Both CD4+ and CD8+ T cells are essential to induce experimental autoimmune myasthenia gravis.

CD4+ T cells have been shown to be crucial in the development of experimental autoimmune myasthenia gravis (EAMG). The role of CD8+ T cells in EAMG is less well established. We previously showed that antibody depletion of CD8+ T cells in rats effectively suppresses EAMG. To further study the role and relationship of CD4+ versus CD8+ T cells in induction of EAMG, CD4-/-, CD8-/-, and CD4-8- mutant C57BL/6 mice and the parent CD4+8- wild-type mice were immunized with Torpedo acetylcholine receptor (AChR) plus complete Freund's adjuvant. Clinical EAMG was nearly completely prevented in CD4-8-, CD4-/-, and CD8-/- mice. This was associated with strongly reduced AChR-specific T and B cell responses, and with reduced levels of AChR-reactive interferon gamma (IFN-gamma) and interleukin 4 (IL-4) mRNA-expressing cells in lymphoid organs when compared with CD4+8+ wild-type mice. We conclude that (a) both CD4+ and CD8+ T cells are essential for development of EAMG, and a collaboration between these cell types may be necessary; (b) CD4+ as well as CD8+ T cells secrete IFN-gamma and IL-4, and both cytokines are involved in the development of EAMG; and (c), besides T cells, other immune cells might also be responsible for help of anti-AChR antibody production.

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Depletion of CD8+ T cells suppresses the development of experimental autoimmune myasthenia gravis in Lewis rats

European Journal of Immunology ◽

10.1002/eji.1830250509 ◽

1995 ◽

Vol 25 (5) ◽

pp. 1191-1198 ◽

Cited By ~ 46

Author(s):

Guang-Xian Zhang ◽

Cun-Gen Ma ◽

Bao-Guo Xiao ◽

Moiz Bakhiet ◽

Hans Link ◽

...

Keyword(s):

T Cells ◽

Myasthenia Gravis ◽

Cd8 T Cells ◽

Lewis Rats ◽

Experimental Autoimmune Myasthenia Gravis ◽

Autoimmune Myasthenia ◽

Experimental Autoimmune

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Faculty Opinions recommendation of IL-17-producing CD4(+) T cells contribute to the loss of B-cell tolerance in experimental autoimmune myasthenia gravis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725354928.793519620 ◽

2016 ◽

Author(s):

Angela Vincent

Keyword(s):

T Cells ◽

Myasthenia Gravis ◽

B Cell ◽

Cd4 T Cells ◽

Cell Tolerance ◽

B Cell Tolerance ◽

Experimental Autoimmune Myasthenia Gravis ◽

Autoimmune Myasthenia ◽

Experimental Autoimmune

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CXCR5-negative natural killer cells ameliorate experimental autoimmune myasthenia gravis by suppressing follicular helper T cells

Journal of Neuroinflammation ◽

10.1186/s12974-019-1687-x ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 2

Author(s):

Chun-Lin Yang ◽

Peng Zhang ◽

Ru-Tao Liu ◽

Na Zhang ◽

Min Zhang ◽

...

Keyword(s):

T Cells ◽

Myasthenia Gravis ◽

Nk Cells ◽

Ex Vivo ◽

Tfh Cells ◽

Follicular Helper ◽

Experimental Autoimmune Myasthenia Gravis ◽

Autoimmune Myasthenia ◽

Experimental Autoimmune ◽

Cell Zone

Abstract Background 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. Methods To address the function of NK cells in experimental autoimmune myasthenia gravis in vivo, EAMG rats were adoptively transferred with splenic NK cells. The serum antibodies, and splenic follicular helper T (Tfh) cells and germinal center B cells were determined by ELISA and flow cytometry. The roles of NK cells in regulating Tfh cells were further verified in vitro by co-culturing splenocytes or isolated T cells with NK cells. Moreover, the phenotype, localization, and function differences between different NK cell subtypes were determined by flow cytometry, immunofluorescence, and ex vivo co-culturation. Results In this study, we found that adoptive transfer of NK cells ameliorated EAMG symptoms by suppressing Tfh cells and germinal center B cells. Ex vivo studies indicated NK cells inhibited CD4+ T cells and Tfh cells by inducing the apoptosis of T cells. More importantly, NK cells could be divided into CXCR5- and CXCR5+ NK subtypes according to the expression of CXCR5 molecular. Compared with CXCR5- NK cells, which were mainly localized outside B cell zone, CXCR5+ NK were concentrated in the B cell zone and exhibited higher expression levels of IL-17 and ICOS, and lower expression level of CD27. Ex vivo studies indicated it was CXCR5- NK cells not CXCR5+ NK cells that suppressed CD4+ T cells and Tfh cells. Further analysis revealed that, compared with CXCR5- NK cells, CXCR5+ NK cells enhanced the ICOS expression of Tfh cells. Conclusions These findings highlight the different roles of CXCR5- NK cells and CXCR5+ NK cells. It was CXCR5- NK cells but not CXCR5+ NK cells that suppressed Tfh cells and inhibited the autoimmune response in EAMG models.

