CCR5调控非经典Th1细胞活化和增殖介导类风湿关节炎发病的新机制

Rheumatoid arthritis (RA) is a serious and common systemic autoimmune disease that threatens human's health. Studies have shown that immune imbalance of T cells play important roles in the pathogenesis of RA. Non-classical Th1 cells (CD161+ Th1, derived from Th17 cells) are enriched in the inflammatory site of RA, and participate in RA pathogenesis, however, the mechanism is still unclear. CCR5, as a chemokine receptor, is involved in chemotaxis, activation and proliferation of T cells. In our present study, we found that the enriched non-classic Th1 cells were found to be abnormally activated and proliferated in RA synovial fluid, and CCR5 expression was significantly increased; Additionally, CCR5 expression was closely related to the levels of activation and phosphorylation of ZAP70, a signal related to T cell activation. Our team intends to investigate the regulating effect and underlying mechanism of CCR5 on the activation and proliferation of non-classic Th1 in RA, which may be helpful to elucidate the pathogenesis of RA, and may provide a potential therapeutic target for RA treatment.

类风湿关节炎（RA）是一种严重危害人类健康的常见自身免疫病。研究表明T细胞免疫失衡是RA发病的中心环节，其中由Th17细胞转变而来的非经典Th1细胞（CD161+ Th1）在RA病灶增多，对RA发生发展起重要作用，但其调控机制尚不明确。CCR5是一种趋化因子受体，参与T细胞趋化、活化和增殖。我们最近在检测RA滑液T细胞亚群时对比了非经典Th1及其表面CCR5的表达，发现RA滑液中显著增多的非经典Th1存在异常活化和增殖，并高表达CCR5；且CCR5表达水平与非经典Th1的活化及活化相关信号ZAP70的磷酸化密切相关。本课题拟在此基础上，深入研究CCR5对非经典Th1活化和增殖的调控作用及分子机制，阐明CCR5通路在RA发病中的作用和功能意义。本研究可拓展对RA发病机制的认识，还可发现RA病灶中非经典Th1应答调控的新机制，为RA靶向治疗提供依据和潜在靶点，具有重要的理论和实际意义。

类风湿关节炎（RA）是一种以关节内炎性细胞浸润、滑膜增生和系统性炎症为主要特征的常见自身免疫性疾病，但迄今为止，其病因及发病机制尚不明确。近年来关于RA发病机制的研究表明，非经典Th1细胞（CD161+ Th1）在RA病灶增多，在RA发生发展中起重要作用，但其调控机制尚不明确。在本研究中，通过收集RA患者和相匹配健康人（HC）的外周血（PB）和滑液（SF）样本，进行流式细胞术检测、细胞分选和体外培养等。研究数据表明，RA患者炎症病灶中CD161+ Th1细胞显著升高，并呈现活化、高增殖状态和高表达CCR5。此外，发现RA滑液中的CD161+ Th1及其CD25、CCR5表达水平与疾病活动度指标DAS28显著正相关。同时，体外抗体阻断实验和进一步的机制研究结果表明CCR5可通过pZAP70/NFAT信号通路促进CD161+ Th1细胞活化、增殖和细胞因子产生，进而参与RA慢性炎症进程。本研究进一步拓展对RA发病机制的认识，并发现RA炎症病灶调控非经典CD161+Th1应答的新机制，为RA提供潜在的治疗靶点。