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Immature dendritic cell-derived exosomes (iMDEX) display a certain degree of immunosuppressive activity in autoimmune diseases. However, the role of iMDEX in experimental autoimmune myasthenia gravis (EAMG) is still unclear. Therefore, we tested the effects of mouse bone marrow (BM)-derived iMDEX on tolerance induction in a mouse model of EAMG. In this study, we found that the CELLine culture system produced more exosomes, the morphology and phenotype of these exosomes were found to be identical when compared with traditional cell culture. And, iMDEX(1000) ameliorated the progression of EAMG by reducing AChR-reactive lymphocyte proliferation, AChR antibody levels and pro-inflammatory cytokine levels.
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.
Myasthenia Gravis (MG) is a T cell-driven, autoantibody-mediated disease. Here we show that oral Berberine (BBR) ameliorated clinical symptoms of experimental autoimmune myasthenia gravis(EAMG) rat model via decreasing the frequencies of Th1, Th17, Th1/17 cell subsets. JAK-STAT pathway was highlighted by transcriptomic analysis with EAMG mononuclear cells (MNCs). Surface plasmon resonance identified ligand binding interaction between BBR and JAK2, and electrostatic interaction was proposed by molecular dynamic simulation. Reduced phosphorylated JAK1/2/3 and STAT1/3 in MNCs from BBR-fed EAMG rats were demonstrated. These results suggest that BBR might improve EAMG by rebalancing T cell subsets through targeting JAK-STAT pathway.
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.
Suppressive effects of the synthetic immunomodulatory drug Linomide have been shown in several autoimmune models, including antibody-mediated experimental autoimmune myasthenia gravis (EAMG), a model for human myasthenia gravis (MG). To define the mechanisms underlying EAMG suppression, we injected Linomide subcutaneously at different doses into Lewis rats immunized with Torpedo acetylcholine receptor (AChR) in complete Freund's adjuvant (CFA), and investigated AChR-specific T and B cell responses, and the levels of lymph node cells expressing mRNA of different cytokines after AChR stimulation in vitro. Both 160 and 16, but not 1.6, mg/kg/day of Linomide effectively suppressed clinical muscle weakness, accompanied by decreased AChR-induced T and B cell responses. Linomide also suppressed the mRNA expression of the Th1 cytokines IFN-gamma, IL-12 and TNF-alpha as well as the Th2 cytokines IL-4 and IL-10, which are important in the immunopathogenesis of EAMG by promoting antibody production. There were no differences for IL-1beta, IL-6, lymphotoxin or TGF-beta expression in Linomide-treated vs nontreated control EAMG rats. We conclude that Linomide suppresses clinical EAMG as well as B and T cell responses to AChR by counteracting the production of AChR-induced Th1 and Th2 cytokines.
IL-10-competent subset within CD1d(hi)CD5(+) B cells, also known as B10 cells, has been shown to regulate autoimmune diseases. In our previous study, adoptive transfer of CD1d(hi)CD5(+) B cells expanded in vivo by GM-CSF prevented and suppressed experimental autoimmune myasthenia gravis (EAMG). The goal of this study was to further examine the role and mechanism of IL-10 in the regulatory function of B10 cells in EAMG. We found that only IL-10 competent CD1d(hi)CD5(+) B cells sorted from WT mice, but not IL-10 deficient CD1d(hi)CD5(+) B cells exhibited regulatory function in vitro and in vivo. Adoptive transfer of IL-10 competent CD1d(hi)CD5(+) B cells led to higher frequency of Tregs and B10 cells, and low levels of proinflammatory cytokines and autoantibody production. We conclude that IL-10 production within CD1d(hi)CD5(+) B cells plays an important role in immune regulation of EAMG.
Recent studies have demonstrated the important role of toll-like receptor 9 (TLR9) signalling in autoimmune diseases, but its role in myasthenia gravis (MG) has not been fully established. We show herein that blocking TLR9 signalling via the suppressive oligodeoxynucleotide (ODN) H154 alleviated the symptoms of experimental autoimmune myasthenia gravis (EAMG). With the downregulation of dendritic cells (DCs), TLR9 interruption reduced follicular helper T cells (Tfh) and germinal centre (GC) B cells, leading to decreased antibody production. In addition, TLR9+ B cells as well as total B cells in the spleen were inhibited by H154. These findings highlight the critical role of TLR9 in EAMG and suggest that the inhibition of the TLR9 pathway might be a potential pharmacological strategy for the treatment of myasthenia gravis.
