IL-17F在原发性干燥综合征中的致病作用及机制研究

原发性干燥综合征（pSS）是发病率最高的系统性自身免疫性疾病之一。大量研究表明Th17在pSS发病中起着重要作用，但它在pSS多系统受累中的作用还有待进一步阐明。本课题组首次在pSS患者体内发现IL-17F显著升高，且与患者的自身抗体反应及多系统受累密切相关，并且与IL-17A相比，IL-17F与疾病的严重程度关系更密切。进一步研究发现IL-17F可促进Tfh的分化、增强Tfh的功能，因此IL-17F可能在pSS发病尤其是过度活化的自身抗体反应中发挥关键作用。本项目将利用IL-17F敲除的干燥综合征小鼠模型，通过系统的分子实验、细胞实验、动物实验和针对患者的临床研究，探讨pSS中IL-17F对Tfh的分化及功能的影响及具体的调控机制，从而明确IL-17F在pSS中的致病作用，为探索pSS新的治疗靶标提供前期实验依据。

Primary Sjögren’s Syndrome (pSS) is one of the most common autoimmune diseases. Previous studies have shown that Th17 plays an important role in the pathogenesis of pSS, but the precise mechanism of Th17 on the multi-organ involvements is still elusive. Recently, our group first reported that IL-17F was significantly elevated in pSS and associated with autoantibody reactions and multi-organ involvements, and was more clinically relevant than IL-17A. Our further study has found that IL-17F could promote the differentiation and activation of pathogenic Tfh cells, indicating that IL-17F might play a critical role in the pathogenesis, especially the elevated autoantibody reactions of pSS. In this study, we are going to investigate the pathogenic activities, regulatory molecules and signaling pathways of IL-17F on the differentiation and pathogenic effects of Tfh in pSS in a series of studies in molecule experiments, cell culture systems, animal models and clinical association analysis, by using IL-17F knock-out mouse model of experimental Sjögren’s syndrome. This study will reveal the pathogenic roles of IL-17F in pSS, and may provide novel therapeutic targets for the treatment of pSS.