CTLA-4突变相关自身免疫性疾病的发病机制研究

CTLA-4是一个重要的免疫抑制性受体，在维持自身免疫耐受中起到关键作用。小鼠中CTLA-4的缺失和临床上CTLA-4基因突变均造成机体免疫耐受受损和表型类似的系统性自身免疫性疾病。 尽管如此，CTLA-4的作用机制十分复杂，至今尚未充分阐明。针对致病CTLA-4突变的结构与功能分析显示，致病的突变多发于其配体结合和二聚化功能域，这些功能明确的突变给我们提供了研究CTLA-4介导免疫耐受机制的独特研究工具。我们在前期自身免疫病遗传筛查中发现了一例CTLA-4 Y139C突变。本项目将利用此突变及其它已报导的CTLA-4致病突变，来研究CTLA-4结合CD80/CD86配体介导的机械力、受体二聚化和配体结合诱导的网格状多聚化、及胞内信号传导等在介导其免疫耐受过程中的作用。本项目的完成有助于完整阐明CTLA-4的免疫调控机制，并为今后在自身免疫性疾病和肿瘤中更有效靶向CTLA-4提供新的思路。

CTLA-4 is an important immunosuppressive receptor and plays a key role in maintaining autoimmune tolerance. Both the loss of CTLA-4 in mice and mutations in human resulted in a systemic autoimmune disease with similar phenotype. However， the precise mechanisms of CTLA-4 haven’t been clarified. Structural and functional analysis on the reported cases revealed that pathogenic CTLA-4 mutations occur frequently in their ligand binding and dimerization regions. These well-defined mutations provide us a unique research tool to study CTLA-4-mediated immune tolerance mechanisms. In our previous genetic mutation screening study, we have found a new CTLA-4 point mutation in a patient with recurrent autoimmune inflammation. In this project, we will use these reported disease-associated CTLA-4 mutations to study the roles of ligand binding, receptor dimerization/oligomerization, and intracellular signaling in CTLA-4 mediated immune tolerance. The conclusions from this study will help us elucidate the immunoregulatory mechanisms of CTLA-4 and provide new strategies for more effective targeting of CTLA-4 in autoimmune diseases and tumors.