. Furthermore, in these mice, there was reduced entry of CD3(+)Foxp3(-) cells into the brain. The T. crassiceps-induced immune regulation decreased EAE severity by dampening T cell activation, proliferation and migration to the CNS.

  6. Differential expression of inwardly rectifying K+ channels and aquaporins 4 and 5 in autoimmune uveitis indicates misbalance in Müller glial cell-dependent ion and water homeostasis.

    PubMed

    Eberhardt, Christina; Amann, Barbara; Feuchtinger, Annette; Hauck, Stefanie M; Deeg, Cornelia A

    2011-05-01

    Reactive gliosis is a well-established response to virtually every retinal disease. Autoimmune uveitis, a sight threatening disease, is characterized by recurrent relapses through autoaggressive T-cells. The purpose of this study was to assess retinal Müller glial cell function in equine recurrent uveitis (ERU), a spontaneous disease model resembling the human disease, by investigating membrane proteins implicated in ion and water homeostasis. We found that Kir2.1 was highly expressed in diseased retinas, whereas Kir4.1 was downregulated in comparison to controls. Distribution of Kir2.1 appeared Müller cell associated in controls, whereas staining of cell somata in the inner nuclear layer was observed in uveitis. In contrast to other subunits, Kir4.1 was evenly expressed along equine Müller cells, whereas in ERU, Kir4.1 almost disappeared from Müller cells. Hence, we suggest a different mechanism for potassium buffering in the avascular equine retina and, moreover, an impairment in uveitis. Uveitic retinas showed significantly increased expression of AQP4 as well as a displaced expression from Müller cells in healthy specimens to an intense circular expression pattern in the outer nuclear layer in ERU cases. Most interestingly, we detected the aquaporin family member protein AQP5 to be expressed in Müller cells with strong enrichments in Müller cell secondary processes. This finding indicates that fluid regulation within the equine retina may be achieved by an additional aquaporin. Furthermore, AQP5 was significantly decreased in uveitis. We conclude that the Müller cell response in autoimmune uveitis implies considerable changes in its potassium and water physiology.

  7. Experimental melanin-protein induced uveitis (EMIU) is the sole type of uveitis evoked by a diversity of ocular melanin preparations and melanin-derived soluble polypeptides.

    PubMed

    Broekhuyse, R M; Kuhlmann, E D; Winkens, H J

    1996-01-01

    Experimental melanin-protein induced uveitis (EMIU) is a CD4 T cell-mediated disease involving the choroid and iris, but sparing the retina. The present study was designed to solubilize uveitogenic antigen from melanin granules without enzymatic digestion, and to investigate some of its elements by comparison with different purified melanin preparations. Many melanin surface-derived polypeptides with molecular weights ranging from 1 to > 100 kDa were obtained by extractions of the prepurified granules with hot lithium dodecyl sulfate (LDS). The mixture was electrophoretically separated into seven subfractions, each containing many components and capable of evoking the typical features of EMIU after footpad immunization of Lewis rats. The five low-molecular-weight fractions between M, 1 kDa and 30 kDa exhibited most pathogenicity which was evenly distributed among the fractions. Highly uveitogenic material remained in the melanin preparations even after multiple exhaustive extractions with LDS, and represented about 70% of the detectable protein. The uveal pathogen (UP-X) thus proved to be antigenically stable, and the major part of the pathogenic material was strongly bound to the granule surface layer. Concentrated urea solution was also capable of extracting many uveitogenic melanin polypeptides, but in a different composition than LDS did, and less effectively. Human choroidal melanin provided an LDS-soluble fraction with low pathogenicity. A single intraperitoneal injection of bovine melanin polypeptides together with pertussis toxin, but without footpad immunization in Freund's complete adjuvant, evoked EMIU as well. In all experiments, no uveitis except EMIU was observed, indicating that only one type of uveitogenic epitope was present in a wide variety of carrier molecules. An explanation for this phenomenon is discussed.

  8. Protective effects of intraperitoneal vitamin C, aprotinin and melatonin administration on retinal edema during experimental uveitis in the guinea pig.

    PubMed

    Kükner, A Sahap; Kükner, Aysel; Naziroğlu, Mustafa; Colakoğlu, Neriman; Celebi, Serdal; Yilmaz, Turgut; Aydemir, Orhan

    2004-01-01

    A considerable amount of clinical and experimental evidence exists suggesting the involvement of reactive oxygen substances (ROS) in the aetiology of uveitis. The activated phagocytic system of polymorphonuclear leucocytes in uveitis is involved in the generation of ROS. In addition to their direct free radical scavenging action, aprotinin, melatonin and vitamin C are known to protect against oedema formation and can preserve plasma membrane fluidity and free radical production. Histological changes in the retina that occur during uveitis are not well explained. The purpose of this study was to determine whether vitamin C, aprotinin and melatonin can protect the retina from damage accompanying experimental uveitis (EU). Thirty adult male guinea pigs were divided into five groups of six animals each. The first group was used as control. The right eyes of groups 2, 3, 4 and 5 received an intravitreal injection of bovine serum albumin for induction of experimental uveitis. At the same time and also on the consecutive third day, groups 3, 4 and 5 received intraperitoneal injections of vitamin C (ascorbic acid, 100 mg kg(-1) body wt), aprotinin (20,000 kIU kg(-1) body wt) and melatonin (10 mg kg(-1) body wt), respectively. The animals were killed on the sixth day. The average thickness of the retina and inner plexiform layer for each eye was measured in sagittal section near the optic nerve and expressed in microns. The thickness of the retina and inner plexiform layer in the control group was significantly (p < 0.01) lower than in the group EU as compared with the group EU plus vitamin C, group EU plus aprotinin, group EU plus melatonin (p < 0.05). The thicknesses of the retina and inner plexiform layer in group EU plus vitamin C, group EU plus aprotinin and group EU plus melatonin were significantly (p < 0.01) lower than that in the group EU. The difference in thickness of the retina and inner plexiform layer among the groups 3, 4 and 5 was not significant (p > 0

  9. Invariant natural killer T cells play dual roles in the development of experimental autoimmune uveoretinitis.

    PubMed

    Satoh, Masashi; Namba, Ken-Ichi; Kitaichi, Nobuyoshi; Endo, Noriko; Kitamei, Hirokuni; Iwata, Daiju; Ohno, Shigeaki; Ishida, Susumu; Onoé, Kazunori; Watarai, Hiroshi; Taniguchi, Masaru; Ishibashi, Tatsuro; Stein-Streilein, Joan; Sonoda, Koh-Hei; Van Kaer, Luc; Iwabuchi, Kazuya

    2016-12-01

    Experimental autoimmune uveoretinitis (EAU) represents an experimental model for human endogenous uveitis, which is caused by Th1/Th17 cell-mediated inflammation. Natural killer T (NKT) cells recognize lipid antigens and produce large amounts of cytokines upon activation. To examine the role of NKT cells in the development of uveitis, EAU was elicited by immunization with a peptide from the human interphotoreceptor retinoid-binding protein (hIRBP1-20) in complete Freund's adjuvant and histopathology scores were evaluated in C57BL/6 (WT) and NKT cell-deficient mice. NKT cell-deficient mice developed more severe EAU pathology than WT mice. When WT mice were treated with ligands of the invariant subset of NKT cells (α-GalCer or RCAI-56), EAU was ameliorated in mice treated with RCAI-56 but not α-GalCer. IRBP-specific Th1/Th17 cytokines were reduced in RCAI-56-treated compared with vehicle-treated mice. Although the numbers of IRBP-specific T cells detected by hIRBP3-13/I-A(b) tetramers in the spleen and the draining lymph node were the same for vehicle and RCAI-56 treatment groups, RORγt expression by tetramer-positive cells in RCAI-56-treated mice was lower than in control mice. Moreover, the eyes of RCAI-56-treated mice contained fewer IRBP-specific T cells compared with control mice. These results suggest that invariant NKT (iNKT) cells suppress the induction of Th17 cells and infiltration of IRBP-specific T cells into the eyes, thereby reducing ocular inflammation. However, in sharp contrast to the ameliorating effects of iNKT cell activation during the initiation phase of EAU, iNKT cell activation during the effector phase exacerbated disease pathology. Thus, we conclude that iNKT cells exhibit dual roles in the development of EAU. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Polyreactive myelin oligodendrocyte glycoprotein antibodies: Implications for systemic autoimmunity in progressive experimental autoimmune encephalomyelitis.

    PubMed

    Peterson, Lisa K; Tsunoda, Ikuo; Masaki, Takahisa; Fujinami, Robert S

    2007-02-01

    Two myelin oligodendrocyte glycoprotein (MOG92-106) monoclonal antibodies (mAbs) were produced from an A.SW mouse with progressive experimental autoimmune encephalomyelitis. Polyreactivity/specificity of the mAbs was demonstrated by ELISA. Functionality and a potential role in pathogenesis of systemic autoimmunity were demonstrated in vitro in a lymphocytotoxicity assay and in vivo upon injection into naïve mice. Injection of MOG mAb producing hybridomas into naïve mice resulted in immunoglobulin deposition in kidneys and liver. This model will be useful in determining whether transitional forms between CNS (organ)-specific and systemic autoimmune diseases exist, and whether progressive multiple sclerosis has features of a systemic autoimmune disease.

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

    PubMed

    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.

  12. Mechanisms for inducing nasal mucosal tolerance in experimental autoimmune uveoretinitis.

    PubMed

    Calder, Claudia J; Nicholson, Lindsay B; Dick, Andrew D

    2006-02-01

    Delivering soluble (auto) antigenic peptides via the naso-respiratory route induces tolerance to that peptide and suppression of experimental models of autoimmune disease. In the normal lung, respiratory tract dendritic cells (RTDCs) efficiently endocytose soluble antigens, migrate to regional lymph nodes and present peptide to T cells that subsequently become tolerant. This article describes protocols for inducing tolerance via the naso-respiratory tract in experimental autoimmune uveoretinitis (EAU); for the isolation of RTDCs to facilitate definition of, and conditions for, maturation and activation of cells; and to test RTDC ability to induce tolerance in murine EAU when adoptively transferred.

  13. Infectious Uveitis

    PubMed Central

    2015-01-01

    Infectious uveitis is one of the most common and visually devastating causes of uveitis in the US and worldwide. This review provides a summary of the identification, treatment, and complications associated with certain forms of viral, bacterial, fungal, helminthic, and parasitic uveitis. In particular, this article reviews the literature on identification and treatment of acute retinal necrosis due to herpes simplex virus, varicella virus, and cytomegalovirus. While no agreed-upon treatment has been identified, the characteristics of Ebola virus panuveitis is also reviewed. In addition, forms of parasitic infection such as Toxoplasmosis and Toxocariasis are summarized, as well as spirochetal uveitis. Syphilitic retinitis is reviewed given its increase in prevalence over the last decade. The importance of early identification and treatment of infectious uveitis is emphasized. Early identification can be achieved with a combination of maintaining a high suspicion, recognizing certain clinical features, utilizing multi-modal imaging, and obtaining specimens for molecular diagnostic testing. PMID:26618074

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

    PubMed

    Smith, Wendy M

    2017-03-13

    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.

  15. Trichinella spiralis: modulation of experimental autoimmune encephalomyelitis in DA rats.

    PubMed

    Gruden-Movsesijan, A; Ilic, N; Mostarica-Stojkovic, M; Stosic-Grujicic, S; Milic, M; Sofronic-Milosavljevic, Lj

    2008-04-01

    Helminth infection has a potent systemic immunomodulatory effect on the host immune response, which also affects the development of autoimmune diseases. We investigated the dose-dependent influence of Trichinella spiralis infection on experimental autoimmune encephalomyelitis (EAE). Our model of concomitant T. spiralis infection and EAE demonstrates that established infection of Dark Agouti (DA) rats with the parasite causes amelioration of the clinical course of induced EAE in a dose-dependent way. Infection with T. spiralis L1 stage muscle larvae (TSL1) reduced the severity of the autoimmune disease as judged by lower maximal clinical score, cumulative index, duration of illness and degree of mononuclear cell infiltration in T. spiralis infected animals compared to control, EAE-induced group. This study provides a valuable model of worm infection to investigate helminth-induced regulatory mechanisms for optimal benefit to the host.

  16. Carbon monoxide-releasing molecule-A1 (CORM-A1) improves clinical signs of experimental autoimmune uveoretinitis (EAU) in rats.

    PubMed

    Fagone, Paolo; Mangano, Katia; Mammana, Santa; Cavalli, Eugenio; Di Marco, Roberto; Barcellona, Maria Luisa; Salvatorelli, Lucia; Magro, Gaetano; Nicoletti, Ferdinando

    2015-04-01

    Uveitis is a sight-threatening inflammatory disease of the eye which represents the third leading cause of blindness in the developed countries. The conventional pharmacological treatment includes corticosteroids and immunosuppressive agents, which are limited by their side effects. New therapeutic strategies are thus strongly needed. Exogenously-administered carbon monoxide (CO) may represent an effective treatment for conditions characterized by a dysregulated inflammatory response. Carbon monoxide-releasing molecules (CORMs) are a novel group of compounds capable of carrying and liberating controlled quantities of CO. Among CORMs, CORM-A1 represents the first example of water soluble CO releaser. We show here that CORM-A1 under a late prophylactic regime is able to significantly ameliorate the natural course of experimental autoimmune uveoretinitis, a rodent model of immunoinflammatory posterior uveitis. The present study strongly supports the development of CORM-A1 as a potential new drug for treatment of patients with non-infectious posterior uveitis. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Circulating anti-nuclear antibodies in uveitis.

    PubMed

    Coaccioli, S; Di Cato, L; Panaccione, A; Crapa, M E; Paladini, A; Marinangeli, F

    2013-01-01

    Uveitis represents the inflammatory process of uvea being caused by an autoimmune mechanism. Similarly, systemic connective tissue diseases (CTDs) present as well an autoimmune pathogenesis and numerous are the reports of a correlated association of the two different conditions, according to their serological characteristics. In this work, we have studied a number of subjects affected by uveitis as well as a number of subjects affected by CTDs associated with uveitis (14.2%). Only one significant correlation has been observed here, and it is the one between uveitis and the Systemic Lupus Erythematosus (SLE, 42.8%). The observation has been made up to through a time-lapse of 18 months during which, the signs of uveitis showed a clear trend to faintly diminish till completely disappearing. At the same time, the presence of uveitis has not stressed out any correlation either with the general positivity for the autoantibodies, nor with the titration or the pattern of single fluorescent antibodies. This study seems to confirm the presence of a weak association between uveitis and CTDs (SLE excluded), where the research of antinuclear antibodies does not seem to give any useful element in terms of diagnostics and clinics, able to value the risk of developing CTDs when uveitis is already stated.

  18. Comparative Proteomic Analysis of Two Uveitis Models in Lewis Rats

    PubMed Central

    Pepple, Kathryn L.; Rotkis, Lauren; Wilson, Leslie; Sandt, Angela; Van Gelder, Russell N.

    2015-01-01

    Purpose Inflammation generates changes in the protein constituents of the aqueous humor. Proteins that change in multiple models of uveitis may be good biomarkers of disease or targets for therapeutic intervention. The present study was conducted to identify differentially-expressed proteins in the inflamed aqueous humor. Methods Two models of uveitis were induced in Lewis rats: experimental autoimmune uveitis (EAU) and primed mycobacterial uveitis (PMU). Differential gel electrophoresis was used to compare naïve and inflamed aqueous humor. Differentially-expressed proteins were separated by using 2-D gel electrophoresis and excised for identification with matrix-assisted laser desorption/ionization–time of flight (MALDI-TOF). Expression of select proteins was verified by Western blot analysis in both the aqueous and vitreous. Results The inflamed aqueous from both models demonstrated an increase in total protein concentration when compared to naïve aqueous. Calprotectin, a heterodimer of S100A8 and S100A9, was increased in the aqueous in both PMU and EAU. In the vitreous, S100A8 and S100A9 were preferentially elevated in PMU. Apolipoprotein E was elevated in the aqueous of both uveitis models but was preferentially elevated in EAU. Beta-B2–crystallin levels decreased in the aqueous and vitreous of EAU but not PMU. Conclusions The proinflammatory molecules S100A8 and S100A9 were elevated in both models of uveitis but may play a more significant role in PMU than EAU. The neuroprotective protein β-B2–crystallin was found to decline in EAU. Therapies to modulate these proteins in vivo may be good targets in the treatment of ocular inflammation. PMID:26747776

  19. Evaluation of Neopterin Levels in an Endotoxin-Induced Experimental Uveitis Model.

    PubMed

    Serif, Nigar; Gurelik, Gokhan; Hasanreisoğlu, Murat; Yaman, Halil; Akyurek, Nalan

    2016-01-01

    In this study, NP levels of intraocular fluids and serum were analyzed in the endotoxin-induced uveitis model. Intravitreal injection of 0.05 ml E. Coli lipopolysaccharide (IVT LPS) has been performed into the right eyes of 14 rabbits. Animals were divided into two groups. Group 1 (n = 7) sacrificed 24 hours after the intravitreal injection, and group 2 (n = 7) 72 hours after the intravitreal injection. Aqueous fluid, vitreous and serum samples were drawn at the time of sacrifice; histopathological changes were also examined. Significantly elevated aqueous and vitreous NP levels were observed in IVT LPS injected eyes. In IVT LPS injected eyes, aqueous NP levels showed a significant decrease in 72 hours (p < 0.05), whereas vitreous NP concentrations significantly increased in 72 hours (p < 0.05). Both aqueous and vitreous protein concentrations were significantly higher in IVT LPS injected eyes. Histopathologic evaluation revealed that, in the first 24 hours, inflammation was significant in choroid and ciliary body. Retinal histopathological changes were observed mainly at 72 hours. This study demonstrates that neopterin levels correlate with early intraocular inflammatory response in an endotoxin-induced uveitis model.

  20. Intraocular injection of tamoxifen-loaded nanoparticles: a new treatment of experimental autoimmune uveoretinitis.

    PubMed

    de Kozak, Yvonne; Andrieux, Karine; Villarroya, Henri; Klein, Christophe; Thillaye-Goldenberg, Brigitte; Naud, Marie-Christine; Garcia, Elisabeth; Couvreur, Patrick

    2004-12-01

    In this study, we tested the efficiency of an intravitreal injection of tamoxifen, a non-steroidal estrogen receptor modulator, in retinal soluble antigen (S-Ag)-induced experimental autoimmune uveoretinitis (EAU). To increase the bioavailability of tamoxifen, we incorporated tamoxifen into polyethylene glycol (PEG)-coated nanoparticles (NP-PEG-TAM). The localization of the nanoparticles within the eye was investigated using fluorescent-labeled PEG-coated nanoparticles after injection into the vitreous cavity of rats with EAU. Some nanoparticles were distributed extracellularly throughout the ocular tissues, others were concentrated in resident ocular cells and in infiltrating macrophages. Whereas the injection of free tamoxifen did not alter the course of EAU, injection of NP-PEG-TAM performed 1-2 days before the expected onset of the disease in controls resulted in significant inhibition of EAU. NP-PEG-TAM injection significantly reduced EAU compared to injection of NP-PEG-TAM with 17beta-estradiol (E2), suggesting that tamoxifen is acting as a partial antagonist to E2. Diminished infiltration by MHC class II(+) inflammatory cells and low expression of TNF-alpha, IL-1beta, and RANTES mRNA were noted in eyes of NP-PEG-TAM-treated rats. Intravitreal injection of NP-PEG-TAM decreased S-Ag lymphocyte proliferation, IFN-gamma production by inguinal lymph node cells, and specific delayed-type hypersensitivity indicative of a reduced Th1-type response. It increased the anti-S-Ag IgG1 isotype indicating an antibody class switch to Th2 response. These data suggest that NP-PEG-TAM inhibition of EAU could result from a form of immune deviation. Tamoxifen-loaded nanoparticles may represent a new option for the treatment of experimental uveitis.

  1. Kinetics of tissue iron in experimental autoimmune encephalomyelitis in rats.

    PubMed

    Tota, Marin; Jakovac, Hrvoje; Grebić, Damir; Marinić, Jelena; Broznić, Dalibor; Čanadi-Jurešić, Gordana; Milin, Cedomila; Radošević-Stašić, Biserka

    2011-10-01

    To elucidate the role of iron in the pathomechanisms of autoimmune CNS disorders, we estimated the tissue concentrations of Fe(2+) in the brain, spinal cord, and liver in the chronic relapsing form of experimental autoimmune encephalomyelitis (EAE). The disease was induced in Dark Agouti (DA) strain of rats, by subcutaneous injection of bovine brain homogenate in complete Freund's adjuvant (CFA). Control rats consisted of unsensitized rats and of rats treated with CFA or saline. The data obtained by clinical assessment and by inductively coupled plasma spectrometry have shown that the attacks of disease (on the 12th and 22nd post-immunization day) were followed by high accumulation of iron in the liver. Additionally, during the second attack of disease, the decreased concentration of Fe(2+) was found in cervical spinal cord. The data point to regulatory effects of iron and hepatic trace elements regulating mechanisms in the pathogenesis of EAE.

  2. Redundancy between Cysteine Cathepsins in Murine Experimental Autoimmune Encephalomyelitis.

    PubMed

    Allan, Euan Ramsay Orr; Yates, Robin Michael

    2015-01-01

    The cysteine cathepsins B, S, and L are functionally linked to antigen processing, and hence to autoimmune disorders such as multiple sclerosis. Stemming from several studies that demonstrate that mice can be protected from experimental autoimmune encephalomyelitis (EAE) through the pharmacologic inhibition of cysteine cathepsins, it has been suggested that targeting these enzymes in multiple sclerosis may be of therapeutic benefit. Utilizing mice deficient in cysteine cathepsins both individually and in combination, we found that the myelin-associated antigen myelin oligodendrocyte glycoprotein (MOG) was efficiently processed and presented by macrophages to CD4+ T cells in the individual absence of cathepsin B, S or L. Similarly, mice deficient in cathepsin B or S were susceptible to MOG-induced EAE and displayed clinical progression and immune infiltration into the CNS, similar to their wild-type counterparts. Owing to a previously described CD4+ T cell deficiency in mice deficient in cathepsin L, such mice were protected from EAE. When multiple cysteine cathepsins were simultaneously inhibited via genetic deletion of both cathepsins B and S, or by a cathepsin inhibitor (LHVS), MHC-II surface expression, MOG antigen presentation and EAE were attenuated or prevented. This study demonstrates the functional redundancy between cathepsin B, S and L in EAE, and suggests that the inhibition of multiple cysteine cathepsins may be needed to modulate autoimmune disorders such as multiple sclerosis.

  3. Chronic exercise confers neuroprotection in experimental autoimmune encephalomyelitis.

    PubMed

    Pryor, William M; Freeman, Kimberly G; Larson, Rebecca D; Edwards, Gaylen L; White, Lesley J

    2015-05-01

    Multiple sclerosis (MS) is an autoimmune disease that affects the CNS, resulting in accumulated loss of cognitive, sensory, and motor function. This study evaluates the neuropathological effects of voluntary exercise in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Two groups of C57BL/6J mice were injected with an emulsion containing myelin oligodendrocyte glycoprotein and then randomized to housing with a running wheel or a locked wheel. Exercising EAE mice exhibited a less severe neurological disease score and later onset of disease compared with sedentary EAE animals. Immune cell infiltration and demyelination in the ventral white matter tracts of the lumbar spinal cord were significantly reduced in the EAE exercise group compared with sedentary EAE animals. Neurofilament immunolabeling in the ventral pyramidal and extrapyramidal motor tracts displayed a more random distribution of axons and an apparent loss of smaller diameter axons, with a greater loss of fluorescence immunolabeling in the sedentary EAE animals. In lamina IX gray matter regions of the lumbar spinal cord, sedentary animals with EAE displayed a greater loss of α-motor neurons compared with EAE animals exposed to exercise. These findings provide evidence that voluntary exercise results in reduced and attenuated disability, reductions in autoimmune cell infiltration, and preservation of axons and motor neurons in the lumbar spinal cord of mice with EAE.

  4. Experimental autoimmune orchitis as a model of immunological male infertility.

    PubMed

    Naito, Munekazu; Terayama, Hayato; Hirai, Shuichi; Qu, Ning; Lustig, Livia; Itoh, Masahiro

    2012-12-01

    Clinically, 60-75% of male infertility cases are categorized as idiopathic spermatogenic disturbance. In previous studies of this condition, lymphocytic infiltration and immune deposits were present in several testis biopsy specimens, indicating that inflammatory or immunological factors contribute to the occurrence of the lesions. However, there is currently little evidence regarding immunological infertility in men. Previously, we established an immunological infertility model, experimental autoimmune orchitis (EAO), that can be induced in mice by two subcutaneous injections of viable syngeneic testicular germ cells without the use of any adjuvant. In this EAO model, lymphocytes surround the tubuli recti and then induce spermatogenic disturbance. In addition, after the active inflammation stage of this model, the seminiferous epithelium is damaged irreversibly, resembling the histopathology of human male idiopathic spermatogenic disturbance. In the majority of patients with testicular autoimmunity, there is a chronic and asymptomatic development of the inflammatory reaction. Therefore, this disease is very difficult to diagnose at the ongoing stage, and it is possible that the histopathology of idiopathic spermatogenic disturbance in the clinic is reported at the post-active inflammation stage of autoimmune orchitis. In this review, the histopathology of EAO before and after inflammation is discussed, comparing it with human orchitis.

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

    PubMed

    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.

  6. Uveitis: advances in understanding of pathogenesis and treatment.

    PubMed

    Read, Russell W

    2006-08-01

    Uveitis is a leading cause of blindness affecting individuals of all ages, genders, and races. Uveitis may be due to autoimmune, infectious, toxic, malignant, or traumatic processes. Some evidence supports an association between conditions previously presumed to be autoimmune and viral infectious agents. For autoimmune uveitis, therapy is nonspecific, typically beginning with corticosteroids. For nonresponsive disease or for corticosteroid sparing, recent reports on mycophenolate mofetil, infliximab, and interferon therapy show success for various forms of uveitis. Treatment of the complications of uveitis, especially cystoid macular edema, is difficult. Vitamin E appears to offer little benefit, whereas octreotide may be effective. Recent collaborative efforts at standardization in the field should enhance studies on these conditions.

  7. Clinical Trials in Noninfectious Uveitis

    PubMed Central

    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

  8. The role of lipoprotein-associated phospholipase A2 in a murine model of experimental autoimmune uveoretinitis.

    PubMed

    Crawford, G L; Boldison, J; Copland, D A; Adamson, P; Gale, D; Brandt, M; Nicholson, L B; Dick, A D

    2015-01-01

    Macrophage activation is, in part, regulated via hydrolysis of oxidised low density lipoproteins by Lipoprotein-Associated phospholipase A2 (Lp-PLA2), resulting in increased macrophage migration, pro-inflammatory cytokine release and chemokine expression. In uveitis, tissue damage is mediated as a result of macrophage activation; hence inhibition of Lp-PLA2 may limit macrophage activation and protect the tissue. Utilising Lp-PLA2 gene-deficient (KO) mice and a pharmacological inhibitor of Lp-PLA2 (SB-435495) we aimed to determine the effect of Lp-PLA2 suppression in mediating retinal protection in a model of autoimmune retinal inflammation, experimental autoimmune uveoretinitis (EAU). Following immunisation with RBP-3 (IRBP) 1-20 or 161-180 peptides, clinical disease was monitored and severity assessed, infiltrating leukocytes were enumerated by flow cytometry and tissue destruction quantified by histology. Despite ablation of Lp-PLA2 enzyme activity in Lp-PLA2 KO mice or wild-type mice treated with SB-435495, the number of infiltrating CD45+ cells in the retina was equivalent to control EAU animals, and there was no reduction in disease severity. Thus, despite the reported beneficial effects of therapeutic Lp-PLA2 depletion in a variety of vascular inflammatory conditions, we were unable to attenuate disease, show delayed disease onset or prevent progression of EAU in Lp-PLA2 KO mice. Although EAU exhibits inflammatory vasculopathy there is no overt defect in lipid metabolism and given the lack of effect following Lp-PLA2 suppression, these data support the hypothesis that sub-acute autoimmune inflammatory disease progresses independently of Lp-PLA2 activity.

  9. Inhibition of experimental autoimmune orchitis by fossil diatoms

    NASA Astrophysics Data System (ADS)

    Bustuoabad, Oscar D.; Meiss, Roberto P.; Molinolo, Alfredo R.; Mayer, Alejandro M. S.

    1985-06-01

    Experimental autoimmune orchitis (EAO) induced in Swiss mice could be reduced by means of the utilization of micronized frustules of fossil diatoms (DS) containing 54% of SiO2. Experimental mice were sensitized with testicular Antigen (Ag) in Complete Freund’s Adjuvant (CFA) inoculated twice, on day 0 and day 21. 100 μg of DS suspension was inoculated into sensitized mice 10 times, once every 4 days, subcutaneously, starting on day 7 after the first Ag inoculation. Mice receiving the DS treatment showed a diminution of the delayed hypersensitivity reaction, lower antibody titer and decreased incidence of testicular injury as well as reduced grade and extension of the lesions. Possible explanation of these results would suggest alteration of monocyte and/or macrophage normal behaviour as well as alteration of antibody synthesis by different mechanisms.

  10. IL17 Mediates Pelvic Pain in Experimental Autoimmune Prostatitis (EAP)

    PubMed Central

    Murphy, Stephen F.; Schaeffer, Anthony J.; Done, Joseph; Wong, Larry; Bell-Cohn, Ashlee; Roman, Kenny; Cashy, John; Ohlhausen, Michelle; Thumbikat, Praveen

    2015-01-01

    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. PMID:25933188

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

    PubMed Central

    Allegri, Pia; Mastromarino, Antonio; Neri, Piergiorgio

    2010-01-01

    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 relapse frequency in all treated patients, before and after Norflo treatment, followed by the number of relapses 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. PMID:21060672

  12. Beneficial effects of blueberries in experimental autoimmune encephalomyelitis.

    PubMed

    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 < 0.01). When blueberry-fed mice with EAE were compared with control-fed mice with EAE, blueberry-fed mice had significantly lower motor disability scores (p = 0.03) as well as significantly greater myelin preservation in the lumbar spinal cord (p = 0.04). In a relapsing-remitting EAE model, blueberry-supplemented mice showed improved cumulative and final motor scores compared to control diet-fed mice (p = 0.01 and 0.03, respectively). These data demonstrate that blueberry supplementation is beneficial in multiple EAE models, suggesting that blueberries, which are easily administered orally and well-tolerated, may provide benefit to MS patients.

  13. The Microbiota Determines Susceptibility to Experimental Autoimmune Uveoretinitis

    PubMed Central

    Heissigerova, Jarmila; Seidler Stangova, Petra; Klimova, Aneta; Svozilkova, Petra; Hrncir, Tomas; Stepankova, Renata; Kverka, Miloslav; Tlaskalova-Hogenova, Helena; Forrester, John V.

    2016-01-01

    The microbiota is a crucial modulator of the immune system. Here, we evaluated how its absence or reduction modifies the inflammatory response in the murine model of experimental autoimmune uveoretinitis (EAU). We induced EAU in germ-free (GF) or conventionally housed (CV) mice and in CV mice treated with a combination of broad-spectrum antibiotics either from the day of EAU induction or from one week prior to induction of disease. The severity of the inflammation was assessed by fundus biomicroscopy or by histology, including immunohistology. The immunophenotyping of T cells in local and distant lymph nodes was performed by flow cytometry. We found that GF mice and mice where the microbiota was reduced one week before EAU induction were protected from severe autoimmune inflammation. GF mice had lower numbers of infiltrating macrophages and significantly less T cell infiltration in the retina than CV mice with EAU. GF mice also had reduced numbers of IFN-γ and IL-17-producing T cells and increased numbers of regulatory T cells in the eye-draining lymph nodes. These data suggest that the presence of microbiota during autoantigen recognition regulates the inflammatory response by influencing the adaptive immune response. PMID:27294159

  14. Inflammasome activation in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE).

    PubMed

    Barclay, William; Shinohara, Mari L

    2017-03-01

    The aptly named inflammasomes are powerful signaling complexes that sense inflammatory signals under a myriad of conditions, including those from infections and endogenous sources. The inflammasomes promote inflammation by maturation and release of the pro-inflammatory cytokines, IL-1β and IL-18. Several inflammasomes have been identified so far, but this review focuses mainly on the NLRP3 inflammasome. By still ill-defined activation mechanisms, a sensor molecule, NLRP3 (NACHT, LRR and PYD domains-containing protein 3), responds to danger signals and rapidly recruits ASC (apoptosis-associated speck-like protein containing a CARD) and pro-caspase-1 to form a large oligomeric signaling platform-the inflammasome. Involvement of the NLRP3 inflammasome in infections, metabolic disorders, autoinflammation, and autoimmunity, underscores its position as a central player in sensing microbial and damage signals and coordinating pro-inflammatory immune responses. Indeed, evidence in patients with multiple sclerosis (MS) suggests inflammasome activation occurs during disease. Experiments with the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), specifically describe the NLRP3 inflammasome as critical and necessary to disease development. This review discusses recent studies in EAE and MS which describe associations of inflammasome activation with promotion of T cell pathogenicity, infiltration of cells into the central nervous system (CNS) and direct neurodegeneration during EAE and MS.

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

    SciTech Connect

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

    1983-08-01

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

  16. Translational utility of experimental autoimmune encephalomyelitis: recent developments

    PubMed Central

    Guerreiro-Cacais, Andre Ortlieb; Laaksonen, Hannes; Flytzani, Sevasti; N’diaye, Marie; Olsson, Tomas; Jagodic, Maja

    2015-01-01

    Multiple sclerosis (MS) is a complex autoimmune condition with firmly established genetic and environmental components. Genome-wide association studies (GWAS) have revealed a large number of genetic polymorphisms in the vicinity of, and within, genes that associate to disease. However, the significance of these single-nucleotide polymorphisms in disease and possible mechanisms of action remain, with a few exceptions, to be established. While the animal model for MS, experimental autoimmune encephalomyelitis (EAE), has been instrumental in understanding immunity in general and mechanisms of MS disease in particular, much of the translational information gathered from the model in terms of treatment development (glatiramer acetate and natalizumab) has been extensively summarized. In this review, we would thus like to cover the work done in EAE from a GWAS perspective, highlighting the research that has addressed the role of different GWAS genes and their pathways in EAE pathogenesis. Understanding the contribution of these pathways to disease might allow for the stratification of disease subphenotypes in patients and in turn open the possibility for new and individualized treatment approaches in the future. PMID:26622189

  17. Alterations in the thymopoiesis in experimental autoimmune myasthenia gravis.

    PubMed

    Kosec, Dusko; Vidić-Danković, Biljana; Isaković, Katarina; Leposavić, Gordana

    2005-04-01

    Experimental autoimmune myasthenia gravis (EAGM) was induced in female AO rats, by a single immunization with Torpedo acetylcholine receptor (AChR). Animals injected with saline served as controls. The study showed substantial changes in EAMG rats in the thymopoiesis, causing an increase in the relative proportion of mature CD8+ and, particularly, CD4+ (possibly autoreactive) single positive (SP) cells expressing TCRalphabeta at high level (TCRalphabeta(high)), as well as in that of mature double negative (DN) TCRalphabeta(high) cells, which are believed to be the immunoregulatory cells that augment autoantibody (autoAb) production. These results indicate that an augmented production of autoreactive CD4+ cells, on one side, and an increase of the immunoregulatory T cells that augment autoAb production, on the other side (reflecting, most likely, an increased entry of activated autoreactive CD4+ T cells from the periphery into the thymus), may have a significant role in the sustention of immune response in EAMG, and may suggest a putative mechanism underlying the sustention of autoimmune response in acquired MG.

  18. Plumbagin suppresses dendritic cell functions and alleviates experimental autoimmune encephalomyelitis.

    PubMed

    Zhang, Kai; Ge, Zhenzhen; Da, Yurong; Wang, Dong; Liu, Ying; Xue, Zhenyi; Li, Yan; Li, Wen; Zhang, Lijuan; Wang, Huafeng; Zhang, Huan; Peng, Meiyu; Hao, Junwei; Yao, Zhi; Zhang, Rongxin

    2014-08-15

    Plumbagin (PL, 5-hydroxy-2-methyl-1,4-naphthoquinone) is a herbal compound derived from medicinal plants of the Droseraceae, Plumbaginaceae, Dioncophyllaceae, and Ancistrocladaceae families. Reports have shown that PL exerts immunomodulatory activity and may be a novel drug candidate for immune-related disease therapy. However, its effects on dendritic cells (DCs), the most potent antigen-presenting cells (APCs), remain unclear. In this study, we demonstrate that PL inhibits the differentiation, maturation, and function of human monocyte-derived DCs. PL can also restrict the expression of Th1- and Th17-polarizing cytokines in mDC. In addition, PL suppresses DCs both in vitro and in vivo, as demonstrated by its effects on the mouse DC line DC2.4 and mice with experimental autoimmune encephalomyelitis (EAE), respectively. Notably, PL ameliorated the clinical symptoms of EAE, including central nervous system (CNS) inflammation and demyelination. Our results demonstrate the immune suppressive and anti-inflammatory properties of PL via its effects on DCs and suggest that PL could be a potential treatment for DC-related autoimmune and inflammatory diseases.

  19. Juvenile idiopathic arthritis-associated uveitis.

    PubMed

    Clarke, Sarah L N; Sen, Ethan S; Ramanan, Athimalaipet V

    2016-04-27

    Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood, with JIA-associated uveitis its most common extra-articular manifestation. JIA-associated uveitis is a potentially sight-threatening condition and thus carries a considerable risk of morbidity. The aetiology of the condition is autoimmune in nature with the predominant involvement of CD4(+) T cells. However, the underlying pathogenic mechanisms remain unclear, particularly regarding interplay between genetic and environmental factors. JIA-associated uveitis comes in several forms, but the most common presentation is of the chronic anterior uveitis type. This condition is usually asymptomatic and thus screening for JIA-associated uveitis in at-risk patients is paramount. Early detection and treatment aims to stop inflammation and prevent the development of complications leading to visual loss, which can occur due to both active disease and burden of disease treatment. Visually disabling complications of JIA-associated uveitis include cataracts, glaucoma, band keratopathy and macular oedema. There is a growing body of evidence for the early introduction of systemic immunosuppressive therapies in order to reduce topical and systemic glucocorticoid use. This includes more traditional treatments, such as methotrexate, as well as newer biological therapies. This review highlights the epidemiology of JIA-associated uveitis, the underlying pathogenesis and how affected patients may present. The current guidelines and criteria for screening, diagnosis and monitoring are discussed along with approaches to management.

  20. Hsp70 Regulates Immune Response in Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Mansilla, M. José; Costa, Carme; Eixarch, Herena; Tepavcevic, Vanja; Castillo, Mireia; Martin, Roland; Lubetzki, Catherine; Aigrot, Marie-Stéphane; Montalban, Xavier; Espejo, Carmen

    2014-01-01

    Heat shock protein (Hsp)70 is one of the most important stress-inducible proteins. Intracellular Hsp70 not only mediates chaperone-cytoprotective functions but can also block multiple steps in the apoptosis pathway. In addition, Hsp70 is actively released into the extracellular milieu, thereby promoting innate and adaptive immune responses. Thus, Hsp70 may be a critical molecule in multiple sclerosis (MS) pathogenesis and a potential target in this disease due to its immunological and cytoprotective functions. To investigate the role of Hsp70 in MS pathogenesis, we examined its immune and cytoprotective roles using both in vitro and in vivo experimental procedures. We found that Hsp70.1-deficient mice were more resistant to developing experimental autoimmune encephalomyelitis (EAE) compared with their wild-type (WT) littermates, suggesting that Hsp70.1 plays a critical role in promoting an effective myelin oligodendrocyte glycoprotein (MOG)-specific T cell response. Conversely, Hsp70.1-deficient mice that developed EAE showed an increased level of autoreactive T cells to achieve the same production of cytokines compared with the WT mice. Although a neuroprotective role of HSP70 has been suggested, Hsp70.1-deficient mice that developed EAE did not exhibit increased demyelination compared with the control mice. Accordingly, Hsp70 deficiency did not influence the vulnerability to apoptosis of oligodendrocyte precursor cells (OPCs) in culture. Thus, the immunological role of Hsp70 may be relevant in EAE, and specific therapies down-regulating Hsp70 expression may be a promising approach to reduce the early autoimmune response in MS patients. PMID:25153885

  1. MicroRNAs in multiple sclerosis and experimental autoimmune encephalomyelitis.

    PubMed

    Thamilarasan, Madhan; Koczan, Dirk; Hecker, Michael; Paap, Brigitte; Zettl, Uwe K

    2012-01-01

    MicroRNA (miRNA) are small non-coding RNA molecules about 21-25 nucleotides long. They control gene regulation by translational repression and cleavage. Several studies have shown that many miRNA are associated with the etiology of different diseases. Recent developments in diverse miRNA profiling platforms like microarray and quantitative real-time PCR may enable the identification of specific miRNA as novel diagnostic and predictive markers for various diseases. MiRNAs could even be used as therapeutic drug targets. Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system. Dysregulated immune system processes result in demyelination of neurons and consequently, electrical impulses that travel along the nerves are disrupted resulting in the impairment of organs. In the past three years, there has been an increased interest in establishing miRNA-based biomarkers for MS. So far, there are six studies on miRNA expression in MS patients in which first miRNAs were discovered as potential disease markers. For instance, one study showed that blood levels of miR-145 can discriminate MS patients from healthy controls, and another showed that active lesions in the brain are characterized by a strong up-regulation of miR-155. Studies on experimental autoimmune encephalomyelitis (EAE), the animal model of MS, further support the significance of miRNA as e.g. mice with miR-155 deletion are highly resistant to EAE. Such investigations help to understand the molecular processes involved in the disease. The identification of miRNA markers that are associated with type of MS, individual disease activity or clinical progression under treatment may open new avenues for early diagnosis and optimized therapy of MS.

  2. Treatment of passively transferred experimental autoimmune myasthenia gravis using papain

    PubMed Central

    Poulas, K; Tsouloufis, T; Tzartos, S J

    2000-01-01

    Antibody-mediated acetylcholine receptor (AChR) loss at the neuromuscular junction, the main cause of the symptoms of myasthenia gravis, is induced by bivalent or multivalent antibodies. Passive transfer of experimental autoimmune myasthenia gravis (EAMG) can be induced very efficiently in rats by administration of intact MoAbs directed against the main immunogenic region (MIR) of the AChR, but not by their monovalent Fab fragments. We tested whether papain, which has been used therapeutically in autoimmune and other diseases, is capable of preventing EAMG by in vivo cleavage of the circulating anti-AChR antibodies into Fab fragments. EAMG was induced in 4-week-old female Lewis rats by i.p. injection of anti-MIR mAb35. A total of 0·75 mg of papain was given as one or three injections 3–7 h after MoAb injection. The mAb35 + papain-treated animals developed mild weakness during the first 30 h and subsequently recovered, while all animals that received only mAb35 developed severe myasthenic symptoms and died within 24–30 h. Animals treated only with papain showed no apparent side effects for up to 2 months. Serum anti-AChR levels in mAb35 + papain-treated rats decreased within a few hours, whereas in non-papain-treated rats they remained high for at least 30 h. Muscle AChR in mAb35 + papain-treated animals was partially protected from antibody-mediated degradation. These results show that treatment of rats with papain can prevent passively transferred EAMG without any apparent harm to the animals, and suggest a potential therapeutic use for proteolytic enzymes in myasthenia gravis. PMID:10792389

  3. Equine recurrent uveitis: Human and equine perspectives.

    PubMed

    Malalana, Fernando; Stylianides, Amira; McGowan, Catherine

    2015-10-01

    Equine recurrent uveitis (ERU) is a spontaneous disease characterised by repeated episodes of intraocular inflammation. The epidemiology of ERU has not been fully elucidated, but the condition appears to be much more common in horses than is recurrent uveitis in humans, especially in certain breeds and geographical regions. Both humans and horses show a similarly altered immune response and a marked autoimmune response as the primary disease pathophysiology. However, an inciting cause is not always clear. Potential inciting factors in horses include microbial agents such as Leptospira spp. Microbial factors and genetic predisposition to the disease may provide clues as to why the horse appears so susceptible to this disease. The aim of this review is to discuss the immunology and genetics of ERU, compare the disease in horses with autoimmune anterior uveitis in humans, and discuss potential reasons for the increased prevalence in the horse. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    PubMed

    Kumagami, T; Kato, S; Ohama, E

    1997-04-01

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

  5. Assessment and In Vivo Scoring of Murine Experimental Autoimmune Uveoretinitis Using Optical Coherence Tomography

    PubMed Central

    Chu, Colin J.; Herrmann, Philipp; Carvalho, Livia S.; Liyanage, Sidath E.; Bainbridge, James W. B.; Ali, Robin R.; Dick, Andrew D.; Luhmann, Ulrich F. O.

