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

自身免疫性水疱病(AIBD)是一种严重的自身抗体介导的皮肤病。靶标自身抗原已经确定，但针对这些抗原产生自身抗体的原因仍不清楚。自身反应性的CD4+T细胞能够诱导B细胞产生自身抗体，但在健康人中，自身反应性的CD4+T细胞的活性完全被调节性T细胞(Treg)抑制。因此，问题是，Treg功能缺陷是否会通过缺乏对自身反应性T细胞的抑制而导致AIBD的发生。有间接证据表明Treg功能受损是AIBD的原因，因为已有报道称AIBD患者Treg数量减少。然而，关于Treg功能受损或缺乏会引发AIBD的直接证据仍然缺乏。回答这个核心问题的完美模型是Scurfy小鼠：由于Foxp3基因的突变，Scurfy小鼠会患上一种严重的多器官自身免疫性疾病，这对Treg的正常发育和功能非常重要。除了肺和肝，皮肤也受到严重影响：所有鳞屑小鼠都会出现腐蚀性皮肤损害，在疾病过程中，它们的血清中会出现高滴度的自身抗体。我们有未发表的数据表明，由于缺乏调节性T细胞控制，鳞屑小鼠自发发展为不同的AIBD。基于这些结果，目前的项目旨在解开哪些自身免疫性水泡疾病处于Treg控制之下。此外，我们还想找出不同的AIBD在Treg控制对引发疾病的意义上是否存在差异。此外，我们计划测试自身反应性的CD4+T细胞作为治疗靶点，特别是抗原特异性和多克隆的转化生长因子-β诱导的Treg(ITreg)，作为治疗AIBD的新方法。综上所述，本项目旨在分析CD4+T细胞在自身抗体介导的自身免疫性皮肤病发展中的作用，并评估CD4+T细胞作为基于iTreg的治疗自身免疫性水疱性疾病的新治疗策略的潜在治疗靶点。

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 We have unpublished data indicating that Scurfy mice spontaneously develop different AIBD due to missing regulatory T cell control.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.