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Th17 cells in the pathogenesis of autoimmune arthritis
Th17 cells are implicated in the pathogenesis of various autoimmune diseases, including ankylosing spondylitis and psoriatic arthritis. We could recently show that prostaglandin E2 receptor EP4 signaling contributes to the development of pathogenic Th17 cells in ankylosing spondylitis (Klasen et al., Arthritis Res Ther, 2019;21:159). EP4 drives Th17 cell expansion through upregulation of the interleukin-23 receptor (IL-23R), by suppressing the RORt inhibitor FoxO1 and by enhancing STAT3 phosphorylation. In contrast, Th17 cells from patients with rheumatoid arthritis overexpress the EP2 receptor, which has been previously linked to autoimmune diseases (Kofler et al, J Clin Invest, 2014;124:2513). Interestingly, recent genome-wide association studies (GWAS) have identified five risk alleles for ankylosing spondylitis in PTGER4, the gene encoding for EP4. Our results show that increased EP4 expression by Th17 cells is associated with high disease activity in ankylosing spondylitis.
IL-6 receptor signaling in rheumatoid arthritis
The cytokine IL-6 is a key regulator of Th17 cell induction. Differentiation of Th17 cells is induced by the combination of IL-6 and TGF-β, whereas TGF-β alone promotes the development of regulatory T (Treg) cells. IL-6 is therefore required at inflammatory sites to prevent Treg cell development and is an important modulator of the balance between Th17 cells and Treg cells. We aim to reveal why this balance is dysregulated in rheumatoid arthritis. Th17 and Treg cell plasticity is regulated by a complex network of signaling pathways, which are altered in rheumatoid arthritis. The IL-6 signaling pathway plays a major role in this network. We are investigating this network and try to find out if it can be modified to restore the balance between immune activity and immune tolerance.
Role of CD6 in rheumatic autoimmune diseases
The scavenger-like lymphocyte receptor CD6 is known as a regulator of T cell activity (Meyer et al, Cell Mol Immunol, 2018; Kofler et al, Curr Drug Targets, 2016). It has been previously shown that the multiple sclerosis susceptibility allele in CD6 is associated with alterations in CD4+ T cell proliferation (Kofler et al, J Immunol, 2011). Moreover, CD6 mediates the transmigration of CD4+ T cells into vessels and inflamed tissues. However, the specific contribution of CD6 to autoimmune reactions remains unknown. Our research group investigates the role of CD6 in various rheumatic autoimmune diseases.