    2013-01-01

    Despite advances in clinical imaging and grading our understanding of retinal immune responses and their morphological correlates in experimental autoimmune uveoretinitis (EAU), has been hindered by the requirement for post-mortem histology. To date, monitoring changes occurring during EAU disease progression and evaluating the effect of therapeutic intervention in real time has not been possible. We wanted to establish whether optical coherence tomography (OCT) could detect intraretinal changes during inflammation and to determine its utility as a tool for accurate scoring of EAU. EAU was induced in C57BL/6J mice and animals evaluated after 15, 26, 36 and 60 days. At each time-point, contemporaneous Spectralis-OCT scanning, topical endoscopic fundal imaging (TEFI), fundus fluorescein angiography (FFA) and CD45-immunolabelled histology were performed. OCT features were further characterised on retinal flat-mounts using immunohistochemistry and 3D reconstruction. Optic disc swelling and vitreous opacities detected by OCT corresponded to CD45+ cell infiltration on histology. Vasculitis identified by FFA and OCT matched perivascular myeloid and T-cell infiltrates and could be differentiated from unaffected vessels. Evolution of these changes could be followed over time in the same eye. Retinal folds were visible and found to encapsulate mixed populations of activated myeloid cells, T-cells and microglia. Using these features, an OCT-based EAU scoring system was developed, with significant correlation to validated histological (Pearson r2 = 0.6392, P<0.0001, n = 31 eyes) and TEFI based scoring systems (r2 = 0.6784, P<0.0001). OCT distinguishes the fundamental features of murine EAU in vivo, permits dynamic assessment of intraretinal changes and can be used to score disease severity. As a result, it allows tissue synchronisation with subsequent cellular and functional assessment and greater efficiency of animal usage. By relating OCT signals with

  6. Morphometric analysis of T lymphocyte compartmentation in experimental autoimmune uveoretinitis.

    PubMed Central

    Brown, E C; Kasp, E; Dumonde, D C

    1989-01-01

    Experimental autoimmune uveoretinitis (EAU) in the Lewis rat is characterized by extensive infiltration of inflammatory cells into all compartments of the eye, only some of which become irreversibly damaged. The apparent differences in the pathogenic impact of inflammatory cells within different ocular compartments may suggest that different mechanisms underlie cellular infiltration and selective tissue destruction. In order to investigate the importance of T lymphocyte infiltration, we carried out a precise topographical and temporal analysis of T cell infiltration into five compartments of the eye using an improved method for the fixation of ocular tissue. Our study showed that T cell infiltration began in the ciliary body and was most numerous and sustained in this area during EAU. The peak of T cell infiltration into the retina was comparatively delayed and was of lesser magnitude. Analysis of T cell subsets revealed a tendency for the helper phenotype to predominant during the course of disease in all ocular compartments except the retina where both helper and cytotoxic/suppressor T cells were equally represented at the height of inflammation. We suggest that the pathogenetic impact of autoreactive lymphocytes in EAU depends on the accessibility of relevant tissue antigen and on local microenvironmental features of lymphocytic traffic within different ocular compartments. Images Fig. 1 Fig. 2 PMID:2805411

  7. Regulation of experimental autoimmune encephalomyelitis by TPL-2 kinase

    PubMed Central

    Tsakiri, Niki; Kierdorf, Katrin; Brender, Christine; Ben-Addi, Abduelhakem; Veldhoen, Marc; Tsichlis, Philip N.; Stockinger, Brigitta; O’Garra, Anne; Prinz, Marco; Kollias, George; Ley, Steven C.

    2014-01-01

    TPL-2 expression is required for efficient polarization of naïve T cells to Th1 effector cells in vitro, and for Th1-mediated immune responses. In the present study, we investigated the potential role of TPL-2 in Th17 cells. TPL-2 was found to be dispensable for Th17 cell differentiation in vitro, and for the initial priming of Th17 cells in experimental autoimmune encephalomyelitis (EAE), a Th17 cell-mediated disease model for multiple sclerosis. Nevertheless, TPL-2-deficient mice were protected from EAE, which correlated with reduced immune cell infiltration, demyelination and axonal damage in the CNS. Adoptive transfer experiments demonstrated that there was no T cell-intrinsic function for TPL-2 in EAE, and that TPL-2 signaling was not required in radiation-sensitive hematopoietic cells. Rather, TPL-2 signaling in radiation-resistant stromal cells promoted the effector phase of the disease. Importantly, using a newly generated mouse strain expressing a kinase-inactive form of TPL-2, we demonstrated that stimulation of EAE was dependent on TPL-2’s catalytic activity, and not its adaptor function to stabilize the associated ubiquitin-binding protein ABIN-2. Our data therefore raise the possibility that small molecule inhibitors of TPL-2 may be beneficial in multiple sclerosis therapy. PMID:24639351

  8. Augmenting DAF levels in vivo ameliorates experimental autoimmune encephalomyelitis

    PubMed Central

    Li, Qing; Huang, Danping; Nacion, Kristine; Bu, Hong; Lin, Feng

    2009-01-01

    Recent studies in experimental autoimmune encephalomyelitis (EAE) have found that CNS injury in Daf1-/- mice is much greater than in wild types (WTs), suggesting that upregulating DAF levels in vivo might ameliorate disease. To test this, we generated a Daf1 transgenic (Tg) mouse which had elevated DAF levels on its cell surfaces. In bystand C3b uptake assays, Daf1 Tg mouse erythrocytes took up less C3b on their surfaces than WT erythrocytes. When co-cultured with OT-II CD4+ T cells together with OVA323-339 peptide, Daf1 Tg mouse bone marrow derived dendritic cells (BM-DCs) produced less C5a and C3a than WT BM-DCs and stimulated a lesser T cell response. In MOG35-55 immunization induced EAE model, Daf1 Tg mice exhibited delayed disease onset and decreased clinical scores compared to WTs. Histological analyses showed that there were less inflammation and demyelination in spinal cords in Daf1 Tg mice than those in WTs. In accordance with these results, Daf1 Tg mice had decreased MOG35-55 specific Th1 and Th17 responses. These data provide further evidence that DAF suppresses autoreactive T cell responses in EAE, and indicate that augmenting its expression levels could be effective therapeutically in treating multiple sclerosis as well as other T cell mediated diseases. PMID:19660813

  9. Augmenting DAF levels in vivo ameliorates experimental autoimmune encephalomyelitis.

    PubMed

    Li, Qing; Huang, Danping; Nacion, Kristine; Bu, Hong; Lin, Feng

    2009-09-01

    Recent studies in experimental autoimmune encephalomyelitis (EAE) have found that CNS injury in Daf1(-/-) mice is much greater than in wild types (WTs), suggesting that upregulating DAF levels in vivo might ameliorate disease. To test this, we generated a Daf1 transgenic (Tg) mouse which had elevated DAF levels on its cell surfaces. In by-stand C3b uptake assays, Daf1 Tg mouse erythrocytes took up less C3b on their surfaces than WT erythrocytes. When co-cultured with OT-II CD4(+) T cells together with OVA(323-339) peptide, Daf1 Tg mouse bone marrow derived dendritic cells (BM-DCs) produced less C5a and C3a than WT BM-DCs and stimulated a lesser T cell response. In MOG(35-55) immunization induced EAE model, Daf1 Tg mice exhibited delayed disease onset and decreased clinical scores compared to WTs. Histological analyses showed that there were less inflammation and demyelination in spinal cords in Daf1 Tg mice than those in WTs. In accordance with these results, Daf1 Tg mice had decreased MOG(35-55) specific Th1 and Th17 responses. These data provide further evidence that DAF suppresses autoreactive T cell responses in EAE, and indicate that augmenting its expression levels could be effective therapeutically in treating multiple sclerosis as well as other T cell mediated diseases.

  10. Th1-mediated experimental autoimmune encephalomyelitis is CXCR3 independent.

    PubMed

    Lalor, Stephen J; Segal, Benjamin M

    2013-11-01

    Drugs that block leukocyte trafficking ameliorate multiple sclerosis (MS). Occurrences of opportunistic infection, however, highlight the need for novel drugs that modulate more restricted subsets of T cells. In this context, chemokines and their receptors are attractive therapeutic targets. CXCR3, a Th1-associated chemokine receptor, is preferentially expressed on T cells that accumulate in MS lesions and central nervous system (CNS) infiltrates of mice with experimental autoimmune encephalomyelitis (EAE). Surprisingly, mice genetically deficient in either CXCR3 or CXCL10 succumb to EAE following active immunization with myelin antigens. EAE is mediated by a heterogeneous population of T cells in myelin-immunized mice. Hence, disease might develop in the absence of CXCR3 secondary to the compensatory action of encephalitogenic CCR6(+) Th17 cells. However, in the current study, we show for the first time that blockade or genetic deficiency of either CXCR3 or of its primary ligand has no impact on clinical EAE induced by the adoptive transfer of highly polarized Th1 effector cells. Our data illustrate the fact that, although highly targeted immunotherapies might have more favorable side effect profiles, they are also more likely to be rendered ineffective by inherent redundancies in chemokine and cytokine networks that arise at sites of neuroinflammation.

  11. Induction of experimental autoimmune uveoretinitis by T-cell lines.

    PubMed Central

    Rozenszajn, L A; Muellenberg-Coulombre, C; Gery, I; el-Saied, M; Kuwabara, T; Mochizuki, M; Lando, Z; Nussenblatt, R B

    1986-01-01

    Experimental autoimmune uveoretinitis was induced in genetically susceptible Lewis rats by passive transfer of T-lymphocyte cell lines from long-term cultures primed against soluble retinal antigen (S-Ag). A continuous T-cell line was established from non-adherent lymph node cells of S-Ag-immunized Lewis rats. The lymphoid cells were propagated in vitro by serially restimulating them with S-Ag in the presence of irradiated syngeneic spleen cells and expanding them in IL-2-containing media. The cell lines exhibited markers specific for T lymphocytes and the majority had the helper phenotype. When naïve rats were inoculated intravenously with anti S-Ag T-cell lines re-exposed to the antigen prior to injection, they developed uveoretinitis with both clinical and histological characteristics in half the time required by S-Ag to induce the disease by active immunization. The rats exhibited a delayed hypersensitivity skin reaction towards S-Ag. Images Figure 2 Figure 3 PMID:3485569

  12. R-flurbiprofen attenuates experimental autoimmune encephalomyelitis in mice

    PubMed Central

    Schmitz, Katja; de Bruin, Natasja; Bishay, Philipp; Männich, Julia; Häussler, Annett; Altmann, Christine; Ferreirós, Nerea; Lötsch, Jörn; Ultsch, Alfred; Parnham, Michael J; Geisslinger, Gerd; Tegeder, Irmgard

    2014-01-01

    R-flurbiprofen is the non-cyclooxygenase inhibiting R-enantiomer of the non-steroidal anti-inflammatory drug flurbiprofen, which was assessed as a remedy for Alzheimer's disease. Because of its anti-inflammatory, endocannabinoid-modulating and antioxidative properties, combined with low toxicity, the present study assessed R-flurbiprofen in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis in mice. Oral R-flurbiprofen prevented and attenuated primary progressive EAE in C57BL6/J mice and relapsing-remitting EAE in SJL mice, even if the treatment was initiated on or after the first flare of the disease. R-flurbiprofen reduced immune cell infiltration and microglia activation and inflammation in the spinal cord, brain and optic nerve and attenuated myelin destruction and EAE-evoked hyperalgesia. R-flurbiprofen treatment increased CD4+CD25+FoxP3+ regulatory T cells, CTLA4+ inhibitory T cells and interleukin-10, whereas the EAE-evoked upregulation of pro-inflammatory genes in the spinal cord was strongly reduced. The effects were associated with an increase of plasma and cortical endocannabinoids but decreased spinal prostaglandins, the latter likely due to R to S inversion. The promising results suggest potential efficacy of R-flurbiprofen in human MS, and its low toxicity may justify a clinical trial. PMID:25269445

  13. Adrenomedullin protects from experimental autoimmune encephalomyelitis at multiple levels

    PubMed Central

    Pedreño, Marta; Morell, Maria; Robledo, Gema; Souza-Moreira, Luciana; Forte-Lago, Irene; Caro, Marta; O’Valle, Francisco; Ganea, Doina; Gonzalez-Rey, Elena

    2014-01-01

    Adrenomedullin is a neuropeptide known for its cardiovascular activities and anti-inflammatory effects. Here, we investigated the effect of adrenomedullin in a model of experimental autoimmune encephalomyelitis (EAE) that mirrors chronic progressive multiple sclerosis. A short-term systemic treatment with adrenomedullin reduced clinical severity and incidence of EAE, the appearance of inflammatory infiltrates in spinal cord and the subsequent demyelination and axonal damage. This effect was exerted at multiple levels affecting both early and late events of the disease. Adrenomedullin decreased the presence/activation of encephalitogenic Th1 and Th17 cells and down-regulated several inflammatory mediators in peripheral lymphoid organs and central nervous system. Noteworthy, adrenomedullin inhibited the production by encephalitogenic cells of osteopontin and of Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF), two critical cytokines in the development of EAE. At the same time, adrenomedullin increased the number of IL-10-producing regulatory T cells with suppressive effects on the progression of EAE. Furthermore, adrenomedullin generated dendritic cells with a semi-mature phenotype that impaired encephalitogenic responses in vitro and in vivo. Finally, adrenomedullin regulated glial activity and favored an active program of neuroprotection/regeneration. Therefore, the use of adrenomedullin emerges as a novel multimodal therapeutic approach to treat chronic progressive multiple sclerosis. PMID:24321213

  14. Effect of geranylgeranylacetone on optic neuritis in experimental autoimmune encephalomyelitis.

    PubMed

    Guo, Xiaoli; Harada, Chikako; Namekata, Kazuhiko; Kikushima, Kenji; Mitamura, Yoshinori; Yoshida, Hiroshi; Matsumoto, Yoh; Harada, Takayuki

    2009-10-25

    Optic neuritis is an acute inflammatory demyelinating syndrome of the central nervous system (CNS) that often occurs in multiple sclerosis (MS). Since it can cause irreversible visual loss, especially in the optic-spinal form of MS or neuromyelitis optica (NMO), the present study was conducted to assess the effects of geranylgeranylacetone (GGA) on optic neuritis in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Myelin oligodendrocyte glycoprotein-induced EAE mice received oral administration of GGA at 500 mg/kg or vehicle once daily for 22 days. The effects of GGA on the severity of optic neuritis were examined by morphological analysis on day 22. Visual functions were measured by the multifocal electroretinograms (mfERG). In addition, the effects of GGA on severity of myelitis were monitored both on clinical signs and morphological aspects. The visual function, as assessed by the second-kernel of mfERG, was significantly improved in GGA-treated mice compared with vehicle-treated mice. GGA treatment decreased the number of degenerating axons in the optic nerve and prevented cell loss in the retinal ganglion cell layer. However, the severity of demyelination in the spinal cord remained unaffected with the treatment of GGA. These results suggest that oral GGA administration has beneficial effect on the treatment for optic neuritis in the EAE mouse model of MS.

  15. Control of Experimental Autoimmune Encephalomyelitis by T Cells Responding to Activated T Cells

    NASA Astrophysics Data System (ADS)

    Lohse, Ansgar W.; Mor, Felix; Karin, Nathan; Cohen, Irun R.

    1989-05-01

    T cell vaccination against experimental autoimmune disease is herein shown to be mediated in part by anti-ergotypic T cells, T cells that recognize and respond to the state of activation of other T cells. The anti-ergotypic response thus combines with the previously shown anti-idiotypic T cell response to regulate autoimmunity.

  16. Topical administration of a suppressor of cytokine signaling-1 (SOCS1) mimetic peptide inhibits ocular inflammation and mitigates ocular pathology during mouse uveitis.

    PubMed

    He, Chang; Yu, Cheng-Rong; Sun, Lin; Mahdi, Rashid M; Larkin, Joseph; Egwuagu, Charles E

    2015-08-01

    Uveitis is a diverse group of potentially sight-threatening intraocular inflammatory diseases and pathology derives from sustained production of pro-inflammatory cytokines in the optical axis. Although topical or systemic steroids are effective therapies, their adverse effects preclude prolonged usage and are impetus for seeking alternative immunosuppressive agents, particularly for patients with refractory uveitis. In this study, we synthesized a 16 amino acid membrane-penetrating lipophilic suppressor of cytokine signaling 1 peptide (SOCS1-KIR) that inhibits JAK/STAT signaling pathways and show that it suppresses and ameliorates experimental autoimmune uveitis (EAU), the mouse model of human uveitis. Fundus images, histological and optical coherence tomography analysis of eyes showed significant suppression of clinical disease, with average clinical score of 0.5 compared to 2.0 observed in control mice treated with scrambled peptide. We further show that SOCS1-KIR conferred protection from ocular pathology by inhibiting the expansion of pathogenic Th17 cells and inhibiting trafficking of inflammatory cells into the neuroretina during EAU. Dark-adapted scotopic and photopic electroretinograms further reveal that SOCS1-KIR prevented decrement of retinal function, underscoring potential neuroprotective effects of SOCS1-KIR in uveitis. Importantly, SOCS1-KIR is non-toxic, suggesting that topical administration of SOCS1-Mimetics can be exploited as a non-invasive treatment for uveitis and for limiting cytokine-mediated pathology in other ocular inflammatory diseases including scleritis.

  17. Association of cryptogenic organizing pneumonia in bilateral anterior uveitis.

    PubMed

    Fujimoto, Kaori; Hiraoka, Miki; Inatomi, Shuichiro; Ohguro, Hiroshi

    2014-09-01

    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.

  18. Association of Cryptogenic Organizing Pneumonia in Bilateral Anterior Uveitis

    PubMed Central

    Fujimoto, Kaori; Hiraoka, Miki; Inatomi, Shuichiro; Ohguro, Hiroshi

    2014-01-01

    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. PMID:25520652

  19. The Use of Biologic Therapies in Uveitis.

    PubMed

    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

  20. Experimental autoimmune prostatitis induces microglial activation in the spinal cord

    PubMed Central

    Wong, Larry; Done, Joseph D.; Schaeffer, Anthony J.; Thumbikat, Praveen

    2014-01-01

    Background The pathogenesis of chronic prostatitis/chronic pelvic pain syndrome is unknown and factors including the host’s immune response and the nervous system have been attributed to the development of CP/CPPS. We previously demonstrated that mast cells and chemokines such as CCL2 and CCL3 play an important role in mediating prostatitis. Here, we examined the role of neuroinflammation and microglia in the CNS in the development of chronic pelvic pain. Methods Experimental autoimmune prostatitis (EAP) was induced using a subcutaneous injection of rat prostate antigen. Sacral spinal cord tissue (segments S4–S5) was isolated and utilized for immunofluorescence or QRT-PCR analysis. Tactile allodynia was measured at baseline and at various points during EAP using Von Frey fibers as a function for pelvic pain. EAP mice were treated with minocycline after 30 days of prostatitis to test the efficacy of microglial inhibition on pelvic pain. Results Prostatitis induced the expansion and activation of microglia and the development of inflammation in the spinal cord as determined by increased expression levels of CCL3, IL-1β, Iba1, and ERK1/2 phosphorylation. Microglial activation in mice with prostatitis resulted in increased expression of P2X4R and elevated levels of BDNF, two molecular markers associated with chronic pain. Pharmacological inhibition of microglia alleviated pain in mice with prostatitis and resulted in decreased expression of IL-1β, P2X4R, and BDNF. Conclusion Our data shows that prostatitis leads to inflammation in the spinal cord and the activation and expansion of microglia, mechanisms that may contribute to the development and maintenance of chronic pelvic pain. PMID:25263093

  1. Time course of gene expression in rat experimental autoimmune myocarditis.

    PubMed

    Hanawa, Haruo; Abe, Satoru; Hayashi, Manabu; Yoshida, Tsuyoshi; Yoshida, Kaori; Shiono, Takaaki; Fuse, Koichi; Ito, Masahiro; Tachikawa, Hitoshi; Kashimura, Takeshi; Okura, Yuji; Kato, Kiminori; Kodama, Makoto; Maruyama, Seitaro; Yamamoto, Tadashi; Aizawa, Yoshifusa

    2002-12-01

    Genetic responses that characterize experimental autoimmune myocarditis (EAM) have not yet been determined. To investigate gene expression in the myocardium of EAM, absolute copy numbers of 44 mRNA species [calcium-handling proteins, contractile proteins, natriuretic peptides (NPs), cytokines, chemokines, growth factors, renin-angiotensin-aldosterone (RAA) system, endothelins (ETs) and extracellular matrix] in synthesized cDNA from a fixed quantity of total heart RNA were assessed using real-time reverse-transcriptase PCR at days 0, 14, 21 and 28 after immunization. alpha-Cardiac myosin showed a 26.3-fold decrease and beta-cardiac myosin a 3.75-fold increase at day 14. Atrial NP and brain NP increased 47.7- and 6.35-fold at days 21 and 14 respectively. Angiotensin II type 1 receptor, angiotensin-converting enzyme and ET1 increased 22.3-fold at day 21, 6.30-fold at day 21 and 16.8-fold at day 14 respectively. Aldosterone receptor decreased 2.15-fold at day 14, but aldosterone synthetase was detected only at days 14 and 21. Interleukin (IL)-2, IL-10, interferon-gamma and monocyte chemo-attractant protein-1 increased 9.08-fold at day 14, 398-fold at day 21, 43.1-fold at day 14 and 142-fold at day 14 respectively. Collagen type 3, collagen type 1 and fibronectin increased 34.6-, 1.74- and 44.4-fold respectively at day 21. Interestingly, osteopontin showed a 4540-fold increase and it was the highest mRNA of all at day 14. An isoform of cardiac myosin and NP are dramatically changed in EAM. RAA system and ET expressions are changed differently during the EAM time course. Cytokine, chemokine and extracellular matrix greatly increase and, in particular, large numbers of osteopontin mRNA are expressed in early EAM.

  2. Ocular transfer of retinal glial cells transduced ex vivo with adenovirus expressing viral IL-10 or CTLA4-Ig inhibits experimental autoimmune uveoretinitis.

    PubMed

    Verwaerde, C; Naud, M-C; Delanoye, A; Wood, M; Thillaye-Goldenberg, B; Auriault, C; de Kozak, Y

    2003-11-01

    Gene transfer using immunomodulatory molecules is a promising tool for in vivo regulation of immune responses. Experimental autoimmune uveitis (EAU), which serves as a model for human ocular inflammation, is induced by systemic immunization with autoantigens, but its expression is restricted to the eye. Previously, we reported protection of rodents against EAU by intravenous or/and periocular injection of vIL-10-expressing adenovirus. Here, the expression of vIL-10 was targeted into the rat Lewis eye, by intravitreal injection of either the free virus or ex vivo transfected retinal Müller glial cells (RMG-vIL-10). As shown using GFP-expressing adenovirus, a longer expression of transgene was observed in the eye after transfer of transfected syngeneic RMG cells than was seen after injection of free virus. Intravitreal injection of RMG-vIL-10 led to significant decrease in ocular pathological manifestations, compared to control RMG cells. This was observed when cells were injected simultaneously with autoantigen, but also after a delayed administration of transfected cells. Finally, injection of RMG cells transfected with adenovirus expressing CTLA4 had a strongly protective effect. In conclusion, inhibition of antigen presentation at the site of expression of the autoimmune disorders represents an attractive alternative to treat ocular inflammation, and the transfer of ex vivo genetically modified cells provides a promising method to target the factor of interest into the eye.

  3. Nitric oxide synthase in experimental autoimmune myocarditis dysfunction.

    PubMed

    Goren, N; Leiros, C P; Sterin-Borda, L; Borda, E

    1998-11-01

    This study reports the expression of inducible nitric oxide synthase (NOS) in heart from autoimmune myocarditis mice associated with an alteration in their contractile behavior. By mean of the production of [U-14C]citrulline from [U-14C]arginine and immunoblot assay, the expression of iNOS was demonstrated in autoimmune atria that was normally absent. The iNOS activity decreased with administration of dexamethasone and in mice treated with monoclonal anti-interferon-gamma antibody (anti-IFN-gamma mAb). The inhibitors of protein kinase C activity (staurosporine) but not calcium/calmodulin (trifluoperazine) attenuated the iNOS activity. Moreover, autoimmune atria presented contractile alterations (lower values of dF/dt than control). The in vivo treatment with inhibitors of NOS activity or anti-IFN-gamma mAb or dexamethasone improved the contractile activity of autoimmune atria with no change in the contractility of normal atria. The results suggest that the infiltrative cells in myocarditis heart have a potential role in cardiac dysfunction by production of IFN-gamma and subsequent expression of iNOS, that in turn alter the contractile behavior of the heart. The data indicate that cytokines induced activation of L-arginine nitric oxide pathway in myocarditis atria leading to contractile dysfunction.

  4. Fibroblast Cell-Based Therapy for Experimental Autoimmune Diabetes

    PubMed Central

    Jalili, Reza B.; Zhang, Yun; Hosseini-Tabatabaei, Azadeh; Kilani, Ruhangiz T.; Khosravi Maharlooei, Mohsen; Li, Yunyuan; Salimi Elizei, Sanam; Warnock, Garth L.; Ghahary, Aziz

    2016-01-01

    Type 1 diabetes (T1D) results from autoimmune destruction of insulin producing β cells of the pancreatic islets. Curbing autoimmunity at the initiation of T1D can result in recovery of residual β cells and consequently remission of diabetes. Here we report a cell-based therapy for autoimmune diabetes in non-obese diabetic (NOD) mice using dermal fibroblasts. This was achieved by a single injection of fibroblasts, expressing the immunoregulatory molecule indoleamine 2,3 dioxygenase (IDO), into peritoneal cavity of NOD mice shortly after the onset of overt hyperglycemia. Mice were then monitored for reversal of hyperglycemia and changes in inflammatory / regulatory T cell profiles. Blood glucose levels dropped into the normal range in 82% of NOD mice after receiving IDO-expressing fibroblasts while all control mice remained diabetic. We found significantly reduced islet inflammation, increased regulatory T cells, and decreased T helper 17 cells and β cell specific autoreactive CD8+ T cells following IDO cell therapy. We further showed that some of intraperitoneal injected fibroblasts migrated to local lymph nodes and expressed co-inhibitory molecules. These findings suggest that IDO fibroblasts therapy can reinstate self-tolerance and alleviate β cell autoreactivity in NOD mice, resulting in remission of autoimmune diabetes. PMID:26765526

  5. Fibroblast Cell-Based Therapy for Experimental Autoimmune Diabetes.

    PubMed

    Jalili, Reza B; Zhang, Yun; Hosseini-Tabatabaei, Azadeh; Kilani, Ruhangiz T; Khosravi Maharlooei, Mohsen; Li, Yunyuan; Salimi Elizei, Sanam; Warnock, Garth L; Ghahary, Aziz

    2016-01-01

    Type 1 diabetes (T1D) results from autoimmune destruction of insulin producing β cells of the pancreatic islets. Curbing autoimmunity at the initiation of T1D can result in recovery of residual β cells and consequently remission of diabetes. Here we report a cell-based therapy for autoimmune diabetes in non-obese diabetic (NOD) mice using dermal fibroblasts. This was achieved by a single injection of fibroblasts, expressing the immunoregulatory molecule indoleamine 2,3 dioxygenase (IDO), into peritoneal cavity of NOD mice shortly after the onset of overt hyperglycemia. Mice were then monitored for reversal of hyperglycemia and changes in inflammatory/regulatory T cell profiles. Blood glucose levels dropped into the normal range in 82% of NOD mice after receiving IDO-expressing fibroblasts while all control mice remained diabetic. We found significantly reduced islet inflammation, increased regulatory T cells, and decreased T helper 17 cells and β cell specific autoreactive CD8+ T cells following IDO cell therapy. We further showed that some of intraperitoneal injected fibroblasts migrated to local lymph nodes and expressed co-inhibitory molecules. These findings suggest that IDO fibroblasts therapy can reinstate self-tolerance and alleviate β cell autoreactivity in NOD mice, resulting in remission of autoimmune diabetes.

  6. Uveitis in Children

    PubMed Central

    Kazdan, Jerome J.; McCulloch, J. Clement; Crawford, John S.

    1967-01-01

    Endogenous uveitis in 117 children aged 15 years or under was investigated at The Hospital for Sick Children, Toronto, in a 12-year period from 1953 to 1964. This group included 55 children with anterior uveitis, 59 with posterior uveitis, and three with diffuse uveitis. An etiologic diagnosis could be made or the uveitis recognized as part of a definite clinical syndrome in approximately 47% of the 117 children. The commonest cause of posterior uveitis was toxoplasmosis and the commonest associated finding in anterior uveitis was juvenile rheumatoid arthritis. Chronic cyclitis of unknown etiology was a relatively common disease. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7 PMID:6066889

  7. Inhibition of experimental autoimmune uveoretinitis by systemic and subconjunctival adenovirus-mediated transfer of the viral IL-10 gene

    PubMed Central

    De Kozak, Y; Thillaye-Goldenberg, B; Naud, M -C; Viana Da Costa, A; Auriault, C; Verwaerde, C

    2002-01-01

    Pathological ocular manifestations result from a dysregulation in the balance between proinflammatory type 1 cytokines and regulatory type 2 cytokines. Interleukin-10 (IL-10) is an anti-inflammatory cytokine with potent immunosuppressive effects. We have examined the efficiency of viral IL-10 adenovirus (Ad-vIL-10)-mediated gene transfer on experimental autoimmune uveoretinitis (EAU) induced in mice and rats by purified retinal autoantigens, respectively, interphotoreceptor binding protein (IRBP) and S-antigen (S-Ag). B10-A mice that received a single unilateral injection of Ad-vIL-10 in the retro-orbital sinus venosus performed 1 day before immunization with IRBP in the footpads showed high levels of circulating vIL-10 in their sera and a significant reduction in pathological ocular manifestations. Lower levels of IFN-γ and IL-2 were found in cellular supernatants from IRBP-stimulated splenic cells in these treated mice. The local effect on ocular disease of vIL-10 was neutralized completely by injection of a monoclonal anti-vIL-10 antibody, demonstrating the specificity of the treatment. To determine whether the transfer of the vIL-10 gene within the periocular tissues of the eye could prevent acute EAU, a subconjunctival injection of Ad-vIL-10 was performed in Lewis rats simultaneously with S-antigen in the footpads. This injection determined in situ vIL-10 expression with very low circulating vIL-10 and led to a significant reduction of EAU without affecting the systemic immune response. The present results suggest that Ad-mediated gene transfer resulting in systemic and local expression of vIL-10 provide a promising approach for the treatment of uveitis. PMID:12390308

  8. Experimental autoimmune myocarditis: a suitable model to study neuroimmune crosstalk.

    PubMed

    Leiros, C P; Sterin-Borda, L; Goren, N; Borda, E S

    1995-01-01

    This review regards the main functional characteristics of hearts subjected to an autoimmune response, focusing especially on the role of T lymphocytes and autoantibodies in the development of cardiac dysfunction. Evidence of a strong association in the onset and time-course of immune response and cardiac dysfunction is presented and the results are viewed comparatively with myocarditis models induced by heart, parasite or virus inoculation. Cardiac damage is evaluated regarding various aspects, namely histologic, immunologic, biochemical, pharmacologic, physiologic. Finally, the model, for its characteristics of resulting from an autoimmune response against the heart with functional consequences, has proved its usefulness to study neuroimmune interaction, mainly the immune to nervous direction, as autoantibodies and T cell-derived factors have a role in cardiac failure.

  9. Mesenchymal stem cells in the treatment of inflammatory and autoimmune diseases in experimental animal models

    PubMed Central

    Klinker, Matthew W; Wei, Cheng-Hong

    2015-01-01

    Multipotent mesenchymal stromal cells [also known as mesenchymal stem cells (MSCs)] are currently being studied as a cell-based treatment for inflammatory disorders. Experimental animal models of human immune-mediated diseases have been instrumental in establishing their immunosuppressive properties. In this review, we summarize recent studies examining the effectiveness of MSCs as immunotherapy in several widely-studied animal models, including type 1 diabetes, experimental autoimmune arthritis, experimental autoimmune encephalomyelitis, inflammatory bowel disease, graft-vs-host disease, and systemic lupus erythematosus. In addition, we discuss mechanisms identified by which MSCs mediate immune suppression in specific disease models, and potential sources of functional variability of MSCs between studies. PMID:25914763

  10. Pediatric uveitis: An update

    PubMed Central

    Majumder, Parthopratim Dutta; Biswas, Jyotirmay

    2013-01-01

    Because of their varied spectrum of clinical presentation and difficulty in management, pediatric uveitis remains a challenge to the ophthalmologist. Variations in clinical presentation, difficulties in eye examination, extended burden of the inflammation over quality of life, limited treatment modalities, risk of amblyopia are the main challenges in the management of pediatric uveitis. Pediatric uveitis is a cause of significant ocular morbidity and severe vision loss is found in 25-33% of such cases. This article summarizes the common causes of uveitis in children with special approach to the evaluation and diagnosis of each clinical entity. PMID:24379547

  11. IFNAR signaling directly modulates T lymphocyte activity, resulting in milder experimental autoimmune encephalomyelitis development

    PubMed Central

    Kavrochorianou, Nadia; Evangelidou, Maria; Markogiannaki, Melina; Tovey, Michael; Thyphronitis, George; Haralambous, Sylva

    2016-01-01

    Although interferon-β is used as first-line therapy for multiple sclerosis, the cell type-specific activity of type I interferons in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis, remains obscure. In this study, we have elucidated the in vivo immunomodulatory role of type I interferon signaling in T cells during experimental autoimmune encephalomyelitis by use of a novel transgenic mouse, carrying a cd2–ifnar1 transgene on a interferon-α/β receptor 1 null genetic background, thus allowing expression of the interferon-α/β receptor 1 and hence, a functional type I interferon receptor exclusively on T cells. These transgenic mice exhibited milder experimental autoimmune encephalomyelitis with reduced T cell infiltration, demyelination, and axonal damage in the central nervous system. It is noteworthy that interferon-β administration in transgenic mice generated a more pronounced, protective effect against experimental autoimmune encephalomyelitis compared with untreated littermates. In vivo studies demonstrated that before experimental autoimmune encephalomyelitis onset, endogenous type I interferon receptor signaling in T cells led to impaired T-helper 17 responses, with a reduced fraction of CCR6+ CD4+ T cells in the periphery. At the acute phase, an increased proportion of interleukin-10- and interferon-γ-producing CD4+ T cells was detected in the periphery of the transgenic mice, accompanied by up-regulation of the interferon-γ-induced gene Irgm1 in peripheral T cells. Together, these results reveal a hitherto unknown T cell-associated protective role of type I interferon in experimental autoimmune encephalomyelitis that may provide valuable clues for designing novel therapeutic strategies for multiple sclerosis. PMID:26232452

  12. A Review of the Course and Treatment of Non-Infectious Uveitis during Pregnancy.

    PubMed

    Grotting, Lindsay A; Papaliodis, George N

    2017-01-01

    Inflammatory conditions such as autoimmune uveitis often occur in women of childbearing age. During pregnancy, women may experience exacerbations of their disease in the first trimester. In the later stages of pregnancy, however, the uveitis tends to remain less active. The management of uveitis during pregnancy is a challenging task, forcing the physician to re-evaluate the patient's current therapy and offer alternative options that pose the least risk to the patient and fetus. This article will review treatments widely used for uveitis, including corticosteroid therapy, anti-metabolites, calcineurin inhibitors, and biologic therapy. It will evaluate the use of these medications in pregnancy and the postpartum state.

  13. Drug-induced uveitis

    PubMed Central

    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

  14. Pharmacotherapy for uveitis: current management and emerging therapy

    PubMed Central

    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

  15. Genetic of uveitis.

    PubMed

    Pichi, Francesco; Carrai, Paola; Srivastava, Sunil K; Lowder, Careen Y; Nucci, Paolo; Neri, Piergiorgio

    2016-06-01

    Immune-mediated uveitis may be associated with a systemic disease or may be localized to the eye. T-cell-dependent immunological events are increasingly being regarded as extremely important in the pathogenesis of uveitis. Several studies have also shown that macrophages are major effectors of tissue damage in uveitis. Uveitis phenotypes can differ substantially, and most uveitis diseases are considered polygenic with complex inheritance patterns. This review attempts to present the current state of knowledge from in vitro and in vivo research on the role of genetics in the development and clinical course of uveitis. A review of the literature in the PubMed, MEDLINE, and Cochrane databases was conducted to identify clinical trials, comparative studies, case series, and case reports describing host genetic factors as well as immune imbalance which contribute to the development of uveitis. The search was limited to primary reports published in English with human subjects from 1990 to the present, yielding 3590 manuscripts. In addition, referenced articles from the initial searches were hand searched to identify additional relevant reports. After title and abstract selection, duplicate elimination, and manual search, 55 papers were selected for analysis and reviewed by the authors for inclusion in this review. Studies have demonstrated associations between various genetic factors and the development and clinical course of intraocular inflammatory conditions. Genes involved included genes expressing interleukins, chemokines, chemokine receptors, and tumor necrosis factor and genes involved in complement system. When considering the genetics of uveitis, common threads can be identified. Genome-wide scans and other genetic methods are becoming increasingly successful in identifying genetic loci and candidate genes in many inflammatory disorders that have a uveitic component. It will be important to test these findings as uveitis-specific genetic factors. Therefore, the

  16. Uveitis in Spondyloarthritis: An Overview.

    PubMed

    Cantini, Fabrizio; Nannini, Carlotta; Cassarà, Emanuele; Kaloudi, Olga; Niccoli, Laura

    2015-11-01

    Autoimmune anterior uveitis (AU) accounts for at least half of the cases of noninfectious uveitis, and similarly to spondyloarthritis (SpA), its occurrence is related to HLA-B27 positivity. AU is significantly more frequently found in HLA-B27-positive subjects with SpA and is characterized by unilateral eye involvement, marked tendency to recur with involvement of both eyes in alternate fashion, and has good prognosis in the majority of cases. The estimated frequency of SpA in patients with AU is around 50%, whereas AU in SpA has been reported in at least 30% of cases. Across the SpA disease spectrum, AU has a frequency peak of 33.4% in patients with ankylosing spondylitis, while the estimated prevalence in psoriatic arthritis (PsA) and inflammatory bowel disease-associated SpA is 2%-25%, and 25%, respectively. In early PsA, the frequency of AU has been found in 9% of patients. The wide range of prevalence reported in PsA may be explained by the variable sets of classification criteria used for patient selection and the different length of followup. AU may precede the clinical features of SpA, may be present at diagnosis, or may complicate the SpA clinical course. However, the occurrence of AU in SpA as well as AU flares has been reduced through treatment of SpA with anti-tumor necrosis factor-α agents.

  17. Characterization of cytokines associated with Th17 cells in the eyes of horses with recurrent uveitis.

    PubMed

    Regan, Daniel P; Aarnio, Megan C; Davis, Wesley S; Carmichael, K Paige; Vandenplas, Michel L; Lauderdale, James D; Moore, Phillip A

    2012-05-01

    Equine recurrent uveitis (ERU) is a spontaneous disease that is the most common cause of blindness in horses, affecting up to 15% of the horse population. Th17 cells are a major cell population driving the pathogenesis in several mouse models of autoimmune inflammation, including experimental autoimmune uveitis. The purpose of this study is to investigate the role a Th17 cell-mediated response plays in the pathogenesis of ERU. Banked, Davidson's-fixed equine globes histopathologically diagnosed with ERU (n = 7) were compared immunohistochemically with healthy control globes (n = 7). Immunohistochemical staining was performed using a pan-Leptospira antibody and antibodies against IL-6, IL-17, and IL-23. Additionally, immunostaining was performed for T-cell (CD3) and B-cell (CD79α) markers. Specificity of immunoreactivity was confirmed by western blot analysis. Immunohistochemical staining was positive for IL-6, IL-17, and IL-23 within the cytoplasm of nonpigmented ciliary epithelial cells and mononuclear inflammatory cells infiltrating the iris, and ciliary body of ERU horses (n = 7) but negative in controls (n = 7). ERU-affected eyes were CD3 positive (n = 7) and CD79α negative (n = 7). Staining for Leptospira was negative in all ERU and control globes. Strong immunoreactivity for IL-6, IL-17, and IL-23, in conjunction with the fact that T lymphocytes are the predominating inflammatory cells present in ERU, suggests that IL-17-secreting helper T-cells play a role in the pathogenesis of ERU. These findings suggest that horses with ERU may serve as a naturally occurring animal model for autoimmune uveitis. © 2011 American College of Veterinary Ophthalmologists.

  18. Effects of exercise in experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis)

    PubMed Central

    Klaren, Rachel E.; Motl, Robert W.; Woods, Jeffrey A.; Miller, Stephen D.

    2015-01-01

    Exercise training has improved many outcomes in “clinical” research involving persons with multiple sclerosis (MS), but there is limited understanding of the underlying “basic” pathophysiological mechanisms. The animal model of MS, experimental autoimmune encephalomyelitis (EAE), seems ideal for examining the effects of exercise training on MS-disease pathophysiology. EAE is an autoimmune T-helper cell-mediated disease characterized by T-cell and monocyte infiltration and inflammation in the CNS. To that end, this paper briefly describes common models of EAE, reviews existing research on exercise and EAE, and then identifies future research directions for understanding the consequences of exercise training using EAE. PMID:24999244

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

    PubMed Central

    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

    2012-01-01

    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. PMID:22923621

  20. Prevention of experimental autoimmune uveoretinitis and experimental autoimmune pinealitis in (Lewis x Brown-Norway) F1 rats by HgCl2 injections.

    PubMed Central

    Saoudi, A; Bellon, B; de Kozak, Y; Kuhn, J; Vial, M C; Thillaye, B; Druet, P

    1991-01-01

    Mercuric chloride (HgCl2) induces in Brown-Norway (BN) and (Lewis x Brown-Norway) F1 hybrid rats a transient autoimmune disease characterized by the production of various antibodies to self and non-self antigens and by a dramatic increase of serum IgE. Experimental autoimmune uveoretinitis (EAU) can be induced in Lewis (LEW) and (LEW x BN) F1 hybrid rats by a single immunization with retinal S-antigen (S-Ag). Besides uveoretinitis, animals immunized with S-Ag develop an autoimmune pinealitis (EAP). We demonstrate in this study that (LEW x BN) F1 hybrid rats, injected with HgCl2 7 days before S-Ag immunization, are quite efficiently protected against EAU and EAP. We also show that HgCl2-induced protection is neither due to a cytotoxic effect of HgCl2 nor to CD8+ T-cell dependent mechanisms nor to the HgCl2-induced increase of serum IgE concentration. The role of other hypothetical mechanisms, such as anti-S-Ag anti-idiotypic antibodies and/or HgCl2-induced unbalance between T-helper cell subsets, is discussed. Images Figure 1 Figure 2 PMID:1748484

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

    PubMed

    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.

  2. Increased KPI containing amyloid precursor protein in experimental autoimmune encephalomyelitis brains.

    PubMed

    Beilin, Orit; Karussis, Dimitrios M; Korczyn, Amos D; Gurwitz, David; Aronovich, Ramona; Mizrachi-Kol, Rachel; Chapman, Joab

    2007-04-16

    Amyloid precursor protein can be translated from three alternatively spliced mRNAs. We measured levels of amyloid precursor protein isoforms containing the Kunitz protease inhibitor domain (KPIAPP), and amyloid precursor protein without the Kunitz protease inhibitor domain (KPIAPP) in brain homogenates of acute experimental autoimmune encephalomyelitis mice. At the preclinical phase of the disease, both KPIAPP and KPIAPP levels were significantly higher in homogenates from brains of autoimmune encephalomyelitis mice, whereas at the acute phase of the disease only KPIAPP remained significantly elevated compared with controls. At the recovery phase, no differences were observed between the groups. The early and isoform-specific elevation of KPIAPP in autoimmune encephalomyelitis mice suggests a possible role for amyloid precursor protein in the immune response mediating the disease.