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Disequilibrium of T helper type 1, 2 and 17 cells and regulatory T cells during the development of experimental autoimmune myasthenia gravis

Immunology ◽

10.1111/j.1365-2567.2009.03089.x ◽

2009 ◽

Vol 128 (1pt2) ◽

pp. e826-e836 ◽

Cited By ~ 54

Author(s):

Lili Mu ◽

Bo Sun ◽

Qingfei Kong ◽

Jinghua Wang ◽

Guangyou Wang ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Myasthenia Gravis ◽

T Helper ◽

Experimental Autoimmune Myasthenia Gravis ◽

Autoimmune Myasthenia ◽

Helper Type ◽

Experimental Autoimmune

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

Mediators of Inflammation ◽

10.1155/2015/460610 ◽

2015 ◽

Vol 2015 ◽

pp. 1-16 ◽

Cited By ~ 13

Author(s):

Laura Oliveira ◽

Alexandra Correia ◽

Ana Cristina Costa ◽

Sónia Guerra-Gomes ◽

Fátima Ferreirinha ◽

...

Keyword(s):

T Cells ◽

Myasthenia Gravis ◽

Adenosine Deaminase ◽

Immune Suppression ◽

Neuromuscular Transmission ◽

Therapeutic Potential ◽

Experimental Autoimmune Myasthenia Gravis ◽

Adenosine Deaminase Activity ◽

Autoimmune Myasthenia ◽

Experimental Autoimmune

AMP dephosphorylation via ecto-5′-nucleotidase/CD73 is the rate limiting step to generate extracellular adenosine (ADO) from released adenine nucleotides. ADO, viaA2Areceptors (A2ARs), is a potent modulator of neuromuscular and immunological responses. The pivotal role of ecto-5′-nucleotidase/CD73, in controlling extracellular ADO formation, prompted us to investigate its role in a rat model of experimental autoimmune myasthenia gravis (EAMG). Results show that CD4+CD25+FoxP3+regulatory T cells express lower amounts of ecto-5′-nucleotidase/CD73 as compared to controls. Reduction of endogenous ADO formation might explain why proliferation of CD4+T cells failed upon blockingA2Areceptors activation with ZM241385 or adenosine deaminase in EAMG animals. Deficits in ADO also contribute to neuromuscular transmission failure in EAMG rats. Rehabilitation ofA2AR-mediated immune suppression and facilitation of transmitter release were observed by incubating the cells with the nucleoside precursor, AMP. These findings, together with the characteristic increase in serum adenosine deaminase activity of MG patients, strengthen our hypothesis that the adenosinergic pathway may be dysfunctional in EAMG. Given that endogenous ADO formation is balanced by ecto-5′-nucleotidase/CD73 activity and thatA2ARs exert a dual role to restore use-dependent neurocompetence and immune suppression in myasthenics, we hypothesize that stimulation of the two mechanisms may have therapeutic potential in MG.

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Exosomes derived from statin-modified bone marrow dendritic cells increase thymus-derived natural regulatory T cells in experimental autoimmune myasthenia gravis

Journal of Neuroinflammation ◽

10.1186/s12974-019-1587-0 ◽

2019 ◽

Vol 16 (1) ◽

Author(s):

Peng Zhang ◽

Ru-Tao Liu ◽

Tong Du ◽

Chun-Lin Yang ◽

Yu-Dong Liu ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Myasthenia Gravis ◽

Stromal Cells ◽

Experimental Autoimmune Myasthenia Gravis ◽

Autoimmune Myasthenia ◽

Thymic Stromal Cells ◽

Experimental Autoimmune

Abstract Background The thymus plays an essential role in the pathogenesis of myasthenia gravis (MG). In patients with MG, natural regulatory T cells (nTreg), a subpopulation of T cells that maintain tolerance to self-antigens, are severely impaired in the thymuses. In our previous study, upregulated nTreg cells were observed in the thymuses of rats in experimental autoimmune myasthenia gravis after treatment with exosomes derived from statin-modified dendritic cells (statin-Dex). Methods We evaluated the effects of exosomes on surface co-stimulation markers and Aire expression of different kinds of thymic stromal cells, including cTEC, mTEC, and tDCs, in EAMG rats. The isolated exosomes were examined by western blot and DLS. Immunofluorescence was used to track the exosomes in the thymus. Flow cytometry and western blot were used to analyze the expression of co-stimulatory molecules and Aire in vivo and in vitro. Results We confirmed the effects of statin-Dex in inducing Foxp3+ nTreg cells and found that both statin-Dex and DMSO-Dex could upregulate CD40 but only statin-Dex increased Aire expression in thymic stromal cells in vivo. Furthermore, we found that the role of statin-Dex and DMSO-Dex in the induction of Foxp3+ nTreg cells was dependent on epithelial cells in vitro. Conclusions We demonstrated that statin-Dex increased expression of Aire in the thymus, which may further promote the Foxp3 expression in the thymus. These findings may provide a new strategy for the treatment of myasthenia gravis.

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