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

调节性 T 细胞在自身免疫性水疱病发病机制中的作用

• 批准号: 247638911
• 负责人: Professor Dr. Alexander Enk
• 金额: --
• 依托单位: Klinik für Dermatologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/247638911?language=en
• 关键词: Role; Regulatory; cells; pathogenesis; Autoimmune

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 We have unpublished data indicating that Scurfy mice spontaneously develop different AIBD due to missing regulatory T cell control.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

自身免疫性水疱病（AIBD）是严重的自身抗体介导的皮肤病。靶自身抗原被鉴定，但针对这些抗原的自身抗体产生的原因仍然不清楚。自身反应性CD 4 + T细胞能够诱导B细胞中的自身抗体产生，但在健康个体中，自身反应性CD 4 + T细胞的活性被调节性T细胞（Treg）完全抑制。因此，问题出现了，如果Treg功能缺陷可以通过缺乏对自身反应性T细胞的抑制而导致AIBD的发展。有间接证据表明Treg功能受损是AIBD的原因，因为已报告AIBD患者的Treg数量减少。然而，Treg功能受损或缺乏可引发AIBD的直接证据仍然缺失。回答这个中心问题的完美模型是Scurfy小鼠：Scurfy小鼠由于foxp 3基因突变而发展为严重的多器官自身免疫性疾病，foxp 3基因对Treg的正常发育和功能至关重要。除了肺和肝外，皮肤也受到严重影响：所有Scurfy小鼠都出现糜烂性皮肤病变，在疾病过程中，血清中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，Scurfy小鼠自发地发展不同的AIBD。基于这些结果，目前的项目旨在揭示哪些自身免疫性水疱疾病是在Treg控制下的。此外，我们想知道不同的AIBD在Treg控制触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CD 4 + T细胞作为治疗靶点，特别是关注抗原特异性和多克隆TGF-β诱导的Treg（iTreg）作为治疗AIBD的新治疗方法。总之，本项目旨在分析CD 4 + 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CD 4 + T细胞作为基于iTreg的新治疗策略的潜在治疗靶点，以治愈自身免疫性水疱病。