  3. Microparticles bearing encephalitogenic peptides induce T-cell tolerance and ameliorate experimental autoimmune encephalomyelitis

    PubMed Central

    Getts, Daniel R; Martin, Aaron J; McCarthy, Derrick P; Terry, Rachael L; Hunter, Zoe N; Yap, Woon Teck; Getts, Meghann Teague; Pleiss, Michael; Luo, Xunrong; King, Nicholas JC; Shea, Lonnie D; Miller, Stephen D

    2013-01-01

    Aberrant T-cell activation underlies many autoimmune disorders, yet most attempts to induce T-cell tolerance have failed. Building on previous strategies for tolerance induction that exploited natural mechanisms for clearing apoptotic debris, we show that antigen-decorated microparticles (500-nm diameter) induce long-term T-cell tolerance in mice with relapsing experimental autoimmune encephalomyelitis. Specifically, intravenous infusion of either polystyrene or biodegradable poly(lactide-co-glycolide) microparticles bearing encephalitogenic peptides prevents the onset and modifies the course of the disease. These beneficial effects require microparticle uptake by marginal zone macrophages expressing the scavenger receptor MARCO and are mediated in part by the activity of regulatory T cells, abortive T-cell activation and T-cell anergy. Together these data highlight the potential for using microparticles to target natural apoptotic clearance pathways to inactivate pathogenic T cells and halt the disease process in autoimmunity. PMID:23159881

  4. Amelioration of experimental autoimmune uveoretinitis (EAU) with an inhibitor of nuclear factor-kappaB (NF-kappaB), pyrrolidine dithiocarbamate.

    PubMed

    Kitamei, Hirokuni; Iwabuchi, Kazuya; Namba, Kenichi; Yoshida, Kazuhiko; Yanagawa, Yoshiki; Kitaichi, Nobuyoshi; Kitamura, Mizuki; Ohno, Shigeaki; Onoé, Kazunori

    2006-06-01

    Experimental autoimmune uveoretinitis (EAU) is a T helper type 1 cell-mediated autoimmune disease, which serves as a model of human chronic uveitis. In this model, cells of a monocyte/macrophage lineage and retinal antigen (Ag)-specific T cells infiltrate into the retina and cause inflammatory lesion, where proinflammatory cytokines and various stimuli activate a transcriptional factor, nuclear factor-kappaB (NF-kappaB), which modulates inflammation and enhances immune responses. In the present study, the therapeutic effect of administration of a NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), was examined in a murine EAU model. It was shown that PDTC ameliorated the clinical symptoms of EAU mice and significantly reduced the histopathological score compared with those in untreated mice. mRNA expressions of tumor necrosis factor alpha and interleukin-1beta were suppressed in eyes of PDTC-treated EAU mice. However, when T cells from PDTC-treated EAU mice, Ag-presenting cells (APC), and the retinal Ag peptides were cocultured, these T cells showed the same level of proliferation as those from control mice. Furthermore, addition of PDTC in the culture of T cells from EAU mice, Ag, and APC completely abrogated the T cell-proliferative response and cytokine production. Pretreatment of Ag-primed T cells or APC with PDTC in vitro also reduced these responses. These results indicate that the inhibitory effect of PDTC is attributed mainly to the suppression of effector-phase responses including inflammation but not to the inhibition of T cell priming. Regulation of NF-kappaB pathway in the lesion could be a novel target for the successful control of uveoretinitis.

  5. Systemic Toll-Like Receptor Stimulation Suppresses Experimental Allergic Asthma and Autoimmune Diabetes in NOD Mice

    PubMed Central

    Pham Van, Linh; Bardel, Emilie; Gomez Alcala, Alejandro; Jeannin, Pascale; Akira, Shizuo; Bach, Jean-François; Thieblemont, Nathalie

    2010-01-01

    Background Infections may be associated with exacerbation of allergic and autoimmune diseases. Paradoxically, epidemiological and experimental data have shown that some microorganisms can also prevent these pathologies. This observation is at the origin of the hygiene hypothesis according to which the decline of infections in western countries is at the origin of the increased incidence of both Th1-mediated autoimmune diseases and Th2-mediated allergic diseases over the last decades. We have tested whether Toll-like receptor (TLR) stimulation can recapitulate the protective effect of infectious agents on allergy and autoimmunity. Methods and Findings Here, we performed a systematic study of the disease-modifying effects of a set of natural or synthetic TLR agonists using two experimental models, ovalbumin (OVA)-induced asthma and spontaneous autoimmune diabetes, presenting the same genetic background of the non obese diabetic mouse (NOD) that is highly susceptible to both pathologies. In the same models, we also investigated the effect of probiotics. Additionally, we examined the effect of the genetic invalidation of MyD88 on the development of allergic asthma and spontaneous diabetes. We demonstrate that multiple TLR agonists prevent from both allergy and autoimmunity when administered parenterally. Probiotics which stimulate TLRs also protect from these two diseases. The physiological relevance of these findings is further suggested by the major acceleration of OVA-induced asthma in MyD88 invalidated mice. Our results strongly indicate that the TLR-mediated effects involve immunoregulatory cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-β and different subsets of regulatory T cells, notably CD4+CD25+FoxP3+ T cells for TLR4 agonists and NKT cells for TLR3 agonists. Conclusions/Significance These observations demonstrate that systemic administration of TLR ligands can suppress both allergic and autoimmune responses. They provide a

  6. Retinitis pigmentosa associated with Fuchs' heterochromic uveitis.

    PubMed

    Chowers, I; Zamir, E; Banin, E; Merin, S

    2000-06-01

    To investigate whether the combination of Fuchs' heterochromic uveitis (FHU) and retinitis pigmentosa (RP) in the same patient is coincidental or represents a true association. We have examined the frequency of FHU in 338 patients with RP and in 1984 patients who were seen in our primary care ophthalmic clinic because of reasons other than RP. Of 338 patients with RP, 4 (1.2%) had the typical findings of FHU. Three of them had Usher syndrome type II, and 1 had RP simplex. By contrast, only 1 patient in the control group had FHU (5%), and the difference in the frequency of FHU between the 2 groups was significant (P=.002, Fisher exact test). Fuchs' heterochromic uveitis is associated with RP. Since autoimmune phenomena have been previously described in patients with RP, it is conceivable that RP predisposes to the development of FHU. Arch Ophthalmol. 2000;118:800-802

  7. Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis.

    PubMed

    Girolamo, Francesco; Coppola, Cristiana; Ribatti, Domenico; Trojano, Maria

    2014-07-22

    Angiogenesis, the formation of new vessels, is found in Multiple Sclerosis (MS) demyelinating lesions following Vascular Endothelial Growth Factor (VEGF) release and the production of several other angiogenic molecules. The increased energy demand of inflammatory cuffs and damaged neural cells explains the strong angiogenic response in plaques and surrounding white matter. An angiogenic response has also been documented in an experimental model of MS, experimental allergic encephalomyelitis (EAE), where blood-brain barrier disruption and vascular remodelling appeared in a pre-symptomatic disease phase. In both MS and EAE, VEGF acts as a pro-inflammatory factor in the early phase but its reduced responsivity in the late phase can disrupt neuroregenerative attempts, since VEGF naturally enhances neuron resistance to injury and regulates neural progenitor proliferation, migration, differentiation and oligodendrocyte precursor cell (OPC) survival and migration to demyelinated lesions. Angiogenesis, neurogenesis and oligodendroglia maturation are closely intertwined in the neurovascular niches of the subventricular zone, one of the preferential locations of inflammatory lesions in MS, and in all the other temporary vascular niches where the mutual fostering of angiogenesis and OPC maturation occurs. Angiogenesis, induced either by CNS inflammation or by hypoxic stimuli related to neurovascular uncoupling, appears to be ineffective in chronic MS due to a counterbalancing effect of vasoconstrictive mechanisms determined by the reduced axonal activity, astrocyte dysfunction, microglia secretion of free radical species and mitochondrial abnormalities. Thus, angiogenesis, that supplies several trophic factors, should be promoted in therapeutic neuroregeneration efforts to combat the progressive, degenerative phase of MS.

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

    PubMed

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

    2016-12-01

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

  9. Spleen Tyrosine Kinase Inhibition Attenuates Autoantibody Production and Reverses Experimental Autoimmune GN

    PubMed Central

    McAdoo, Stephen P.; Reynolds, John; Bhangal, Gurjeet; Smith, Jennifer; McDaid, John P.; Tanna, Anisha; Jackson, William D.; Masuda, Esteban S.; Cook, H. Terence; Pusey, Charles D.

    2014-01-01

    Spleen tyrosine kinase (SYK) has an important role in immunoreceptor signaling, and SYK inhibition has accordingly attenuated immune-mediated injury in several in vivo models. However, the effect of SYK inhibition on autoantibody production remains unclear, and SYK inhibition has not been studied in an autoimmune model of renal disease. We, therefore, studied the effect of SYK inhibition in experimental autoimmune GN, a rodent model of antiglomerular basement membrane disease. We show glomerular SYK expression and activation by immunohistochemistry in both experimental and clinical disease, and we show that treatment with fostamatinib, a small molecule kinase inhibitor selective for SYK, completely prevents the induction of experimental autoimmune GN. In established experimental disease, introduction of fostamatinib treatment led to cessation of autoantibody production, reversal of renal injury, preservation of biochemical renal function, and complete protection from lung hemorrhage. B cell ELISpot and flow cytometric analysis suggest that short-term fostamatinib treatment inhibits the generation and activity of antigen-specific B cells without affecting overall B-cell survival. Additionally, fostamatinib inhibited proinflammatory cytokine production by nephritic glomeruli ex vivo and cultured bone marrow-derived macrophages in vitro, suggesting additional therapeutic effects independent of effects on autoantibody production that are likely related to inhibited Fc receptor signaling within macrophages in diseased glomeruli. Given these encouraging results in an in vivo model that is highly applicable to human disease, we believe clinical studies targeting SYK in GN are now warranted. PMID:24700868

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

    PubMed

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

    2016-11-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

    Na, Songqing; Ma, Yanfei; Zhao, Jingyong; Schmidt, Clint; Zeng, Qing Q.; Chandrasekhar, Srinivasan; Chin, William W.; Nagpal, Sunil

    2011-01-01

    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-(OH)2D3], 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-(OH)2D3 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-(OH)2D3. 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. PMID:21318047

  13. Regulatory T cells control strain specific resistance to Experimental Autoimmune Prostatitis.

    PubMed

    Breser, Maria L; Lino, Andreia C; Motrich, Ruben D; Godoy, Gloria J; Demengeot, Jocelyne; Rivero, Virginia E

    2016-09-14

    Susceptibility to autoimmune diseases results from the encounter of a complex and long evolved genetic context with a no less complex and changing environment. Major actors in maintaining health are regulatory T cells (Treg) that primarily dampen a large subset of autoreactive lymphocytes escaping thymic negative selection. Here, we directly asked whether Treg participate in defining susceptibility and resistance to Experimental Autoimmune Prostatitis (EAP). We analyzed three common laboratory strains of mice presenting with different susceptibility to autoimmune prostatitis upon immunization with prostate proteins. The NOD, the C57BL/6 and the BALB/c mice that can be classified along a disease score ranging from severe, mild and to undetectable, respectively. Upon mild and transient depletion of Treg at the induction phase of EAP, each model showed an increment along this score, most remarkably with the BALB/c mice switching from a resistant to a susceptible phenotype. We further show that disease associates with the upregulation of CXCR3 expression on effector T cells, a process requiring IFNγ. Together with recent advances on environmental factors affecting Treg, these findings provide a likely cellular and molecular explanation to the recent rise in autoimmune diseases incidence.

  14. Nonmyeloablative conditioning generates autoantigen-encoding bone marrow that prevents and cures an experimental autoimmune disease.

    PubMed

    Nasa, Z; Chung, J-Y; Chan, J; Toh, B-H; Alderuccio, F

    2012-08-01

    Autoimmune diseases result from chronic targeted immune responses that lead to tissue pathology and disease. The potential of autologous hematopoietic stem cells transplantation as a treatment for autoimmunity is currently being trialled but disease relapse is an issue. We have previously shown in a mouse model of experimental autoimmune encephalomyelitis (EAE) that the transplantation of bone marrow (BM) transduced to encode the autoantigen myelin oligodendrocyte glycoprotein (MOG) can prevent disease induction. However these studies were performed using lethal irradiation to generate BM chimeras and a critical factor for translation to humans would be the ability to utilize low toxic preconditioning regimes. In this study, treosulfan was used as a nonmyeloablative agent to generate BM chimeras encoding MOG and assessed in models of EAE induction and reversal. We find that treosulfan conditioning can promote a low degree of chimerism that is sufficient to promote antigen specific tolerance and protect mice from EAE. When incorporated into a curative protocol for treating mice with established EAE, nonmyeloablative conditioning and low chimerism was equally efficient in maintaining disease resistance. These studies further underpin the potential and feasibility of utilizing a gene therapy approach to treat autoimmune disease. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

  15. Regulatory T cells control strain specific resistance to Experimental Autoimmune Prostatitis

    PubMed Central

    Breser, Maria L.; Lino, Andreia C.; Motrich, Ruben D.; Godoy, Gloria J.; Demengeot, Jocelyne; Rivero, Virginia E.

    2016-01-01

    Susceptibility to autoimmune diseases results from the encounter of a complex and long evolved genetic context with a no less complex and changing environment. Major actors in maintaining health are regulatory T cells (Treg) that primarily dampen a large subset of autoreactive lymphocytes escaping thymic negative selection. Here, we directly asked whether Treg participate in defining susceptibility and resistance to Experimental Autoimmune Prostatitis (EAP). We analyzed three common laboratory strains of mice presenting with different susceptibility to autoimmune prostatitis upon immunization with prostate proteins. The NOD, the C57BL/6 and the BALB/c mice that can be classified along a disease score ranging from severe, mild and to undetectable, respectively. Upon mild and transient depletion of Treg at the induction phase of EAP, each model showed an increment along this score, most remarkably with the BALB/c mice switching from a resistant to a susceptible phenotype. We further show that disease associates with the upregulation of CXCR3 expression on effector T cells, a process requiring IFNγ. Together with recent advances on environmental factors affecting Treg, these findings provide a likely cellular and molecular explanation to the recent rise in autoimmune diseases incidence. PMID:27624792

  16. Suppression of Autoimmune Retinal Inflammation by an Antiangiogenic Drug

    PubMed Central

    Bazinet, Lauren; D’Amato, Robert J.

    2013-01-01

    Chronic and recurrent uveitis account for approximately 10% of legal blindness in the western world. Autoimmune uveitis is driven by activated CD4+ T cells that differentiate into effector T helper cells (Th1, Th2, and Th17) which release proinflammatory cytokines that damage the retina. In this study we investigated the effect of the methionine aminopeptidase 2 (MetAP2) inhibitor, Lodamin, on T cell activation and differentiation. MetAp2 is an enzyme which regulates cellular protein synthesis and is highly expressed in T cells. Lodamin was found to suppress T cell receptor (TCR) mediated T cell proliferation and reduced the production of Th1 and Th17 cells. Further, Lodamin suppressed overall inflammation in the mouse model of experimental autoimmune uveitis (EAU) by a six fold. This effect was attributed in part to a reduction in retinal proinflammatory cytokines, down regulation of MetAP2 expression in purified lymph node CD4+ T cells, and a general normalization of the systemic immune reaction. PMID:23785488

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

    PubMed

    Kaneko, Tetsushi; Itoh, Masahiro; Nakamura, Yoichi; Iimura, Akira; Hayashi, Shogo; Takahashi, Kodo; Stivala, Franca; Bendtzen, Klaus; Nicoletti, Ferdinando

    2003-04-01

    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.

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

    PubMed

    Li, Lu; Itoh, Masahiro; Ablake, Maila; Macrì, Battesimo; Bendtzen, Klaus; Nicoletti, Ferdinando

    2002-02-01

    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 germinal cells. The effect was seen even though the cytokine was administered for only 6 consecutive days and 2 weeks after immunization.

  19. Telmisartan ameliorates experimental autoimmune myocarditis associated with inhibition of inflammation and oxidative stress.

    PubMed

    Sukumaran, Vijayakumar; Watanabe, Kenichi; Veeraveedu, Punniyakoti T; Ma, Meilei; Gurusamy, Narasimman; Rajavel, Varatharajan; Suzuki, Kenji; Yamaguchi, Ken'ichi; Kodama, Makoto; Aizawa, Yoshifusa

    2011-02-10

    Excess cytokine produced by inflammatory stimuli contributes to the progression of myocardial damage in myocarditis. Angiotensin-II has been shown to play a pivotal role in the pathophysiology of various organs, especially the cardiovascular system. Some angiotensin II type 1 receptor antagonists are reported to inhibit proinflammatory cytokine production in vitro and in vivo. We investigated whether telmisartan, an angiotensin II type 1 receptor antagonist protects against experimental autoimmune myocarditis by suppression of inflammatory cytokines and oxidative stress. Experimental autoimmune myocarditis was induced in Lewis rats by immunization with porcine cardiac myosin. The rats were divided into two groups and treated with either telmisartan (10mg/kg/day) or vehicle for 21days. Age-matched normal rats without immunization were also included in this study. Myocardial functional parameters were significantly improved by treatment with telmisartan compared with vehicle-treated rats. Increased myocardial mRNA expressions of inflammatory cytokines [interleukin (IL-6), IL-1β, tumor necrosis factor-α and interferon-γ] were also suppressed by telmisartan treatment compared with vehicle-treated rats. Myocardial protein expressions of NADPH oxidase subunits p47phox, Nox-4, and gp91phox, myocardial levels of 8-hydroxydeoxyguanosine and 4-hydroxy-2-nonenal, and myocardial apoptosis were also significantly decreased by telmisartan treatment compared with vehicle-treated rats. Further, telmisartan significantly decreased endoplasmic reticulum stress markers in experimental autoimmune myocarditis rats. These findings suggest that telmisartan protects against experimental autoimmune myocarditis in rats, at least in part by suppressing inflammatory cytokines and oxidative stress; however, further investigations are needed before clinical use. 2010 Elsevier B.V. All rights reserved.

  20. Passive transfer of experimental autoimmune myasthenia by lymph node cells in inbred guinea pigs

    PubMed Central

    1975-01-01

    Passive transfer of experimental autoimmune myasthenia (EAM) was performed with lymph node cells from donor guinea pigs immunized with purified acetylcholine receptor (AChR) from Torpedo californica. Recipient animals revealed the same clinical signs and electromyographic patterns as observed in actively challenged animals. These phenomena are parallel to the clinical manifestations of the human disease myasthenia gravis, in which cellular response to AChR was recently demonstrated. PMID:1165476

  1. Interleukin-28A enhances autoimmune disease in a retinal autoimmunity model.

    PubMed

    Ren, Xiangrong; Zhou, Hongyan; Liu, Xialin; Su, Shao Bo

    2014-12-01

    Interleukin-28A (IL-28A), a member of type III interferons (IFN-λs), promotes antiviral, antitumor and immune responses. However, its ability to regulate autoimmune diseases is poorly understood. In this study, we examined the effect of IL-28A on retinal antigen-induced experimental autoimmune uveoretinitis (EAU), a mouse model of human T-cell-mediated autoimmune eye disease. We found that administration of IL-28A enhanced EAU scores and autoimmune response parameters including delayed-type hypersensitivity (DTH), Ag-specific T cell proliferation and the production of Ag-specific IL-17 and IFN-γ in the priming phase. The effect of IL-28A was abrogated by administration of a neutralizing antibody against IL-28A. Our results suggest that IL-28A is capable of exacerbating a T-cell-mediated autoimmune disease. Thus, targeting IL-28A may provide a new therapeutic approach to T cell-mediated autoimmune diseases such as uveitis.

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

    PubMed

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

    2016-11-10

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

  3. Myocardial dysfunction in an experimental model of autoimmune myocarditis: role of IFN-gamma.

    PubMed

    Pérez Leirós, C; Goren, N; Sterin-Borda, L; Borda, E S

    1997-01-01

    Experimental autoimmune myocarditis obtained in mice by immunization with heart antigens is characterized by the presence of lymphomononuclear infiltrates in atria and ventricles. Here we show the ability of soluble factors released by immune cells from mice immunized with heart antigens to decrease heart contractility in a similar way to a muscarinic agonist. These effects appear to be mediated by IFN-gamma since all of them could be blocked by an anti-IFN-gamma monoclonal antibody. Moreover, the negative inotropic effect induced by immune cell-conditioned media was blocked by atropine, confirming previous findings that IFN acts as a muscarinic agonist on isolated atria. The role of locally released cytokines and especially of IFN-gamma was also evaluated in infiltrated autoimmune myocarditis hearts; thus, the addition of monoclonal anti-IFN-gamma antibody reversed the decreased contractility characteristics of this model. We conclude that IFN released both systemically and locally by autoreactive T cells may contribute to the impaired cardiac function in this experimental model of autoimmune myocarditis.

  4. The effect of a newly synthesized indazole compound, TAS-3-124, on experimental autoimmune disease.

    PubMed

    Akabane, Hirotomo; Miyagawa, Naoki; Nii, Hiroaki; Inami, Yoshihiro; Togawa, Michinori; Tanaka, Hiroyuki; Inagaki, Naoki; Nagai, Hiroichi

    2004-08-01

    The effects of a newly synthesized compound, 6-acetoamido-1-acetyl-1-indazole (TAS-3-124), on autoimmune diseases were studied. We used animal models of collagen-induced arthritis (CIA) in mice and experimental autoimmune encephalomyelitis (EAE) in rats to evaluate the efficacy of TAS-3-124. TAS-3-124 at doses of 100 and 300 mg/kg p.o. inhibited the development of CIA, decreasing the swelling of fore- and hind-limbs and bone destruction in knee joints. This agent also suppressed the delayed type hypersensitivity reaction (DTH) against type II collagen. These effects were confirmed by histopathological examination and measurement of the expression of mRNA of proinflammatory cytokines in the knee joint. In addition, TAS-3-124 at a dose of 300 mg/kg inhibited the development of EAE and the DTH to myelin basic protein (MBP) in rats. Moreover, TAS-3-124 inhibited the production of proinflammatory cytokines including interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and IL-6 but not T cell derived cytokines in mice. These demonstrate the efficacy of TAS-3-124 against experimental autoimmune disease, probably due to the suppression of the production of proinflammatory cytokines in the pathological lesion.

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

    PubMed Central

    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 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. PMID:28928747

  6. Kappa opioid receptor activation alleviates experimental autoimmune encephalomyelitis and promotes oligodendrocyte-mediated remyelination.

    PubMed

    Du, Changsheng; Duan, Yanhui; Wei, Wei; Cai, Yingying; Chai, Hui; Lv, Jie; Du, Xiling; Zhu, Jian; Xie, Xin

    2016-04-04

    Multiple sclerosis (MS) is characterized by autoimmune damage to the central nervous system. All the current drugs for MS target the immune system. Although effective in reducing new lesions, they have limited effects in preventing the progression of disability. Promoting oligodendrocyte-mediated remyelination and recovery of neurons are the new directions of MS therapy. The endogenous opioid system, consisting of MOR, DOR, KOR and their ligands, has been suggested to participate in the pathogenesis of MS. However, the exact receptor and mechanism remain elusive. Here we show that genetic deletion of KOR exacerbates experimental autoimmune encephalomyelitis, whereas activating KOR with agonists alleviates the symptoms. KOR does not affect immune cell differentiation and function. Instead, it promotes oligodendrocyte differentiation and myelination both in vitro and in vivo. Our study suggests that targeting KOR might be an intriguing way to develop new MS therapies that may complement the existing immunosuppressive approaches.

  7. Microbial Epitopes Act as Altered Peptide Ligands to Prevent Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Ruiz, Pedro J.; Garren, Hideki; Hirschberg, David L.; Langer-Gould, Annette M.; Levite, Mia; Karpuj, Marcela V.; Southwood, Scott; Sette, Alessandro; Conlon, Paul; Steinman, Lawrence

    1999-01-01

    Molecular mimicry refers to structural homologies between a self-protein and a microbial protein. A major epitope of myelin basic protein (MBP), p87–99 (VHFFKNIVTPRTP), induces experimental autoimmune encephalomyelitis (EAE). VHFFK contains the major residues for binding of this self-molecule to T cell receptor (TCR) and to the major histocompatibility complex. Peptides from papilloma virus strains containing the motif VHFFK induce EAE. A peptide from human papilloma virus type 40 (HPV 40) containing VHFFR, and one from HPV 32 containing VHFFH, prevented EAE. A sequence from Bacillus subtilis (RKVVTDFFKNIPQRI) also prevented EAE. T cell lines, producing IL-4 and specific for these microbial peptides, suppressed EAE. Thus, microbial peptides, differing from the core motif of the self-antigen, MBPp87–99, function as altered peptide ligands, and behave as TCR antagonists, in the modulation of autoimmune disease. PMID:10209044

  8. Kappa opioid receptor activation alleviates experimental autoimmune encephalomyelitis and promotes oligodendrocyte-mediated remyelination

    PubMed Central

    Du, Changsheng; Duan, Yanhui; Wei, Wei; Cai, Yingying; Chai, Hui; Lv, Jie; Du, Xiling; Zhu, Jian; Xie, Xin

    2016-01-01

    Multiple sclerosis (MS) is characterized by autoimmune damage to the central nervous system. All the current drugs for MS target the immune system. Although effective in reducing new lesions, they have limited effects in preventing the progression of disability. Promoting oligodendrocyte-mediated remyelination and recovery of neurons are the new directions of MS therapy. The endogenous opioid system, consisting of MOR, DOR, KOR and their ligands, has been suggested to participate in the pathogenesis of MS. However, the exact receptor and mechanism remain elusive. Here we show that genetic deletion of KOR exacerbates experimental autoimmune encephalomyelitis, whereas activating KOR with agonists alleviates the symptoms. KOR does not affect immune cell differentiation and function. Instead, it promotes oligodendrocyte differentiation and myelination both in vitro and in vivo. Our study suggests that targeting KOR might be an intriguing way to develop new MS therapies that may complement the existing immunosuppressive approaches. PMID:27040771

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

    PubMed

    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.

  10. Proteomic analysis of rat tibialis anterior muscles at different stages of experimental autoimmune myasthenia gravis.

    PubMed

    Gomez, Alejandro M; Vanheel, Annelies; Losen, Mario; Molenaar, Peter C; De Baets, Marc H; Noben, Jean-Paul; Hellings, Niels; Martinez-Martinez, Pilar

    2013-08-15

    Myasthenia gravis (MG) is an autoimmune disease in which autoantibodies, most commonly directed against the acetylcholine receptor (AChR), impair neuromuscular transmission and cause muscle weakness. In this study, we utilized two-dimensional difference in-gel electrophoresis (2D-DIGE) to analyze the muscle's proteomic profile at different stages of experimental autoimmune myasthenia gravis (EAMG). We identified twenty-two differentially expressed proteins, mainly related to metabolic and stress-response pathways. Interestingly, these identified proteins have also been associated with other contraction-impairing muscle pathologies (e.g. inclusion body myositis), suggesting a similar response of the muscle to such conditions. Copyright © 2013 Elsevier B.V. All rights reserved.

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

    PubMed Central

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

    2015-01-01

    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. PMID:25619397

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

    PubMed

    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.

  13. Oral Tolerance: Therapeutic Implications for Autoimmune Diseases

    PubMed Central

    Faria, Ana M. C.; Weiner, Howard L.

    2006-01-01

    Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-β) regulatory T cells (Tregs) plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-β, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy and early therapy. PMID:17162357

  14. Administration of Murine Stromal Vascular Fraction Ameliorates Chronic Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Semon, Julie A.; Zhang, Xiujuan; Pandey, Amitabh C.; Alandete, Sandra M.; Maness, Catherine; Zhang, Shijia; Scruggs, Brittni A.; Strong, Amy L.; Sharkey, Steven A.; Beuttler, Marc M.; Gimble, Jeffrey M.

    2013-01-01

    Administration of adipose-derived stromal/stem cells (ASCs) represents a promising therapeutic approach for autoimmune diseases since they have been shown to have immunomodulatory properties. The uncultured, nonexpanded counterpart of ASCs, the stromal vascular fraction (SVF), is composed of a heterogeneous mixture of cells. Although administration of ex vivo culture-expanded ASCs has been used to study immunomodulatory mechanisms in multiple models of autoimmune diseases, less is known about SVF-based therapy. The ability of murine SVF cells to treat myelin oligodendrocyte glycoprotein35–55-induced experimental autoimmune encephalitis (EAE) was compared with that of culture-expanded ASCs in C57Bl/6J mice. A total of 1 × 106 SVF cells or ASCs were administered intraperitoneally concomitantly with the induction of disease. The data indicate that intraperitoneal administration of ASCs significantly ameliorated the severity of disease course. They also demonstrate, for the first time, that the SVF effectively inhibited disease severity and was statistically more effective than ASCs. Both cell therapies also demonstrated a reduction in tissue damage, a decrease in inflammatory infiltrates, and a reduction in sera levels of interferon-γ and interleukin-12. Based on these data, SVF cells effectively inhibited EAE disease progression more than culture-expanded ASCs. PMID:23981726

  15. Anti-inflammatory effects of luteolin on experimental autoimmune thyroiditis in mice

    PubMed Central

    Xia, Nan; Chen, Gang; Liu, Min; Ye, Xiaozhen; Pan, Yahui; Ge, Jiuyu; Mao, Yanting; Wang, Hongwei; Wang, Jian; Xie, Sijing

    2016-01-01

    Hashimoto's thyroiditis (HT) is the most common organ-specific autoimmune disease and is believed to be a predominately T cell-mediated autoimmunity. Signal transducer and activator of transcription (STAT)3 is a crucial transcription factor of T cell-mediated immunity, with key roles in the proliferation and migration of T helper (Th) cells, differentiation of Th cells into Th17 cells, and the balance between Treg cells and Th17 cells. Flavonoid luteolin has been shown to markedly inhibit Tyr705 activation/phosphorylation of STAT3 and exert anti-inflammatory effects in multiple sclerosis. In the present study, the effect of luteolin on experimental autoimmune thyroiditis (EAT) was analyzed in C57BL/6 mice. Hematoxylin and eosin examination showed that luteolin attenuated lymphocytic infiltration and follicle destruction in thyroid glands. Immunohistochemistry results demonstrated that luteolin significantly reduced the phosphorylation of STAT3 within the thyroid. An in vitro study was carried out in a RAW264.7 macrophage cell line. Western blot findings demonstrated that luteolin significantly inhibited interferon-γ-induced increases in cyclooxygenase 2, phosphorylated STAT1 and phosphorylated STAT3 expression levels and the secretion of the proinflammatory cytokine tumor necrosis factor-α in supernatants. The present findings indicated that luteolin may exert potent anti-inflammatory effects on murine EAT, which may provide a novel therapeutic medication strategy for the early intervention of HT. PMID:28101184

  16. MS-275, an histone deacetylase inhibitor, reduces the inflammatory reaction in rat experimental autoimmune neuritis.

    PubMed

    Zhang, Z Y; Zhang, Z; Schluesener, H J

    2010-08-11

    Experimental autoimmune neuritis (EAN) is a T cell-mediated autoimmune inflammatory demyelinating disease of the peripheral nervous system and serves as the animal model of human inflammatory demyelinating polyradiculoneuropathies. MS-275, a potent histone deacetylase inhibitor currently undergoing clinical investigations for various malignancies, has been reported to demonstrate promising anti-inflammatory activities. In our present study, MS-275 administration (3.5 mg/kg i.p.) to EAN rats once daily from the appearance of first neurological signs greatly reduced the severity and duration of EAN and attenuated local accumulation of macrophages, T cells and B cells, and demyelination of sciatic nerves. Further, significant reduction of mRNA levels of pro-inflammatory interleukin-1beta, interferon-gamma, interleukine-17, inducible nitric oxide synthase and matrix metalloproteinase-9 was observed in sciatic nerves of MS-275 treated EAN rats. In lymph nodes, MS-275 depressed pro-inflammatory cytokines as well, but increased expression of anti-inflammatory cytokine interleukine-10 and of foxhead box protein3 (Foxp3), a unique transcription factor of regulatory T cells. In addition, MS-275 treatment increased proportion of infiltrated Foxp3(+) cells and anti-inflammatory M2 macrophages in sciatic nerves of EAN rats. In summary, our data demonstrated that MS-275 could effectively suppress inflammation in EAN, through suppressing inflammatory T cells, macrophages and cytokines, and inducing anti-inflammatory immune cells and molecules, suggesting MS-275 as a potent candidate for treatment of autoimmune neuropathies.

  17. Novel sinomenine derivative 1032 improves immune suppression in experimental autoimmune encephalomyelitis.

    PubMed

    Yan, Ling-Chen; Bi, En-Guang; Lou, Yang-Tong; Wu, Xiao-Dong; Liu, Zhi-Duo; Zou, Jia; Zhou, Jia; Wang, Yuan; Ma, Zhao; Lin, Guo-Mei; Sun, Shu-Hui; Bian, Chao; Chen, Ai-Zhong; Yao, Zhu-Jun; Sun, Bing

    2010-01-01

    Sinomenine (SIN) is an alkaloid isolated from the Chinese medicinal plant Sinomenium acutum. It is widely used as an immunosuppressive drug for treating autoimmune diseases. Due to its poor efficiency, the large-dose treatment presents some side effects and limits its further applications. In this study, we used chemical modification to improve the therapeutic effect of SIN in vitro and in vivo. A new derivative of sinomenine, named 1032, demonstrates significantly improved immunosuppressive activity over that of its parent natural compound (SIN). In an experimental autoimmune encephalomyelitis (EAE) model, 1032 significantly reduced encephalitogenic T cell responses and induced amelioration of EAE, which outcome was related to its selective inhibitory effect on the production of IL-17. By contrast, SIN treatment only led to a moderate alleviation of EAE severity and the expression level of IL-17 was not significantly reduced. Furthermore, 1032 exhibited suppression of Th17, but not Treg, cell differentiation, a result probably related to its inhibitory effect on IkappaB-alpha degradation as well as on IL-6 and TNF-alpha secretion in BMDCs. We speculate that 1032 as a novel anti-inflammatory agent may target DC to block IL-6 production, which in turn would terminate Th17 cell development. Thus, SIN derivative 1032 presents considerable potential in new drug development for treating autoimmune and inflammatory disease.

  18. Monocyte chemoattractant protein-1 (MCP-1/CCL2) in experimental autoimmune orchitis.

    PubMed

    Guazzone, Vanesa A; Rival, Claudia; Denduchis, Berta; Lustig, Livia

    2003-12-01

    Experimental autoimmune orchitis (EAO) is characterized by an interstitial mononuclear cell infiltrate and a severe lesion of seminiferous tubules with germ cells that undergo apoptosis and sloughing. The mechanism by which immune cells migrate and extravasate in the testicular interstitium is poorly understood. The aim of this study was to detect the variations in the expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and its receptor in the testis of rats undergoing autoimmune orchitis. EAO was induced in Sprague-Dawley adult rats by active immunization with an emulsion of testicular homogenate and complete Freund adjuvant using Bordetella pertussis as co-adjuvant. Control rats injected with saline and adjuvants and normal untreated rats were also studied. By ELISA we observed a significant increase of MCP-1 in the testicular fluid (TF) and in the conditioned medium obtained from cultures of testicular macrophages of rats with EAO compared with control groups. By immunohistochemistry, an increase in MCP-1 expression was observed in mononuclear, endothelial, Leydig and peritubular cells. MCP-1 immunoreactivity was also detected in Sertoli cell cytoplasm of rats with severe orchitis. A 2-fold increase in the number of mononuclear cells that express CCR2 was also found in rats with orchitis compared with controls. In conclusion, we demonstrated in vivo that MCP-1 is highly expressed in testicular interstitial cells suggesting that this chemokine has an important role in recruiting immune cells to the testis in rats undergoing autoimmune orchitis.

  19. CXCR7 suppression modulates microglial chemotaxis to ameliorate experimentally-induced autoimmune encephalomyelitis.

    PubMed

    Bao, Jianhong; Zhu, Jinying; Luo, Sheng; Cheng, Ying; Zhou, Saijun

    2016-01-01

    Multiple sclerosis (MS) is the prototypical inflammatory demyelinating disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE), widely used as an animal model of MS, classically manifests as an ascending paralysis that is characterized by extensive infiltration of the CNS by inflammatory cells. Although several studies uncover the significant role of microglia in the development of EAE, the cellular mechanisms of microglia that govern EAE pathogenesis remain unknown. In the current study, we report that CXCR7 expression is dynamic regulated in activated microglia during CNS autoimmunity and positively correlates with the clinical severity of EAE. In addition, microglial chemotaxis is mediated by CXCR7 during CNS autoimmunity, signaling through extracellular signal-regulated kinase (ERK)1/2 activation, whereas p38 mitogen-activated protein kinase (MAPK) and (c-Jun N-terminal kinase) JNK are not involved. Most importantly, CXCR7 neutralizing treatment ameliorates the clinical severity of EAE along with ERK1/2 phosphorylation reduction. Collectively, our data demonstrate that CXCR7 suppression modulates microglial chemotaxis to ameliorate EAE.

  20. An aza-anthrapyrazole negatively regulates Th1 activity and suppresses experimental autoimmune encephalomyelitis.

    PubMed

    Clark, Matthew P; Leaman, Douglas W; Hazelhurst, Lori A; Hwang, Eun S; Quinn, Anthony

    2016-02-01

    Previously we showed that BBR3378, a novel analog of the anticancer drug mitoxantrone, had the ability to ameliorate ascending paralysis in MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), a murine model of human multiple sclerosis, without the drug-induced cardiotoxicity or lymphopenia associated with mitoxantrone therapy. Chemotherapeutic drugs like mitoxantrone, a topoisomerase inhibitor, are thought to provide protection in inflammatory autoimmune diseases like EAE by inducing apoptosis in rapidly proliferating autoreactive lymphocytes. Here, we show that while BR3378 blocked cell division, T cells were still able to respond to antigenic stimulation and upregulate surface molecules indicative of activation. However, in contrast to mitoxantrone, BBR3378 inhibited the production of the proinflammatory cytokine IFN-γ both in recently activated T cell blasts and established Th1 effectors, while sparing the activities of IL-13-producing Th2 cells. IFN-γ is known to be regulated by the transcription factor T-bet. In addition to IFN-γ, in vitro and in vivo exposure to BBR3378 suppressed the expression of other T-bet regulated proteins, including CXCR3 and IL-2Rβ. Microarray analysis revealed BBR3378-induced suppression of additional T-bet regulated genes, suggesting that the drug might disrupt global Th1 programming. Importantly, BBR3378 antagonized ongoing Th1 autoimmune responses in vivo, modulated clinical disease and CNS inflammation in acute and relapsing forms of EAE. Therefore, BBR3378 may be a unique inhibitor of T-bet regulated genes and may have potential as a therapeutic intervention in human autoimmune disease.

  1. Deletion of the G2A receptor fails to attenuate experimental autoimmune encephalomyelitis

    PubMed Central

    Osmers, Inga; Smith, Sherry S.; Parks, Brian W.; Yu, Shaohua; Srivastava, Roshni; Wohler, Jillian E.; Barnum, Scott R.; Kabarowski, Janusz H.S.

    2009-01-01

    Lysophosphatidylcholine (LPC) is a chemotactic lysolipid produced during inflammation by the hydrolytic action of phospholipase A2 enzymes. LPC stimulates chemotaxis of T cells in vitro through activation of the G protein-coupled receptor, G2A. This has led to the proposition that G2A contributes to the recruitment of T cells to sites of inflammation and thus promotes chronic inflammatory autoimmune diseases associated with the generation and subsequent tissue infiltration of auto-antigen-specific effector T cells. However, one study suggests that G2A may negatively regulate T cell proliferative responses to antigen receptor engagement and thereby attenuates autoimmunity by reducing the generation of autoreactive T cells. To address the relative contribution of these G2A-mediated effects to the pathophysiology of T cell-mediated autoimmune disease, we examined the impact of G2A inactivation on the onset and severity of murine experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Wild type (G2A+/+) and G2A-deficient (G2A-/-) C57BL/6J mice exhibited a similar incidence and onset of disease following immunization with MOG35-55 peptide. Disease severity was only moderately reduced in G2A-/- mice. Similar numbers of MOG35-55 specific T cells were generated in secondary lymphoid organs of MOG35-55-immunized G2A+/+ and G2A-/- mice. Comparable numbers of T cells were detected in spinal cords of G2A+/+ and G2A-/- mice. We conclude that the proposed anti-proliferative and chemotactic functions of G2A are not manifested in vivo and therefore therapeutic targeting of G2A is unlikely to be beneficial in the treatment of MS. PMID:19135725

  2. Pentoxifylline attenuates cytokine stress and Fas system in syngeneic liver proteins induced experimental autoimmune hepatitis.

    PubMed

    Hendawy, Nevien

    2017-08-01

    Apoptosis is a hallmark in the pathogenesis of autoimmune hepatitis (AIH). Cytokine stresses and extrinsic apoptotic pathway have been implicated in this type of hepatic injury. Pentoxifylline plays an important role in controlling inflammation and apoptosis in different autoimmune diseases. To assess the protective effect of pentoxifylline for 30days against pro-inflammatory cytokines as tumor necrosis factor-alpha (TNF-α), interferon-gamma (INF-γ) and mediators of extrinsic apoptotic pathway involving TNF receptor 1 (TNFR1) and its ligand TNF-α and Fas receptor and its ligand (FasL) in experimental autoimmune hepatitis (EAH) model. EAH was induced by intraperitoneal injection of syngeneic liver antigen emulsified in complete Freund's adjuvant (CFA) in male C57BL/6 mice. Five groups of mice were used: two control groups; Control PBS group and Control CFA group, EAH group and two EAH+pentoxifylline treated groups in doses (100 or 200mg/kg/d, given by oral gavage). Serum transaminase, pro-inflammatory cytokines (TNF-α and interferon-γ) and hepatic caspase-8 and 3 activities were evaluated. Signs of autoimmune hepatitis were confirmed by liver histology. In addition, hepatic TNFR1, Fas and FasL mRNA expression were assayed. Serum transaminase levels and signs of AIH observed in EAH mice were significantly reduced by pentoxifylline. Upregulated serum TNF-α, IFN-γ, hepatic caspase-8 and 3 activities and TNFR1, Fas and FasL mRNA expression in liver tissues in EAH group were significantly downregulated by pentoxifylline. Pentoxifylline protects against syngeneic liver antigen induced hepatitis and associating apoptosis through attenuating the exaggerated cytokine release and extrinsic apoptotic pathway. Thus, this may represent a new therapeutic strategy for hepatitis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  3. Parthenolide Modulates Immune Response in Cells from C57BL/6 Mice Induced with Experimental Autoimmune Encephalomyelitis.

    PubMed

    de Carvalho, Lara Soares Aleixo; Fontes, Lívia Beatriz Almeida; Gazolla, Matheus Coutinho; Dias, Débora Dos Santos; Juliano, Maria Aparecida; Macedo, Gilson Costa; Otávio do Amaral Corrêa, José; Da Silva Filho, Ademar A

    2017-05-01

    Multiple sclerosis is a chronic inflammatory and autoimmune disease of the central nervous system that affects more than 2.5 million people worldwide. Experimental autoimmune encephalomyelitis is a murine autoimmune disease used to study multiple sclerosis. Parthenolide, a natural sesquiterpene lactone found in Tanacetum parthenium L., is known for its strong anti-inflammatory activity. Herein, we have investigated the in vitro immunomodulatory effects of parthenolide on cytokine production and nitric oxide in cultured cells from myelin oligodendrocyte glycoprotein 35-55 amino acid peptide mice. Experimental autoimmune encephalomyelitis was induced in C57BL/6 mice with myelin oligodendrocyte glycoprotein 35-55 amino acid peptide, and parthenolide was isolated from T. parthenium. Splenocytes and peritoneal cells were obtained from experimental autoimmune encephalomyelitis-induced mice and incubated with parthenolide (1, 5, and 20 µM). After in vitro treatment with parthenolide, supernatants were collected, and nitric oxide and cytokines were measured. The results suggested that parthenolide may regulate the activity of Th17 and Th1 cells, mainly by decreasing IL-17, TNF-α, and interferon gamma production. This modulation may be related to the lower levels of IL-12p40 and IL-6 after treatment with parthenolide. It was shown, for the first time, that parthenolide presents in vitro immunomodulatory effects on inflammatory mediators produced by cells from experimental autoimmune encephalomyelitis-induced mice. Georg Thieme Verlag KG Stuttgart · New York.

