Role of Regulatory T cells for the pathogenesis of Autoimmune Blistering Diseases

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Autoimmune blistering diseases (AIBD) are severe autoantibody-mediated skin diseases. The target autoantigens are identified, but the reason for autoantibody production against these antigens still remains unclear. Autoreactive CD4+ T cells are able to induce autoantibody production in B cells, but in a healthy individual the activity of autoreactive CD4 + T cells is completely suppressed by regulatory T cells (Treg). Therefore the question rises, if defects in Treg function can lead to development of AIBD via lack of suppression of autoreactive T cells. There is indirect evidence for impaired Treg function as cause for AIBD, as reduced Treg numbers in patients with AIBD have been reported. However, direct evidence that impaired or lacking Treg function can trigger AIBD is still missing.The perfect model to answer this central question is the Scurfy mouse: Scurfy mice develop a severe multiorgan autoimmune disease due to a mutation in the foxp3 gene, which is important for normal Treg development and function. Besides lung and liver the skin is severely affected: All Scurfy mice develop erosive skin lesions and during the course of disease high titers of autoantibodies emerge in their sera. We have unpublished data indicating that Scurfy mice spontaneously develop different AIBD due to missing regulatory T cell control. Based on these results the current project aims to unravel which autoimmune blistering diseases are under Treg control. In addition we want to find out if there are differences for the different AIBD in the significance of Treg control for triggering disease. Furthermore we plan to test autoreactive CD4+ T cells as a therapeutical target especially focussing on antigen-specific and polyclonal TGF-beta-induced Treg (iTreg) as new therapeutic approach to cure AIBD. In summary the current project aims to analyze the role of CD4+ T cell help for the development of autoantibody-mediated autoimmune skin diseases and to evaluate CD4+ T cells as potential therapeutic targets for iTreg-based new therapeutic strategies to cure autoimmune blistering diseases.