Contribution of T cells to immune complex-induced tissue damage

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Autoimmune bullous dermatoses (AIBD) are characterized by autoantibodies against cutaneous structural proteins and mucocutaneous tissue injury. Despite improved therapeutic options, mortality of patients with AIBD is still significantly increased, which can be partially attributed to the extent of immunosuppressive therapy. Therefore and due to the rising incidence there is a clear and so far unmet medical need for the development of effective and save therapeutic strategies for these patients. In addition, the understanding of AIBD pathogenesis is far from complete. While the contribution of T cells to the loss of tolerance and maintenance of the autoimmune response has clearly been demonstrated, it remains unclear, if T cells contribute to the immune complex-induced, neutrophil-dependent tissue injury in AIBD. Interestingly, detailed investigation of the dermal leukocyte infiltration in patients with bullous pemphigoid, an AIBD with autoantibodies directed against type XVII collagen, clearly documented, that the vast majority (60%) of the inflammatory cells are CD3+ cells. We recently demonstrated an increased expression of CD3 in the skin of mice with experimental epidermolysis bullosa acquisita (EBA), an AIBD with autoantibodies directed against type VII collagen (COL7). Based on this observation, we addressed the functional contribution of T cells in experimental EBA induced by transfer of anti-COL7 antibodies into T cell-deficient and control mice. In this model, we observed a significant reduction of EBA severity in T cell deficient mice. Control experiments showed, that this effect was independent on an immune response against the transferred antibody, differences in neutrophil counts, or the mouse strain used. Based on these data, we here now aim to test the following hypothesis: (i) T cells modulate neutrophil-depended, immune complex-induced tissue damage, (ii) Different T cell subsets differentially modulate neutrophil-depended, immune complex-induced tissue damage; i.e. activated and/or Th17 T cells enhance, while Treg inhibit tissue injury, and (iii) Targeting different T cell subsets can be used therapeutically in AIBD. Given, that these assumptions can be experimentally validated, modulation of T cell subsets in AIBD may offer novel therapeutic options that target both the generation/maintenance of the loss of tolerance, as well as the autoantibody-induced, neutrophil-dependent tissue injury.