  4. Experimental Autoimmune Myasthenia Gravis (EAMG): from immunochemical characterization to therapeutic approaches.

    PubMed

    Fuchs, Sara; Aricha, Revital; Reuveni, Debby; Souroujon, Miriam C

    2014-11-01

    Myasthenia Gravis (MG) is an organ-specific autoimmune disease. In high percentage of patients there are autoantibodies to the nicotinic acetylcholine receptor (AChR) that attack AChR on muscle cells at the neuromuscular junction, resulting in muscle weakness. Experimental Autoimmune Myasthenia Gravis (EAMG) is an experimental model disease for MG. EAMG is induced in several animal species by immunization with acetylcholine receptor (AChR), usually isolated from the electric organ of electric fish, which is a rich source for this antigen. Our lab has been involved for several decades in research of AChR and of EAMG. The availability of an experimental autoimmune disease that mimics in many aspects the human disease, provides an excellent model system for elucidating the immunological nature and origin of MG, for studying various existing treatment modalities and for attempting the development of novel treatment approaches. In this review in honor of Michael Sela and Ruth Arnon, we report first on our early pioneering contributions to research on EAMG. These include the induction of EAMG in several animal species, early attempts for antigen-specific treatment for EAMG, elicitation and characterization of monoclonal antibodies and anti-idiotypic antibodies, measuring humoral and cellular AChR-specific immune responses in MG patient and more. In the second part of the review we discuss more recent studies from our lab towards developing and testing novel treatment approaches for myasthenia. These include antigen-dependent treatments aimed at specifically abrogating the humoral and cellular anti-AChR responses, as well as immunomodulatory approaches that could be used either alone, or in conjunction with antigen-specific treatments, or alternatively, serve as steroid-sparing agents.

  5. The complement inhibitor FUT-175 suppresses T cell autoreactivity in experimental autoimmune encephalomyelitis.

    PubMed

    Li, Qing; Nacion, Kristine; Bu, Hong; Lin, Feng

    2009-08-01

    Several recent studies have shown that interacting antigen presenting cells and/or T cells produced complement activation products C5a and C3a, are integrally involved in T-cell activation, and promote the generation of myelin oligodendrocyte glycoprotein (MOG(35-55))-specific interferon-gamma and interleukin-17-producing T cells in experimental autoimmune encephalomyelitis, a rodent model of multiple sclerosis. In this study, we tested whether FUT-175, a clinical pharmaceutical that has been shown to inhibit the formation of C3/C5 convertases, can attenuate myelin-specific T-cell responses, as well as disease severity in experimental autoimmune encephalomyelitis. In vitro, FUT-175 inhibited local C5a/C3a production by antigen presenting cell-T-cell complexes and attenuated MOG(35-55)-specific Th1 and Th17 responses with little nonspecific cytotoxicity. In vivo administration of FUT-175 delayed experimental autoimmune encephalomyelitis disease onset, lowered clinical scores, decreased central nervous system inflammation, and reduced demyelination. The FUT-175-treated mice exhibited decreased numbers of MOG(35-55)-specific interferon-gamma- and interleukin-17-producing T cells. In addition, results from the FUT-175 treatment of naive recipients of adoptively transferred splenocytes from MOG(35-55)-immunized mice suggested that the effect of FUT-175 was on MOG-specific cellular responses and not on anti-MOG antibodies. These results argue that complement regulators, which inhibit C5a/C3a production, may have therapeutic efficacy in multiple sclerosis and in other clinical conditions in which T cells drive disease pathogenesis.

  6. The Complement Inhibitor FUT-175 Suppresses T Cell Autoreactivity in Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Li, Qing; Nacion, Kristine; Bu, Hong; Lin, Feng

    2009-01-01

    Several recent studies have shown that interacting antigen presenting cells and/or T cells produced complement activation products C5a and C3a, are integrally involved in T-cell activation, and promote the generation of myelin oligodendrocyte glycoprotein (MOG35–55)-specific interferon-γ and interleukin-17-producing T cells in experimental autoimmune encephalomyelitis, a rodent model of multiple sclerosis. In this study, we tested whether FUT-175, a clinical pharmaceutical that has been shown to inhibit the formation of C3/C5 convertases, can attenuate myelin-specific T-cell responses, as well as disease severity in experimental autoimmune encephalomyelitis. In vitro, FUT-175 inhibited local C5a/C3a production by antigen presenting cell–T-cell complexes and attenuated MOG35–55-specific Th1 and Th17 responses with little nonspecific cytotoxicity. In vivo administration of FUT-175 delayed experimental autoimmune encephalomyelitis disease onset, lowered clinical scores, decreased central nervous system inflammation, and reduced demyelination. The FUT-175-treated mice exhibited decreased numbers of MOG35–55-specific interferon-γ- and interleukin-17-producing T cells. In addition, results from the FUT-175 treatment of naive recipients of adoptively transferred splenocytes from MOG35–55-immunized mice suggested that the effect of FUT-175 was on MOG-specific cellular responses and not on anti-MOG antibodies. These results argue that complement regulators, which inhibit C5a/C3a production, may have therapeutic efficacy in multiple sclerosis and in other clinical conditions in which T cells drive disease pathogenesis. PMID:19608865

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

    PubMed

    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.

  8. Protective DNA vaccination against experimental autoimmune encephalomyelitis is associated with induction of IFNbeta.

    PubMed

    Wefer, Judit; Harris, Robert A; Lobell, Anna

    2004-04-01

    DNA vaccines encoding encephalitogenic peptides protect against subsequent development of rat experimental autoimmune encephalomyelitis (EAE) through unknown mechanisms. We investigated immune cell phenotypes at different time points after DNA vaccination with vaccine encoding myelin oligodendrocyte glycoprotein peptide 91-108 and subsequent induction of EAE. In protected rats, we observed (i) no alterations in antigen-specific Th2 or Th3 responses, (ii) reduced MHC II expression on splenocytes early after EAE induction, (iii) antigen-specific upregulation of IFNbeta upon recall stimulation and (iv) reduced IL-12Rbeta2 on lymphocytes. We suggest that the underlying mechanism of DNA vaccination is associated with immunomodulation exerted by induced IFNbeta.

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

    PubMed

    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.

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed Central

    Stormanns, Eva R.; Recks, Mascha S.; Kuerten, Stefanie

    2015-01-01

    Background 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. Limited availability of human tissue underscores the importance of animal models to study the pathology of MS. Methods 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. Results B6 mice demonstrated increasing demyelination and severe axonal pathology in the course of MP4-induced EAE. In addition, 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. Conclusions Our results complement our previous ultrastructural studies of B6 EAE models and suggest that B6 mice immunized with different antigens constitute

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

    PubMed

    Prinz, Johanna; Karacivi, Aylin; Stormanns, Eva R; Recks, Mascha S; Kuerten, Stefanie

    2015-01-01

    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 histopathological

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

    PubMed

    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.

  14. Tolerance induction in experimental autoimmune encephalomyelitis using non-myeloablative hematopoietic gene therapy with autoantigen.

    PubMed

    Eixarch, Herena; Espejo, Carmen; Gómez, Alba; Mansilla, María José; Castillo, Mireia; Mildner, Alexander; Vidal, Francisco; Gimeno, Ramón; Prinz, Marco; Montalban, Xavier; Barquinero, Jordi

    2009-05-01

    Experimental autoimmune encephalomyelitis (EAE) constitutes a paradigm of antigen (Ag)-specific T cell driven autoimmune diseases. In this study, we transferred bone marrow cells (BMCs) expressing an autoantigen (autoAg), the peptide 40-55 of the myelin oligodendrocytic glycoprotein (MOG(40-55)), to induce preventive and therapeutic immune tolerance in a murine EAE model. Transfer of BMC expressing MOG(40-55) (IiMOG-BMC) into partially myeloablated mice resulted in molecular chimerism and in robust protection from the experimental disease. In addition, in mice with established EAE, transfer of transduced BMC with or without partial myeloablation reduced the clinical and histopathological severity of the disease. In these experiments, improvement was observed even in the absence of engraftment of the transduced hematopoietic cells, probably rejected due to the previous immunization with the autoAg. Splenocytes from mice transplanted with IiMOG-BMC produced significantly higher amounts of interleukin (IL)-5 and IL-10 upon autoAg challenge than those of control animals, suggesting the participation of regulatory cells. Altogether, these results suggest that different tolerogenic mechanisms may be mediating the preventive and the therapeutic effects. In conclusion, this study demonstrates that a cell therapy using BMC expressing an autoAg can induce Ag-specific tolerance and ameliorate established EAE even in a nonmyeloablative setting.

  15. Tolerance Induction in Experimental Autoimmune Encephalomyelitis Using Non-myeloablative Hematopoietic Gene Therapy With Autoantigen

    PubMed Central

    Eixarch, Herena; Espejo, Carmen; Gómez, Alba; Mansilla, María José; Castillo, Mireia; Mildner, Alexander; Vidal, Francisco; Gimeno, Ramón; Prinz, Marco; Montalban, Xavier; Barquinero, Jordi

    2009-01-01

    Experimental autoimmune encephalomyelitis (EAE) constitutes a paradigm of antigen (Ag)-specific T cell driven autoimmune diseases. In this study, we transferred bone marrow cells (BMCs) expressing an autoantigen (autoAg), the peptide 40–55 of the myelin oligodendrocytic glycoprotein (MOG40–55), to induce preventive and therapeutic immune tolerance in a murine EAE model. Transfer of BMC expressing MOG40–55 (IiMOG-BMC) into partially myeloablated mice resulted in molecular chimerism and in robust protection from the experimental disease. In addition, in mice with established EAE, transfer of transduced BMC with or without partial myeloablation reduced the clinical and histopathological severity of the disease. In these experiments, improvement was observed even in the absence of engraftment of the transduced hematopoietic cells, probably rejected due to the previous immunization with the autoAg. Splenocytes from mice transplanted with IiMOG-BMC produced significantly higher amounts of interleukin (IL)-5 and IL-10 upon autoAg challenge than those of control animals, suggesting the participation of regulatory cells. Altogether, these results suggest that different tolerogenic mechanisms may be mediating the preventive and the therapeutic effects. In conclusion, this study demonstrates that a cell therapy using BMC expressing an autoAg can induce Ag-specific tolerance and ameliorate established EAE even in a nonmyeloablative setting. PMID:19277013

  16. Bidirectional Estrogen-Like Effects of Genistein on Murine Experimental Autoimmune Ovarian Disease.

    PubMed

    Ding, Qiao; Wang, Yuxiao; Li, Na; Zhu, Kexue; Hu, Jielun; Wang, Sunan; Zhu, Fan; Nie, Shaoping

    2016-11-08

    This study was to investigate the bidirectional estrogen-like effects of genistein on murine experimental autoimmune ovarian disease (AOD). Female BALB/c mice were induced by immunization with a peptide from murine zona pellucida. The changes of estrous cycle, ovarian histomorphology were measured, and the levels of serum sex hormone were analyzed using radioimmunoassay. Proliferative responses of the ovary were also determined by immunohistochemistry. Administration of 25 or 45 mg/kg body weight genistein enhanced ovary development with changes in serum sex hormone levels and proliferative responses. Meanwhile, the proportions of growing and mature follicles increased and the incidence of autoimmune oophoritis decreased, which exhibited normal ovarian morphology in administration of 25 or 45 mg/kg body weight genistein, while a lower dose (5 mg/kg body weight genistein) produced the opposite effect. These findings suggest that genistein exerts bidirectional estrogen-like effects on murine experimental AOD, while a high dose (45 mg/kg body weight) of genistein may suppress AOD.

  17. Tryptase - PAR2 axis in Experimental Autoimmune Prostatitis, a model for Chronic Pelvic Pain Syndrome

    PubMed Central

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

    2014-01-01

    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 experimental autoimmune prostatitis (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 lead to ERK1/2 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. PMID:24726923

  18. Bidirectional Estrogen-Like Effects of Genistein on Murine Experimental Autoimmune Ovarian Disease

    PubMed Central

    Ding, Qiao; Wang, Yuxiao; Li, Na; Zhu, Kexue; Hu, Jielun; Wang, Sunan; Zhu, Fan; Nie, Shaoping

    2016-01-01

    This study was to investigate the bidirectional estrogen-like effects of genistein on murine experimental autoimmune ovarian disease (AOD). Female BALB/c mice were induced by immunization with a peptide from murine zona pellucida. The changes of estrous cycle, ovarian histomorphology were measured, and the levels of serum sex hormone were analyzed using radioimmunoassay. Proliferative responses of the ovary were also determined by immunohistochemistry. Administration of 25 or 45 mg/kg body weight genistein enhanced ovary development with changes in serum sex hormone levels and proliferative responses. Meanwhile, the proportions of growing and mature follicles increased and the incidence of autoimmune oophoritis decreased, which exhibited normal ovarian morphology in administration of 25 or 45 mg/kg body weight genistein, while a lower dose (5 mg/kg body weight genistein) produced the opposite effect. These findings suggest that genistein exerts bidirectional estrogen-like effects on murine experimental AOD, while a high dose (45 mg/kg body weight) of genistein may suppress AOD. PMID:27834809

  19. Experimental autoimmune encephalomyelitis is a good model of multiple sclerosis if used wisely.

    PubMed

    Baker, David; Amor, Sandra

    2014-09-01

    Although multiple sclerosis is a uniquely human disease, many pathological features can be induced in experimental autoimmune encephalomyelitis (EAE) models following induction of central nervous system-directed autoimmunity. Whilst it is an imperfect set of models, EAE can be used to identify pathogenic mechanisms and therapeutics. However, the failure to translate many treatments from EAE into human benefit has led some to question the validity of the EAE model. Whilst differences in biology between humans and other species may account for this, it is suggested here that the failure to translate may be considerably influenced by human activity. Basic science contributes to failings in aspects of experimental design and over-interpretation of results and lack of transparency and reproducibility of the studies. Importantly issues in trial design by neurologists and other actions of the pharmaceutical industry destine therapeutics to failure and terminate basic science projects. However animal, particularly mechanism-orientated, studies have increasingly identified useful treatments and provided mechanistic ideas on which most hypothesis-led clinical research is based. Without EAE and other animal studies, clinical investigations will continue to be "look-see" exercises, which will most likely provide more misses than hits and will fail the people with MS that they aim to serve. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Reduction in parvalbumin-positive interneurons and inhibitory input in the cortex of mice with experimental autoimmune encephalomyelitis.

    PubMed

    Falco, Anna; Pennucci, Roberta; Brambilla, Elena; de Curtis, Ivan

    2014-07-01

    In multiple sclerosis (MS), inflammation leads to damage of central nervous system myelin and axons. Previous studies have postulated impaired GABA transmission in MS, and recent postmortem analysis has shown that GABAergic parvalbumin (PV)-positive interneurons are decreased in the primary motor cortex (M1) of patients with MS. In this report, we present evidence for the loss of a specific population of GABAergic interneurons in the experimental autoimmune encephalomyelitis mouse model of MS. Using experimental autoimmune encephalomyelitis, we evaluated the distribution of both PV-positive interneurons and of the inhibitory presynaptic input in the M1 of experimental autoimmune encephalomyelitis and control mice. Our results demonstrate a specific decrease in the number of PV-positive interneurons in the M1 of mice with experimental autoimmune encephalomyelitis. We detected a significant reduction in the number of PV-positive interneurons in the layers II and III of the M1 of diseased mice, while there was no difference in the number of calretinin (CR)-positive cells between animals with experimental autoimmune encephalomyelitis and control animals. Moreover, we observed a significant reduction in the inhibitory presynaptic input in the M1 of treated mice. These changes were specific for the mice with elevated clinical score, while they were not detectable in the mice with low clinical score. Our results support the hypothesis that reinforcing the action of the GABAergic network may represent a therapeutic alternative to limit the progression of the neuronal damage in MS patients.

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

    PubMed Central

    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

  2. Pathological mechanisms in experimental autoimmune myasthenia gravis. II. Passive transfer of experimental autoimmune myasthenia gravis in rats with anti-acetylcholine recepotr antibodies

    PubMed Central

    1976-01-01

    Passive transfer of experimental autoimmune myasthenia gravis (EAMG) was achieved using the gamma globulin fraction and purified IgG from sera of rats immunized with Electrophus electricus (eel) acetylcholine receptor (AChR). This demonstrates the critical role of anti-AChR antibodies in impairing neuromuscular transmission in EAMG. Passive transfer of anti-AChR antibodies from rats with chronic EAMG induced signs of the acute phase of EAMG in normal recipient rats, including invasion of the motor end-plate region by mononuclear inflammatory cells. Clinical, eletrophysiological, histological, and biochemical signs of acute EAMG were observed by 24 h after antibody transfer. Recipient rats developed profound weakness and fatigability, and the posture characteristic of EAMG. Striking weight loss was attributable to dehydration. Recipient rats showed large decreases in amplitude of muscle responses to motor nerve stimulation, and repetitive nerve stimulation induced characteristic decrementing responses. End-plate potentials were not detectable in many muscle fibers, and the amplitudes of miniature end-plate potentials were reduced in the others. Passively transferred EAMG more severely affected the forearm muscles than diaphragm muscles, though neuromuscular transmission was impaired and curare sensitivity was increased in both muscles. Some AChR extracted from the muscles of rats with passively transferred EAMG was found to be complexed with antibody, and the total yield of AChR per rat was decreased. The quantitative decrease in AChR approximately paralleled in time the course of clinical and electrophysiological signs. The amount of AChR increased to normal levels and beyond at the time neuromuscular transmission was improving. The excess of AChR extractable from muscle as the serum antibody level decreased probably represented extrajunctional receptors formed in response to functional denervation caused by phagocytosis of the postsynaptic membrane by macrophages

  3. Phospholipase D1 is up-regulated in the retina of Lewis rats with experimental autoimmune uveoretinitis.

    PubMed

    Kang, JongChul; Ahn, Meejung; Moon, Changjong; Min, Do Sik; Matsumoto, Yoh; Shin, Taekyun

    2005-01-01

    To investigate whether phospholipase D1 (PLD1) is involved in autoimmune damage to the eyes, we used Western blotting and immunohistochemistry to examine the expression and distribution of PLD1 in the retinas of Lewis rats with experimental autoimmune uveoretinitis (EAU). Western blot analysis showed that the level of expression of PLD1 was significantly increased in EAU-affected retinas compared to that of control. Immunohistochemical analysis showed that ganglion cells and Muller cells, which express PLD1 weakly in the normal retina, showed increased expression of PLD1 in EAU-affected retinas; some ED1-immunopositive cells were also immunopositive for PLD1 in lesions at post-immunization days 14 and 21. These results suggest that the increased expression of PLD1 in inflammatory cells exacerbates an autoimmune response in EAU, while its expression in ganglion cells limits cell loss by activation of survival factors in eyes with autoimmune injury.

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

    PubMed

    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.

  5. Non-human primate models of experimental autoimmune encephalomyelitis: Variations on a theme.

    PubMed

    't Hart, Bert A; Bauer, Jan; Brok, Herbert P M; Amor, Sandra

    2005-11-01

    Despite years of intensive research into multiple sclerosis (MS) scientists have not yet succeeded in developing an absolute therapy for the treatment of this disabling disease of the human central nervous system. The wide immunological gap between inbred rodent strains and the heterogeneous human population is probably the single most important factor that hampers the translation of scientific principles developed in rodents into effective therapies for MS. Because of the closer immunological proximity to humans, non-human primates provide useful experimental models that may help to bridge this gap. Here we review the models of experimental autoimmune encephalomyelitis in rhesus macaques and common marmosets. We will discuss the salient points of the models and suggest how these may represent the spectrum of inflammatory demyelinating diseases of the central nervous system in humans.

  6. Strain-related effects of fenbendazole treatment on murine experimental autoimmune encephalomyelitis.

    PubMed

    Ramp, A A; Hall, C; Orian, J M

    2010-07-01

    Parasitic infections are a concern in animal facilities, in view of their influence on physiological processes and the immune status of animals. Pinworms are effectively controlled with the anthelminthic fenbendazole (FBZ, [5-(phenylthio)-1H-benzamidazol-2-yl]carbamic acid methyl ester; C(15)H(13)N(3)O(2)S); however, questions remain as to whether prolonged FBZ exposure alters the disease course in specific experimental models, such as those pertaining to the immune system. We report that a three-month regimen of FBZ-medicated feed severely affected the onset and disease severity of murine experimental autoimmune encephalomyelitis (EAE), a disease that mimics multiple sclerosis. Differences were recorded between mouse strains used. Our data suggest that where the use of FBZ is mandatory, its full effect should be verified on the particular EAE variant adopted by the laboratory.

  7. Identification in Silico and Experimental Validation of Novel Phosphodiesterase 7 Inhibitors with Efficacy in Experimental Autoimmune Encephalomyelitis Mice

    PubMed Central

    2012-01-01

    A neural network model has been developed to predict the inhibitory capacity of any chemical structure to be a phosphodiesterase 7 (PDE7) inhibitor, a new promising kind of drugs for the treatment of neurological disorders. The numerical definition of the structures was achieved using CODES program. Through the validation of this neural network model, a novel family of 5-imino-1,2,4-thiadiazoles (ITDZs) has been identified as inhibitors of PDE7. Experimental extensive biological studies have demonstrated the ability of ITDZs to inhibit PDE7 and to increase intracellular levels of cAMP. Among them, the derivative 15 showed a high in vitro potency with desirable pharmacokinetic profile (safe genotoxicity and blood brain barrier penetration). Administration of ITDZ 15 in an experimental autoimmune encephalomyelitis (EAE) mouse model results in a significant attenuation of clinical symptoms, showing the potential of ITDZs, especially compound 15, for the effective treatment of multiple sclerosis. PMID:23077723

  8. Correlation of Gut Microbiota Composition with Resistance to Experimental Autoimmune Encephalomyelitis in Rats

    PubMed Central

    Stanisavljević, Suzana; Lukić, Jovanka; Soković, Svetlana; Mihajlovic, Sanja; Mostarica Stojković, Marija; Miljković, Djordje; Golić, Natasa

    2016-01-01

    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 toward gut associated lymphoid tissues (GALTs) 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 feces of DA rats at the peak of the disease (between 13 and 16 days after induction). Interestingly, in contrast to our previous study where Turicibacter sp. was found exclusively in non-immunized AO, but not in DA rats, in this study it was detected in DA rats that remained healthy 16 days after induction, as well as in four of 12 DA rats at the peak of the disease. Similar observation was obtained for the members of Lachnospiraceae. Further, production of a typical regulatory cytokine interleukin-10 was compared in GALT cells of AO and DA rats, and higher production was observed in DA rats. Our data contribute to the idea that gut microbiota and GALT considerably influence multiple sclerosis pathogenesis. PMID:28018327

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

    PubMed

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

    2015-01-01

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

  10. PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis.

    PubMed

    Webb, Lindsay M; Amici, Stephanie A; Jablonski, Kyle A; Savardekar, Himanshu; Panfil, Amanda R; Li, Linsen; Zhou, Wei; Peine, Kevin; Karkhanis, Vrajesh; Bachelder, Eric M; Ainslie, Kristy M; Green, Patrick L; Li, Chenglong; Baiocchi, Robert A; Guerau-de-Arellano, Mireia

    2017-02-15

    In the autoimmune disease multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), expansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted at a role for protein arginine methylation in immune responses, including T cell-mediated autoimmunity and EAE. However, a conclusive role for the protein arginine methyltransferase (PRMT) enzymes that catalyze these reactions has been lacking. PRMT5 is the main PRMT responsible for symmetric dimethylation of arginine residues of histones and other proteins. PRMT5 drives embryonic development and cancer, but its role in T cells, if any, has not been investigated. In this article, we show that PRMT5 is an important modulator of CD4(+) T cell expansion. PRMT5 was transiently upregulated during maximal proliferation of mouse and human memory Th cells. PRMT5 expression was regulated upstream by the NF-κB pathway, and it promoted IL-2 production and proliferation. Blocking PRMT5 with novel, highly selective small molecule PRMT5 inhibitors severely blunted memory Th expansion, with preferential suppression of Th1 cells over Th2 cells. In vivo, PRMT5 blockade efficiently suppressed recall T cell responses and reduced inflammation in delayed-type hypersensitivity and clinical disease in EAE mouse models. These data implicate PRMT5 in the regulation of adaptive memory Th cell responses and suggest that PRMT5 inhibitors may be a novel therapeutic approach for T cell-mediated inflammatory disease. Copyright © 2017 by The American Association of Immunologists, Inc.

  11. PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Webb, Lindsay M.; Amici, Stephanie A.; Jablonski, Kyle A.; Savardekar, Himanshu; Panfil, Amanda R.; Li, Linsen; Zhou, Wei; Peine, Kevin; Karkhanis, Vrajesh; Bachelder, Eric M.; Ainslie, Kristy M.; Green, Patrick L.; Li, Chenglong; Baiocchi, Robert A.

    2017-01-01

    In the autoimmune disease multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), expansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted at a role for protein arginine methylation in immune responses, including T cell–mediated autoimmunity and EAE. However, a conclusive role for the protein arginine methyltransferase (PRMT) enzymes that catalyze these reactions has been lacking. PRMT5 is the main PRMT responsible for symmetric dimethylation of arginine residues of histones and other proteins. PRMT5 drives embryonic development and cancer, but its role in T cells, if any, has not been investigated. In this article, we show that PRMT5 is an important modulator of CD4+ T cell expansion. PRMT5 was transiently upregulated during maximal proliferation of mouse and human memory Th cells. PRMT5 expression was regulated upstream by the NF-κB pathway, and it promoted IL-2 production and proliferation. Blocking PRMT5 with novel, highly selective small molecule PRMT5 inhibitors severely blunted memory Th expansion, with preferential suppression of Th1 cells over Th2 cells. In vivo, PRMT5 blockade efficiently suppressed recall T cell responses and reduced inflammation in delayed-type hypersensitivity and clinical disease in EAE mouse models. These data implicate PRMT5 in the regulation of adaptive memory Th cell responses and suggest that PRMT5 inhibitors may be a novel therapeutic approach for T cell–mediated inflammatory disease. PMID:28087667

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

    PubMed Central

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

    2015-01-01

    MicroRNAs have been shown to be important regulators of immune homeostasis as patients with aberrant microRNA expression appeared to be more susceptible to autoimmune diseases. We recently found that miR-146a was up-regulated in activated B cells in response to rat acetylcholine receptor (AChR) α-subunit 97-116 peptide, and this up-regulation was significantly attenuated by AntagomiR-146a. Our data also demonstrated that silencing miR-146a with its inhibitor AntagomiR-146a effectively ameliorated clinical myasthenic symptoms in mice with ongoing experimental autoimmune myasthenia gravis. Furthermore, multiple defects were observed after miR-146a was knocked down in B cells, including decreased anti-R97-116 antibody production and class switching, reduced numbers of plasma cells, memory B cells and B-1 cells, and weakened activation of B cells. Previously, miR-146a has been identified as a nuclear factor-κB-dependent gene and predicted to base pair with the tumour necrosis factor receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1) genes to regulate the immune response. However, our study proved that miR-146a inhibition had no effect on the expression of TRAF6 and IRAK1 in B cells. This result suggests that the function of miR-146a in B cells does not involve these two target molecules. We conclude that silencing miR-146a exerts its therapeutic effects by influencing the B-cell functions that contribute to the autoimmune pathogenesis of myasthenia gravis. PMID:24962817

  13. RNA interference targeting Bcl-6 ameliorates experimental autoimmune myasthenia gravis in mice.

    PubMed

    Xin, Ning; Fu, Linlin; Shao, Zhen; Guo, Mingfeng; Zhang, Xiuying; Zhang, Yong; Dou, Changxin; Zheng, Shuangshuang; Shen, Xia; Yao, Yuanhu; Wang, Jiao; Wang, Jinhua; Cui, Guiyun; Liu, Yonghai; Geng, Deqin; Xiao, Chenghua; Zhang, Zunsheng; Dong, Ruiguo

    2014-01-01

    Follicular helper T (Tfh) cells are dedicated to providing help to B cells and are strongly associated with antibody-mediated autoimmune disease. B cell lymphoma 6 (Bcl-6) is a key transcription factor of Tfh cells, and IL-21 is known to be a critical cytokine produced by Tfh cells. We silenced Bcl-6 gene expression using RNA interference (RNAi) delivered by a lentiviral vector, to evaluate the therapeutic role of Bcl-6 short hairpin RNAs (shRNAs) in experimental autoimmune myasthenia gravis (EAMG). Our data demonstrate that CD4(+)CXCR5(+)PD-1(+) Tfh cells, Bcl-6 and IL-21 were significantly increased in EAMG mice, compared with controls. In addition, we found that frequencies of Tfh cells were positively correlated with the levels of serum anti-AChR Ab. In-vivo transduction of lenti-siRNA-Bcl6 ameliorates the severity of ongoing EAMG with decreased Tfh cells, Bcl-6 and IL-21 expression, and leads to decreased anti-AChR antibody levels. Furthermore, we found that siRNA knockdown of Bcl-6 expression increases the expression of Th1(IFN-γ, T-bet) and Th2 markers (IL-4 and GATA3), but failed to alter the expression of Th17-related markers (RORγt, IL-17) and Treg markers (FoxP3). Our study suggests that Tfh cells contribute to the antibody production and could be one of the most important T cell subsets responsible for development and progression of EAMG or MG. Bcl-6 provides a promising therapeutic target for immunotherapy not only for MG, but also for other antibody-mediated autoimmune diseases. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Correlation between inhibin secretion and damage of seminiferous tubules in a model of experimental autoimmune orchitis.

    PubMed

    Suescun, M O; Suescun, M O; Lustig, L; Calandra, R S; Calandra, R S; Groome, N P; Campo, S

    2001-07-01

    The aim of the present study was to evaluate inhibin secretion in rats with autoimmune orchitis. As we have previously described, experimental autoimmune orchitis (EAO) induced in rats by active immunization with testis homogenate and adjuvants is characterized by an interstitial mononuclear cell infiltrate and sloughing of the germinal epithelium. At 120 days after the first immunization 60% of the rats exhibited a severe orchitis with large areas of aspermatogenic seminiferous tubules in which only spermatogonia and Sertoli cells with cytoplasmic vacuolization remained attached to the tubular wall. None of the untreated (N) or control (C) rats revealed pathological alterations. Sixty percent decrease in testis weight was observed in rats with EAO compared with N or C groups. A 3-fold increase in serum FSH levels was observed in rats with EAO compared with N or C groups (19.8+/-3.7 vs 5.6+/-0.3 and 5.9+/-0.1 ng/ml respectively). A significant decrease in inhibin B levels was observed in rats with EAO when compared with N or C groups (40+/-4.6 vs 207+/-38.8 and 221.4+/-28.6 pg/ml respectively). An inverse correlation between inhibin B and FSH serum levels and a direct correlation between inhibin B and testis weight were found. Strong expression of the inhibin alpha-subunit in Sertoli cells of untreated and control rats was observed; this subunit was undetectable or poorly detectable in rats with orchitis. Positive staining for the inhibin alpha-subunit was also observed in Leydig cells of all groups studied. In conclusion, using a model of autoimmune orchitis our results show that circulating inhibin B levels and inhibin alpha-subunit expression in Sertoli cell cytoplasm closely correlate with the degree of damage of the germinal epithelium.

  15. Interleukin-10 influences susceptibility to experimental autoimmune thyroiditis independently of the H-2 gene.

    PubMed

    Yu, Zhenqian; Liu, Tong; Liu, Shanshan; Zou, Hongjin; Sun, Xuren; Shi, Xiaoguang; Li, Yushu; Shan, Zhongyan; Teng, Weiping

    2015-02-01

    Both BALB/c and C57BL/6 mice are relatively resistant to experimental autoimmune thyroiditis (EAT) due to their histocompatibility (H-2) genetic background; however, susceptibility to EAT is also influenced by other genetic factors. Given the curative effect of interleukin-10 (IL-10) on thyroiditis, in the present study, we investigated whether IL-10 functions as a non-H-2 genetic factor that influences the development of EAT in mice with an EAT-resistant genetic background. In this study, we observed that the development of EAT could be induced in both C57BL/6 IL-10‑deficient (IL-10-/-) and BALB/c IL-10-/- female mice following immunization with mTg, which indicated that IL-10 may be a non-H-2 factor that affects susceptibility to EAT. However, the role of the H-2 factor remained dominant, as the incidence of EAT was low and its severity was mild. We further investigated the underlying pathogenic mechanisms of EAT in IL-10-/- female mice. We found that Th1 cells, Th17 cells, CD4+CD25+Foxp3+ regulatory T cells, and their associated cytokines were all involved in the development of EAT. The absence of IL-10 promoted the polarization of pathogenic cells and the production of associated cytokines, and suppressed the proliferation of protective T cell clones. Together, these factors may contribute to the development of EAT in IL-10-/- mice. In conclusion, our data demonstrate that IL-10 plays a critical role in the susceptibility to EAT, and a better understanding of the role of IL-10 in autoimmune thyroiditis may facilitate the development of novel strategies for the treatment of autoimmune thyroid diseases.

  16. Functional macrophage heterogeneity in a mouse model of autoimmune central nervous system pathology.

    PubMed

    London, Anat; Benhar, Inbal; Mattapallil, Mary J; Mack, Matthias; Caspi, Rachel R; Schwartz, Michal

    2013-04-01

    Functional macrophage heterogeneity is well appreciated outside the CNS in wound healing and cancer, and was recently also demonstrated in several CNS compartments after "sterile" insults. Yet, such heterogeneity was largely overlooked in the context of inflammatory autoimmune pathology, in which macrophages were mainly associated with disease induction and propagation. In this article, we show the diversity of monocyte-derived macrophages along the course of experimental autoimmune uveitis, an inflammatory condition affecting the ocular system, serving as a model for CNS autoimmune pathology. Disease induction resulted in the appearance of a distinct myeloid population in the retina, and in the infiltration of monocyte-derived macrophages that were absent from control eyes. During the disease course, the frequency of CX3CR1(high) infiltrating macrophages that express markers associated with inflammation-resolving activity was increased, along with a decrease in the frequency of inflammation-associated Ly6C(+) macrophages. Inhibition of monocyte infiltration at the induction phase of experimental autoimmune uveitis prevented disease onset, whereas monocyte depletion at the resolution phase resulted in a decrease in Foxp3(+) regulatory T cells and in exacerbated disease. Thus, monocyte-derived macrophages display distinct phenotypes throughout the disease course, even in an immune-induced pathology, reflecting their differential roles in disease induction and resolution.

  17. Role of IL-22- and TNF-α-producing Th22 cells in uveitis patients with Behcet's disease.

    PubMed

    Sugita, Sunao; Kawazoe, Yuko; Imai, Ayano; Kawaguchi, Tatsushi; Horie, Shintaro; Keino, Hiroshi; Takahashi, Masayo; Mochizuki, Manabu

    2013-06-01

    Behçet's disease is a systemic inflammatory disorder with recurrent episodes of oral ulceration, skin lesions, genital ulceration, and intraocular inflammation (uveitis). The intraocular inflammation is strictly associated with Th effector cells. IL-22 is a member of the IL-10 cytokine family that is involved in inflammatory processes. Recently, Th22 cells were identified as a Th cell population that produces IL-22 and TNF-α and are distinct from Th1, Th2, and Th17 cells. In this study, we established Th22-type T cell clones from ocular samples taken from Behçet's disease patients with active uveitis. These clones produced large amounts of IL-22 and TNF-α but not the Th1 cytokine IFN-γ and the Th17 cytokine IL-17. CD4(+) T cells from the peripheral blood of Behçet's disease patients differentiated into Th22 cells in the presence of IL-6 and TNF-α in vitro. The polarized Th22 cell lines produced large amounts of IL-22, and the polarized Th1 and Th17 cells also produced IL-22. In the presence of anti-TNF-α- and anti-IL-6-blocking Abs, Behçet's disease Th22-type T cells failed to produce IL-22. In addition, infliximab-pretreated Th22 cells and Th22-type ocular T cells produced less IL-22 and TNF-α. Moreover, IL-22-producing T cells were isolated from mice with experimental autoimmune uveitis, an animal model of Behçet's disease, and the intraocular T cells from uveitis models produced large amounts of IL-22 in the presence of retinal Ags. Our results suggest that inflammatory cytokines IL-22 and TNF-α may play a key role in the ocular immune response in Behçet's disease.

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

    PubMed Central

    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

  19. Apigenin Attenuates Experimental Autoimmune Myocarditis by Modulating Th1/Th2 Cytokine Balance in Mice.

    PubMed

    Zhang, Shouxin; Liu, Xiaoyan; Sun, Chengming; Yang, Jun; Wang, Lihong; Liu, Jie; Gong, Lei; Jing, Yanyan

    2016-04-01

    This study aims to investigate the protective effect of apigenin on the development of experimental autoimmune myocarditis (EAM) and the underlying mechanisms. An EAM model was induced in BALB/c mice by the injection of porcine cardiac myosin. Apigenin was orally administered from day 1 to 21. The severity of myocarditis was assessed by determination of heart weight/body weight ratio (HW/BW) and histopathological evaluation. Echocardiography was conducted to evaluate the cardiac function and heart structure. Antigen-specific T cell proliferation responses to cardiac myosin were evaluated by the lymphocyte proliferation assay. ELISA was used to determine serum levels of type 1 helper (Th1) and Th2 cytokines. Apigenin treatment significantly decreased HW/BW. Histopathologic analysis showed that the infiltration of inflammatory cells was reduced significantly by apigenin treatment. Meanwhile, apigenin administration effectively ameliorated autoimmune myocarditis-induced cardiac hypertrophy and cardiac dysfunction as well as inhibited lymphocyte proliferation in mice immunized with myosin. Furthermore, Th1 cytokines tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and interleukin-2 (IL-2) were significantly downregulated, while Th2 cytokines IL-4 and IL-10 were markedly upregulated. The results indicated that apigenin can alleviate EAM due to its immunomodulatory reactions in modification of helper T cell balance.

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

    PubMed

    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.

  1. Hydrogen-rich water improves neurological functional recovery in experimental autoimmune encephalomyelitis mice.

    PubMed

    Zhao, Ming; Liu, Ming-Dong; Pu, Ying-Yan; Wang, Dan; Xie, Yu; Xue, Gai-Ci; Jiang, Yong; Yang, Qian-Qian; Sun, Xue-Jun; Cao, Li

    2016-05-15

    Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS). The high costs, inconvenient administration, and side effects of current Food and Drug Administration (FDA)-approved drugs often lead to poor adherence to the long-term treatment of MS. Molecular hydrogen (H2) has been reported to exhibit anti-oxidant, anti-apoptotic, anti-inflammatory, anti-allergy, and anti-cancer effects. In the present study, we explored the prophylactic and therapeutic effects of hydrogen-rich water (HRW) on the progress of experimental autoimmune encephalomyelitis (EAE), the animal model for MS. We found that prophylactic administration of both 0.36mM and 0.89mM HRW was able to delay EAE onset and reduce maximum clinical scores. Moreover, 0.89mM HRW also reduced disease severity, CNS infiltration, and demyelination when administered after the onset of disease. Furthermore, HRW treatment prevented infiltration of CD4(+) T lymphocytes into the CNS and inhibited Th17 cell development without affecting Th1 cell populations. Because HRW is non-toxic, inexpensive, easily administered, and can readily cross the blood-brain barrier, our experiments suggest that HRW may have great potential in the treatment of MS.

  2. Carboxypeptidase N-Deficient Mice Present With Polymorphic Disease Phenotypes on Induction of Experimental Autoimmune Encephalomyelitis

    PubMed Central

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

    2015-01-01

    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. PMID:24028840

  3. Helminth-induced Ly6Chi monocyte-derived alternatively activated macrophages suppress experimental autoimmune encephalomyelitis

    PubMed Central

    Terrazas, Cesar; de Dios Ruiz-Rosado, Juan; Amici, Stephanie A.; Jablonski, Kyle A.; Martinez-Saucedo, Diana; Webb, Lindsay M.; Cortado, Hanna; Robledo-Avila, Frank; Oghumu, Steve; Satoskar, Abhay R.; Rodriguez-Sosa, Miriam; Terrazas, Luis I.; Guerau-de-Arellano, Mireia; Partida-Sánchez, Santiago

    2017-01-01

    Helminths cause chronic infections and affect the immune response to unrelated inflammatory diseases. Although helminths have been used therapeutically to ameliorate inflammatory conditions, their anti-inflammatory properties are poorly understood. Alternatively activated macrophages (AAMϕs) have been suggested as the anti-inflammatory effector cells during helminth infections. Here, we define the origin of AAMϕs during infection with Taenia crassiceps, and their disease-modulating activity on the Experimental Autoimmune Encephalomyelitis (EAE). Our data show two distinct populations of AAMϕs, based on the expression of PD-L1 and PD-L2 molecules, resulting upon T. crassiceps infection. Adoptive transfer of Ly6C+ monocytes gave rise to PD-L1+/PD-L2+, but not PD-L1+/PD-L2− cells in T. crassiceps-infected mice, demonstrating that the PD-L1+/PD-L2+ subpopulation of AAMϕs originates from blood monocytes. Furthermore, adoptive transfer of PD-L1+/PD-L2+ AAMϕs into EAE induced mice reduced disease incidence, delayed disease onset, and diminished the clinical disability, indicating the critical role of these cells in the regulation of autoimmune disorders. PMID:28094319

  4. c-kit plays a critical role in induction of intravenous tolerance in experimental autoimmune encephalomyelitis.

    PubMed

    Safavi, Farinaz; Li, Hongmei; Gonnella, Patricia; Mari, Elisabeth Rose; Rasouli, Javad; Zhang, Guang Xian; Rostami, Abdolmohamad

    2015-03-01

    c-kit (CD117) is a tyrosine kinase receptor found in various types of immune cells. It has been shown that c-kit plays a role in the pathogenesis of multiple sclerosis, an inflammatory demyelinating disorder of the CNS. Recent data have suggested an immunoregulatory effect of c-kit. We therefore examined the role of c-kit in autoantigen-induced i.v. tolerance in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Our results show that induction of intravenous tolerance against EAE in B6 mice is characterized by increased numbers of CD117(+) cells and altered mast cell-associated molecules in the periphery and in the CNS. W(-sh) (c-kit-deficient) mice were resistant to i.v autoantigen-induced tolerance, with increased proinflammatory cytokine production in the periphery. I.v. autoantigen in WT mice suppressed the production of proinflammatory cytokines IFN-γ and IL-6 and up-regulated the expression of FoxP3, a transcription factor of Tregs; however, in W(-sh) mice, IFN-γ and IL-6 were increased with a failure of FoxP3 induction upon i.v. autoantigen injection and is thus a mechanism for resistance to i.v. tolerance induction in these mice. We conclude that c-kit signaling has a regulatory role in i.v. tolerance and could be a target for potential immunotherapy in autoimmune disorders.

  5. Gestational hypothyroidism increases the severity of experimental autoimmune encephalomyelitis in adult offspring.

    PubMed

    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; Riedel, Claudia A

    2013-12-01

    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. 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. 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. 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.

  6. Erythropoietin-Derived Nonerythropoietic Peptide Ameliorates Experimental Autoimmune Neuritis by Inflammation Suppression and Tissue Protection

    PubMed Central

    Liu, Yuqi; Luo, Bangwei; Han, Fuyu; Li, Xiaoming; Xiong, Jian; Jiang, Man; Yang, Xioafeng; Wu, Yuzhang; Zhang, Zhiren

    2014-01-01

    Experimental autoimmune neuritis (EAN) is an autoantigen-specific T-cell-mediated disease model for human demyelinating inflammatory disease of the peripheral nervous system. Erythropoietin (EPO) has been known to promote EAN recovery but its haematopoiesis stimulating effects may limit its clinic application. Here we investigated the effects and potential mechanisms of an EPO-derived nonerythropoietic peptide, ARA 290, in EAN. Exogenous ARA 290 intervention greatly improved EAN recovery, improved nerve regeneration and remyelination, and suppressed nerve inflammation. Furthermore, haematopoiesis was not induced by ARA 290 during EAN treatment. ARA 290 intervention suppressed lymphocyte proliferation and altered helper T cell differentiation by inducing increase of Foxp3+/CD4+ regulatory T cells and IL-4+/CD4+ Th2 cells and decrease of IFN-γ+/CD4+ Th1 cells in EAN. In addition, ARA 290 inhibited inflammatory macrophage activation and promoted its phagocytic activity. In vitro, ARA 290 was shown to promote Schwann cell proliferation and inhibit its inflammatory activation. In summary, our data demonstrated that ARA 290 could effectively suppress EAN by attenuating inflammation and exerting direct cell protection, indicating that ARA 290 could be a potent candidate for treatment of autoimmune neuropathies. PMID:24603865

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

    PubMed Central

    Herrmann, Martin M.; Barth, Silvia; Greve, Bernhard; Schumann, Kathrin M.; Bartels, Andrea

    2016-01-01

    ABSTRACT 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. PMID:27519689

  8. Ceruloplasmin gene-deficient mice with experimental autoimmune encephalomyelitis show attenuated early disease evolution.

