CD4+ T Cells of Myasthenia Gravis Patients Are Characterized by Increased IL-21, IL-4, and IL-17A Productions and Higher Presence of PD-1 and ICOS
Merve Çebi, Hacer Durmuş, Fikret Aysal, Berker Özkan, Gizem Engin Gül, Arman Çakar, Mehmet Hocaoǧlu, Metin Mercan, Sibel P. Yentür, Melih Tütüncü, Vıldan Yayla, Onur Akan, Öner Doğan, Yeşim Parman, Güher Saruhan‐Direskeneli
Abstract
Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies predominantly against the acetylcholine receptor (AChR). Specific T cells subsets are required for long-term antibody responses and cytokines secreted mainly from CD4+ T cells regulate B cell antibody production. The aim of this study was to assess the differences in the cytokines of CD4+ T cells and their characterization in MG subgroups as well as the effect of immunosuppressive (IS) therapy on cytokine activity. Clinically diagnosed MG patients with AChR antibodies (AChR-MG) or without detectable antibodies (SN-MG) were included. AChR-MG patients were grouped as IS positive and negative and compared with age- and sex-matched healthy controls (HC). Peripheral blood mononuclear cells were used for ex vivo intracellular cytokine production and subsets of CD4+ T cells and circulating follicular helper T (cTfh) cells were detected phenotypically by the expression of the chemokine and costimulatory receptors. Thymocytes from patients were isolated from thymectomy samples for comparison. IL-21, IL-4 and IL-17A productions in CD4+ T cells were increased in AChR-MG and SN-MG patients compared to HC. IS treatment enhanced IL-10 and reduced IFN- production in AChR-MG patients compared to IS negative patients. Among the CD4+ T cells, Th17 cells were increased in both disease groups. Treatment induced higher proportions of Th2 cells in AChR-MG patients. Both CXCR5+ and CXCR5- CD4+ T cells expressed higher PD-1 and ICOS in AChR-MG and SN-MG groups irrespective of the treatment. Based on chemokine receptors on CXCR5+PD-1+ in CD4+ T (cTfh) cells, the proportions of Tfh17 cells of AChR-MG patients, especially without treatment, were higher and Tfh1 cells were lower. The relevance of PD-1 and CXCR5 in the pathogenesis of AChR-MG was supported by the increased presence of these molecules on mature CD4 single positive thymocytes from thymic samples. The study provides further evidence for the importance of IL-21, IL-17A and IL-4. Disease related CD4+T cells are identified mainly as PD-1+ or ICOS+ with or without CXCR5, resembling cTfh cells in the circulation and in the thymus. Similarities between AChR-MG and SN-MG are demonstrated and the effects of IS treatment on cytokines are shown.