Beneficial effects of probiotics on gut microbiota homeostasis and inflammatory immune responses suggested the investigation of their potential clinical efficacy in experimental models of autoimmune diseases. Indeed, administration of two bifidobacteria and lactobacilli probiotic strains prevented disease manifestations in the Lewis rat model of Myasthenia Gravis (EAMG). Here, we demonstrate the clinical efficacy of therapeutic administration of vital bifidobacteria (i.e., from EAMG onset). The mechanisms involved in immunomodulation were investigated with ex vivo and in vitro experiments. Improvement of EAMG symptoms was associated to decreased anti-rat AChR antibody levels, and differential expression of TGFβ and FoxP3 immunoregulatory transcripts in draining lymph nodes and spleen of treated-EAMG rats. Exposure of rat bone marrow-derived dendritic cells to bifidobacteria or lactobacilli strains upregulated toll-like receptor 2 mRNA expression, a key molecule involved in bacterium recognition via lipotheicoic acid. Live imaging experiments of AChR-specific effector T cells, co-cultured with BMDCs pre-exposed to bifidobacteria, demonstrated increased percentages of motile effector T cells, suggesting a hindered formation of TCR-peptide-MHC complex. Composition of gut microbiota was studied by 16S rRNA gene sequencing, and α and β diversity were determined in probiotic treated EAMG rats, with altered ratios between Tenericutes and Verrucomicrobia (phylum level), and Ruminococcaceae and Lachnospiraceae (family level). Moreover, the relative abundance of Akkermansia genus was found increased compared to healthy and probiotic treated EAMG rats. In conclusion, our findings confirms that the administration of vital bifidobacteria at EAMG onset has beneficial effects on disease progression; this study further supports preclinical research in human MG to evaluate probiotic efficacy as supplementary therapy in MG.
C57Bl6 mice (B6 mice) immunized with Torpedo acetylcholine receptor (TAChR) in Freund's adjuvants (FA) develop Experimental Autoimmune Myasthenia Gravis (EAMG). In mouse EAMG Th2 cytokines may be protective. Aluminum hydroxide (Alum) was used to immunize B6 mice to the TAChR and prime CD4+ T and B cells secreting Th2 cytokines. Mice immunized with TAChR/Alum developed anti-AChR CD4+ T cells response, but minimal antibody levels and symptoms. TAChR/Alum treatments prior immunization with TAChR/FA protected mice from EAMG. Cell transfer experiments demonstrated that B and CD4+ T cells mediated the protective effect by causing intense reduction of complement-fixing anti-TAChR IgG subclasses.
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.
Recent studies have demonstrated that natural killer (NK) cells can modulate other immune components and are involved in the development or progression of several autoimmune diseases. However, the roles and mechanisms of NK cells in regulating experimental autoimmune myasthenia gravis (EAMG) remained to be illustrated.
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.
Myasthenia gravis (MG) is an antibody-mediated autoimmune disease and its pathogenesis is closely related to CD4 + T cells. In recent years, gut microbiota is considered to play an important role in the pathogenesis of MG. Astragaloside IV (AS-IV) is one of the main active components extracted from Astragalus membranaceus and has immunomodulatory effects. To study the immunomodulatory effect of AS-IV and the changes of gut microbiota on experimental autoimmune myasthenia gravis (EAMG) mice, we explore the possible mechanism of AS-IV in improving MG.
Accumulating evidence shows that the immunoproteasome participates in the immune response, beyond its initial role in the protein degradation. Here, we tested the effects of the selective immunoproteasome inhibitor, ONX-0914, on experimental autoimmune myasthenia gravis (EAMG). We found that ONX-0914 ameliorated the severity of ongoing EAMG by reducing the autoantibody affinity, accompanied with decreased Tfh cells and antigen presenting cells. Also it reduced the percentage of Th17 cells and inhibited the secretion of IL-17. Our data indicated ONX-0914 may bring benefit for MG therapy.
Myasthenia gravis (MG) and animal model of experimental autoimmune myasthenia gravis (EAMG) is the most common autoimmune disorder of neuromuscular transmission. The disease is caused by the breakdown of the acetylcholine receptor (AChR) which is largely due to complement activation at the neuromuscular junction (NMJ). Limited knowledge exists to the extent that complement receptor 1-related gene/protein y deficiency (Crry -/-) modulates the adaptive immune response and EAMG outcome.