    PubMed

    Gresle, Melissa M; Schulz, Katrin; Jonas, Anna; Perreau, Victoria M; Cipriani, Tania; Baxter, Alan G; Miranda-Hernandez, Socorro; Field, Judith; Jokubaitis, Vilija G; Cherny, Robert; Volitakis, Irene; David, Samuel; Kilpatrick, Trevor J; Butzkueven, Helmut

    2014-06-01

    We conducted a microarray study to identify genes that are differentially regulated in the spinal cords of mice with the inflammatory disease experimental autoimmune encephalomyelitis (EAE) relative to healthy mice. In total 181 genes with at least a two-fold increase in expression were identified, and most of these genes were associated with immune function. Unexpectedly, ceruloplasmin (Cp), a ferroxidase that converts toxic ferrous iron to its nontoxic ferric form and also promotes the efflux of iron from astrocytes in the CNS, was shown to be highly upregulated (13.2-fold increase) in EAE spinal cord. Expression of Cp protein is known to be increased in several neurological conditions, but the role of Cp regulation in CNS autoimmune disease is not known. To investigate this, we induced EAE in Cp gene knockout, heterozygous, and wild-type mice. Cp knockout mice were found to have slower disease evolution than wild-type mice (EAE days 13-17; P = 0.05). Interestingly, Cp knockout mice also exhibited a significant increase in the number of astrocytes with reactive morphology in early EAE compared with wild-type mice at the same stage of disease. CNS iron levels were not increased with EAE in these mice. Based on these observations, we propose that an increase in Cp expression could contribute to tissue damage in early EAE. In addition, endogenous CP either directly or indirectly inhibits astrocyte reactivity during early disease, which could also worsen early disease evolution.

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

    PubMed Central

    Pierson, Emily R.; Goverman, Joan M.

    2017-01-01

    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. PMID:28405624

  10. Functional and phenotypic characteristics of testicular macrophages in experimental autoimmune orchitis.

    PubMed

    Rival, C; Theas, M S; Suescun, M O; Jacobo, P; Guazzone, V; van Rooijen, N; Lustig, L

    2008-06-01

    Testicular inflammation with compromised fertility can occur despite the fact that the testis is considered an immunoprivileged organ. Testicular macrophages have been described as cells with an immunosuppressor profile, thus contributing to the immunoprivilege of the testis. Experimental autoimmune orchitis (EAO) is a model of organ-specific autoimmunity and testicular inflammation. EAO is characterized by an interstitial inflammatory mononuclear cell infiltration, damage of the seminiferous tubules and germ cell apoptosis. Here we studied the phenotype and functions of testicular macrophages during the development of EAO. By stereological analysis, we detected an increased number of resident (ED2+) and non-resident (ED1+) macrophages in the testicular interstitium of rats with orchitis. We showed that this increase was mainly due to monocyte recruitment. The in vivo administration of liposomes containing clodronate in rats undergoing EAO led to a reduction in the number of testicular macrophages, which correlated with a decreased incidence and severity of the testicular damage and suggests a pathogenic role of macrophages in EAO. By immunohistochemistry and flow cytometry we detected an increased number of testicular macrophages expressing MHC class II, CD80 and CD86 costimulatory molecules in rats with orchitis. Also, testicular macrophages from rats with EAO showed a higher production of IFNgamma (ELISA). We conclude that testicular macrophages participate in EAO development, and the ED1+ macrophage subset is the main pathogenic subpopulation. They stimulate the immune response through the production of pro-inflammatory cytokines and antigen presentation and thus activation of T cells in the target organ.

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

    PubMed Central

    Ledesma-Soto, Yadira; Olguín, Jonadab E.; Bautista-Donis, Marcel

    2017-01-01

    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. PMID:28744067

  12. PD-1 deletion restores susceptibility to experimental autoimmune encephalomyelitis in miR-155-deficient mice.

    PubMed

    Zhang, Jinyu; Braun, Michel Y

    2014-07-01

    MiR-155 (-/-) mice are highly resistant to experimental autoimmune encephalomyelitis (EAE), while Pdcd1 (-/-) mice develop a more severe form of the disease. To determine the conflicting roles of these two molecules in the disease, we generated miR-155 (-/-) Pdcd1 (-/-) double knockout (DKO) mice. We found that ablation of programmed cell death protein 1 (PD-1) expression in miR-155-deficient mice restored the susceptibility to EAE. The increased severity of the disease in DKO mice was accompanied by an enhanced T-cell infiltration into the brain as well as an increased production of pro-inflammatory cytokines IFN-γ and IL-17. Furthermore, the major contribution of the DKO to EAE was T-cell intrinsic since adoptive transfer of CD4(+) T cells from DKO donors promoted the disease in lymphopenic recipients. These results define PD-1 deficiency in miR-155 (-/-) mice as a promoting factor of autoimmune inflammation by increasing antigen-driven T-cell expansion and infiltration.

  13. 2-Methoxyestradiol inhibits experimental autoimmune encephalomyelitis through suppression of immune cell activation

    PubMed Central

    Duncan, Gordon S.; Brenner, Dirk; Tusche, Michael W.; Brüstle, Anne; Knobbe, Christiane B.; Elia, Andrew J.; Mock, Thomas; Bray, Mark R.; Krammer, Peter H.; Mak, Tak W.

    2012-01-01

    The endogenous metabolite of estradiol, 2-Methoxyestradiol (2ME2), is an antimitotic and antiangiogenic cancer drug candidate that also exhibits disease-modifying activity in animal models of rheumatoid arthritis (RA). We found that 2ME2 dramatically suppresses development of mouse experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis (MS). 2ME2 inhibits in vitro lymphocyte activation, cytokine production, and proliferation in a dose-dependent fashion. 2ME2 treatment of lymphocytes specifically reduced the nuclear translocation and transcriptional activity of nuclear factor of activated T-cells (NFAT) c1, whereas NF-κB and activator protein 1 (AP-1) activation were not adversely affected. We therefore propose that 2ME2 attenuates EAE through disruption of the NFAT pathway and subsequent lymphocyte activation. By extension, our findings provide a molecular rationale for the use of 2ME2 as a tolerable oral immunomodulatory agent for the treatment of autoimmune disorders such as MS in humans. PMID:23213242

  14. Effect of transgenic overexpression of FLIP on lymphocytes on development and resolution of experimental autoimmune thyroiditis.

    PubMed

    Fang, Yujiang; Sharp, Gordon C; Braley-Mullen, Helen

    2011-09-01

    In our previous studies, resolution of granulomatous experimental autoimmune thyroiditis (G-EAT) was promoted when thyroid epithelial cells were protected from Fas-mediated apoptosis due to transgenic overexpression of FLIP. We hypothesized that if FLIP were overexpressed on lymphocytes, CD4(+) effector cells would be protected from Fas-mediated apoptosis, and resolution would be delayed. To test this hypothesis, we generated transgenic (Tg) mice overexpressing FLIP under the CD2 promoter. Transgenic FLIP was expressed on CD4(+) and CD8(+) T cells and B cells. Transgenic overexpression of FLIP protected cultured splenocytes from Fas-mediated, but not irradiation-induced, apoptosis in vitro. Unexpectedly, Tg(+) donor cells transferred minimal G-EAT, which was partially overcome by depleting donor CD8(+) T cells. When Tg(+) and Tg(-) donors transferred equivalent disease, G-EAT resolution was delayed in FLIP transgenic mice. However, CD2-FLIP Tg(+) donors often transferred less severe G-EAT, even after depletion of CD8(+) T cells. This influenced the rate of G-EAT resolution, resulting in little difference in G-EAT resolution between groups. Tg(+) mice always had reduced anti-mouse thyroglobulin autoantibody responses, compared with Tg(-) littermates, presumably because of FLIP overexpression on B cells. These results suggest that effects of transgenic FLIP on a particular autoimmune disease vary, depending on what cells express the transgene and whether those cells are effector cells or if they function to modulate disease.

  15. Chloroquine Treatment Enhances Regulatory T Cells and Reduces the Severity of Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Thomé, Rodolfo; Moraes, Adriel S.; Bombeiro, André Luis; Farias, Alessandro dos Santos; Francelin, Carolina; da Costa, Thiago Alves; Di Gangi, Rosária; dos Santos, Leonilda Maria Barbosa; de Oliveira, Alexandre Leite Rodrigues; Verinaud, Liana

    2013-01-01

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

  16. Uveitis (acute anterior).

    PubMed

    Islam, Niaz; Pavesio, Carlos

    2010-04-08

    Anterior uveitis is rare, with an annual incidence of 12/100,000 population, although it is more common in Finland (annual incidence of 23/100,000), probably because of genetic factors, such as high frequency of HLA-B27 in the population. It is often self-limiting, but can, in some cases, lead to complications such as posterior synechiae, cataract, glaucoma, and chronic uveitis. We conducted a systematic review and aimed to answer the following clinical question: What are the effects of anti-inflammatory eye drops on acute anterior uveitis? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found six systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: corticosteroids, mydriatics, and non-steroidal anti-inflammatory drug eye drops.

  17. Tattoo-associated uveitis.

    PubMed

    Ostheimer, Trucian A; Burkholder, Bryn M; Leung, Theresa G; Butler, Nicholas J; Dunn, James P; Thorne, Jennifer E

    2014-09-01

    To describe the clinical presentation of uveitis with coincident onset of raised and indurated tattooed skin. Case series. Seven consecutive patients were evaluated at a tertiary ophthalmologic facility with coincident uveitis and cutaneous tattoo induration over an 18-month period. All subjects underwent complete ophthalmic examination and a focused systemic medical evaluation including serologic testing and imaging studies. Two participants underwent biopsy of their tattoos. The patients' clinical courses and responses to treatment over a follow-up period of 1-20 months are reported (mean follow-up = 9 months). Main outcome measures included degree of intraocular inflammation, ocular complications, visual acuity, clinically observable tattooed skin changes, and biopsy results. Five of 7 patients had bilateral nongranulomatous anterior uveitis: 4 with chronic and 1 with recurrent disease. The remaining 2 patients had bilateral chronic granulomatous panuveitis. Biopsies of raised and indurated tattoos were performed in 2 patients and demonstrated noncaseating granulomatous inflammation surrounding tattoo ink in the dermis. The skin changes resolved in all patients, with a faster response noted in those treated with high-dose oral prednisone for intraocular inflammation. Five patients subsequently experienced recurrent flares of intraocular inflammation in conjunction with the recurrence of raised and indurated tattoos. These cases represent a subset of patients in whom skin tattooing may have incited an immune response leading to simultaneous inflammation of the eyes and tattooed skin. Copyright © 2014 Elsevier Inc. All rights reserved.

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

    PubMed Central

    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

    2017-01-01

    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. PMID:28245629

  19. Eicosapentaenoic acid (EPA) induces peroxisome proliferator-activated receptors and ameliorates experimental autoimmune encephalomyelitis.

    PubMed

    Unoda, Kiichi; Doi, Yoshimitsu; Nakajima, Hideto; Yamane, Kazushi; Hosokawa, Takafumi; Ishida, Shimon; Kimura, Fumiharu; Hanafusa, Toshiaki

    2013-03-15

    Eicosapentaenoic acid (EPA), one of the n-3 polyunsaturated fatty acids, is a neuroprotective lipid with anti-inflammatory properties. We investigated the possible therapeutic effect of EPA on experimental autoimmune encephalomyelitis (EAE). EAE mice were fed a diet with or without EPA. The clinical EAE scores of the EPA-fed mice were significantly lower than those of the non-EPA mice. In the EPA-treated mice, IFN-γ and IL-17 productions were remarkably inhibited and the expression levels of peroxisome proliferator-activated receptors were significantly enhanced in the CNS-infiltrating CD4T cells. Thus EPA shows promise as a potential new therapeutic agent against multiple sclerosis. Copyright © 2012 Elsevier B.V. All rights reserved.

  20. Rituximab Therapy Reduces Organ-Specific T Cell Responses and Ameliorates Experimental Autoimmune Encephalomyelitis

    PubMed Central

    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.

    2011-01-01

    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. PMID:21359213

  1. Gonadotropin-releasing hormone reduces the severity of experimental autoimmune encephalomyelitis, a model of multiple sclerosis.

    PubMed

    Quintanar, J Luis; Salinas, Eva; Quintanar-Stephano, Andrés

    2011-02-01

    It has been reported that the spinal cord possesses Gonadotropin-releasing hormone (GnRH) receptor and that GnRH has neurotrophic properties. Experimental autoimmune encephalomyelitis (EAE) causes neurodegeneration in spinal cord. Thus, the present study was designed to determine whether administration of GnRH reduces the severity of EAE. The clinical signs of locomotion, axonal morphometry and neurofilaments (NFs) expression were evaluated. Clinical signs remained significantly lower in EAE rats with GnRH administration compared to animals without treatment. Morphometric analysis, there were more axons of larger areas in the spinal cord of EAE+GnRH group compared to EAE animals. Western blot analysis demonstrated that GnRH administration significantly increased the expression of NFs of 68, 160 and 200kDa in the spinal cord of EAE animals. Our results indicate that GnRH administration reduces the severity of EAE in the rat.

  2. The role of apolipoprotein E in Guillain-Barré syndrome and experimental autoimmune neuritis.

    PubMed

    Zhang, Hong-liang; Wu, Jiang; Zhu, Jie

    2010-01-01

    Apolipoprotein E (apoE) is a 34.2 kDa glycosylated protein characterized by its wide tissue distribution and multiple functions. ApoE has been widely studied in lipid metabolism, cardiocerebrovascular diseases, and neurodegenerative diseases like Alzheimer's disease and mild cognitive impairment, and so forth. Recently, a growing body of evidence has pointed to nonlipid related properties of apoE, including suppression of T cell proliferation, regulation of macrophage function, facilitation of lipid antigen presentation by CD1 molecules to natural killer T (NKT) cells, and modulation of inflammation and oxidation. By these properties, apoE impacts physiology and pathophysiology at multiple levels. The present paper summarizes updated studies on the immunoregulatory function of apoE, with special focus on isoform-specific effects of apoE on Guillain-Barré syndrome (GBS) and its animal model experimental autoimmune neuritis (EAN).

  3. The Role of Apolipoprotein E in Guillain-Barré Syndrome and Experimental Autoimmune Neuritis

    PubMed Central

    Zhang, Hong-liang; Wu, Jiang; Zhu, Jie

    2010-01-01

    Apolipoprotein E (apoE) is a 34.2 kDa glycosylated protein characterized by its wide tissue distribution and multiple functions. ApoE has been widely studied in lipid metabolism, cardiocerebrovascular diseases, and neurodegenerative diseases like Alzheimer's disease and mild cognitive impairment, and so forth. Recently, a growing body of evidence has pointed to nonlipid related properties of apoE, including suppression of T cell proliferation, regulation of macrophage function, facilitation of lipid antigen presentation by CD1 molecules to natural killer T (NKT) cells, and modulation of inflammation and oxidation. By these properties, apoE impacts physiology and pathophysiology at multiple levels. The present paper summarizes updated studies on the immunoregulatory function of apoE, with special focus on isoform-specific effects of apoE on Guillain-Barré syndrome (GBS) and its animal model experimental autoimmune neuritis (EAN). PMID:20182542

  4. Soluble complement receptor 1 (sCR1) protects against experimental autoimmune myasthenia gravis.

    PubMed

    Piddlesden, S J; Jiang, S; Levin, J L; Vincent, A; Morgan, B P

    1996-12-01

    The loss of muscle function seen in myasthenia gravis and in the animal model of the disease, experimental autoimmune myasthenia gravis (EAMG) is in part due to the activation of complement by anti-acetylcholine receptor (AChR) antibodies at the motor end-plate. In this study we describe the effects of a soluble recombinant form of human complement receptor 1 (sCR1) on the development of clinical disease and receptor loss in EAMG induced passively by administration of anti-AChR antibodies. Daily intraperitoneal injection of sCR1 significantly reduced the weight loss and severity of clinical symptoms seen and allowed treated animals to recover normal muscle function. These data suggest that sCR1 could provide a useful additional therapeutic agent in myasthenia.

  5. C5a is not involved in experimental autoimmune myasthenia gravis pathogenesis

    PubMed Central

    Qi, Huibin; Tüzün, Erdem; Allman, Windy; Saini, Shamsher S.; Penabad, Zurina R.; Pierangeli, Silvia; Christadoss, Premkumar

    2013-01-01

    C5 deficient mice are highly resistant to experimental autoimmune myasthenia gravis (EAMG) despite intact immune response to acethylcholine receptor (AChR), validating the pivotal role played by membrane attack complex (MAC, C5b-9) in neuromuscular junction destruction. To distinguish the significance of C5a from that of C5b in EAMG pathogenesis, C5a receptor (C5aR) knockout (KO) and wild-type (WT) mice were immunized with AChR to induce pathogenic anti-AChR antibodies. In contrast with C5 deficient mice, C5aR KO mice were equally susceptible to EAMG as WT mice and exhibited comparable antibody and lymphocyte proliferation response to AChR implicating that C5a is not involved in EAMG development. PMID:18455242

  6. Amelioration of experimental autoimmune encephalomyelitis through transplantation of placental derived mesenchymal stem cells

    PubMed Central

    Jiang, Hong; Zhang, Yuanyuan; Tian, Kewei; Wang, Beibei; Han, Shu

    2017-01-01

    Placental derived mesenchymal stem cells (PMSCs) have been suggested as a possible source of cells to treat multiple sclerosis (MS) due to their immunomodulatory functions, lack of ethical concerns, and potential to differentiate into neurons and oligodendrocytes. To investigate whether PMSCs share similar characteristics with embryonic mesenchymal stem cells (EMSCs), and if transplanted PMSCs have the ability to integrate and replace degenerated neural cells, we transplanted rat PMSCs and EMSCs into the central nervous system (CNS) of Lewis rats with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Our findings demonstrated that transplanted PMSCs, similar to EMSCs, were effective in decreasing infiltrating inflammatory cells, preserving axons, and ameliorating demyelination, thereby improving the neurological functions of animals. Moreover, both PMSCs and EMSCs had the ability to migrate into inflamed tissues and express neural–glial lineage markers. These findings suggest that PMSCs may replace EMSCs as a source of cells in MS stem cell therapy. PMID:28186117

  7. IL-12Rβ2 has a protective role in relapsing-remitting experimental autoimmune encephalomyelitis

    PubMed Central

    Xie, Chong; Ciric, Bogoljub; Yu, Shuo; Zhang, Guang-Xian; Rostami, Abdolmohamad

    2016-01-01

    IL-12Rβ2 participates in the receptors of IL-12 and IL-35, two cytokines that are involved in a variety of immune responses. In this study we evaluate the role of IL-12Rβ2 in relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE). We found that the IL-12Rβ2 deficient SJL/J EAE mice presented more severe symptoms and had more frequent, more severe relapses compared with wild type controls. IL-12Rβ2 deficient EAE mice also had more infiltrating mononuclear cells in the central nervous system, as well as higher splenic proliferative capacity and decreased IFN-γ production at the periphery. These findings suggest a protective role of IL-12Rβ2 in RR-EAE, an animal model of RR-MS, the most prevalent form of MS. PMID:26857496

  8. Satellite glial cells in dorsal root ganglia are activated in experimental autoimmune encephalomyelitis.

    PubMed

    Warwick, Rebekah A; Ledgerwood, Craig J; Brenner, Talma; Hanani, Menachem

    2014-05-21

    Pain is a serious and common problem with patients suffering from multiple sclerosis (MS). Very little has been done to investigate the peripheral mechanisms of pain in MS. Here we used a mouse model of experimental autoimmune encephalomyelitis (EAE) to investigate the possible contribution of satellite glial cells (SGCs) to pain in MS. EAE mice had reduced pain thresholds 10 days after disease induction. We examined dorsal root ganglia and found increased expression of glial fibrillary acidic protein in SGCs, a marker of SGC activation, and increased coupling among SGCs, a known component of activated SGCs. Activated SGCs have previously been shown to contribute to pain in other classical neuropathic pain models, suggesting that pain in multiple sclerosis has a peripheral component.

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

    PubMed Central

    Herrera, Sheryl L; Palmer, Vanessa L; Whittaker, Heather; Smith, Blair Cardigan; Kim, Annie; Schellenberg, Angela E; Thiessen, Jonathan D; Buist, Richard; Del Bigio, Marc R; Martin, Melanie

    2014-01-01

    Optic chiasm lesions in myelin oligodendrocyte glycoprotein (MOG)–experimental autoimmune encephalomyelitis (EAE) mice were characterized using magnetic resonance imaging (MRI) and validated using electron microscopy (EM). MR images were collected from 3 days after induction to remission, approximately 20 days after induction. Hematoxylin and eosin, solochrome cyanin–stained sections, and EM images were obtained from the optic chiasms of some mice approximately 4 days after disease onset when their scores were thought to be the highest. T2-weighted imaging and apparent diffusion coefficient map hyperintensities corresponded to abnormalities in the optic chiasms of EAE mice. Mixed inflammation was concentrated at the lateral surface. Degeneration of oligodendrocytes, myelin, and early axonal damage were also apparent. A marked increase in chiasm thickness was observed. T2-weighted and diffusion-weighted MRI can detect abnormalities in the optic chiasms of MOG-EAE mice. MRI is an important method in the study of this model toward understanding optic neuritis. PMID:25520558

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

    SciTech Connect

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

    1983-01-01

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

  11. Involvement of CD44 in leukocyte recruitment to the rat testis in experimental autoimmune orchitis.

    PubMed

    Guazzone, V A; Denduchis, B; Lustig, L

    2005-05-01

    Experimental autoimmune orchitis (EAO) is characterized by an interstitial mononuclear cell infiltrate and a severe lesion of the seminiferous tubules with germ cells that undergo apoptosis and sloughing. The aim of this study was to determine the role of CD44 in testicular leukocyte recruitment in EAO. The biological functions of CD44 have been attributed to the generation of a functionally active hyaluronan-binding phenotype. Orchitis was induced in Sprague-Dawley adult rats by active immunization with an emulsion of testicular homogenate and complete Freund's adjuvant using Bordetella pertussis as co-adjuvant. Control rats (C) injected with saline and adjuvants and normal (N) untreated rats were also studied. CD44 expression was analyzed by flow cytometry in peripheral blood mononuclear cells (PBMC) and lymph node cells isolated from rats at different times after the first immunization. We observed an increase in the mean fluorescence intensity of both samples in the C and experimental (E) groups only after the immunization period. A significant decrease in percentage of CD44+PBMC and in mean fluorescence intensity was observed in rats with orchitis compared with the C group. By in vitro hyaluronic acid-binding assay we demonstrated that the percentage of PBMC adhesion was higher in the E group compared with the C and N groups. By immunohistochemistry, we observed a significant increase in the number of CD44+cells in the testicular interstitium of rats with severe orchitis compared with the N and C groups. These results suggested that the CD44 molecule is involved in the homing of lymphomonocytes into the testes of rats with autoimmune orchitis.

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

    PubMed Central

    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

  13. Implanting Glass Spinal Cord Windows in Adult Mice with Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Fenrich, Keith K.; Weber, Pascal; Rougon, Genevieve; Debarbieux, Franck

    2013-01-01

    Experimental autoimmune encephalomyelitis (EAE) in adult rodents is the standard experimental model for studying autonomic demyelinating diseases such as multiple sclerosis. Here we present a low-cost and reproducible glass window implantation protocol that is suitable for intravital microscopy and studying the dynamics of spinal cord cytoarchitecture with subcellular resolution in live adult mice with EAE. Briefly, we surgically expose the vertebrae T12-L2 and construct a chamber around the exposed vertebrae using a combination of cyanoacrylate and dental cement. A laminectomy is performed from T13 to L1, and a thin layer of transparent silicone elastomer is applied to the dorsal surface of the exposed spinal cord. A modified glass cover slip is implanted over the exposed spinal cord taking care that the glass does not directly contact the spinal cord. To reduce the infiltration of inflammatory cells between the window and spinal cord, anti-inflammatory treatment is administered every 2 days (as recommended by ethics committee) for the first 10 days after implantation. EAE is induced only 2-3 weeks after the cessation of anti-inflammatory treatment. Using this approach we successfully induced EAE in 87% of animals with implanted windows and, using Thy1-CFP-23 mice (blue axons in dorsal spinal cord), quantified axonal loss throughout EAE progression. Taken together, this protocol may be useful for studying the recruitment of various cell populations as well as their interaction dynamics, with subcellular resolution and for extended periods of time. This intravital imaging modality represents a valuable tool for developing therapeutic strategies to treat autoimmune demyelinating diseases such as EAE. PMID:24378439

  14. Implanting glass spinal cord windows in adult mice with experimental autoimmune encephalomyelitis.

    PubMed

    Fenrich, Keith K; Weber, Pascal; Rougon, Genevieve; Debarbieux, Franck

    2013-12-21

    Experimental autoimmune encephalomyelitis (EAE) in adult rodents is the standard experimental model for studying autonomic demyelinating diseases such as multiple sclerosis. Here we present a low-cost and reproducible glass window implantation protocol that is suitable for intravital microscopy and studying the dynamics of spinal cord cytoarchitecture with subcellular resolution in live adult mice with EAE. Briefly, we surgically expose the vertebrae T12-L2 and construct a chamber around the exposed vertebrae using a combination of cyanoacrylate and dental cement. A laminectomy is performed from T13 to L1, and a thin layer of transparent silicone elastomer is applied to the dorsal surface of the exposed spinal cord. A modified glass cover slip is implanted over the exposed spinal cord taking care that the glass does not directly contact the spinal cord. To reduce the infiltration of inflammatory cells between the window and spinal cord, anti-inflammatory treatment is administered every 2 days (as recommended by ethics committee) for the first 10 days after implantation. EAE is induced only 2-3 weeks after the cessation of anti-inflammatory treatment. Using this approach we successfully induced EAE in 87% of animals with implanted windows and, using Thy1-CFP-23 mice (blue axons in dorsal spinal cord), quantified axonal loss throughout EAE progression. Taken together, this protocol may be useful for studying the recruitment of various cell populations as well as their interaction dynamics, with subcellular resolution and for extended periods of time. This intravital imaging modality represents a valuable tool for developing therapeutic strategies to treat autoimmune demyelinating diseases such as EAE.

  15. Recurrent anterior uveitis in Henoch Schonlein's vasculitis.

    PubMed

    Erer, Burak; Kamali, Sevil; Cingu, Kursat; Kilicaslan, Isin; Gul, Ahmet; Inanc, Murat; Aral, Orhan; Tugal-Tutkun, Ilknur

    2010-08-01

    Uveitis is an important component of many rheumatic diseases. The main causes of recurrent uveitis are seronegative spondylarthropathies and Behçet's disease. We describe a rare case of Henoch Schönlein vasculitis (HSV) along with multiple recurrences of acute anterior uveitis. In cases of skin rash and recurrent anterior uveitis, HSV should be considered in the differential diagnosis.

  16. Effect of vitamin E in the treatment of bovine-albumin-induced uveitis in rabbits.

    PubMed

    Yücel, I; Paksoy, N; Yücel, G; Aksu, G; Aksu, T A

    1992-01-01

    In order to assess the role of vitamin E, an antioxidant, in the treatment of uveitis, a controlled experimental study was carried out on 20 New Zealand albino rabbits with bovine-albumin-induced uveitis. In all vitamin-E-treated animals, clinical and histopathological study of the retina and uvea revealed no significant changes in comparison with those in untreated rabbits.

  17. Ocular immunology in equine recurrent uveitis.

    PubMed

    Deeg, Cornelia A

    2008-09-01

    Equine recurrent uveitis (ERU) is a disease with high prevalence and relevance for the equine population, since it results in blindness. Over the last decade, important advancements have been made in our understanding of the underlying immune responses in this disease. ERU is mediated by an autoaggressive Th1 response directed against several retinal proteins. Interphotoreceptor-retinoid binding protein (IRBP) and cellular retinaldehyde-binding protein (CRALBP) are capable to induce ERU-like disease in experimental horses, with the unique possibility to activate relapses in a well-defined manner. Further, proteomic evidence now suggests that retinal Mueller glial cells (RMG) may play a fatal role in uveitic disease progression by directly triggering inflammation processes through the expression and secretion of interferon-gamma. Ongoing relapses in blind eyes can be associated with stable expression of the major autoantigens in ERU retinas. This review briefly summarizes the most significant developments in uveitis immune response research.

  18. The Brain Proteome of the Ubiquitin Ligase Peli1 Knock-Out Mouse during Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Lereim, Ragnhild Reehorst; Oveland, Eystein; Xiao, Yichuan; Torkildsen, Øivind; Wergeland, Stig; Myhr, Kjell-Morten; Sun, Shao-Cong; Berven, Frode S

    2016-01-01

    The ubiquitin ligase Peli1 has previously been suggested as a potential treatment target in multiple sclerosis. In the multiple sclerosis disease model, experimental autoimmune encephalomyelitis, Peli1 knock-out led to less activated microglia and less inflammation in the central nervous system. Despite being important in microglia, Peli1 expression has also been detected in glial and neuronal cells. In the present study the overall brain proteomes of Peli1 knock-out mice and wild-type mice were compared prior to experimental autoimmune encephalomyelitis induction, at onset of the disease and at disease peak. Brain samples from the frontal hemisphere, peripheral from the extensive inflammatory foci, were analyzed using TMT-labeling of sample pools, and the discovered proteins were verified in individual mice using label-free proteomics. The greatest proteomic differences between Peli1 knock-out and wild-type mice were observed at the disease peak. In Peli1 knock-out a higher degree of antigen presentation, increased activity of adaptive and innate immune cells and alterations to proteins involved in iron metabolism were observed during experimental autoimmune encephalomyelitis. These results unravel global effects to the brain proteome when abrogating Peli1 expression, underlining the importance of Peli1 as a regulator of the immune response also peripheral to inflammatory foci during experimental autoimmune encephalomyelitis. The proteomics data is available in PRIDE with accession PXD003710. PMID:27746629

  19. Experimental autoimmune anti-glomerular basement membrane glomerulonephritis: a protective role for IFN-gamma.

    PubMed

    Kitching, A Richard; Turner, Amanda L; Semple, Timothy; Li, Ming; Edgtton, Kristy L; Wilson, Gabrielle R; Timoshanko, Jennifer R; Hudson, Billy G; Holdsworth, Stephen R

    2004-07-01

    IL-12 and IFN-gamma play key roles in murine lupus and planted antigen models of glomerulonephritis. However, their roles in renal organ-specific autoimmunity are unknown. To establish the roles of endogenous IFN-gamma and IL-12 in experimental autoimmune anti-glomerular basement membrane (GBM) glomerulonephritis (EAG), EAG was induced in normal C57BL/6 mice (WT), IL-12p40-deficient (IL-12p40-/-) mice, and IFN-gamma-deficient (IFN-gamma-/-) mice by immunization with alpha3-alpha5(IV)NC1 heterodimers. At 13 wk, WT mice developed EAG with linear mouse anti-GBM antibody deposition, histologic injury, proteinuria, and mild tubulointerstitial disease. Compared with WT mice, IL-12p40-/- mice had decreased histologic injury and trends to decreased leukocyte infiltrates. In contrast, 40% (4 of 10) of IFN-gamma-/- mice developed significant crescent formation and focal or diffuse interstitial infiltrates (WT, 0 of 8). Compared with WT and/or IL-12p40-/- mice, IFN-gamma-/- mice developed increased injury: histologic injury, total glomerular cell numbers, leukocytes in glomeruli, and renal expression of P-selectin and intercellular adhesion molecule 1. All groups developed similar serum anti-alpha3-alpha5(IV)NC1 antibodies and glomerular Ig deposition, but IFN-gamma-/- mice had decreased anti-alpha3-alpha5(IV)NC1 IgG2a. Therefore, IFN-gamma-/- mice developed increased cellular reactants despite a potentially less damaging antibody response. Dermal delayed-type hypersensitivity was increased in alpha3-alpha5(IV)NC1 immunized IFN-gamma-/- mice and was suppressed by recombinant murine IFN-gamma. CD4+ cells from draining nodes of immunized IFN-gamma-/- mice showed increased proportions of proliferating CD4+ cells but similar numbers of apoptotic cells. These studies demonstrate that in renal organ-specific autoimmunity, IL-12 is pathogenetic but IFN-gamma is protective. They lend weight to the hypothesis that depending on the context/severity of the nephritogenic immune response

  20. Glatiramer acetate guards against rapid memory decline during relapsing-remitting experimental autoimmune encephalomyelitis.

    PubMed

    LoPresti, Patrizia

    2015-03-01

    Cognitive decline presents a therapeutic challenge for patients with multiple sclerosis (MS), a disease characterized by recurrent autoimmune demyelination and by progressive CNS degeneration. Glatiramer acetate (GA, also known as Copolymer 1, Cop-1, or Copaxone), commonly used to treat MS, reduces the frequency of relapses; it has both anti-inflammatory and neuroprotective properties. However, clinical trials have not definitively shown that GA improves cognitive impairment during MS. Using an in vivo animal model of autoimmune demyelination, i.e., relapsing-remitting experimental autoimmune encephalomyelitis (EAE), we tested short-term memory in EAE mice (EAE), in EAE mice treated with GA for 10 days starting at the time of immunization (EAE + GA), and in age-matched healthy, naïve mice (Naïve). Short-term memory was assessed using the cross-maze test at 10, 20, and 30 days post-immunization (d.p.i.); data were analyzed at each time point and over time. At 10 d.p.i., EAE and EAE + GA mice had better memory function than Naïve mice. However, at the later time points, EAE mice had a steep negative slope of memory function (indicating decline), whereas EAE + GA mice had a flatter, less-negative slope of memory function. Notably, the memory function of EAE mice significantly decreased over time compared with that of Naïve mice, indicating that EAE had a negative impact on cognitive ability. In contrast, there was no statistically significant difference between the slopes of memory function in mice with EAE treated with GA versus Naïve mice, which revealed effective, albeit partial, protection by GA treatment against progressive memory decline during EAE disease. Of particular interest, although EAE mice had memory decline over 30 d.p.i., their clinical disease scores improved during that time. Thus, our results suggest that EAE mice had a significant progressive memory decline and that GA, administered at the time of immunization, partially guards against rapid

  1. Nogo receptor complex expression dynamics in the inflammatory foci of central nervous system experimental autoimmune demyelination.

    PubMed

    Theotokis, Paschalis; Touloumi, Olga; Lagoudaki, Roza; Nousiopoulou, Evangelia; Kesidou, Evangelia; Siafis, Spyridon; Tselios, Theodoros; Lourbopoulos, Athanasios; Karacostas, Dimitrios; Grigoriadis, Nikolaos; Simeonidou, Constantina

    2016-10-11

    Nogo-A and its putative receptor NgR are considered to be among the inhibitors of axonal regeneration in the CNS. However, few studies so far have addressed the issue of local NgR complex multilateral localization within inflammation in an MS mouse model of autoimmune demyelination. Chronic experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice. Analyses were performed on acute (days 18-22) and chronic (day 50) time points and compared to controls. The temporal and spatial expression of the Nogo receptor complex (NgR and coreceptors) was studied at the spinal cord using epifluorescent and confocal microscopy or real-time PCR. Data are expressed as cells/mm(2), as mean % ± SEM, or as arbitrary units of integrated density. Animals developed a moderate to severe EAE without mortality, followed by a progressive, chronic clinical course. NgR complex spatial expression varied during the main time points of EAE. NgR with coreceptors LINGO-1 and TROY was increased in the spinal cord in the acute phase whereas LINGO-1 and p75 signal seemed to be dominant in the chronic phase, respectively. NgR was detected on gray matter NeuN(+) neurons of the spinal cord, within the white matter inflammatory foci (14.2 ± 4.3 % NgR(+) inflammatory cells), and found to be colocalized with GAP-43(+) axonal growth cones while no β-TubIII(+), SMI-32(+), or APP(+) axons were found as NgR(+). Among the NgR(+) inflammatory cells, 75.6 ± 9.0 % were microglial/macrophages (lectin(+)), 49.6 ± 14.2 % expressed CD68 (phagocytic ED1(+) cells), and no cells were Mac-3(+). Of these macrophages/monocytes, only Arginase-1(+)/NgR(+) but not iNOS(+)/NgR(+) were present in lesions both in acute and chronic phases. Our data describe in detail the expression of the Nogo receptor complex within the autoimmune inflammatory foci and suggest a possible immune action for NgR apart from the established inhibitory one on axonal growth. Its expression by inflammatory

  2. A Cannabigerol Derivative Suppresses Immune Responses and Protects Mice from Experimental Autoimmune Encephalomyelitis

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2014-01-01

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

  4. 11C-Methionine PET of Myocardial Inflammation in a Rat Model of Experimental Autoimmune Myocarditis.

    PubMed

    Maya, Yoshifumi; Werner, Rudolf A; Schütz, Claudia; Wakabayashi, Hiroshi; Samnick, Samuel; Lapa, Constantin; Zechmeister, Christina; Jahns, Roland; Jahns, Valérie; Higuchi, Takahiro

    2016-12-01

    Myocarditis represents a major cause of dilated cardiomyopathy and sudden cardiac death in younger adults. Currently, definitive diagnosis of myocarditis requires endomyocardial biopsy, which is highly invasive and has the drawback of variable sensitivity due to inherent sampling error. Therefore, reliable noninvasive methods to detect and monitor cardiac inflammation are clinically relevant. In this study, we explored the potential of radiolabeled methionine to assess myocardial inflammatory activity in a rat model of experimental autoimmune myocarditis (EAM). Autoimmune myocarditis was induced by immunizing Lewis rats twice with porcine cardiac myosin and Freund complete adjuvant. Control animals were treated with adjuvant alone. Dual-tracer autoradiography was performed to assess (14)C-methionine uptake and to compare the distributions of (14)C-methionine versus (18)F-FDG. Hematoxylin and eosin staining and anti-CD68 macrophage staining were performed for histologic analysis. Additionally, cardiac (11)C-methionine PET was performed to evaluate the feasibility of in vivo imaging. (18)F-FDG PET was also conducted to compare the in vivo uptake of (11)C-methionine and (18)F-FDG. Multiple focal cardiac inflammatory lesions were histologically identified in myosin-immunized rats, whereas no cardiac lesions were observed in the controls. Autoradiographic images clearly showed a high-density accumulation of (14)C-methionine in inflammatory lesions of EAM rats, whereas no significant uptake was observed in the control animals. (14)C-methionine uptake was significantly higher in inflammatory lesions than in remote noninflammatory areas and control rat hearts. The distribution of (14)C-methionine correlated well with that of (18)F-FDG and with macrophage density. The contrast between inflammatory and noninflammatory areas was higher for (18)F-FDG than for (14)C-methionine (3.45 ± 0.68 vs. 2.07 ± 0.21, respectively; P < 0.05). In the PET imaging study, the regional (11)C

  5. Treatment of experimental autoimmune uveoretinitis with peroxisome proliferator-activated receptor α agonist fenofibrate.

    PubMed

    Osada, Miho; Sakai, Tsutomu; Kuroyanagi, Kana; Kohno, Hideo; Tsuneoka, Hiroshi

    2014-01-01

    The peroxisome proliferator-activated receptor α (PPARα) agonist has been approved for treating hypercholesterolemia and lipid abnormalities. Researchers have recently discovered that an anti-inflammatory effect of PPAR agonist may have the potential to treat autoimmune disease. This study aims to investigate the therapeutic effects of fenofibrate on experimental autoimmune uveoretinitis (EAU). EAU was induced in Lewis rats using bovine S-antigen (S-Ag) peptide. Fenofibrate was suspended in 3% arabic gum and administered orally at a high dose of 100 mg/kg and at a low dose of 20 mg/kg every day. Fenofibrate treatment was initiated after the clinical onset once daily for 14 days. The rats were examined every other day for clinical signs of EAU. The histological scores and delayed-type hypersensitivity (DTH) were evaluated on day 28 post-immunization. Morphologic and immunohistochemical examinations were performed with light and confocal microscopy, respectively. Lymphocyte proliferation was measured with [3H] thymidine incorporation into antigen-stimulated T cells from inguinal lymph nodes. Clinical and histological scores of EAU were decreased in the fenofibrate-treated groups. The expression of inflammatory cytokines and Müller cell proliferation were inhibited in the fenofibrate-treated groups. DTH was significantly inhibited in the fenofibrate-treated groups, compared with the vehicle-treated groups (controls). Lymphocyte proliferation assay demonstrated decreased proliferation in the presence of 25 mg/ml S-Ag peptide in the fenofibrate-treated groups compared with controls. The current results indicate that fenofibrate administered orally following clinical onset has therapeutic effect in EAU. Fenofibrate may be useful for treating intraocular inflammation.

  6. Treatment of experimental autoimmune uveoretinitis with peroxisome proliferator-activated receptor α agonist fenofibrate

    PubMed Central

    Osada, Miho; Kuroyanagi, Kana; Kohno, Hideo; Tsuneoka, Hiroshi

    2014-01-01

    Purpose The peroxisome proliferator-activated receptor α (PPARα) agonist has been approved for treating hypercholesterolemia and lipid abnormalities. Researchers have recently discovered that an anti-inflammatory effect of PPAR agonist may have the potential to treat autoimmune disease. This study aims to investigate the therapeutic effects of fenofibrate on experimental autoimmune uveoretinitis (EAU). Methods EAU was induced in Lewis rats using bovine S-antigen (S-Ag) peptide. Fenofibrate was suspended in 3% arabic gum and administered orally at a high dose of 100 mg/kg and at a low dose of 20 mg/kg every day. Fenofibrate treatment was initiated after the clinical onset once daily for 14 days. The rats were examined every other day for clinical signs of EAU. The histological scores and delayed-type hypersensitivity (DTH) were evaluated on day 28 post-immunization. Morphologic and immunohistochemical examinations were performed with light and confocal microscopy, respectively. Lymphocyte proliferation was measured with [3H] thymidine incorporation into antigen-stimulated T cells from inguinal lymph nodes. Results Clinical and histological scores of EAU were decreased in the fenofibrate-treated groups. The expression of inflammatory cytokines and Müller cell proliferation were inhibited in the fenofibrate-treated groups. DTH was significantly inhibited in the fenofibrate-treated groups, compared with the vehicle-treated groups (controls). Lymphocyte proliferation assay demonstrated decreased proliferation in the presence of 25 mg/ml S-Ag peptide in the fenofibrate-treated groups compared with controls. Conclusions The current results indicate that fenofibrate administered orally following clinical onset has therapeutic effect in EAU. Fenofibrate may be useful for treating intraocular inflammation. PMID:25489225

  7. Analysis of neurogenesis during experimental autoimmune encephalomyelitis reveals pitfalls of bioluminescence imaging.

