Background and objectives Juvenile Idiopathic Arthritis (JIA) is a debilitating autoimmune disease with an important role for aberrant T cell homeostasis in the pathogenesis. Autophagy is a process of lysosomal degradation that is important for (T) cellular homeostasis that has previously been genetically correlated to several auto-immune diseases. We investigated the role of autophagy in JIA synovial inflammation and its effect on T cell activity.
Materials and methods PBMC from healthy donors, and PBMC and Synovial fluid cells (SFMC) from 21 JIA patients were used. Cells were cultured overnight with or without hydroxychloroquin to investigate the autophagic flux. Synovial fluid was added to HC cell cultures to investigate the role of inflammatory mediators on autophagy. Autophagy was measured with flow cytometry using the specific dye Cyto-ID or by western blot of LC3-II. The importance of autophagy for inflammatory activity of T cells in the synovium was investigated by blockade of autophagy during anti-CD3 activation and measuring proliferation and cytokine production during 4 day cultures.
Results Autophagy was significantly increased in CD4+, and CD8+ T cells from SFMC which was due to a higher basal level of autophagy in SFMC and not to an increase in susceptibility to HCQ.
Culturing HC and JIA PBMC and SFMC with SF or inflammatory cytokines did not affect autophagy levels, indicating that the increased autophagy in SFMC is related to a cell intrinsic phenomenon rather than induced by soluble mediators of inflammation. Indeed, cellular activation related to levels of autophagy. Additionally, blocking autophagy reduced proliferation and cytokine production.
Conclusions T cells from the inflamed synovium of JIA patients show significantly increased autophagy. This phenomenon is not affected by cytokines in the SF or SF itself, but is related to cellular activation. Moreover, blocking autophagy reduces cellular activity and cytokine production. We conclude that targeting autophagy in JIA has a major potential for future therapy.
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