Antibody-induced complement activation may cause injury of the neuromuscular junction (NMJ) and is thus considered as a primary pathogenic factor in human myasthenia gravis (MG) and animal models of experimental autoimmune myasthenia gravis (EAMG). In this study, we tested whether CRIg/FH, a targeted complement inhibitor, could attenuate NMJ injury in rat MG models. We first demonstrated that CRIg/FH could inhibit complement-dependent cytotoxicity on human rhabdomyosarcoma TE671 cells induced by MG patient-derived IgG in vitro. Furthermore, we investigated the therapeutic effect of CRIg/FH in a passive and an active EAMG rodent model. In both models, administration of CRIg/FH could significantly reduce the complement-mediated end-plate damage and suppress the development of EAMG. In the active EAMG model, we also found that CRIg/FH treatment remarkably reduced the serum concentration of autoantibodies and of the cytokines including IFN-γ, IL-2, IL-6, and IL-17, and upregulated the percentage of Treg cells in the spleen, which was further verified in vitro. Therefore, our findings indicate that CRIg/FH may hold the potential for the treatment of MG via immune modulation.
BACKGROUND Myasthenia gravis (MG) is an autoimmune neurological disorder of neuromuscular junctions. In this study we established experimental autoimmune myasthenia gravis (EAMG) rat models to investigate the effects of AEB-071 (AEB), which is a specific inhibitor of protein kinase C that prevents T lymphocyte activation. MATERIAL AND METHODS We utilized animals divided into 4 groups: (1) control rats, (2) EAMG, (3) AEB-071+EAMG, and (4) AZP+EAMG. Drug treatment was continued for 10 days. Ten weeks after immunization we measured body weights, assessed mortality rates, and used Lennon scores to evaluate EAMG grades. We also assessed the proportions of Treg, Th1, Th2, Th17, and lymphocytes using flow cytometry. RESULTS In the absence of drug treatment, we found a significant decline in body weights in the EAMG group in comparison to control rats, and EAMG group rats also had higher Lennon scores (P<0.05). Interestingly, we found that AEB-071 restored the body weight of EAMG rats and the decreased mortality rate compared to AZP treatment. Although a decrease in the number of Treg cells was observed, the proportion of Th lymphocytes was significantly increased in the EAMG group, and AEB-071 treatment decreased the proportion of Th lymphocytes. CONCLUSIONS We concluded that AEB-071 treatment imparts beneficial effects in EAMG rat models by reducing mortality rate and restoring Th lymphocyte balance, and thus may be an attractive candidate for use in MG treatment.
Reinstating tissue-specific tolerance has attracted much attention as a means to treat autoimmune diseases. However, despite promising results in rodent models of autoimmune diseases, no established tolerogenic therapy is clinically available yet. In the experimental autoimmune myasthenia gravis (EAMG) model several protocols have been reported that induce tolerance against the prime disease-associated antigen, the acetylcholine receptor (AChR) at the neuromuscular junction. Using the whole AChR, the extracellular part or peptides derived from the receptor, investigators have reported variable success with their treatments, though, usually relatively large amounts of antigen has been required. Hence, there is a need for better formulations and strategies to improve on the efficacy of the tolerance-inducing therapies. Here, we report on a novel targeted fusion protein carrying the immunodominant peptide from AChR, mCTA1-T146, which given intranasally in repeated microgram doses strongly suppressed induction as well as ongoing EAMG disease in mice. The results corroborate our previous findings, using the same fusion protein approach, in the collagen-induced arthritis model showing dramatic suppressive effects on Th1 and Th17 autoaggressive CD4 T cells and upregulated regulatory T cell activities with enhanced IL10 production. A suppressive gene signature with upregulated expression of mRNA for TGFβ, IL10, IL27, and Foxp3 was clearly detectable in lymph node and spleen following intranasal treatment with mCTA1-T146. Amelioration of EAMG disease was accompanied by reduced loss of muscle AChR and lower levels of anti-AChR serum antibodies. We believe this targeted highly effective fusion protein mCTA1-T146 is a promising candidate for clinical evaluation in myasthenia gravis patients.
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