    PubMed

    Ayzenberg, Ilya; Schlevogt, Sibylle; Metzdorf, Judith; Stahlke, Sarah; Pedreitturia, Xiomara; Hunfeld, Anika; Couillard-Despres, Sebastien; Kleiter, Ingo

    2015-01-01

    Bioluminescence imaging is a sensitive approach for longitudinal neuroimaging. Transgenic mice expressing luciferase under the promoter of doublecortin (DCX-luc), a specific marker of neuronal progenitor cells (NPC), allow monitoring of neurogenesis in living mice. Since the extent and time course of neurogenesis during autoimmune brain inflammation are controversial, we investigated neurogenesis in MOG-peptide induced experimental allergic encephalomyelitis (EAE) using DCX-luc reporter mice. We observed a marked, 2- to 4-fold increase of the bioluminescence signal intensity 10 days after EAE induction and a gradual decline 1-2 weeks thereafter. In contrast, immunostaining for DCX revealed no differences between EAE and control mice 2 and 4 weeks after immunization in zones of adult murine neurogenesis such as the dentate gyrus. Ex vivo bioluminescence imaging showed similar luciferase expression in brain homogenates of EAE and control animals. Apart from complete immunization including MOG-peptide also incomplete immunization with complete Freund´s adjuvant and pertussis toxin resulted in a rapid increase of the in vivo bioluminescence signal. Blood-brain barrier (BBB) leakage was demonstrated 10 days after both complete and incomplete immunization and might explain the increased bioluminescence signal in vivo. We conclude, that acute autoimmune inflammation in EAE does not alter neurogenesis, at least at the stage of DCX-expressing NPC. Effects of immunization on the BBB integrity must be considered when luciferase is used as a reporter within the CNS during the active stage of EAE. Models with stable CNS-restricted luciferase expression could serve as technically convenient way to evaluate BBB integrity in a longitudinal manner.

  8. PGE2/EP4 signaling in peripheral immune cells promotes development of experimental autoimmune encephalomyelitis.

    PubMed

    Schiffmann, Susanne; Weigert, Andreas; Männich, Julia; Eberle, Max; Birod, Kerstin; Häussler, Annett; Ferreiros, Nerea; Schreiber, Yannick; Kunkel, Hana; Grez, Manuel; Weichand, Benjamin; Brüne, Bernhard; Pfeilschifter, Waltraud; Nüsing, Rolf; Niederberger, Ellen; Grösch, Sabine; Scholich, Klaus; Geisslinger, Gerd

    2014-02-15

    Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated inflammatory autoimmune disease model of multiple sclerosis (MS). The inflammatory process is initiated by activation and proliferation of T cells and monocytes and by their subsequent migration into the central nervous system (CNS), where they induce demyelination and neurodegeneration. Prostaglandin E2 (PGE2) - synthesized by cyclooxygenase 2 (COX-2) - has both pro- and anti-inflammatory potential, which is translated via four different EP receptors. We hypothesized that PGE2 synthesized in the preclinical phase by peripheral immune cells exerts pro-inflammatory properties in the EAE model. To investigate this, we used a bone marrow transplantation model, which enables PGE2 synthesis or EP receptor expression to be blocked specifically in peripheral murine immune cells. Our results reveal that deletion of COX-2 or its EP4 receptor in bone marrow-derived cells leads to a significant delay in the onset of EAE. This effect is due to an impaired preclinical inflammatory process indicated by a reduced level of the T cell activating interleukin-6 (IL-6), reduced numbers of T cells and of the T cell secreted interleukin-17 (IL-17) in the blood of mice lacking COX-2 or EP4 in peripheral immune cells. Moreover, mice lacking COX-2 or EP4 in bone marrow-derived cells show a reduced expression of matrix metalloproteinase 9 (MMP9), which results in decreased infiltration of monocytes and T cells into the CNS. In conclusion, our data demonstrate that PGE2 synthesized by monocytes in the early preclinical phase promotes the development of EAE in an EP4 receptor dependent manner. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Activation of Wnt signaling promotes hippocampal neurogenesis in experimental autoimmune encephalomyelitis.

    PubMed

    Schneider, Reiner; Koop, Barbara; Schröter, Friederike; Cline, Jason; Ingwersen, Jens; Berndt, Carsten; Hartung, Hans-Peter; Aktas, Orhan; Prozorovski, Tim

    2016-07-14

    Disease progression in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), as one of its animal models, is characterized by demyelination and neuronal damage in white and gray matter structures, including the hippocampus. It is thought that dysfunction of the hippocampus, a primary locus of learning and memory consolidation, may contribute to cognitive impairment in MS patients. Previously, we reported an increased generation of hippocampal neuronal progenitors in the acute stage of EAE, whereas the microenvironmental signals triggering this process remained uninvestigated. In the present study, we used the Wnt signaling reporter mouse Axin2(LacZ), to elucidate the molecular mechanisms underlying the activation of the hippocampal neurogenic niche upon autoimmune neuroinflammation. Histological and enzymatic examinations of β-gal during the disease course of EAE, allowed us to survey hippocampal Wnt/β-catenin activity, one of the key signaling pathways of adult neurogenesis. We found that Wnt signaling is transiently upregulated in the acute stage of disease, consistent with a timely induction of canonical Wnt ligands. The enhancement of signaling coincided with hippocampal neuronal damage and local expression of immune cytokines such as TNFα and IFNγ, implicating the role of the inflammatory milieu in activation of the Wnt/β-catenin pathway. Supporting this finding, we show that transient exposure to pro-inflammatory cytokine TNFα triggers Wnt signaling in hippocampal organotypic slice cultures. Importantly, inflammation-mediated activation of the Wnt/β-catenin pathway was associated with enhanced neurogenesis in vitro and in vivo, indicating its potential role in hippocampal tissue regeneration and repair. This study raises the possibility that enhancement of Wnt signaling may support neurogenic processes to cope with neuronal deficits upon immune-mediated neuroinflammation.

  10. Coumestrol inhibits autoantibody production through modulating Th1 response in experimental autoimmune thyroiditis

    PubMed Central

    Zhao, Xuemin; Jin, Qian; Fan, Chenling; Li, Jing; Shan, Zhongyan; Teng, Weiping

    2016-01-01

    Coumestrol is a common phytoestrogen found in plants and Chinese medicinal herbs. Its influences on experimental autoimmune thyroiditis (EAT) were investigated in this study. Female adult CBA/J mice were fed with drinking water containing 1% Tween80 only (Control group), 0.8 mg/l (L group) and 8 mg/l coumestrol (H group) from 6 to 15 weeks of age, respectively. Their serum coumestrol concentrations were determined by high performance liquid chromatography, which were undetectable, 43.70 ± 21.74 ng/ml and 135.07 ± 70.40 ng/ml, respectively. In addition, the mice (n = 14–16/group) were immunized twice with thyroglobulin (Tg) and Freund's adjuvant to induce EAT during the meantime. Although no overt changes in the extent of intrathyroidal mononuclear cell infiltration were shown in the two coumestrol-treated groups as compared with the controls, serum anti-Tg IgG2a, IgG3 and IgG1 titers, ratio of IgG2a to IgG1 and the percentage of T helper (Th)1 cells in the splenocytes were significantly reduced in the L group. Another consistent change was the significantly decreased expression of splenic IFN-γ mRNA after low dose of coumestrol exposure. Uterine weight was also markedly reduced in the mice of L group. These findings suggest that coumestrol treatment may have some beneficial actions against thyroid-specific autoantibody production in the development of autoimmune thyroiditis through suppression of Th1 response due to its anti-estrogenic activity. PMID:27384679

  11. The mechanism of sesame oil in ameliorating experimental autoimmune encephalomyelitis in C57BL/6 mice.

    PubMed

    Ghazavi, A; Mosayebi, G

    2012-01-01

    Experimental autoimmune encephalomyelitis (EAE) is a Th1 cell-mediated autoimmune disease of the CNS that serves as an animal model for multiple sclerosis (MS). The study investigated the effectiveness of treatment with sesame oil on the development of EAE. EAE was induced in 8 week old C57BL/6 mice with an emulsion of MOG35-55. Therapy with sesame oil (4 mL/kg/day as oral gavage) was started on day 3 before the immunization. IFN-gamma and IL-10 production from cultured spleen supernatants were determined by the ELISA method. The results showed that daily oral gavage of sesame oil significantly reduced the clinical symptoms of EAE in C57BL/6 mice. In addition, sesame oil-treated mice displayed a significantly delayed disease onset. Mononuclear cells isolated from spleen of sesame oil-treated mice showed a significant decrease in the production of IFN-gamma compared with control mice (p = 0.001). IL-10 production was also enhanced in splenic mononuclear cells in sesame oil-treated mice. The ratio of IFN-gamma to IL-10 in sesame oil-treated EAE mice was significantly less than in non-treated EAE mice (p = 0.01). This report indicates that sesame oil therapy protected mice from developing EAE by reducing IFN-gamma secretion. Thus, sesame oil treatment may be effective in MS patients by immunomodulating the Th1 immune response. Copyright © 2011 John Wiley & Sons, Ltd.

  12. Forced Exercise Preconditioning Attenuates Experimental Autoimmune Neuritis by Altering Th1 Lymphocyte Composition and Egress.

    PubMed

    Calik, Michael W; Shankarappa, Sahadev A; Langert, Kelly A; Stubbs, Evan B

    2015-01-01

    A short-term exposure to moderately intense physical exercise affords a novel measure of protection against autoimmune-mediated peripheral nerve injury. Here, we investigated the mechanism by which forced exercise attenuates the development and progression of experimental autoimmune neuritis (EAN), an established animal model of Guillain-Barré syndrome. Adult male Lewis rats remained sedentary (control) or were preconditioned with forced exercise (1.2 km/day × 3 weeks) prior to P2-antigen induction of EAN. Sedentary rats developed a monophasic course of EAN beginning on postimmunization day 12.3 ± 0.2 and reaching peak severity on day 17.0 ± 0.3 (N = 12). By comparison, forced-exercise preconditioned rats exhibited a similar monophasic course but with significant (p < .05) reduction of disease severity. Analysis of popliteal lymph nodes revealed a protective effect of exercise preconditioning on leukocyte composition and egress. Compared with sedentary controls, forced exercise preconditioning promoted a sustained twofold retention of P2-antigen responsive leukocytes. The percentage distribution of pro-inflammatory (Th1) lymphocytes retained in the nodes from sedentary EAN rats (5.1 ± 0.9%) was significantly greater than that present in nodes from forced-exercise preconditioned EAN rats (2.9 ± 0.6%) or from adjuvant controls (2.0 ± 0.3%). In contrast, the percentage of anti-inflammatory (Th2) lymphocytes (7-10%) and that of cytotoxic T lymphocytes (∼20%) remained unaltered by forced exercise preconditioning. These data do not support an exercise-inducible shift in Th1:Th2 cell bias. Rather, preconditioning with forced exercise elicits a sustained attenuation of EAN severity, in part, by altering the composition and egress of autoreactive proinflammatory (Th1) lymphocytes from draining lymph nodes.

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

    PubMed

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

    2015-04-15

    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 that IgG1, which does not activate complement through the classical pathway, may suppress EAMG. In this study, we show that AChR-immunized BALB/c mice genetically deficient for IgG1 produce higher levels of complement-activating isotypes of anti-AChR, especially IgG3 and IgG2a, and develop increased IgG3/IgG2a deposits at the NMJ, as compared to wild type (WT) BALB/c mice. Consistent with this, AChR-immunized IgG1(-/-) BALB/c mice lose muscle strength and muscle AChR to a greater extent than AChR-immunized WT mice. These observations demonstrate that IgG1 deficiency leads to increased severity of EAMG associated with an increase in complement activating IgG isotypes. Further studies are needed to dissect the specific role or mechanism of IgG1 in limiting EAMG and that of EAMG exacerbating role of complement activating IgG3 and IgG2a in IgG1 deficiency.

  14. The injury-induced myokine insulin-like 6 is protective in experimental autoimmune myositis

    PubMed Central

    2014-01-01

    Background The idiopathic inflammatory myopathies represent a group of autoimmune diseases that are characterized by lymphocyte infiltration of muscle and muscle weakness. Insulin-like 6 (Insl6) is a poorly characterized member of the insulin-like/relaxin family of secreted proteins, whose expression is upregulated upon acute muscle injury. Methods In this study, we employed Insl6 gain or loss of function mice to investigate the role of Insl6 in a T cell-mediated model of experimental autoimmune myositis (EAM). EAM models in rodents have involved immunization with human myosin-binding protein C with complete Freund’s adjuvant (CFA) emulsions and pertussis toxin. Results Insl6-deficiency in mice led to a worsened myositis phenotype including increased infiltration of CD4 and CD8 T cells and the elevated expression of inflammatory cytokines. Insl6-deficient mice show significant motor function impairment when tested with treadmill or Rotarod devices. Conversely, muscle-specific overexpression of Insl6 protected against the development of myositis as indicated by reduced lymphocyte infiltration in muscle, diminished inflammatory cytokine expression and improved motor function. The improvement in myositis by Insl6 could also be demonstrated by acute hydrodynamic delivery of a plasmid encoding murine Insl6. In cultured cells, Insl6 inhibits Jurkat cell proliferation and activation in response to phytohemagglutinin/phorbol 12-myristate 13-acetate stimulation. Insl6 transcript expression in muscle was reduced in a cohort of dermatomyositis and polymyositis patients. Conclusions These data suggest that Insl6 may have utility for the treatment of myositis, a condition for which few treatment options exist. PMID:25161767

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

    PubMed

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

    2013-06-01

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

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

    PubMed

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

    2014-10-01

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

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

    PubMed

    He, Yixin; Du, Min; Gao, Yan; Liu, Hongshuai; Wang, Hongwei; Wu, Xiaojun; Wang, Zhengtao

    2013-01-01

    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.

  18. Oral testosterone in male rats and the development of experimental autoimmune encephalomyelitis.

    PubMed

    Macció, Daniela R; Calfa, Gastón; Roth, German A

    2005-01-01

    Considering that sex steroids can influence the immune system, we studied the development of experimental autoimmune encephalomyelitis (EAE), a T-cell-mediated autoimmune disease of the central nervous system, and the concomitant cell-mediated immunity in gonadally intact and gonadectomized male Wistar rats given testosterone supplementation. Sham-operated rats and surgically castrated animals were orally self-administered with vehicle or testosterone added in the water bottle for 20 days before EAE induction. The androgenic effect of oral testosterone self-administration was evidenced by changes in body weight, and in the weights of androgen-dependent testes and seminal vesicles. Testosterone administration reduced the incidence of clinical signs of EAE in sham-operated animals and reversed the clinical symptoms of the disease associated with castrated EAE animals. The clinical signs observed in the different groups correlated with changes in delayed-type hypersensitivity and mononuclear cell-proliferative responses to the encephalitogenic myelin basic protein. Moreover, testosterone but not cholesterol supplementation in vitro suppressed the proliferative response of mononuclear cells to myelin basic protein suggesting that testosterone may affect specific immune functions through direct actions on immune cells. Finally, self-administration of testosterone induced also elevated corticosterone levels that in sham-operated rats correlated with the low incidence of the disease and in gonadectomized animals could be involved in the remission of clinical symptoms of EAE. These results suggest that orally self-administered testosterone can modulate specific cellular immune responses and serum corticosterone levels leading to changes in the development of EAE. Copyright 2005 S. Karger AG, Basel.

  19. Role of tolerogen conformation in induction of oral tolerance in experimental autoimmune myasthenia gravis.

    PubMed

    Im, S H; Barchan, D; Souroujon, M C; Fuchs, S

    2000-10-01

    We recently demonstrated that oral or nasal administration of recombinant fragments of the acetylcholine receptor (AChR) prevents the induction of experimental autoimmune myasthenia gravis (EAMG) and suppresses ongoing EAMG in rats. We have now studied the role of spatial conformation of these recombinant fragments in determining their tolerogenicity. Two fragments corresponding to the extracellular domain of the human AChR alpha-subunit and differing in conformation were tested: Halpha1-205 expressed with no fusion partner and Halpha1-210 fused to thioredoxin (Trx), and designated Trx-Halpha1-210. The conformational similarity of the fragments to intact AChR was assessed by their reactivity with alpha-bungarotoxin and with anti-AChR mAbs, specific for conformation-dependent epitopes. Oral administration of the more native fragment, Trx-Halpha1-210, at the acute phase of disease led to exacerbation of EAMG, accompanied by an elevation of AChR-specific humoral and cellular reactivity, increased levels of Th1-type cytokines (IL-2, IL-12), decreased levels of Th2 (IL-10)- or Th3 (TGF-beta)-type cytokines, and higher expression of costimulatory factors (CD28, CTLA4, B7-1, B7-2, CD40L, and CD40). On the other hand, oral administration of the less native fragments Halpha1-205 or denatured Trx-Halpha1-210 suppressed ongoing EAMG and led to opposite changes in the immunological parameters. It thus seems that native conformation of AChR-derived fragments renders them immunogenic and immunopathogenic and therefore not suitable for treatment of myasthenia gravis. Conformation of tolerogens should therefore be given careful attention when considering oral tolerance for treatment of autoimmune diseases.

  20. Connexin43 and connexin47 alterations after neural precursor cells transplantation in experimental autoimmune encephalomyelitis.

    PubMed

    Theotokis, Paschalis; Kleopa, Kleopas A; Touloumi, Olga; Lagoudaki, Roza; Lourbopoulos, Athanasios; Nousiopoulou, Evangelia; Kesidou, Evangelia; Poulatsidou, Kyriaki-Nepheli; Dardiotis, Efthimios; Hadjigeorgiou, Georgios; Karacostas, Dimitris; Cifuentes-Diaz, Carmen; Irinopoulou, Theano; Grigoriadis, Nikolaos

    2015-10-01

    Exogenous transplanted neural precursor cells (NPCs) exhibit miscellaneous immune-modulatory effects in models of autoimmune demyelination. However, the regional interactions of NPCs with the host brain tissue in remissive inflammatory events have not been adequately studied. In this study we used the chronic MOG-induced Experimental Autoimmune Encephalomyelitis (EAE) model in C57BL/six mice. Based on previous data, we focused on neuropathology at Day 50 post-induction (D50) and studied the expression of connexin43 (Cx43) and Cx47, two of the main glial gap junction (GJ) proteins, in relation to the intraventricular transplantation of GFP(+) NPCs and their integration with the host tissue. By D50, NPCs had migrated intraparenchymally and were found in the corpus callosum at the level of the lateral ventricles and hippocampus. The majority of GFP(+) cells differentiated with simple or ramified processes expressing mainly markers of mature GLIA (GFAP and NogoA) and significantly less of precursor glial cells. GFP(+) NPCs expressed connexins and formed GJs around the hippocampus more than lateral ventricles. The presence of NPCs did not alter the increase in Cx43 GJ plaques at D50 EAE, but prevented the reduction of oligodendrocytic Cx47, increased the number of oligodendrocytes, local Cx47 levels and Cx47 GJ plaques per cell. These findings suggest that transplanted NPCs may have multiple effects in demyelinating pathology, including differentiation and direct integration into the panglial syncytium, as well as amelioration of oligodendrocyte GJ loss, increasing the supply of potent myelinating cells to the demyelinated tissue.

  1. Epstein-Barr virus latent membrane protein 2A exacerbates experimental autoimmune encephalomyelitis and enhances antigen presentation function

    PubMed Central

    Chang, Rhoda A.; Miller, Stephen D.; Longnecker, Richard

    2012-01-01

    Multiple sclerosis (MS) is an inflammatory, autoimmune disease of the central nervous system. The cause of MS is still unknown but epidemiological and immunological studies have implicated Epstein-Barr virus (EBV), which infects B cells, as a possible etiological agent involved in disease. Of particular interest is EBV latent membrane protein 2A (LMP2A) because previous studies have demonstrated that LMP2A enhances the expansion and differentiation of B cells upon antigen stimulation, revealing a potential contribution of this protein in autoimmunity. Since B cells are thought to contribute to MS, we examined the role of LMP2A in the animal model experimental autoimmune encephalomyelitis (EAE). In this model, transgenic mice in which B cells express LMP2A show increased severity and incidence of disease. This difference was not due to lymphocyte recruitment into the CNS or differences in T cell activation, rather, we show that LMP2A enhances antigen presentation function. PMID:22616025

  2. Functional Magnetic Resonance Imaging of Rats with Experimental Autoimmune Encephalomyelitis Reveals Brain Cortex Remodeling

    PubMed Central

    Tambalo, Stefano; Peruzzotti-Jametti, Luca; Rigolio, Roberta; Fiorini, Silvia; Bontempi, Pietro; Mallucci, Giulia; Balzarotti, Beatrice; Marmiroli, Paola; Sbarbati, Andrea; Cavaletti, Guido

    2015-01-01

    Cortical reorganization occurring in multiple sclerosis (MS) patients is thought to play a key role in limiting the effect of structural tissue damage. Conversely, its exhaustion may contribute to the irreversible disability that accumulates with disease progression. Several aspects of MS-related cortical reorganization, including the overall functional effect and likely modulation by therapies, still remain to be elucidated. The aim of this work was to assess the extent of functional cortical reorganization and its brain structural/pathological correlates in Dark Agouti rats with experimental autoimmune encephalomyelitis (EAE), a widely accepted preclinical model of chronic MS. Morphological and functional MRI (fMRI) were performed before disease induction and during the relapsing and chronic phases of EAE. During somatosensory stimulation of the right forepaw, fMRI demonstrated that cortical reorganization occurs in both relapsing and chronic phases of EAE with increased activated volume and decreased laterality index versus baseline values. Voxel-based morphometry demonstrated gray matter (GM) atrophy in the cerebral cortex, and both GM and white matter atrophy were assessed by ex vivo pathology of the sensorimotor cortex and corpus callosum. Neuroinflammation persisted in the relapsing and chronic phases, with dendritic spine density in the layer IV sensory neurons inversely correlating with the number of cluster of differentiation 45-positive inflammatory lesions. Our work provides an innovative experimental platform that may be pivotal for the comprehension of key mechanisms responsible for the accumulation of irreversible brain damage and for the development of innovative therapies to reduce disability in EAE/MS. SIGNIFICANCE STATEMENT Since the early 2000s, functional MRI (fMRI) has demonstrated profound modifications in the recruitment of cortical areas during motor, cognitive, and sensory tasks in multiple sclerosis (MS) patients. Experimental autoimmune

  3. Equine recurrent uveitis: the European viewpoint.

    PubMed

    Spiess, B M

    2010-03-01

    Equine recurrent uveitis (ERU) has always been and still is an important disease with a significant impact on the horse industry in Europe, with a prevalence of 8-10%. The need to understand and manage the disease has spurred the development of veterinary ophthalmology in general, although the aetiology of the disease remains the subject of intense discussion. It is most probably an autoimmune disease triggered, at least in Europe, in the majority of cases by Leptospira spp. The therapy of ERU has evolved over the centuries from various methods of bloodletting to rational medical therapy using mydriatics and steroidal and nonsteroidal anti-inflammatory drugs, to surgical therapies, such as vitrectomy or implantation of cyclosporin-releasing devices. In Europe, pars plana vitrectomy in horses testing positive for Leptospira spp. appears to be the most successful form of therapy at the present time.

  4. Mesenchymal Stem Cells Lack Efficacy in the Treatment of Experimental Autoimmune Neuritis despite In Vitro Inhibition of T-Cell Proliferation

    PubMed Central

    Lee, Woojin; Compston, D. Alastair S.; Schweimer, Judith V.; Gregson, Norman A.; Chandran, Siddharthan; Smith, Kenneth J.

    2012-01-01

    Mesenchymal stem cells have been demonstrated to ameliorate experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, prompting clinical trials in multiple sclerosis which are currently ongoing. An important question is whether this therapeutic effect generalises to other autoimmune neurological diseases. We performed two trials of efficacy of MSCs in experimental autoimmune neuritis (EAN) in Lewis (LEW/Han MHsd) rats, a model of human autoimmune inflammatory neuropathies. No differences between the groups were found in clinical, histological or electrophysiological outcome measures. This was despite the ability of mesenchymal stem cells to inhibit proliferation of CD4+ T-cells in vitro. Therefore the efficacy of MSCs observed in autoimmune CNS demyelination models do not necessarily generalise to the treatment of other forms of neurological autoimmunity. PMID:22359549

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

    PubMed

    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.

  6. Evoked potential and behavioral outcomes for experimental autoimmune encephalomyelitis in Lewis rats.

    PubMed

    All, Angelo H; Agrawal, Gracee; Walczak, Piotr; Maybhate, Anil; Bulte, Jeff W M; Kerr, Douglas A

    2010-10-01

    A reliable outcome measurement is needed to assess the effects of experimental lesions in the rat spinal cord as well as to assess the benefits of therapies designed to modulate them. The Basso, Beattie, and Bresnahan (BBB) behavioral scores can be indicative of the functionality in motor pathways. However, since lesions are often induced in the more accessible dorsal parts associated with the sensory pathways, the BBB scores may not be ideal measure of the disability. We propose somatosensory evoked potential (SEP) as a complementary measure to assess the integrity of sensory pathways. We used the focal experimental autoimmune encephalomyelitis (EAE) model, in which focal demyelinating lesions were induced by injecting cytokine-ethidium bromide into dorsal white matter after MOG-IFA immunization. Both the SEP and BBB measures reflected injury; however, the SEP was uniformly and consistently altered after the injury whereas the BBB varied widely. The results suggest that the SEP measures are more sensitive and reliable markers of focal spinal cord demyelination compared to the behavioral measures like the BBB score.

  7. Pediatric Uveitis: Experience in Colombia.

    PubMed

    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) (p<0.05). This is the first study to report the clinical features of pediatric uveitis 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.

  8. Complement factor B expression profile in a spontaneous uveitis model.

    PubMed

    Zipplies, Johanna K; Kirschfink, Michael; Amann, Barbara; Hauck, Stefanie M; Stangassinger, Manfred; Deeg, Cornelia A

    2010-12-01

    Equine recurrent uveitis serves as a spontaneous model for human autoimmune uveitis. Unpredictable relapses and ongoing inflammation in the eyes of diseased horses as well as in humans lead to destruction of the retina and finally result in blindness. However, the molecular mechanisms leading to inflammation and retinal degeneration are not well understood. An initial screening for differentially regulated proteins in sera of uveitic cases compared to healthy controls revealed an increase of the alternative pathway complement component factor B in ERU cases. To determine the activation status of the complement system, sera were subsequently examined for complement split products. We could demonstrate a significant higher concentration of the activation products B/Ba, B/Bb, Bb neoantigen, iC3b and C3d in uveitic condition compared to healthy controls, whereas for C5b-9 no differences were detected. Additionally, we investigated complement activation directly in the retina by immunohistochemistry, since it is the main target organ of this autoimmune disease. Interestingly, infiltrating cells co-expressed activated factor Bb neoantigen, complement split product C3d as well as CD68, a macrophage marker. In this study, we could demonstrate activation of the complement system both systemically as well as in the eye, the target organ of spontaneous recurrent uveitis. Based on these novel findings, we postulate a novel role for macrophages in connection with complement synthesis at the site of inflammation.

  9. Tubulointerstitial nephritis and uveitis.

    PubMed

    Pakzad-Vaezi, Kaivon; Pepple, Kathryn L

    2017-08-12

    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.

  10. Emergent Infectious Uveitis

    PubMed Central

    Khairallah, Moncef; Jelliti, Bechir; Jenzeri, Salah

    2009-01-01

    Infectious causes should always be considered in all patients with uveitis and it should be ruled out first. The differential diagnosis includes multiple well-known diseases including herpes, syphilis, toxoplasmosis, tuberculosis, bartonellosis, Lyme disease, and others. However, clinicians should be aware of emerging infectious agents as potential causes of systemic illness and also intraocular inflammation. Air travel, immigration, and globalization of business have overturned traditional pattern of geographic distribution of infectious diseases, and therefore one should work locally but think globally, though it is not possible always. This review recapitulates the systemic and ocular mainfestations of several emergent infectious diseases relevant to the ophthalmologist including Rickettsioses, West Nile virus infection, Rift valley fever, dengue fever, and chikungunya. Retinitis, chorioretinitis, retinal vasculitis, and optic nerve involvement have been associated with these emergent infectious diseases. The diagnosis of any of these infections is usually based on pattern of uveitis, systemic symptoms and signs, and specific epidemiological data and confirmed by detection of specific antibody in serum. A systematic ocular examination, showing fairly typical fundus findings, may help in establishing an early clinical diagnosis, which allows prompt, appropriate management. PMID:20404989

  11. Mincle activation and the Syk/Card9 signaling axis are central to development of autoimmune disease of the eye

    PubMed Central

    Lee, Ellen J.; Brown, Brieanna R.; Vance, Emily E.; Snow, Paige E.; Silver, Phyllis B.; Heinrichs, David; Lin, Xin; Iwakura, Yoichiro; Wells, Christine A.; Caspi, Rachel R.; Rosenzweig, Holly L.

    2016-01-01

    Uveitis, which occurs in association with systemic immunological diseases, presents a considerable medical challenge due to incomplete understanding of its pathogenesis. The signals that initiate T cells to target the eye, which may be of infectious or non-infectious origin, are poorly understood. Experimental autoimmune uveoretinitis (EAU) develops in mice immunized with the endogenous retinal protein interphotoceptor retinoid binding protein (IRBP) in the presence of the adjuvant CFA. EAU manifests as posterior ocular inflammation consisting of vasculitis, granulomas, retinal damage and invasion of self-reactive T cells, which are key clinical features of human uveitis. Our studies uncover Card9 as a critical genetic determinant for EAU. Card9 was responsible for Th17 polarization and Th17-associated antigen-specific responses, but not Th1-associated responses. Nonetheless, Card9 expression was essential for accumulation of both lineages within the eye. Consistent with its recently identified role as an intracellular signaling mediator for C-type lectin receptors (CLRs), a Card9-dependent transcriptional response in the neuroretina was observed involving genes encoding the CLRs Dectin-1, Dectin-2 and Mincle. Genetic deletion of these individual CLRs revealed an essential role for Mincle. Mincle activation was sufficient to generate the EAU phenotype, and this required activation of both Syk and Card9. In contrast, Dectin-1 contributed minimally and a possible repressive role was shown for Dectin-2. These findings extend our understanding of CLRs in autoimmune uveitis. The newly identified role of Mincle and Syk/Card9-coupled signaling axis in autoimmune uveitis could provide novel targets for treatment of patients with ocular inflammatory disease. PMID:26921309

  12. Modulation of the expression of integrins on glial cells during experimental autoimmune encephalomyelitis. A central role for TNF-alpha.

    PubMed Central

    Previtali, S. C.; Archelos, J. J.; Hartung, H. P.

    1997-01-01

    Integrins comprise a group of adhesion receptors involved in cell-cell and cell-extracellular matrix interactions. Evidence is accumulating that integrins expressed on mononuclear cells play a central role in the induction of autoimmune diseases of the central nervous system. The effects of integrins on glial cell behavior, myelination, and angiogenesis suggest that they may also have a role in resolving inflammation in the nervous system and in promoting tissue repair. We investigated the temporospatial expression of integrins in the rat central nervous system during the course of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. A higher expression of alpha v- and beta 4-integrin subunits in astrocytes and alpha 2 integrin in oligodendrocytes was observed in active lesions of experimental autoimmune encephalomyelitis, in comparison with controls. Proinflammatory cytokines, primarily TNF-alpha, also enhanced alpha v, beta 4, and alpha 2 expression in purified glial cells ex vivo. Furthermore, we observed that the expression of some integrin subunits was modulated in the cerebral vasculature during inflammation. Our results suggest an active role for glial and vascular integrins in the regulation of autoimmune diseases of the central nervous system, opening an avenue for new potential immunotherapies. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 9 PMID:9358769

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

    PubMed

    DellaValle, Brian; Brix, Gitte S; Brock, Birgitte; Gejl, Michael; Landau, Anne M; Møller, Arne; Rungby, Jørgen; Larsen, Agnete

    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 (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 2 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 = 0.09). Conclusion: 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

  14. The Role of Gender in Uveitis and Ocular Inflammation

    PubMed Central

    Yeung, Ian YL; Popp, Nicholas A; Chan, Chi-Chao

    2015-01-01

    Uveitides can be due to non-infectious and infectious etiologies. It has been observed that there is a gender difference with a greater preponderance of non-infectious uveitis in women than in men. This review will describe both non-infectious and infectious uveitides and describes some of the current autoimmune mechanisms thought to be underlying the gender difference. It will specifically look at non-infectious uveitides with systemic involvement including juvenile idiopathic arthritis, spondyloarthopathies, sarcoidosis, Behçet’s disease, and Vogt-Koyanagi-Harada disease and at uveitides without systemic involvement including sympathetic ophthalmia, birdshot chorioretinitis, and the white dot syndromes. Infectious uveitides like acute retinal necrosis, progressive outer retinal necrosis, and cytomegalovirus mediated uveitis will be mentioned. Different uveitides with female- or male- predominance are presented and discussed. PMID:26035764

  15. CCR5 knockout suppresses experimental autoimmune encephalomyelitis in C57BL/6 mice

    PubMed Central

    Yun, Hyung Mun; Han, Sang Bae; Oh, Ki Wan; Son, Dong Ju; Yun, Jae Suk; Hong, Jin Tae

    2016-01-01

    Multiple sclerosis (MS) is an inflammatory disease in which myelin in the spinal cord is damaged. C-C chemokine receptor type 5 (CCR5) is implicated in immune cell migration and cytokine release in central nervous system (CNS). We investigated whether CCR5 plays a role in MS progression using a murine model, experimental autoimmune encephalomyelitis (EAE), in CCR5 deficient (CCR5−/−) mice. CCR5−/− and CCR5+/+ (wild-type) mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) followed by pertussis toxin, after which EAE paralysis was scored for 28 days. We found that clinical scoring and EAE neuropathology were lower in CCR5−/− mice than CCR5+/+ mice. Immune cells (CD3+, CD4+, CD8+, B cell, NK cell and macrophages) infiltration and astrocytes/microglial activation were attenuated in CCR5−/− mice. Moreover, levels of IL-1β, TNF-α, IFN-γ and MCP-1 cytokine levels were decreased in CCR5−/− mice spinal cord. Myelin basic protein (MBP) and CNPase were increased while NG2 and O4 were decreased in CCR5−/− mice, indicating that demyelination was suppressed by CCR5 gene deletion. These findings suggest that CCR5 is likely participating in demyelination in the spinal cord the MS development, and that it could serve as an effective therapeutic target for the treatment of MS. PMID:26985768

  16. Prevention of experimental autoimmune encephalomyelitis by antibodies against α4βl integrin

    NASA Astrophysics Data System (ADS)

    Yednock, Ted A.; Cannon, Catherine; Fritz, Lawrence C.; Sanchez-Madrid, Francisco; Steinman, Lawrence; Karin, Nathan

    1992-03-01

    EXPERIMENTAL autoimmune encephalomyelitis (EAE) is an inflammatory condition of the central nervous system with similarities to multiple sclerosis1,2. In both diseases, circulating leukocytes penetrate the blood-brain barrier and damage myelin, resulting in impaired nerve conduction and paralysis3-5. We sought to identify the adhesion receptors that mediate the attachment of circulating leukocytes to inflamed brain endothelium in EAE, because this interaction is the first step in leukocyte entry into the central nervous system. Using an in vitro adhesion assay on tissue sections, we found that lymphocytes and monocytes bound selectively to inflamed EAE brain vessels. Binding was inhibited by antibodies against the integrin molecule α4βl, but not by antibodies against numerous other adhesion receptors. When tested in vivo, anti-α4 integrin effectively prevented the accumulation of leukocytes in the central nervous system and the development of EAE. Thus, therapies designed to interfere with α4βl integrin may be useful in treating inflammatory diseases of the central nervous system, such as multiple sclerosis.

  17. Anti-IL-17A autovaccination prevents clinical and histological manifestations of experimental autoimmune encephalomyelitis.

    PubMed

    Uyttenhove, Catherine; Sommereyns, Caroline; Théate, Ivan; Michiels, Thomas; Van Snick, Jacques

    2007-09-01

    Excessive or inappropriate production of IL-17A has been reported in diseases such as rheumatoid arthritis, asthma, and multiple sclerosis. The potential clinical relevance of these correlations was suggested by the protective effects of anti-IL-17A monoclonal antibodies in various mouse disease models. However, the chronic nature of the corresponding human afflictions raises great challenges for Ab-based therapies. An alternative to passive Ab therapy is autovaccination. Covalent association of self-cytokines with foreign proteins has been reported to induce the production of antibodies capable of neutralizing the biological activity of the target cytokine. We recently reported that cross-linking of IL-17A to ovalbumin produced highly immunogenic complexes that induced long-lasting IL-17A-neutralizing antibodies. Vaccinated SJL mice were completely protected against experimental autoimmune encephalomyelitis (EAE) induced by proteolipid protein peptide (PLP 139-151), and a monoclonal anti-IL-17A Ab (MM17F3), derived from C57Bl/6 mice vaccinated against IL-17A-OVA, also prevented disease development. Here we report that this Ab also protects C57Bl/6 mice from myelin oligdendrocyte glycoprotein (MOG)-induced EAE. Histological analysis of brain sections of C57Bl/6 mice treated with MM17F3 showed a complete absence of inflammatory infiltrates and evidence for a marked inhibition of chemokine and cytokine messages in the spinal cord. These results further extend the analytical and therapeutic potential of the autovaccine procedure.

  18. Significant Contribution of Mouse Mast Cell Protease 4 in Early Phases of Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Gharagozloo, Marjan; Mahmoud, Shaimaa; Gris, Denis

    2016-01-01

    Experimental autoimmune encephalomyelitis (EAE) is a mouse model that reproduces cardinal signs of clinical, histopathological, and immunological features found in Multiple Sclerosis (MS). Mast cells are suggested to be involved in the main inflammatory phases occurring during EAE development, possibly by secreting several autacoids and proteases. Among the latter, the chymase mouse mast cell protease 4 (mMCP-4) can contribute to the inflammatory response by producing endothelin-1 (ET-1). The aim of this study was to determine the impact of mMCP-4 on acute inflammatory stages in EAE. C57BL/6 wild type (WT) or mMCP-4 knockout (KO) mice were immunized with MOG35–55 plus complete Freund's adjuvant followed by pertussis toxin. Immunized WT mice presented an initial acute phase characterized by progressive increases in clinical score, which were significantly reduced in mMCP-4 KO mice. In addition, higher levels of spinal myelin were found in mMCP-4 KO as compared with WT mice. Finally, whereas EAE triggered significant increases in brain levels of mMCP-4 mRNA and immunoreactive ET-1 in WT mice, the latter peptide was reduced to basal levels in mMCP-4 KO congeners. Together, the present study supports a role for mMCP-4 in the early inflammatory phases of the disease in a mouse model of MS. PMID:27610007

  19. Accumulation of protein carbonyls within cerebellar astrocytes in murine experimental autoimmune encephalomyelitis

    PubMed Central

    Zheng, Jianzheng; Bizzozero, Oscar A.

    2010-01-01

    Recent work from our laboratory has implicated protein carbonylation in the pathophysiology of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). The present study was designed to determine the changes in protein carbonylation during the disease progression, and to identify the target cells and modified proteins in the cerebellum of EAE animals, prepared by active immunization of C57/BL6 mice with MOG35-55 peptide. In this model, protein carbonylation was maximal at the peak of the disease (acute phase) to decrease thereafter (chronic phase). Double immunofluorescence microscopy of affected cerebella showed that carbonyls accumulate in white matter astrocytes, and to a lesser extent in microglia/macrophages, both in the acute and chronic phase. Surprisingly, T cells, oligodendrocytes and neurons were barely stained. By 2D-oxyblot and mass spectrometry, β-actin, β-tubulin, GFAP and HSC-71 were identified as the major targets of carbonylation throughout disease. Using a pull-down/western blot method we found a significant increase in the proportion of carbonylated β-actin, β-tubulin and GFAP in the chronic phase but not in the acute phase. These results suggest that as disease progresses from the inflammatory to the neurodegenerative phase there may be an inappropriate removal of oxidized cytoskeletal proteins. Additionally, the extensive accumulation of carbonylated GFAP in the chronic phase of EAE may be responsible for the abnormal shape of astrocytes observed at this stage. PMID:20857508

  20. Nigella sativa amliorates inflammation and demyelination in the experimental autoimmune encephalomyelitis-induced Wistar rats

    PubMed Central

    Noor, Neveen A; Fahmy, Heba M; Mohammed, Faten F; Elsayed, Anwar A; Radwan, Nasr M

    2015-01-01

    Multiple sclerosis (MS) is the major, immune-mediated, demyelinating neurodegenerative disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model of MS. The aim of the present study was to investigate the protective and ameliorative effects of N. sativa seeds (2.8 g/kg body weight) in EAE-induced Wistar rats. EAE-induced rats were divided into: 1- EAE-induced rats (“EAE” group). 2- “N. sativa + EAE” group received daily oral administration of N. sativa 2 weeks prior EAE induction until the end of the experiment. 3- “EAE + N. sativa” group received daily oral administration of N. sativa after the appearance of first clinical signs until the end of the experiment. All animals were decapitated at the 28th day post EAE-induction. EAE was investigated using histopathological, immunohistochemical and ultrastructural examinations in addition to determination of some oxidative stress parameters in the cerebellum and medulla. N. sativa suppressed inflammation observed in EAE-induced rats. In addition, N. sativa enhanced remyelination in the cerebellum. Moreover, N. sativa reduced the expression of transforming growth factor beta 1 (TGF β1). N. sativa seeds could provide a promising agent effective in both the protection and treatment of EAE. PMID:26261504

  1. Nigella sativa amliorates inflammation and demyelination in the experimental autoimmune encephalomyelitis-induced Wistar rats.

    PubMed

    Noor, Neveen A; Fahmy, Heba M; Mohammed, Faten F; Elsayed, Anwar A; Radwan, Nasr M

    2015-01-01

    Multiple sclerosis (MS) is the major, immune-mediated, demyelinating neurodegenerative disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model of MS. The aim of the present study was to investigate the protective and ameliorative effects of N. sativa seeds (2.8 g/kg body weight) in EAE-induced Wistar rats. EAE-induced rats were divided into: 1- EAE-induced rats ("EAE" group). 2- "N. sativa + EAE" group received daily oral administration of N. sativa 2 weeks prior EAE induction until the end of the experiment. 3- "EAE + N. sativa" group received daily oral administration of N. sativa after the appearance of first clinical signs until the end of the experiment. All animals were decapitated at the 28th day post EAE-induction. EAE was investigated using histopathological, immunohistochemical and ultrastructural examinations in addition to determination of some oxidative stress parameters in the cerebellum and medulla. N. sativa suppressed inflammation observed in EAE-induced rats. In addition, N. sativa enhanced remyelination in the cerebellum. Moreover, N. sativa reduced the expression of transforming growth factor beta 1 (TGF β1). N. sativa seeds could provide a promising agent effective in both the protection and treatment of EAE.

  2. The extent of ultrastructural spinal cord pathology reflects disease severity in experimental autoimmune encephalomyelitis.

    PubMed

    Gruppe, Traugott L; Recks, Mascha S; Addicks, Klaus; Kuerten, Stefanie

    2012-09-01

    Experimental autoimmune encephalomyelitis (EAE) has been studied for decades as an animal model for human multiple sclerosis (MS). Here we performed ultrastructural analysis of corticospinal tract (CST) and motor neuron pathology in myelin oligodendrocyte glycoprotein (MOG) peptide 35-55- and MP4-induced EAE of C57BL/6 mice. Both models were clinically characterized by ascending paralysis. Our data show that CST and motor neuron pathology differentially contributed to the disease. In both MOG peptide- and MP4-induced EAE pathological changes in the CST were evident. While the MP4 model also encompassed severe motor neuron degeneration in terms of rough endoplasmic reticulum alterations, the presence of intracytoplasmic vacuoles and nuclear dissolution, both models showed motor neuron atrophy. Features of axonal damage covered mitochondrial swelling, a decrease in nearest neighbor neurofilament distance (NNND) and an increase of the oligodendroglial cytoplasm inner tongue. The extent of CST and motor neuron pathology was reflective of the severity of clinical EAE in MOG peptide- and MP4-elicited EAE. Differential targeting of CNS gray and white matter are typical features of MS pathology. The MOG peptide and MP4 model may thus be valuable tools for downstream studies of the mechanisms underlying these morphological disease correlates.

  3. Involvement of calcitonin gene-related peptide and receptor component protein in experimental autoimmune encephalomyelitis

    PubMed Central

    Sardi, Claudia; Zambusi, Laura; Finardi, Annamaria; Ruffini, Francesca; Tolun, Adviye A.; Dickerson, Ian M.; Righi, Marco; Zacchetti, Daniele; Grohovaz, Fabio; Provini, Luciano; Furlan, Roberto; Morara, Stefano

    2015-01-01

    Calcitonin Gene-Related Peptide (CGRP) inhibits microglia inflammatory activation in vitro. We here analyzed the involvement of CGRP and Receptor Component Protein (RCP) in experimental autoimmune encephalomyelitis (EAE). Alpha-CGRP deficiency increased EAE scores which followed the scale alpha-CGRP null > heterozygote > wild type. In wild type mice, CGRP delivery into the cerebrospinal fluid (CSF) 1) reduced chronic EAE (C-EAE) signs, 2) inhibited microglia activation (revealed by quantitative shape analysis), and 3) did not alter GFAP expression, cell density, lymphocyte infiltration, and peripheral lymphocyte production of IFN-gamma, TNF-alpha, IL-17, IL-2, and IL-4. RCP (probe for receptor involvement) was expressed in white matter microglia, astrocytes, oligodendrocytes, and vascular-endothelial cells: in EAE, also in infiltrating lymphocytes. In relapsing–remitting EAE (R-EAE) RCP increased during relapse, without correlation with lymphocyte density. RCP nuclear localization (stimulated by CGRP in vitro) was I) increased in microglia and decreased in astrocytes (R-EAE), and II) increased in microglia by CGRP CSF delivery (C-EAE). Calcitonin like receptor was rarely localized in nuclei of control and relapse mice. CGRP increased in motoneurons. In conclusion, CGRP can inhibit microglia activation in vivo in EAE. CGRP and its receptor may represent novel protective factors in EAE, apparently acting through the differential cell-specific intracellular translocationof RCP. PMID:24746422

  4. Mice lacking Axl and Mer tyrosine kinase receptors are susceptible to experimental autoimmune orchitis induction.

    PubMed

    Li, Nan; Liu, Zhenghui; Zhang, Yue; Chen, Qiaoyuan; Liu, Peng; Cheng, C Yan; Lee, Will M; Chen, Yongmei; Han, Daishu

    2015-03-01

    The mammalian testis is an immunoprivileged organ where male germ cell autoantigens are immunologically ignored. Both systemic immune tolerance to autoantigens and local immunosuppressive milieu contribute to the testicular immune privilege. Testicular immunosuppression has been intensively studied, but information on systemic immune tolerance to autoantigens is lacking. In the present study, we aimed to determine the role of Axl and Mer receptor tyrosine kinases in maintaining the systemic tolerance to male germ cell antigens using the experimental autoimmune orchitis (EAO) model. Axl and Mer double-knockout (Axl(-/-)Mer(-/-)) mice developed evident EAO after a single immunization with germ cell homogenates emulsified with complete Freund's adjuvant. EAO was characterized by the accumulation of macrophages and T lymphocytes in the testis. Damage to the seminiferous epithelium was also observed. EAO induction was associated with pro-inflammatory cytokine upregulation in the testes, impaired permeability of the blood-testis barrier and generation of autoantibodies against germ cell antigens in Axl(-/-)Mer(-/-) mice. Immunization also induced mild EAO in Axl or Mer single-gene-knockout mice. By contrast, a single immunization failed to induce EAO in wild-type mice. The results indicate that Axl and Mer receptors cooperatively regulate the systemic immune tolerance to male germ cell antigens.

  5. Blocking glutamate carboxypeptidase II inhibits glutamate excitotoxicity and regulates immune responses in experimental autoimmune encephalomyelitis.

    PubMed

    Ha, Danbee; Bing, So Jin; Ahn, Ginnae; Kim, Jinhee; Cho, Jinhee; Kim, Areum; Herath, Kalahe H I N M; Yu, Hak Sun; Jo, Sangmee Ahn; Cho, Ik-Hyun; Jee, Youngheun

    2016-09-01

    Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease in the murine central nervous system (CNS) and recapitulates the clinical and pathological features of human multiple sclerosis (MS). Glutamate carboxipeptidase II (GCPII), an enzyme expressed exclusively on astrocytes, is known to affect the disease progression of various neurological disorders by producing glutamate. Despite several findings indicating possible link between glutamate and MS/EAE, however, the involvement of astrocyte or GCPII on glutamate excitotoxicity has not received much attention in MS/EAE. When we examined GCPII expression during EAE progression in this study, we observed significantly elevated GCPII expression in peak stage of disease localized mainly in astrocytes. Intrigued by these results, we tried a potent GCPII inhibitor, 2-phosphonomethyl pentanedioic acid (2-PMPA), on EAE mice and noticed markedly attenuated EAE clinical signs along with significantly inhibited infiltration of inflammatory cells into CNS. Furthermore, 2-PMPA dampened the function of Th1 cell lineage and down-regulated mGluR1 expression in both periphery and CNS contributing to glutamate-mediated immune regulation. Our observations identify a sequence of events triggering EAE through GCPII overexpression, which may offer a novel therapeutic approach to the treatment of MS. © 2016 Federation of European Biochemical Societies.

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

    PubMed

    Robinson, Andrew P; Harp, Christopher T; Noronha, Avertano; Miller, Stephen D

    2014-01-01

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

  7. Complement in Experimental Autoimmune Encephalomyelitis Revisited: C3 is Required for Development of Maximal Disease

    PubMed Central

    Szalai, Alexander J.; Hu, Xianzhen; Adams, Jillian E.; Barnum, Scott R.

    2007-01-01

    Complement per se has been shown to play an important role in demyelinating disease but controversy remains regarding the role of C3 in the development and progression of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. In this study we used C3-/- mice to confirm previous findings that C3 is required for full development of EAE. Furthermore, C3+/- mice (with serum C3 levels 50% that of wild type mice) developed EAE with a severity intermediate between wild type and C3-/- mice. Importantly transfer of wild type encephalitogenic T cells to C3-/- mice resulted in attenuated EAE. C3-/- mice with EAE had fewer CD4+ and CD8+ T cells in the CNS and 50% fewer of these cells produced IFN-γ compared to wild type mice. When treated with anti-CD3 antibody, CD4+ T cell from wild type and C3-/- mice had similar activation profiles as judged by IFN-γ production and CD25 and CD69 expression, indicating there is no gross or intrinsic defect in T cells from C3-/- mice. T cells from primed C3-/- mice proliferated comparably to that of control T cells on re-stimulation with MOG peptide. Our results confirm a requirement for C3 for maximal development of EAE and suggest that receptors for C3-derived activation fragments might be a viable therapeutic target for prevention and treatment demyelinating disease. PMID:17353050

  8. Effector and Suppressor Roles for LFA-1 During the Development of Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Dugger, Kari J.; Zinn, Kurt R.; Weaver, Casey; Bullard, Daniel C.; Barnum, Scott R.

    2009-01-01

    LFA-1 (CD11a/CD18) is a member of the β2-integrin family of adhesion molecules important in leukocyte trafficking and activation. Although LFA-1 is thought to contribute to the development of experimental autoimmune encephalomyelitis (EAE) primarily through its functions on effector T cells, its importance on other leukocyte populations remains unexplored. To address this question, we performed both adoptive transfer EAE experiments involving CD11a-/- mice and trafficking studies using bioluminescent T cells expressing luciferase under the control of a CD2 promoter (T-lux cells). Transfer of encephalitogenic CD11a-/- T cells to wild type mice resulted in a significant reduction in overall EAE severity compared to control transfers. We also observed, using in vivo imaging techniques, that CD11a-/- T-lux cells readily infiltrated lymph nodes and the CNS of wild type recipients with kinetics comparable to CD11a+/+ transfers, although their overall numbers in these organs were reduced. Surprisingly, transfer of encephalitogenic wild type T cells to CD11a-/- mice induced a severe and sometimes fatal EAE disease course, associated with massive T cell infiltration and proliferation in the CNS. These data indicate that LFA-1 expression on leukocytes in recipient mice plays an important immunomodulatory role in EAE. Thus, LFA-1 acts as a key regulatory adhesion molecule during the development of EAE, serving both pro- and anti-inflammatory roles in disease pathogenesis. PMID:19010554

  9. Abrogation of Rbpj Attenuates Experimental Autoimmune Uveoretinitis by Inhibiting IL-22-Producing CD4+ T Cells

    PubMed Central

    Ishifune, Chieko; Maekawa, Yoichi; Shimada, Mitsuo; Yasutomo, Koji

    2014-01-01

    Experimental autoimmune uveoretinitis (EAU) is an organ-specific T cell-mediated disease induced by immunizing mice with interphotoreceptor retinoid binding protein (IRBP). Autoaggressive CD4+ T cells are the major pathogenic population for EAU. We investigated the contribution of Notch signaling in T cells to EAU pathogenesis because Notch signaling regulates various aspects of CD4+ T cell functions. Rbpj is required for Notch signaling, and Rbpj deficiency in T cells inhibited EAU disease severity. The amelioration of EAU in T cell-specific Rbpj-deficient mice correlated with low levels of IL-22 production from CD4+ T cells, although IRBP-specific CD4+ T cell proliferation and Th17 differentiation were unaffected. Administration of recombinant IL-22 during the late phase, but not the early phase, of EAU increased EAU clinical scores in T cell-specific Rbpj-deficient mice. Notch inhibition in mice immunized with IRBP with a γ-secretase inhibitor (GSI) suppressed EAU progression, even when GSI was administered as late as 13 days after IRBP immunization. Our data demonstrate that Rbpj/Notch-mediated IL-22 production in T cells has a key pathological role in the late phase of EAU, and suggest that Notch blockade might be a useful therapeutic approach for treating EAU. PMID:24586644

  10. Expression Analysis of Cytokine and Chemokine Genes during the Natural Course of Murine Experimental Autoimmune Uveoretinitis

    PubMed Central

    Hashida, Noriyasu; Ohguro, Nobuyuki; Nishida, Kohji

    2012-01-01

    C57BL/6 mice were immunized with human interphotoreceptor retinoid-binding protein peptides to induce experimental autoimmune uveoretinitis (EAU). From the day of immunization to 30 days later, RNA was isolated daily from the mouse eyes. Dynamic changes in gene expression during the pathogenesis of EAU were analyzed by TaqMan gene expression assay that contained most chemokines/cytokines and their receptors, and signal transducer and activator of transcription (STAT) family genes, using beta-actin as the endogenous control. Gene clusters based on their expression profiles were analyzed to determine the candidate genes for the pathogenesis of inflammation. Hierarchical cluster analysis showed gene expression during EAU development in seven clustering patterns. Hierarchical cluster analysis also identified four distinct phases in daily expression: entrance, acceleration, deceleration, and remission. Gene expression changes in the EAU active phase showed synergetic upregulation of Th1-type genes (IFN-gamma and CXCL10/IP-10) with elevated Th2-type genes (CCL17/TARC and IL-5). Sequential expression changes of STAT1, STAT6, and STAT3 genes represented the dynamic changes of Th1, Th2, and Th17-type inflammatory genes, respectively. The expression pattern of STAT1 was representative of many gene movements. Our results suggested that coordinated action of Th1, Th2, and Th17 genes and STAT family genes are involved in EAU development and resolution. PMID:24049648

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

    PubMed

    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.

  12. Angiogenesis is regulated by angiopoietins during experimental autoimmune encephalomyelitis and is indirectly related to vascular permeability.

    PubMed

    Macmillan, Carolyn J; Starkey, Ryan J; Easton, Alexander S

    2011-12-01

    The regulation of angiogenesis was studied over the course of the animal model of multiple sclerosis, acute experimental autoimmune encephalomyelitis (EAE) in mice using immunohistochemistry. During EAE, angiogenesis peaked 21 days after disease induction, with significant increases in gray matter and adjacent to the leptomeninges. Angiogenesis correlated with clinical and pathologic scores. Spinal cord expression of angiopoietin 1 (Ang-1) by neurons and glia was reduced at Day 14, but expression by inflammatory cells restored earlier levels at Day 21. Angiopoietin 2 expression increased markedly at Day 21 and was mostly associated with inflammatory cells. Levels of the angiopoietin receptor Tie-2 were reduced at Day 14, but recovered by day D21. Double labeling demonstrated Ang-1 expression on infiltrating CD3-positive T cells; Ang-2 was expressed by monocytes/macrophages. During EAE, the expression of vascular endothelial growth factor peaked at Day 14 and began to decrease by Day 21. Double labeling showed expression of Tie-2 and vascular endothelial growth factor receptor 2 but not Ang-2 in blood vessels at Day 21. Vascular permeability increased early in EAE, but was reduced by Day 21. Although individual values did not correlate with angiogenesis, the volume of permeable tissue showed a weak positive correlation with angiogenesis. These temporal changes in angiogenic factors suggest an integral role during EAE-related angiogenesis.

  13. Thiamine Deficiency Promotes T Cell Infiltration in Experimental Autoimmune Encephalomyelitis: the Involvement of CCL2

    PubMed Central

    Ji, Zhe; Fan, Zhiqin; Zhang, Ying; Yu, Ronghuan; Yang, Haihua; Zhou, Chenghua; Luo, Jia; Ke, Zun-Ji

    2014-01-01

    Multiple sclerosis (MS) is a complex multifactorial disease that results from the interplay between environmental factors and a susceptible genetic background. Experimental autoimmune encephalomyelitis (EAE) has been widely used to investigate the mechanisms underlying MS pathogenesis. Chemokines, such as C-C Chemokine Ligand 2 (CCL2), are involved in the development of EAE. We have previously shown that thiamine deficiency (TD) induced CCL2 in neurons. We hypothesized that TD may affect the pathogenesis of EAE. In this study, EAE was induced in C57BL/6J mice by the injection of myelin oligodendroglial glycoprotein (MOG) peptide 35–55 with/without TD. TD aggravated the development of EAE which was indicated by clinical scores and pathological alterations in the spinal cord. TD also accelerated the development of EAE in an adoptive transfer EAE model. TD caused microglial activation and a drastic increase (up 140%) in leukocyte infiltration in the spinal cord of the EAE mice; specifically TD increased Th-1 and Th-17 cells. TD upregulated the expression of CCL2 and its receptor CCR2 in the spinal cord of EAE mice. Cells in peripheral lymph node and spleen isolated from MOG-primed TD mice showed much stronger proliferative responses to MOG. CCL2 stimulated the proliferation and migration of T lymphocytes in vitro. Our results suggested that TD exacerbated the development of EAE through activating CCL2 and inducing pathological inflammation. PMID:25063874

  14. Peripheral sensory neuron injury contributes to neuropathic pain in experimental autoimmune encephalomyelitis

    PubMed Central

    Wang, I-Ching; Chung, Chen-Yen; Liao, Fang; Chen, Chih-Cheng; Lee, Cheng-Han

    2017-01-01

    Multiple sclerosis (MS)-induced neuropathic pain deteriorates quality of life in patients but is often refractory to treatment. In experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, animals develop neuropathy and inflammation-induced tissue acidosis, which suggests the involvement of acid-sensing ion channels (ASICs). Also, peripheral neuropathy is reported in MS patients. However, the involvement of the peripheral nervous system (PNS) in MS neuropathic pain remains elusive. This study investigated the contribution of ASICs and peripheral neuropathy in MS-induced neuropathic pain. Elicited pain levels were as high in Asic1a−/−, Asic2−/− and Asic3−/− mice as wild-type mice even though only Asic1a−/− mice showed reduced EAE disease severity, which indicates that pain in EAE was independent of disease severity. We thus adopted an EAE model without pertussis toxin (EAEnp) to restrain activated immunity in the periphery and evaluate the PNS contribution to pain. Both EAE and EAEnp mice showed similar pain behaviors and peripheral neuropathy in nerve fibers and DRG neurons. Moreover, pregabalin significantly reduced neuropathic pain in both EAE and EAEnp mice. Our findings highlight the essential role of the PNS in neuropathic pain in EAE and pave the way for future development of analgesics without side effects in the CNS. PMID:28181561

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

    PubMed

    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.

  16. Antiinflammatory activity of glucomoringin isothiocyanate in a mouse model of experimental autoimmune encephalomyelitis.

    PubMed

    Galuppo, Maria; Giacoppo, Sabrina; De Nicola, Gina Rosalinda; Iori, Renato; Navarra, Michele; Lombardo, Giovanni Enrico; Bramanti, Placido; Mazzon, Emanuela

    2014-06-01

    Glucomoringin (4(α-L-rhamnosyloxy)-benzyl glucosinolate) (GMG) is an uncommon member of glucosinolate group belonging to the Moringaceae family, of which Moringa oleifera Lam. is the most widely distributed. Bioactivation of GMG with the enzyme myrosinase forms the corresponding isothiocyanate (4(α-L-rhamnosyloxy)-benzyl isothiocyanate) (GMG-ITC), which can play a key role in antitumoral activity and counteract the inflammatory response. The aim of this study was to assess the effect of GMG-ITC treatment in an experimental mouse model of multiple sclerosis (MS), an inflammatory demyelinating disease with neurodegeneration characterized by demyelinating plaques, neuronal, and axonal loss. For this reason, C57Bl/6 male mice were injected with myelin oligodendrocyte glycoprotein35-55 which is able to evoke an autoimmune response against myelin fibers miming human multiple sclerosis physiopatogenesis. Results clearly showed that the treatment was able to counteract the inflammatory cascade that underlies the processes leading to severe MS. In particular, GMG-ITC was effective against proinflammatory cytokine TNF-α. Oxidative species generation including the influence of iNOS, nitrotyrosine tissue expression and cell apoptotic death pathway was also evaluated resulting in a lower Bax/Bcl-2 unbalance. Taken together, this work adds new interesting properties and applicability of GMG-ITC and this compound can be suggested as a useful drug for the treatment or prevention of MS, at least in association with current conventional therapy.

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

    PubMed Central

    2011-01-01

    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. PMID:21696593

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

    PubMed

    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

    2012-08-03

    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 neurological symptoms, and proteomics analysis was performed using nano-LC-Orbitrap mass spectrometry. Additionally, the minocycline concentration in CSF was determined using quantitative matrix-assisted laser desorption/ionization-triple-quadrupole tandem mass spectrometry (MALDI-MS/MS) in the selected reaction monitoring (SRM) mode. Fifty percent of the minocycline-treated EAE animals did not show neurological symptoms on day 14 ("responders"), while the other half displayed neurological symptoms ("nonresponders"), indicating that minocycline delayed disease onset and attenuated disease severity in some, but not all, animals. Neither CSF nor plasma minocycline concentrations correlated with the onset of symptoms or disease severity. Analysis of the proteomics data resulted in a list of 20 differentially abundant proteins between the untreated animals and the responder group of animals. Two of these proteins, complement C3 and carboxypeptidase B2, were validated by quantitative LC-MS/MS in the SRM mode. Differences in the CSF proteome between untreated EAE animals and minocycline-treated responders were similar to the differences between minocycline-treated responders and nonresponders (70% overlap). Six proteins that remained unchanged in the minocycline-treated animals but were elevated in untreated EAE animals may be related to the mechanism of action of minocycline.

  19. Regular exercise promotes memory function and enhances hippocampal neuroplasticity in experimental autoimmune encephalomyelitis mice.

    PubMed

    Kim, Tae-Woon; Sung, Yun-Hee

    2017-03-27

    Multiple sclerosis (MS) is a progressive condition affecting the central nervous system (CNS), and is characterized by the development of demyelinated lesions and plaques in the brain and spinal cord. Exercise is beneficial against dementia in elderly patients, so we investigated the effects of exercise on memory in relation to hippocampal demyelination and neuroplasticity in a mouse model of MS (experimental autoimmune encephalomyelitis [EAE]). Mice were randomly divided into three groups: Sham, EAE, and EAE and exercise (EAE+EX). EAE+EX mice exercised five times a week for 4weeks, and all mice performed step-down avoidance tasks in order to verify memory ability. We analyzed changes in myelin basic protein (MBP), 2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNPase), 5-bromo-2'-deoxyuridine (brdU), doublecortin (DCX), bcl-2, bax, TUNEL, caspase-3, and brain derived neurotrophic factor (BDNF) via immunoassay or histological staining. We found decreased memory ability in EAE mice, accompanied by impaired myelination, increased apoptosis and cell proliferation, and decreased BDNF in the hippocampus. The memory decline and changes in demyelination, apoptosis, BDNF, and cell proliferation were partially reversed in EAE+EX mice. Our findings suggest that in patients with MS, regular exercise may benefit cognitive function by rescuing some hippocampal cellular and molecular impairments.

  20. SAP suppresses the development of experimental autoimmune encephalomyelitis in C57BL/6 mice.

    PubMed

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

    2012-04-01

    Experimental autoimmune encephalomyelitis (EAE) is a CD4(+) T cell-mediated disease of the central nervous system. Serum amyloid P component (SAP) is a highly conserved plasma protein named for its universal presence in amyloid deposits. Here we report that SAP-transgenic mice had unexpectedly attenuated EAE due to impaired encephalitogenic responses. Following induction with myelin oligodendroglial glycoprotein (MOG) peptide 35-55 in complete Freund's adjuvant, SAP-transgenic mice showed reduced spinal cord inflammation with lower severity of EAE attacks as compared with control C57BL/6 mice. However, in SAP-Knockout 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 interleukin-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.

  1. Demyelination arrest and remyelination induced by glatiramer acetate treatment of experimental autoimmune encephalomyelitis

    PubMed Central

    Aharoni, Rina; Herschkovitz, Avia; Eilam, Raya; Blumberg-Hazan, Michal; Sela, Michael; Bruck, Wolfgang; Arnon, Ruth

    2008-01-01

    The interplay between demyelination and remyelination is critical in the progress of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). In the present study, we explored the capacity of glatiramer acetate (GA, Copaxone) to affect the demyelination process and/or lead to remyelination in mice inflicted by chronic EAE, using both scanning electron microscopy and immunohistological methods. Spinal cords of untreated EAE mice revealed substantial demyelination accompanied by tissue destruction and axonal loss. In contrast, in spinal cords of GA-treated mice, in which treatment started concomitantly with disease induction (prevention), no pathology was observed. Moreover, when treatment was initiated after the appearance of clinical symptoms (suppression) or even in the chronic disease phase (delayed suppression) when substantial demyelination was already manifested, it resulted in a significant decrease in the pathological damage. Detection of oligodendrocyte progenitor cells (OPCs) expressing the NG2 or O4 markers via colocalization with the proliferation marker BrdU indicated their elevated levels in spinal cords of GA-treated mice. The mode of action of GA in this system is attributed to increased proliferation, differentiation, and survival of OPCs along the oligodendroglial maturation cascade and their recruitment into injury sites, thus enhancing repair processes in situ. PMID:18678887

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

    PubMed

    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.

  3. Paeoniflorin Ameliorates Experimental Autoimmune Encephalomyelitis via Inhibition of Dendritic Cell Function and Th17 Cell Differentiation

    PubMed Central

    Zhang, Han; Qi, Yuanyuan; Yuan, Yuanyang; Cai, Li; Xu, Haiyan; Zhang, Lili; Su, Bing; Nie, Hong

    2017-01-01

    Paeoniflorin (PF) is a monoterpene glycoside and exhibits multiple effects, including anti-inflammation and immunoregulation. To date, the effect of PF on multiple sclerosis (MS) has not been investigated. In this study, we investigated the effect of PF in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. After administered with PF, the onset and clinical symptoms of EAE mice were significantly ameliorated, and the number of Th17 cells infiltrated in central nervous system (CNS) and spleen was also dramatically decreased. Instead of inhibiting the differentiation of Th17 cells directly, PF influenced Th17 cells via suppressing the expression of costimulatory molecules and the production of interlukin-6 (IL-6) of dendritic cells (DCs) in vivo and in vitro, which may be attributable to the inhibition of IKK/NF-κB and JNK signaling pathway. When naïve CD4+ T cells were co-cultured with PF-treated dendritic cells under Th17-polarizing condition, the percentage of Th17 cells and the phosphorylation of STAT3 were decreased, as well as the mRNA levels of IL-17, RORα, and RORγt. Our study provided insights into the role of PF as a unique therapeutic agent for the treatment of multiple sclerosis and illustrated the underlying mechanism of PF from a new perspective. PMID:28165507

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

    PubMed

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

    2015-01-01

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

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

    PubMed

    Amir-Levy, Yifat; Mausner-Fainberg, Karin; Karni, Arnon

    2014-01-01

    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.

  6. Breast regression protein-39 is not required for experimental autoimmune encephalomyelitis induction.

    PubMed

    Cantó, Ester; Espejo, Carmen; Costa, Carme; Montalban, Xavier; Comabella, Manuel

    2015-10-01

    Increasing evidence points to a role for chitinase 3-like 1 (CHI3L1) in multiple sclerosis (MS). Here, we aimed to explore the potential involvement of CHI3L1 in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). EAE was induced by immunization with MOG 35-55 peptide in wild-type (WT) and knock-out (KO) mice for breast regression protein 39 (BRP-39), the mouse homologue of human CHI3L1. Immunological responses in splenocytes were assessed by means of polyclonal and antigen-specific proliferation assays. Central nervous system pathology and chitinase gene expression were also investigated. BRP-39 expression was increased in WT MOG 35-55-immunized mice compared to saline-immunized controls. No differences were found between WT and BRP-39 KO mice regarding EAE clinical course, day of disease onset, mortality rate, splenocyte proliferative responses or histopathological findings. These results do not support a role of BRP-39 in the pathogenesis of EAE.

  7. C-Phycocyanin ameliorates experimental autoimmune encephalomyelitis and induces regulatory T cells.

    PubMed

    Pentón-Rol, Giselle; Martínez-Sánchez, Gregorio; Cervantes-Llanos, Majel; Lagumersindez-Denis, Nielsen; Acosta-Medina, Emilio Felino; Falcón-Cama, Viviana; Alonso-Ramírez, Ruby; Valenzuela-Silva, Carmen; Rodríguez-Jiménez, Efraín; Llópiz-Arzuaga, Alexey; Marín-Prida, Javier; López-Saura, Pedro Antonio; Guillén-Nieto, Gerardo Emilio; Pentón-Arias, Eduardo

    2011-01-01

    For decades Experimental Autoimmune Encephalitis (EAE) has remained as an unsurpassed multiple sclerosis (MS) animal model. C-Phycocyanin (C-Pc) has been reported to exhibit pharmacological properties that may be expected to symptomatically improve EAE and MS. However, in this paper we reveal a basic underlying mechanism that may provide a new approach to the rationale of the overall beneficial effect of this natural antioxidant. We demonstrate that C-Pc is able to trigger mechanisms preventing or downgrading EAE expression and induces a regulatory T cell (Treg) response, in peripheral blood mononuclear cells (PBMC) from MS patients. These results agree with reports suggesting that Treg limit acute MS attacks and that C-Pc may act as a neuroprotector and thereby reverts the organic and functional damage in neurodegenerative disorders of the central nervous system (CNS). Moreover, evidence is provided on the antioxidant activity of C-Pc within the CNS, intended to improve the myelin and axonal damage of EAE induced Lewis rats. Our results indicate that specific Treg activation may represent a central and essential mechanism in supporting the therapeutic potential of C-Pc for MS and may lead to new and more effective therapies; this property would then complement and enhance other proven active principles such as interferons (IFN), giving rise to combined therapies.

  8. Endogenous Erythropoietin as Part of the Cytokine Network in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Mengozzi, Manuela; Cervellini, Ilaria; Bigini, Paolo; Martone, Sara; Biondi, Antonella; Pedotti, Rosetta; Gallo, Barbara; Barbera, Sara; Mennini, Tiziana; Boraso, Mariaserena; Marinovich, Marina; Petit, Edwige; Bernaudin, Myriam; Bianchi, Roberto; Viviani, Barbara; Ghezzi, Pietro

    2008-01-01

    Erythropoietin (EPO) is of great interest as a therapy for many of the central nervous system (CNS) diseases and its administration is protective in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Endogenous EPO is induced by hypoxic/ischemic injury, but little is known about its expression in other CNS diseases. We report here that EPO expression in the spinal cord is induced in mouse models of chronic or relapsing-remitting EAE, and is prominently localized to motoneurons. We found a parallel increase of hypoxia-inducible transcription factor (HIF)-1α, but not HIF-2α, at the mRNA level, suggesting a possible role of non-hypoxic factors in EPO induction. EPO mRNA in the spinal cord was co-expressed with interferon (IFN)–γ and tumor necrosis factor (TNF), and these cytokines inhibited EPO production in vitro in both neuronal and glial cells. Given the known inhibitory effect of EPO on neuroinflammation, our study indicates that EPO should be viewed as part of the inflammatory/anti-inflammatory network in MS. PMID:18670620

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

    PubMed Central

    Kaminski, Henry J.; Himuro, Keiichi; Alshaikh, Jumana; Gong, Bendi; Cheng, Georgiana; Kusner, Linda L.

    2016-01-01

    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, 359 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. PMID:27891095

  10. Voluntary wheel running differentially affects disease outcomes in male and female mice with experimental autoimmune encephalomyelitis.

    PubMed

    Mifflin, Katherine A; Frieser, Emma; Benson, Curtis; Baker, Glen; Kerr, Bradley J

    2017-04-15

    Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system. The primary symptoms of MS include the loss of sensory and motor function. Exercise has been shown to modulate disease parameters in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by reducing immune cell infiltration and oxidative stress. However, these initial studies were carried out exclusively in female mice. The present study compared the effects of daily voluntary wheel running on several disease parameters in male and female mice with EAE. Male and female mice were given access to a running wheel for 1h a day for 30 consecutive days. Daily wheel running significantly improved clinical scores in males with EAE but had little effect on clinical signs in females with the disease. Direct comparison of inflammation, axonal injury, and oxidative stress in male and female mice with EAE revealed significant differences in the amount of T-cell infiltration, microglia reactivity, demyelination and axon integrity. Male mice with EAE given daily access to running wheels also had significantly less ongoing oxidative stress compared to all other groups. Taken together, our results indicate that the inflammatory response generated in EAE is distinct between the sexes and its modulation by daily exercise can have sex-specific effects on disease-related outcomes. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Cannabinoid CB1 receptors regulate neuronal TNF-α effects in experimental autoimmune encephalomyelitis.

    PubMed

    Rossi, Silvia; Furlan, Roberto; De Chiara, Valentina; Muzio, Luca; Musella, Alessandra; Motta, Caterina; Studer, Valeria; Cavasinni, Francesca; Bernardi, Giorgio; Martino, Gianvito; Cravatt, Benjamin F; Lutz, Beat; Maccarrone, Mauro; Centonze, Diego

    2011-08-01

    Cannabinoid CB1 receptors (CB1Rs) regulate the neurodegenerative damage of experimental autoimmune encephalomyelitis (EAE) and of multiple sclerosis (MS). The mechanism by which CB1R stimulation exerts protective effects is still unclear. Here we show that pharmacological activation of CB1Rs dampens the tumor necrosis factor α (TNFα)-mediated potentiation of striatal spontaneous glutamate-mediated excitatory postsynaptic currents (EPSCs), which is believed to cogently contribute to the inflammation-induced neurodegenerative damage observed in EAE mice. Furthermore, mice lacking CB1Rs showed a more severe clinical course and, in parallel, exacerbated alterations of sEPSC duration after induction of EAE, indicating that endogenous cannabinoids activate CB1Rs and mitigate the synaptotoxic action of TNFα in EAE. Consistently, we found that mice lacking the fatty acid amide hydrolase (FAAH), and thus expressing abnormally high brain levels of the endocannabinoid anandamide, developed a less severe EAE associated with preserved TNFα-induced sEPSC alterations. CB1Rs are important modulators of EAE pathophysiology, and might play a mechanistic role in the neurodegenerative damage of MS patients.

  12. Perivascular iron deposits are associated with protein nitration in cerebral experimental autoimmune encephalomyelitis.

    PubMed

    Sands, Scott A; Williams, Rachel; Marshall, Sylvester; LeVine, Steven M

    2014-10-17

    Nitration of proteins, which is thought to be mediated by peroxynitrite, is a mechanism of tissue damage in multiple sclerosis (MS). However, protein nitration can also be catalyzed by iron, heme or heme-associated molecules independent of peroxynitrite. Since microhemorrhages and perivascular iron deposits are present in the CNS of MS patients, we sought to determine if iron is associated with protein nitration. A cerebral model of experimental autoimmune encephalomyelitis (cEAE) was utilized since this model has been shown to have perivascular iron deposits similar to those present in MS. Histochemical staining for iron was used together with immunohistochemistry for nitrotyrosine, eNOS, or iNOS on cerebral sections. Leakage of the blood-brain barrier (BBB) was studied by albumin immunohistochemistry. Iron deposits were colocalized with nitrotyrosine staining around vessels in cEAE mice while control animals revealed minimal staining. This finding supports the likelihood that nitrotyrosine formation was catalyzed by iron or iron containing molecules. Examples of iron deposits were also observed in association with eNOS and iNOS, which could be one source of substrates for this reaction. Extravasation of albumin was present in cEAE mice, but not in control animals. Extravasated albumin may act to limit tissue injury by binding iron and/or heme as well as being a target of nitration, but the protection is incomplete. In summary, iron-catalyzed nitration of proteins is a likely mechanism of tissue damage in MS.

  13. Immune mechanisms in the transfer of experimental autoimmune encephalomyelitis without adjuvant

    SciTech Connect

    Silberg, D.G.

    1985-01-01

    Experimental autoimmune encephalomyelitis (EAE) can be induced in Lewis rats without the use of adjuvant. Spleen cells of naive rats were sensitized to myelin basic protein (MBP) in vitro. Transfer of these cells did not result in the development of EAE. However, spleen cells from primary recipients, taken 10 days post transfer, and cultured with MBP (secondary culture, transferred EAE to secondary recipients. EAE can be induced in primary recipients by the transfer of secondary cultured cells or cultured cells or challenge with MBP in complete Freund's adjuvant (CFA) or incomplete Freund's adjuvant (IFA) 10 days after injection of naive cultured cells. The finding that MBP-CFA challenged 1' recipients developed EAE, suggests that the rats have been primed to MBP through the naive cultured cell transfer. The cells from naive culture that sensitize the primary recipient were radioresistant (1500 R), probably macrophages. This is in contrast to the cells transferring EAE to the secondary recipient, which were radiosensitive. Unlike the spleen cells which transfer EAE from MBP-CFA sensitized rats, the cells in the secondary transfer could not be activated to transfer EAE when cultured with concanavalin A. Clinical EAE in the secondary recipient was more severe when these rats were irradiated (200 R) prior to transfer. There is evidence that low dose irradiation eliminates naturally occurring suppressor cells. EAE also developed in lethally irradiated (850 R) recipients of secondary cultured cells, suggesting that the transferred cells can induce EAE alone or by recruiting radioresistant cells in the secondary host.

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

    PubMed

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

    2016-11-01

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

  15. Routes of Administration and Dose Optimization of Soluble Antigen Arrays in Mice with Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Thati, Shara; Kuehl, Christopher; Hartwell, Brittany; Sestak, Joshua; Siahaan, Teruna; Forrest, Laird; Berkland, Cory

    2014-01-01

    Soluble Antigen Arrays (SAgAs) were developed for treating mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. SAgAs are composed of hyaluronan with grafted EAE antigen and LABL peptide (a ligand of ICAM-1). SAgA dose was tested by varying injection volume, SAgA concentration, and administration schedule. Routes of administration were explored to determine the efficacy of SAgAs when injected intramuscularly, subcutaneously, intraperitoneally, intravenously, or instilled into lungs. Injections proximal to the central nervous system (CNS) were compared to distal injection sites. Intravenous dosing was included to determine if SAgA efficiency results from systemic exposure. Pulmonary instillation was included since reports suggest T cells are licensed in the lungs before moving onto the CNS1,2. Decreasing the volume of injection or SAgA dose reduced treatment efficacy. Treating mice with a single injection on day 4, 7, or 10 also reduced efficacy compared to injecting on all three days. Surprisingly, changing the injection site did not lead to a significant difference in efficacy. Intravenous administration showed efficacy similar to other routes, suggesting SAgAs act systemically. When SAgAs were delivered via pulmonary instillation, however, EAE mice failed to develop any symptoms, suggesting a unique lung mechanism to ameliorate EAE in mice. PMID:25447242

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

    PubMed Central

    Chiuso-Minicucci, Fernanda; Ishikawa, Larissa Lumi Watanabe; Mimura, Luiza Ayumi Nishiyama; Fraga-Silva, Thais Fernanda de Campos; França, Thais Graziela Donegá; Zorzella-Pezavento, Sofia Fernanda Gonçalves; Marques, Camila; Ikoma, Maura Rosane Valerio; Sartori, Alexandrina

    2015-01-01

    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 0,1μg of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) every other day during 15 days (on days 1, 3, 5, 7, 9, 11, 13 and 15). MOG (150μg) was co-administered on days 3 and 11. The administration of 1,25(OH) 2D3 or MOG determined significant reduction in EAE incidence and in clinical scores. When MOG was associated with 1,25(OH) 2D3 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(OH) 2D3 was able to control EAE development. PMID:25965341

  17. CCR5 knockout suppresses experimental autoimmune encephalomyelitis in C57BL/6 mice.

    PubMed

    Gu, Sun Mi; Park, Mi Hee; Yun, Hyung Mun; Han, Sang Bae; Oh, Ki Wan; Son, Dong Ju; Yun, Jae Suk; Hong, Jin Tae

    2016-03-29

    Multiple sclerosis (MS) is an inflammatory disease in which myelin in the spinal cord is damaged. C-C chemokine receptor type 5 (CCR5) is implicated in immune cell migration and cytokine release in central nervous system (CNS). We investigated whether CCR5 plays a role in MS progression using a murine model, experimental autoimmune encephalomyelitis (EAE), in CCR5 deficient (CCR5-/-) mice. CCR5-/- and CCR5+/+ (wild-type) mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) followed by pertussis toxin, after which EAE paralysis was scored for 28 days. We found that clinical scoring and EAE neuropathology were lower in CCR5-/- mice than CCR5+/+ mice. Immune cells (CD3+, CD4+, CD8+, B cell, NK cell and macrophages) infiltration and astrocytes/microglial activation were attenuated in CCR5-/- mice. Moreover, levels of IL-1β, TNF-α, IFN-γ and MCP-1 cytokine levels were decreased in CCR5-/- mice spinal cord. Myelin basic protein (MBP) and CNPase were increased while NG2 and O4 were decreased in CCR5-/- mice, indicating that demyelination was suppressed by CCR5 gene deletion. These findings suggest that CCR5 is likely participating in demyelination in the spinal cord the MS development, and that it could serve as an effective therapeutic target for the treatment of MS.

  18. Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor

    PubMed Central

    Kaye, Joel; Piryatinsky, Victor; Birnberg, Tal; Hingaly, Tal; Raymond, Emanuel; Kashi, Rina; Amit-Romach, Einat; Caballero, Ignacio S.; Towfic, Fadi; Ator, Mark A.; Rubinstein, Efrat; Laifenfeld, Daphna; Orbach, Aric; Shinar, Doron; Marantz, Yael; Grossman, Iris; Knappertz, Volker; Hayden, Michael R.; Laufer, Ralph

    2016-01-01

    Laquinimod is an oral drug currently being evaluated for the treatment of relapsing, remitting, and primary progressive multiple sclerosis and Huntington’s disease. Laquinimod exerts beneficial activities on both the peripheral immune system and the CNS with distinctive changes in CNS resident cell populations, especially astrocytes and microglia. Analysis of genome-wide expression data revealed activation of the aryl hydrocarbon receptor (AhR) pathway in laquinimod-treated mice. The AhR pathway modulates the differentiation and function of several cell populations, many of which play an important role in neuroinflammation. We therefore tested the consequences of AhR activation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) using AhR knockout mice. We demonstrate that the pronounced effect of laquinimod on clinical score, CNS inflammation, and demyelination in EAE was abolished in AhR−/− mice. Furthermore, using bone marrow chimeras we show that deletion of AhR in the immune system fully abrogates, whereas deletion within the CNS partially abrogates the effect of laquinimod in EAE. These data strongly support the idea that AhR is necessary for the efficacy of laquinimod in EAE and that laquinimod may represent a first-in-class drug targeting AhR for the treatment of multiple sclerosis and other neurodegenerative diseases. PMID:27671624

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

    PubMed Central

    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

  20. Stage-Specific Role of Interferon-Gamma in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

    PubMed Central

    Arellano, Gabriel; Ottum, Payton A.; Reyes, Lilian I.; Burgos, Paula I.; Naves, Rodrigo

    2015-01-01

    The role of interferon (IFN)-γ in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), has remained as an enigmatic paradox for more than 30 years. Several studies attribute this cytokine a prominent proinflammatory and pathogenic function in these pathologies. However, accumulating evidence shows that IFN-γ also plays a protective role inducing regulatory cell activity and modulating the effector T cell response. Several innate and adaptive immune cells also develop opposite functions strongly associated with the production of IFN-γ in EAE. Even the suppressive activity of different types of regulatory cells is dependent on IFN-γ. Interestingly, recent data supports a stage-specific participation of IFN-γ in EAE providing a plausible explanation for previous conflicting results. In this review, we will summarize and discuss such literature, emphasizing the protective role of IFN-γ on immune cells. These findings are fundamental to understand the complex role of IFN-γ in the pathogenesis of these diseases and can provide basis for potential stage-specific therapy for MS targeting IFN-γ-signaling or IFN-γ-producing immune cells. PMID:26483787

  1. Celastrol Attenuates Multiple Sclerosis and Optic Neuritis in an Experimental Autoimmune Encephalomyelitis Model

    PubMed Central

    Yang, Hongbin; Liu, Chang; Jiang, Jie; Wang, Yuena; Zhang, Xiaoyu

    2017-01-01

    This study was aimed to evaluate the effects of celastrol, a natural compound with multiple bioactivities, on multiple sclerosis and optic neuritis (ON) in rat experimental autoimmune encephalomyelitis (EAE). EAE was induced in Sprague Dawley rats using myelin basic protein, and the animals received daily intraperitoneal injections of celastrol or vehicle for 13 days. The EAE rats showed abnormal neurobehavior and inflammatory infiltration and demyelination in the spinal cord. Significantly upregulated mRNA expression of pro-inflammatory cytokines interferon-γ and interleukin-17 and downregulated anti-inflammatory cytokines interleukin-4 were found in the spinal cord of EAE rats. In the study of ON, severely inflammatory responses like in the spinal cord were also seen in the optic nerve, as well as obvious microgliosis. Furthermore, activation of nuclear factor kappa-B and upregulated inducible nitric oxide synthase was observed in the optic nerve. In addition, apoptosis of retinal ganglion cells and dysregulation of apoptotic-associated proteins in the optic nerve were found in EAE rats. Treatment of celastrol potently restored these changes. In most of the indexes, the effects of high dose of celastrol were better than the low dose. Our data conclude that administration of celastrol attenuates multiple sclerosis and ON in EAE via anti-inflammatory and anti-apoptotic effects. These findings provide new pre-clinical evidence for the use of celastrol in treatment of multiple sclerosis. PMID:28239352

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

    PubMed Central

    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

  3. Early handling increases susceptibility to experimental autoimmune encephalomyelitis (EAE) in C57BL/6 male mice.

    PubMed

    Columba-Cabezas, Sandra; Iaffaldano, Grazia; Chiarotti, Flavia; Alleva, Enrico; Cirulli, Francesca

    2009-07-25

    Brief maternal separations of neonatal animals can exert long-lasting effects on the reactivity of the neuroendocrine system. The aim of the present study was to investigate whether manipulations of the mother-infant interaction could affect susceptibility to immune-mediated diseases, such experimental autoimmune encephalomyelitis (EAE), and whether this effect would be mediated by changes in leptin which has been shown to regulate disease susceptibility and severity at adulthood. Given the different gender susceptibility to EAE previously described, we tested also whether early experiences could differentially affect the two genders. To this purpose, female and male C56BL/6 mice were subjected to handling (15 min daily) postnatally, from day 2 until day 14. All subjects were weaned at 21 days. At 7 weeks of age mice were immunized with MOG(35-55) to actively induce EAE. We thus determined the effect of neonatal handling on plasma concentrations of testosterone in male mice and leptin in both genders at different times post EAE induction. Our results show that early experiences influence susceptibility to EAE in a gender-specific manner, early manipulations resulting in an enhancement of sex-related differences in susceptibility. These effects were associated with changes in the testosterone profile of male subjects. Changes in leptin levels during the preclinical stage of EAE may predict a more severe disease course.

  4. Prostaglandin I2 Signaling Drives Th17 Differentiation and Exacerbates Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Zhou, Weisong; Dowell, Dustin R.; Huckabee, Matthew M.; Newcomb, Dawn C.; Boswell, Madison G.; Goleniewska, Kasia; Lotz, Matthew T.; Toki, Shinji; Yin, Huiyong; Yao, Songyi; Natarajan, Chandramohan; Wu, Pingsheng; Sriram, Subramaniam; Breyer, Richard M.; FitzGerald, Garret A.; Peebles, R. Stokes

    2012-01-01

    Background Prostaglandin I2 (PGI2), a lipid mediator currently used in treatment of human disease, is a critical regulator of adaptive immune responses. Although PGI2 signaling suppressed Th1 and Th2 immune responses, the role of PGI2 in Th17 differentiation is not known. Methodology/Principal Findings In mouse CD4+CD62L+ naïve T cell culture, the PGI2 analogs iloprost and cicaprost increased IL-17A and IL-22 protein production and Th17 differentiation in vitro. This effect was augmented by IL-23 and was dependent on PGI2 receptor IP signaling. In mouse bone marrow-derived CD11c+ dendritic cells (BMDCs), PGI2 analogs increased the ratio of IL-23/IL-12, which is correlated with increased ability of BMDCs to stimulate naïve T cells for IL-17A production. Moreover, IP knockout mice had delayed onset of a Th17-associated neurological disease, experimental autoimmune encephalomyelitis (EAE), and reduced infiltration of IL-17A-expressing mononuclear cells in the spinal cords compared to wild type mice. These results suggest that PGI2 promotes in vivo Th17 responses. Conclusion The preferential stimulation of Th17 differentiation by IP signaling may have important clinical implications as PGI2 and its analogs are commonly used to treat human pulmonary hypertension. PMID:22590492

  5. Chaperone Activity of Small Heat Shock Proteins Underlies Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis*

    PubMed Central

    Kurnellas, Michael P.; Brownell, Sara E.; Su, Leon; Malkovskiy, Andrey V.; Rajadas, Jayakumar; Dolganov, Gregory; Chopra, Sidharth; Schoolnik, Gary K.; Sobel, Raymond A.; Webster, Jonathan; Ousman, Shalina S.; Becker, Rachel A.; Steinman, Lawrence; Rothbard, Jonathan B.

    2012-01-01

    To determine whether the therapeutic activity of αB crystallin, small heat shock protein B5 (HspB5), was shared with other human sHsps, a set of seven human family members, a mutant of HspB5 G120 known to exhibit reduced chaperone activity, and a mycobacterial sHsp were expressed and purified from bacteria. Each of the recombinant proteins was shown to be a functional chaperone, capable of inhibiting aggregation of denatured insulin with varying efficiency. When injected into mice at the peak of disease, they were all effective in reducing the paralysis in experimental autoimmune encephalomyelitis. Additional structure activity correlations between chaperone activity and therapeutic function were established when linear regions within HspB5 were examined. A single region, corresponding to residues 73–92 of HspB5, forms amyloid fibrils, exhibited chaperone activity, and was an effective therapeutic for encephalomyelitis. The linkage of the three activities was further established by demonstrating individual substitutions of critical hydrophobic amino acids in the peptide resulted in the loss of all of the functions. PMID:22955287

  6. NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis

    PubMed Central

    Inoue, Makoto; Williams, Kristi L.; Gunn, Michael D.; Shinohara, Mari L.

    2012-01-01

    The NLRP3 inflammasome is a multiprotein complex consisting of three kinds of proteins, NLRP3, ASC, and pro-caspase-1, and plays a role in sensing pathogens and danger signals in the innate immune system. The NLRP3 inflammasome is thought to be involved in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, the mechanism by which the NLRP3 inflammasome induces EAE is not clear. In this study, we found that the NLRP3 inflammasome played a critical role in inducing T-helper cell migration into the CNS. To gain migratory ability, CD4+ T cells need to be primed by NLRP3 inflammasome-sufficient antigen-presenting cells to up-regulate chemotaxis-related proteins, such as osteopontin, CCR2, and CXCR6. In the presence of the NLRP3 inflammasome, dendritic cells and macrophages also induce chemotactic ability and up-regulate chemotaxis-related proteins, such as α4β1 integrin, CCL7, CCL8, and CXCL16. On the other hand, reduced Th17 cell population size in immunized Nlrp3−/− and Asc−/− mice is not a determinative factor for their resistance to EAE. As currently applied in clinical interventions of MS, targeting immune cell migration molecules may be an effective approach in treating MS accompanied by NLRP3 inflammasome activation. PMID:22699511

  7. Immunomodulation by Transplanted Human Embryonic Stem Cell-Derived Oligodendroglial Progenitors in Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Kim, Heechul; Walczak, Piotr; Kerr, Candace; Galpoththawela, Chulani; Gilad, Assaf A.; Muja, Naser; Bulte, Jeff W.M.

    2013-01-01

    Transplantation of embryonic stem cells and their neural derivatives can lead to amelioration of the disease symptoms of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Oligodendroglial progenitors (OPs), derived from human embryonic stem cells (hESC, HES-1), were labeled with superparamagnetic iron oxide and transduced with luciferase. At 7 days following induction of EAE in C57/BL6 mice, 1 × 106 cells were transplanted in the ventricles of C57/BL6 mice and noninvasively monitored by magnetic resonance and bioluminescence imaging. Cells were found to remain within the cerebroventricular system and did not survive for more than 10 days. However, EAE mice that received hESC-OPs showed a significant improvement in neurological disability scores (0.9 ± 0.2; n = 12) compared to that of control animals (3.3 ± 0.4; n = 12) at day 15 post-transplantation. Histopathologically, transplanted hESC-OPs generated TREM2-positive CD45 cells, increased TIMP-1 expression, confined inflammatory cells within the subarachnoid space, and gave rise to higher numbers of Foxp3-positive regulatory T cells in the spinal cord and spleen. Our results suggest that transplantation of hESC-OPs can alter the pathogenesis of EAE through immunomodulation, potentially providing new avenues for stem cell-based treatment of MS. PMID:22949039

  8. Targeting MOG expression to dendritic cells delays onset of experimental autoimmune disease.

    PubMed

    Ko, Hyun-Ja; Chung, Jie-Yu; Nasa, Zeyad; Chan, James; Siatskas, Christopher; Toh, Ban-Hock; Alderuccio, Frank

    2011-05-01

    Haematopoietic stem cell (HSC) transfer coupled with gene therapy is a powerful approach to treating fatal diseases such as X-linked severe combined immunodeficiency. This ability to isolate and genetically manipulate HSCs also offers a strategy for inducing immune tolerance through ectopic expression of autoantigens. We have previously shown that retroviral transduction of bone marrow (BM) with vectors encoding the autoantigen, myelin oligodendrocyte glycoprotein (MOG), can prevent the induction of experimental autoimmune encephalomyelitis (EAE). However, ubiquitous cellular expression of autoantigen driven by retroviral promoters may not be the best approach for clinical translation and a targeted expression approach may be more acceptable. As BM-derived dendritic cells (DCs) play a major role in tolerance induction, we asked whether targeted expression of MOG, a target autoantigen in EAE, to DCs can promote tolerance induction and influence the development of EAE. Self-inactivating retroviral vectors incorporating the mouse CD11c promoter were generated and used to transduce mouse BM cells. Transplantation of gene-modified cells into irradiated recipients resulted in the generation of chimeric mice with transgene expression limited to DCs. Notably, chimeric mice transplanted with MOG-expressing BM cells manifest a significant delay in the development of EAE suggesting that targeted antigen expression to tolerogenic cell types may be a feasible approach to inducing antigen-specific tolerance.

  9. Histopathology of the tubuli recti at the start of experimental autoimmune orchitis in mice.

    PubMed

    Naito, Munekazu; Terayama, Hayato; Hirai, Shuichi; Qu, Ning; Kawata, Shinichi; Itoh, Masahiro

    2009-12-01

    We previously established an experimental model of autoimmune orchitis (EAO) by means of immunization with testicular germ cells (TGC) alone in mice and confirmed that the disease can be transferred to mice that had received CD4+ but not CD8+ or B lymphocytes obtained from TGC-immunized donor mice. The tubuli recti (TR) are special in that lymphocytes first accumulate around them before spreading to the peripheral seminiferous tubules in EAO. However, the minute changes in the TR remain unknown. Therefore, we investigated the histopathology of the TR before the induction of spermatogenic disturbance. The results revealed that the first infiltrating lymphocytes around the TR were not only of T-cell but also of B-cell lineage. Moreover, it was also shown that some of these infiltrating lymphocytes migrated into the TR, with resultant degeneration of the TR epithelium before damage to the seminiferous epithelium. These findings indicate that TR epithelial cells are the first targets of autoreactive T and B lymphocytes in EAO.

  10. Treatment of experimental autoimmune encephalomyelitis with antisense oligonucleotides against the low affinity neurotrophin receptor.

    PubMed

    Soilu-Hänninen, M; Epa, R; Shipham, K; Butzkueven, H; Bucci, T; Barrett, G; Bartlett, P F; Kilpatrick, T J

    2000-03-15

    Upregulated expression of the low-affinity neurotrophin receptor (p75) in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE) has recently been demonstrated. To investigate whether p75 plays a role in disease pathogenesis, we adopted a gene therapy approach, utilizing antisense oligonucleotides to downregulate p75 expression during EAE. Phosphorothioate antisense oligonucleotides (AS), nonsense oligonucleotides (NS) or phosphate buffered saline (PBS) were injected daily for 18 days after immunization of SJL/J (H-2s)-mice with myelin proteolipid protein (PLP) peptide 139-151. In the AS group, there was a statistically significant reduction in both the mean maximal disease score (1.85 in the AS, 2.94 in the NS and 2.75 in the PBS-groups, respectively, P < 0.025) and in the cumulative disease incidence ( approximately 60% in the AS group and approximately 90% in the control groups). Histological and immunohistochemical analysis showed reduced inflammation and demyelination, as well as reduced p75 expression at the blood-brain barrier (BBB) in the AS-treated mice in comparison with both control groups. There was no difference, however, in p75 expression on neural cells within the CNS between the three groups of mice. We conclude that p75 could play a proactive role in the pathogenesis of EAE and may exert its effect at the level of the BBB.

  11. Routes of administration and dose optimization of soluble antigen arrays in mice with experimental autoimmune encephalomyelitis.

    PubMed

    Thati, Sharadvi; Kuehl, Christopher; Hartwell, Brittany; Sestak, Joshua; Siahaan, Teruna; Forrest, M Laird; Berkland, Cory

    2015-02-01

    Soluble antigen arrays (SAgAs) were developed for treating mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. SAgAs are composed of hyaluronan with grafted EAE antigen and LABL peptide (a ligand of ICAM-1). SAgA dose was tested by varying injection volume, SAgA concentration, and administration schedule. Routes of administration were explored to determine the efficacy of SAgAs when injected intramuscularly, subcutaneously, intraperitoneally, intravenously, or instilled into lungs. Injections proximal to the central nervous system (CNS) were compared with distal injection sites. Intravenous dosing was included to determine if SAgA efficiency results from systemic exposure. Pulmonary instillation (p.i.) was included as reports suggest T cells are licensed in the lungs before moving to the CNS. Decreasing the volume of injection or SAgA dose reduced treatment efficacy. Treating mice with a single injection on day 4, 7, and 10 also reduced efficacy compared with injecting on all three days. Surprisingly, changing the injection site did not lead to a significant difference in efficacy. Intravenous administration showed efficacy similar to other routes, suggesting SAgAs act systemically. When SAgAs were delivered via p.i., however, EAE mice failed to develop any symptoms, suggesting a unique lung mechanism to ameliorate EAE in mice.

  12. The Experimental Autoimmune Encephalomyelitis Disease Course Is Modulated by Nicotine and Other Cigarette Smoke Components

    PubMed Central

    Gao, Zhen; Nissen, Jillian C.; Ji, Kyungmin; Tsirka, Stella E.

    2014-01-01

    Epidemiological studies have reported that cigarette smoking increases the risk of developing multiple sclerosis (MS) and accelerates its progression. However, the molecular mechanisms underlying these effects remain unsettled. We have investigated here the effects of the nicotine and the non-nicotine components in cigarette smoke on MS using the experimental autoimmune encephalomyelitis (EAE) model, and have explored their underlying mechanism of action. Our results show that nicotine ameliorates the severity of EAE, as shown by reduced demyelination, increased body weight, and attenuated microglial activation. Nicotine administration after the development of EAE symptoms prevented further disease exacerbation, suggesting that it might be useful as an EAE/MS therapeutic. In contrast, the remaining components of cigarette smoke, delivered as cigarette smoke condensate (CSC), accelerated and increased adverse clinical symptoms during the early stages of EAE, and we identify a particular cigarette smoke compound, acrolein, as one of the potential mediators. We also show that the mechanisms underlying the opposing effects of nicotine and CSC on EAE are likely due to distinct effects on microglial viability, activation, and function. PMID:25250777

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

    PubMed

    Hirakawa, Hiroyuki; Zempo, Hirofumi; Ogawa, Masahito; Watanabe, Ryo; Suzuki, Jun-Ichi; Akazawa, Hiroshi; Komuro, Issei; Isobe, Mitsuaki

    2015-01-01

    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.

  14. Mechanisms of modulation of experimental autoimmune encephalomyelitis by chronic Trichinella spiralis infection in Dark Agouti rats.

    PubMed

    Gruden-Movsesijan, A; Ilic, N; Mostarica-Stojkovic, M; Stosic-Grujicic, S; Milic, M; Sofronic-Milosavljevic, L

    2010-06-01

    Trichinella spiralis is a helminth that provokes Th2 and anti-inflammatory type responses in an infected host. Our previous studies using Dark Agouti (DA) rats indicated that T. spiralis infection reduced experimental autoimmune encephalomyelitis (EAE) severity in rats. The aim of this study was to analyse the mechanisms underlying EAE suppression driven by T. spiralis infection. Reduced clinical and histological manifestations of the disease were accompanied by increased IL-4 and IL-10 production and decreased IFN-gamma and IL-17 production in draining lymph node cells. This indicates that T. spiralis infection successfully maintains a Th2 cytokine bias regardless of EAE induction. High IL-10 signifies parasite-induced anti-inflammatory and/or regulatory cell responses. Transfer of splenic T cell-enriched population of cells from T. spiralis-infected rats into EAE immunized rats caused amelioration of EAE and in some cases protection from disease development. This population of cells contained higher proportion of CD4(+) CD25(+) Foxp3(+) regulatory cells and produced high level of IL-10 when compared with uninfected rats.

  15. Collagenase-2 deficiency or inhibition impairs experimental autoimmune encephalomyelitis in mice.

    PubMed

    Folgueras, Alicia R; Fueyo, Antonio; García-Suárez, Olivia; Cox, Jennifer; Astudillo, Aurora; Tortorella, Paolo; Campestre, Cristina; Gutiérrez-Fernández, Ana; Fanjul-Fernández, Miriam; Pennington, Caroline J; Edwards, Dylan R; Overall, Christopher M; López-Otín, Carlos

    2008-04-04

    Matrix metalloproteinases (MMPs) have been implicated in a variety of human diseases, including neuroimmunological disorders such as multiple sclerosis. However, the recent finding that some MMPs play paradoxical protective roles in these diseases has made necessary the detailed study of the specific function of each family member in their pathogenesis. To determine the relevance of collagenase-2 (MMP-8) in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, we have performed two different analyses involving genetic and biochemical approaches. First, we have analyzed the development of EAE in mutant mouse deficient in MMP-8, with the finding that the absence of this proteolytic enzyme is associated with a marked reduction in the clinical symptoms of EAE. We have also found that MMP-8(-/-) mice exhibit a marked reduction in central nervous system-infiltrating cells and demyelinating lesions. As a second approach, we have carried out a pharmacological inhibition of MMP-8 with a selective inhibitor against this protease (IC(50) = 0.4 nM). These studies have revealed that the administration of the MMP-8 selective inhibitor to mice with EAE also reduces the severity of the disease. Based on these findings, we conclude that MMP-8 plays an important role in EAE development and propose that this enzyme may be a novel therapeutic target in human neuro-inflammatory diseases such as multiple sclerosis.

  16. Murine complement C4 is not required for experimental autoimmune encephalomyelitis.

    PubMed

    Boos, Laura A; Szalai, Alexander J; Barnum, Scott R

    2005-01-01

    In vitro studies have demonstrated that myelin and myelin-derived proteins activate both the classical and alternative complement pathways. More recently, studies have shown that mice deficient in factor B, a protein required for activation of the alternative pathway, have attenuated experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. The relative contribution of the classical pathway to the pathogenesis of EAE has remained unexplored. To address this question, we performed EAE using mice deficient in C4 (C4-/-), a protein required for full activation of the classical pathway. We found that deletion of the C4 gene does not significantly change either the time of onset or the severity and tempo of myelin oligodendrocyte-induced EAE compared with controls with a fully intact complement system. We observed similar levels of cellular infiltration (CD11b+ macrophages and CD3+ T cells) and demyelination in the two kinds of mice. Despite this, ribonuclease protection assays demonstrated a two- to fourfold increase in several pro-inflammatory cytokines in C4-/- mice with EAE, including interleukin-beta (IL-1beta), IL-18, tumor necrosis factor-alpha (TNF-alpha), IP-10, and RANTES. These results support the conclusion that the contribution of murine complement to the pathogenesis of demyelinating disease is realized via the alternative pathway. copyright (c) 2004 Wiley-Liss, Inc.

  17. [GAP-43 and its proteolytic fragment in spinal cord cells of rats with experimental autoimmune encephalomyelitis].

    PubMed

    Tikhomirova, M S; Karpenko, M N; Kirik, O V; Sukhorukova, E G; Korzhevskiĭ, D É; Klimenko, V M

    2015-01-01

    The regenerative capacity of the Central Nervous System (CNS) is a key factor implicated in the pathogenesis of neurodegenerative diseases. In the present study, the regenerative capacity of the CNS is considered using one of the markers of regeneration, Growth Associated Protein-43 (GAP-43) and its proteolytic fragment GAP-43-3 in the Experimental Autoimmune Encephalomyelitis (EAE) animal model of multiple sclerosis. The EAE on Wistar rats was characterized as an adequate model of multiple sclerosis, with typical clinical (pares and paralysis) and morphological (infiltration of spinal cord and deformation of motoneurons) disorders. Normally about 60% of GAP-43 is cleaved by m-calpain and stays in the form of GAP-43-3. During severe form of EAE up to 85% of GAP-43 can be found cleaved. We speculated that the cleavage of GAP-43 can play a crucial role for regenerative capacity of CNS during EAE development. Thus the distribution of GAP-43 and GAP-43-3 in the spinal cord was analyzed. The manifestation of clinical signs of EAE has been found to be in correlation with the levels of GAP-43 proteolysis both in the homogenate of the spinal cord and on the spinal cord slices. The immunoreactive staining enabled the observation of the accumulation of GAP-43-3 predominantly in microglial cells.

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

    PubMed

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

    2011-06-01

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

  19. Lisinopril has a cardio-protective effect on experimental acute autoimmune myocarditis in rats.

    PubMed

    Atteya, Muhammad; Mohamed, Raeesa A; Ahmed, Aly M; Abdel-Baky, Nayira A; Alfayez, Musaad A; Almalke, Hatim D; El Fouhil, Ahmed F

    2017-04-01

    The present study investigated the effect of lisinopril on experimental autoimmune myocarditis (EAM) in rats, a histologically similar model to human acute myocarditis. Twenty four, six week-old male Wistar rats were randomly allocated into 4 groups of 6 rats each. Group I received no treatment. Group II received lisinopril at a dose of 15 mg/kg/day suspended in 1 ml of 2% gum acacia daily, from day 1 to day 21. To induce myocarditis, animals of groups III and IV were injected by 1 mg of porcine cardiac myosin on days 1 and 8. In addition, animals of group IV received lisinopril in gum acacia daily, from day 1 to day 21. All rats were sacrificed on day 21. Serum levels of creatine phosphokinase, troponin-T, tumor necrosis factor-α and interleukin-6 were estimated. Hearts were processed for histopathological, as well as immunohistochemical study for thioredoxin (TRX) immunoreactivity. The wall of hearts from rats of myocarditis-lisinopril group showed mild focal myocarditis and a significant decrease of the mean percentage of pyknotic nuclei in cardiomyocytes, coincident with a significant decrease in serum biomarkers levels and TRX immunoreactivity, compared to myocarditis group. The present study suggested a cardio-protective effect of lisinopril on acute EAM in rats, probably through a mechanism related to its suppressive effect on angiotensin II formation.

  20. Uncovering Cryptic Glycan Markers in Multiple Sclerosis (MS) and Experimental Autoimmune Encephalomyelitis (EAE)

    PubMed Central

    Wang, Denong; Bhat, Roopa; Sobel, Raymond A.; Huang, Wei; Wang, Lai-Xi; Olsson, Tomas; Steinman, Lawrence

    2014-01-01

    Strategy, Management and Health PolicyEnabling Technology, Genomics, ProteomicsPreclinical ResearchPreclinical Development Toxicology, Formulation Drug Delivery, PharmacokineticsClinical Development Phases I-III Regulatory, Quality, ManufacturingPostmarketing Phase IV Using an integrated antigen microarray approach, we observed epitope-spreading of autoantibody responses to a variety of antigenic structures in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) and in the serum of mice with experimental autoimmune encephalomyelitis (EAE). These included previously described protein- and lipid-based antigenic targets and newly discovered autoimmunogenic sugar moieties, notably, autoantibodies specific for the oligomannoses in both MS patient CSF and the sera of mice with EAE. These glycans are often masked by other sugar moieties and belong to a class of cryptic autoantigens. We further determined that these targets are highly expressed on multiple cell types in MS and EAE lesions. Co-immunization of SJL/J mice with a Man9-KLH conjugate at the time of EAE induction elicited highly significant levels of anti-Man9-cluster autoantibodies. Nevertheless, this anti-glycan autoantibody response was associated with a significantly reduced clinical severity of EAE. The potential of these cryptic glycan markers and targeting antibodies for diagnostic and therapeutic interventions of neurological disorders has yet to be explored. PMID:24648292

  1. CD20 therapies in multiple sclerosis and experimental autoimmune encephalomyelitis - Targeting T or B cells?

    PubMed

    Agahozo, Marie Colombe; Peferoen, Laura; Baker, David; Amor, Sandra

    2016-09-01

    MS is widely considered to be a T cell-mediated disease although T cell immunotherapy has consistently failed, demonstrating distinct differences with experimental autoimmune encephalomyelitis (EAE), an animal model of MS in which T cell therapies are effective. Accumulating evidence has highlighted that B cells also play key role in MS pathogenesis. The high frequency of oligoclonal antibodies in the CSF, the localization of immunoglobulin in brain lesions and pathogenicity of antibodies originally pointed to the pathogenic role of B cells as autoantibody producing plasma cells. However, emerging evidence reveal that B cells also act as antigen presenting cells, T cell activators and cytokine producers suggesting that the strong efficacy of anti-CD20 antibody therapy observed in people with MS may reduce disease progression by several different mechanisms. Here we review the evidence and mechanisms by which B cells contribute to disease in MS compared to findings in the EAE model. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Oligodendrocyte-specific activation of PERK signaling protects mice against experimental autoimmune encephalomyelitis.

    PubMed

    Lin, Wensheng; Lin, Yifeng; Li, Jin; Fenstermaker, Ali G; Way, Sharon W; Clayton, Benjamin; Jamison, Stephanie; Harding, Heather P; Ron, David; Popko, Brian

    2013-04-03

    There is compelling evidence that oligodendrocyte apoptosis, in response to CNS inflammation, contributes significantly to the development of the demyelinating disorder multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Therefore, approaches designed to protect oligodendrocytes would likely have therapeutic value. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum (ER) stress increases cell survival under various cytotoxic conditions. Moreover, there is evidence that PERK signaling is activated in oligodendrocytes within demyelinating lesions in multiple sclerosis and EAE. Our previous study demonstrated that CNS delivery of the inflammatory cytokine interferon-γ before EAE onset protected mice against EAE, and this protection was dependent on PERK signaling. In our current study, we sought to elucidate the role of PERK signaling in oligodendrocytes during EAE. We generated transgenic mice that allow for temporally controlled activation of PERK signaling, in the absence of ER stress, specifically in oligodendrocytes. We demonstrated that persistent activation of PERK signaling was not deleterious to oligodendrocyte viability or the myelin of adult animals. Importantly, we found that enhanced activation of PERK signaling specifically in oligodendrocytes significantly attenuated EAE disease severity, which was associated with reduced oligodendrocyte apoptosis, demyelination, and axonal degeneration. This effect was not the result of an altered degree of the inflammatory response in EAE mice. Our results provide direct evidence that activation of PERK signaling in oligodendrocytes is cytoprotective, protecting mice against EAE.

  3. [Semiology and classification of uveitis].

    PubMed

    Brézin, A P

    1999-11-15

    Defined as an intraocular inflammation, uveitis may be linked to a systemic disease or represent an isolated entity. Screening for associated extra-ocular manifestations is mandatory in uveitis patients. The localisation of inflammation may be uni- or bilateral, anterior, intermediate or diffuse (panuveitis). Other main elements of the evaluation are the acute or chronic mode and the detection of a granulomatous presentation. In some cases, the examination of intraocular structures may be enough for the diagnosis of uveitis. When a correct approach is taken to the diagnosis of uveitis, causes are identified in approximately 50% of cases and presumed in 25% of patients; in one-fourth of cases, the origin of inflammation remains idiopathic.

  4. Functional and Pathogenic Differences of Th1 and Th17 Cells in Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Domingues, Helena S.; Mues, Marsilius; Lassmann, Hans; Wekerle, Hartmut; Krishnamoorthy, Gurumoorthy

    2010-01-01

    Background There is consensus that experimental autoimmune encephalomyelitis (EAE) can be mediated by myelin specific T cells of Th1 as well as of Th17 phenotype, but the contribution of either subset to the pathogenic process has remained controversial. In this report, we compare functional differences and pathogenic potential of “monoclonal” T cell lines that recognize myelin oligodendrocyte glycoprotein (MOG) with the same transgenic TCR but are distinguished by an IFN-γ producing Th1-like and IL-17 producing Th17-like cytokine signature. Methods and Findings CD4+ T cell lines were derived from the transgenic mouse strain 2D2, which expresses a TCR recognizing MOG peptide 35–55 in the context of I-Ab. Adoptive transfer of Th1 cells into lymphopenic (Rag2−/−) recipients, predominantly induced “classic” paralytic EAE, whereas Th17 cells mediated “atypical” ataxic EAE in approximately 50% of the recipient animals. Combination of Th1 and Th17 cells potentiated the encephalitogenicity inducing classical EAE exclusively. Th1 and Th17 mediated EAE lesions differed in their composition but not in their localization within the CNS. While Th1 lesions contained IFN-γ, but no IL-17 producing T cells, the T cells in Th17 lesions showed plasticity, substantially converting to IFN-γ producing Th1-like cells. Th1 and Th17 cells differed drastically by their lytic potential. Th1 but not Th17 cells lysed autoantigen presenting astrocytes and fibroblasts in vitro in a contact-dependent manner. In contrast, Th17 cells acquired cytotoxic potential only after antigenic stimulation and conversion to IFN-γ producing Th1 phenotype. Conclusions Our data demonstrate that both Th1 and Th17 lineages possess the ability to induce CNS autoimmunity but can function with complementary as well as differential pathogenic mechanisms. We propose that Th17-like cells producing IL-17 are required for the generation of atypical EAE whereas IFN-γ producing Th1 cells induce

  5. Neuroprotective arylpiperazine dopaminergic/serotonergic ligands suppress experimental autoimmune encephalomyelitis in rats.

    PubMed

    Popovic, Marjan; Stanojevic, Zeljka; Tosic, Jelena; Isakovic, Aleksandra; Paunovic, Verica; Petricevic, Sasa; Martinovic, Tamara; Ciric, Darko; Kravic-Stevovic, Tamara; Soskic, Vukic; Kostic-Rajacic, Sladjana; Shakib, Kaveh; Bumbasirevic, Vladimir; Trajkovic, Vladimir

    2015-10-01

    Arylpiperazine-based dopaminergic/serotonergic ligands exert neuroprotective activity. We examined the effect of arylpiperazine D2 /5-HT1A ligands, N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl}-phenyl]-picolinamide (6a) and N-{3-[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-picolinamide (6b), in experimental autoimmune encephalomyelitis (EAE), a model of neuroinflammation. Both compounds (10 mg/kg i.p.) reduced EAE clinical signs in spinal cord homogenate-immunized Dark Agouti rats. Compound 6b was more efficient in delaying the disease onset and reducing the maximal clinical score, which correlated with its higher affinity for D2 and 5-HT1A receptors. The protection was retained if treatment was limited to the effector (from day 8 onwards), but not the induction phase (day 0-7) of EAE. Compound 6b reduced CNS immune infiltration and expression of mRNA encoding the proinflammatory cytokines tumor necrosis factor, IL-6, IL-1, and GM-CSF, TH 1 cytokine IFN-γ, TH 17 cytokine IL-17, as well as the signature transcription factors of TH 1 (T-bet) and TH 17 (RORγt) cells. Arylpiperazine treatment reduced apoptosis and increased the activation of anti-apoptotic mediators Akt and p70S6 kinase in the CNS of EAE animals. The in vitro treatment with 6b protected oligodendrocyte cell line OLN-93 and neuronal cell line PC12 from mitogen-activated normal T cells or myelin basic protein-activated encephalitogenic T cells. In conclusion, arylpiperazine dopaminergic/serotonergic ligands suppress EAE through a direct neuroprotective action and decrease in CNS inflammation. Arylpiperazine dopaminergic/serotonergic ligands reduce neurological symptoms of acute autoimmune encephalomyelitis in rats without affecting the activation of autoreactive immune response, through mechanisms involving a decrease in CNS immune infiltration, as well as direct protection of CNS from immune-mediated damage. These data indicate potential usefulness of arylpiperazine-based compounds in the treatment of

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

    PubMed Central

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

    2016-01-01

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

  7. Absence of system xc(-) on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis.

    PubMed

    Merckx, Ellen; Albertini, Giulia; Paterka, Magdalena; Jensen, Cathy; Albrecht, Philipp; Dietrich, Michael; Van Liefferinge, Joeri; Bentea, Eduard; Verbruggen, Lise; Demuyser, Thomas; Deneyer, Lauren; Lewerenz, Jan; van Loo, Geert; De Keyser, Jacques; Sato, Hideyo; Maher, Pamela; Methner, Axel; Massie, Ann

    2017-01-13

    Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System xc(-) or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration. Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system xc(-), as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT(-/-)) mice and irradiated mice reconstituted in xCT(-/-) bone marrow (BM), to their proper wild type (xCT(+/+)) controls. xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT(+/+) mice, xCT(-/-) mice were equally susceptible to EAE, whereas mice transplanted with xCT(-/-) BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected. Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system xc(-) on immune cells invading the CNS participates to EAE. Since a total loss of system xc(-) had no

  8. Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient Kit W-sh/W-sh mice.

    PubMed

    Piconese, Silvia; Costanza, Massimo; Musio, Silvia; Tripodo, Claudio; Poliani, Pietro L; Gri, Giorgia; Burocchi, Alessia; Pittoni, Paola; Gorzanelli, Andrea; Colombo, Mario P; Pedotti, Rosetta

    2011-04-01

    Mast cell (MC)-deficient c-Kit mutant Kit(W/W-v) mice are protected against experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, suggesting a detrimental role for MCs in this disease. To further investigate the role of MCs in EAE, we took advantage of a recently characterized model of MC deficiency, Kit(W-sh/W-sh). Surprisingly, we observed that myelin oligodendrocyte glycoprotein (MOG)(35-55)-induced chronic EAE was exacerbated in Kit(W-sh/W-sh) compared with Kit(+/+) mice. Kit(W-sh/W-sh) mice showed more inflammatory foci in the central nervous system (CNS) and increased T-cell response against myelin. To understand whether the discrepant results obtained in Kit(W-sh/W-sh) and in Kit(W/W-v) mice were because of the different immunization protocols, we induced EAE in these two strains with varying doses of MOG(35-55) and adjuvants. Although Kit(W-sh/W-sh) mice exhibited exacerbated EAE under all immunization protocols, Kit(W/W-v) mice were protected from EAE only when immunized with high, but not low, doses of antigen and adjuvants. Kit(W-sh/W-sh) mice reconstituted systemically, but not in the CNS, with bone marrow-derived MCs still developed exacerbated EAE, indicating that protection from disease could be exerted by MCs mainly in the CNS, and/or by other cells possibly dysregulated in Kit(W-sh/W-sh) mice. In summary, these data suggest to reconsider MC contribution to EAE, taking into account the variables of using different experimental models and immunization protocols.

  9. High-affinity σ1 protein agonist reduces clinical and pathological signs of experimental autoimmune encephalomyelitis

    PubMed Central

    Oxombre, B; Lee-Chang, C; Duhamel, A; Toussaint, M; Giroux, M; Donnier-Maréchal, M; Carato, P; Lefranc, D; Zéphir, H; Prin, L; Melnyk, P; Vermersch, P

    2015-01-01

    Background and Purpose Selective agonists of the sigma-1 receptor (σ1 protein) are generally reported to protect against neuronal damage and modulate oligodendrocyte differentiation. Human and rodent lymphocytes possess saturable, high-affinity binding sites for compounds binding to the σ1 protein and potential immunomodulatory properties have been described for σ1 protein ligands. Experimental autoimmune encephalomyelitis (EAE) is recognized as a valuable model of the inflammatory aspects of multiple sclerosis (MS). Here, we have assessed the role of a σ1 protein agonist, containing the tetrahydroisoquinoline-hydantoin structure, in EAE. Experimental Approach EAE was induced in SJL/J female mice by active immunization with myelin proteolipid protein (PLP)139–151 peptide. The σ1 protein agonist was injected i.p. at the time of immunization (day 0). Disease severity was assessed clinically and by histopathological evaluation of the CNS. Phenotyping of B-cell subsets and regulatory T-cells were performed by flow cytometry in spleen and cervical lymph nodes. Key Results Prophylactic treatment of EAE mice with the σ1 protein agonist prevented mononuclear cell accumulation and demyelination in brain and spinal cord and increased T2 B-cells and regulatory T-cells, resulting in an overall reduction in the clinical progression of EAE. Conclusions and Implications This σ1 protein agonist, containing the tetrahydroisoquinoline-hydantoin structure, decreased the magnitude of inflammation in EAE. This effect was associated with increased proportions of B-cell subsets and regulatory T-cells with potential immunoregulatory functions. Targeting of the σ1 protein might thus provide new therapeutic opportunities in MS. PMID:25521311

  10. Natural killer T cells in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis.

    PubMed

    Van Kaer, Luc; Wu, Lan; Parekh, Vrajesh V

    2015-09-01

    Multiple sclerosis (MS) is a chronic inflammatory disease that causes demyelination of neurons in the central nervous system. Traditional therapies for MS have involved anti-inflammatory and immunosuppressive drugs with significant side effects that often only provide short-term relief. A more desirable outcome of immunotherapy would be to protect against disease before its clinical manifestation or to halt disease after its initiation. One attractive approach to accomplish this goal would be to restore tolerance by targeting immunoregulatory cell networks. Although much of the work in this area has focused on CD4(+) Foxp3(+) regulatory T cells, other studies have investigated natural killer T (NKT) cells, a subset of T cells that recognizes glycolipid antigens in the context of the CD1d glycoprotein. Studies with human MS patients have revealed alterations in the numbers and functions of NKT cells, which have been partially supported by studies with the experimental autoimmune encephalomyelitis model of MS. Additional studies have shown that activation of NKT cells with synthetic lipid antigens can, at least under certain experimental conditions, protect mice against the development of MS-like disease. Although mechanisms of this protection remain to be fully investigated, current evidence suggests that it involves interactions with other immunoregulatory cell types such as regulatory T cells and immunosuppressive myeloid cells. These studies have provided a strong foundation for the rational design of NKT-cell-based immunotherapies for MS that induce tolerance while sparing overall immune function. Nevertheless, additional pre-clinical and clinical studies will be required to bring this goal to fruition. © 2015 John Wiley & Sons Ltd.

  11. Comparative assessment of PDE 4 and 7 inhibitors as therapeutic agents in experimental autoimmune encephalomyelitis

    PubMed Central

    González-García, C; Bravo, B; Ballester, A; Gómez-Pérez, R; Eguiluz, C; Redondo, M; Martínez, A; Gil, C; Ballester, S

    2013-01-01

    BACKGROUND AND PURPOSE PDE4 inhibition suppresses experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, side effects hinder PDE4 inhibitors clinical use. PDE7 inhibition might constitute an alternative therapeutic strategy, but few data about the anti-inflammatory potential of PDE7 inhibitors are currently available. We have used the EAE model to perform a comparative evaluation of PDE4 and PDE7 inhibition as strategies for MS treatment. EXPERIMENTAL APPROACH Two PDE7 inhibitors, the sulfonamide derivative BRL50481 and the recently described quinazoline compound TC3.6, were assayed to modulate EAE in SJL mice, in comparison with the well-known PDE4 inhibitor Rolipram. We evaluated clinical signs, presence of inflammatory infiltrates in CNS and anti-inflammatory markers. We also analysed the effect of these inhibitors on the inflammatory profile of spleen cells in vitro. KEY RESULTS TC3.6 prevented EAE with efficacy similar to Rolipram, while BRL50481 had no effect on the disease. Differences between both PDE7 inhibitors are discussed. Data from Rolipram and TC3.6 showed that PDE4 and PDE7 inhibition work through both common and distinct pathways. Rolipram administration caused an increase in IL-10 and IL-27 expression which was not found after TC3.6 treatment. On the other hand, both inhibitors reduced IL-17 levels, prevented infiltration in CNS and increased the expression of the T regulator cell marker Foxp3. CONCLUSIONS AND IMPLICATIONS These results provide new information about the effects of Rolipram on EAE, underline PDE7 inhibition as a new therapeutic target for inflammatory diseases and show the value of TC3.6 to prevent EAE, with possible consequences for new therapeutic tools in MS. PMID:23869659

  12. Activated T lymphocytes in uveitis.

    PubMed Central

    Deschênes, J.; Char, D. H.; Kaleta, S.

    1988-01-01

    Two colour flow cytometry techniques were used to assess the activation stages of peripheral and intraocular T lymphocytes in uveitis. Increased numbers of T lymphocytes bearing the interleukin-2 (IL-2) receptors were found in intraocular fluids or peripheral blood or both of 35/51 patients with uveitis. This increased expression of IL-2 receptors on lymphocytes correlated with increased expression of other early T lymphocyte activation markers, HLA-DR and L-35. Both T helper cells (Leu-3A+) and suppressor cells (Leu 2A+) were activated in vivo. A positive correlation was seen between lymphocyte activation and clinical uveitis activity. In idiopathic uveitis activation of Leu-3A lymphocytes (helper/inducer) was significantly increased, and intraocular activation of the Leu-2A lymphocytes (cytotoxic/suppressor) was significantly decreased. These data show that some patients with idiopathic uveitis have a perturbation of T helper cells. Twenty-two of 31 patients with idiopathic uveitis, not associated with systemic disease, had increased peripheral T lymphocyte activation. This finding indicates that in some inflammations believed to be restricted to the eye an abnormal systemic immune activation exists. PMID:2964862

  13. Localization of interferon-gamma and Ia-antigen in T cell line-mediated experimental autoimmune encephalomyelitis.

    PubMed Central

    Stoll, G.; Müller, S.; Schmidt, B.; van der Meide, P.; Jung, S.; Toyka, K. V.; Hartung, H. P.

    1993-01-01

    This study reports the cellular localization of interferon-gamma (IFN-gamma) and MHC class II antigen (Ia) in the spinal cord of rats with experimental autoimmune encephalomyelitis induced by adoptive transfer of myelin basic protein-specific T cells. Numerous IFN-gamma-positive cells, stained with two different monoclonal antibodies against IFN-gamma, were present from days 3 to 7 after cell transfer. Their number was greatly reduced on day 10. A subpopulation of T cells was IFN-gamma positive. Moreover, a large number of ED1-positive macrophages contained IFN-gamma immunoreactivity. The transient presence of immune cells containing IFN-gamma immunoreactivity in experimental autoimmune encephalomyelitis suggests a pathogenic role of this cytokine in immune-mediated demyelination of the central nervous system. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:7685153

  14. Carbon nanospheres mediated delivery of nuclear matrix protein SMAR1 to direct experimental autoimmune encephalomyelitis in mice

    PubMed Central

    Chemmannur, Sijo V; Bhagat, Prasad; Mirlekar, Bhalchandra; Paknikar, Kishore M; Chattopadhyay, Samit

    2016-01-01

    Owing to the suppression of immune responses and associated side effects, steroid based treatments for inflammatory encephalitis disease can be detrimental. Here, we demonstrate a novel carbon nanosphere (CNP) based treatment regime for encephalomyelitis in mice by exploiting the functional property of the nuclear matrix binding protein SMAR1. A truncated part of SMAR1 ie, the DNA binding domain was conjugated with hydrothermally synthesized CNPs. When administered intravenously, the conjugate suppressed experimental animal encephalomyelitis in T cell specific conditional SMAR1 knockout mice (SMAR−/−). Further, CNP-SMAR1 conjugate delayed the onset of the disease and reduced the demyelination significantly. There was a significant decrease in the production of IL-17 after re-stimulation with MOG. Altogether, our findings suggest a potential carbon nanomaterial based therapeutic intervention to combat Th17 mediated autoimmune diseases including experimental autoimmune encephalomyelitis. PMID:27274234

  15. [Uveitis: diagnostic approach].

    PubMed

    Martínez-Berriotxoa, A; Fonollosa, A; Artaraz, J

    2012-10-01

    A 32 year-old woman was referred from the Ophthalmology Department to rule out a possible systemic disease. Her only past medical history of relevance was a tuberculosis contact during childhood. She complained of floaters and progressive blurring of vision in both eyes for some months, as well as arthralgia and cough. Her visual acuity was 0.3 in the right eye and 0.4 in the left eye. Biomicroscopy showed bilateral anterior granulomatous uveitis (1+ cells). Funduscopy showed bilateral vitritis 3+, snow banking and peripheral phlebitis. Fluorescein angiography did not show central vasculitis, and optical coherence tomography showed bilateral cystoid macular oedema. Fundus autofluorescence was normal. How would you initially assess this patient in order to decide which systemic examination should be performed, bearing in mind the ophthalmological manifestations?

  16. Herbal medicine Gamgungtang down-regulates autoimmunity through induction of TH2 cytokine production by lymphocytes in experimental thyroiditis model.

    PubMed

    Sa, Eun-Ho; Jin, Un-Ho; Kim, Dong-Soo; Kang, Bong-Seok; Ha, Ki-Tae; Kim, June-Ki; Park, Won-Hwan; Kim, Cheorl-Ho

    2007-02-12

    The crude herbal formulation, Gamgungtang (GGT), has been shown to protect animals against a wide range of spontaneously developing or induced autoimmune diseases. We have previously reported that GGT shows marked down-regulation of several experimental autoimmune diseases. Although very effective at preventing thyroid infiltrates in mice immunized with mouse deglycosylated thyroglobulin and complete Freund's adjuvant and in spontaneous models of thyroiditis, it completely failed to modify experimental autoimmune thyroiditis (EAT) induced in mice immunized with mouse thyroglobulin and lipopolysaccharide. In this study, in an effort to elucidate the mechanisms by which GGT suppresses EAT, and autoimmunity in general, we investigated the in vivo effects of this drug on the Th1/Th2 lymphocyte balance, which is important for the induction or inhibition of autoreactivity. Naive SJL/J mice were treated orally for 5 days with GGT (80 mg/(kg day)). Spleen cells were obtained at various time points during the treatment period and were stimulated in vitro with concanavalin A. Interleukins IL-4, IL-10 and IL-12, transforming growth factor-beta (TGF-beta) and interferon-gamma (IFN-gamma) cytokine production was evaluated at the protein levels of the cytokines in the medium and mRNA expressions. A significant upregulation of IL-4, IL-10 and TGF-beta was observed following treatment with GGT, which peaked at day 5 (IL-10) or day 10 (IL-4). On the other hand, IL-12 and IFN-gamma production were either unchanged or decreased. It seems therefore that GGT induces in vivo a shift towards Th2 lymphocytes which may be one of the mechanisms of down-regulation of the autoimmune reactivity in EAT. Our observations indicate that down-regulation of TH1 cytokines (especially IL-12) and enhancement of Th2 cytokine production may play an important role in the control of T-cell-mediated autoimmunity. These data may contribute to the design of new immunomodulating treatments for a group of

  17. BJ-3105, a 6-Alkoxypyridin-3-ol Analog, Impairs T Cell Differentiation and Preve