IL-21调控STAT3和Akt通路介导Tfh/Tfr平衡偏移在RA疾病进展中的作用研究

项目名称： IL-21调控STAT3和Akt通路介导Tfh/Tfr平衡偏移在RA疾病进展中的作用研究

项目编号： No.81501816

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 牛倩

作者单位： 四川大学

项目金额： 18万元

中文摘要： CD4+T细胞免疫紊乱与B细胞体液免疫异常活化是RA疾病发生发展的关键因素。两个新的CD4+T细胞亚群滤泡辅助性T细胞（Tfh）和滤泡调节性T细胞（Tfr）被证实在调控B细胞活化和抗体分泌中具有重要作用。课题组前期初步分析发现RA患者循环Tfh比率增高而Tfr降低，增高的Tfh与CCP抗体水平呈正相关，但Tfh/Tfr平衡偏移与RA疾病的关系目前尚无报道。最新研究发现，IL-21一方面可通过激活STAT3促进Tfh细胞分化，另一方面可通过抑制Akt磷酸化而抑制Tfr分化。结合前期，课题组提出“IL-21调控JAK-STAT3和PI3K-Akt通路介导Tfh/Tfr失衡而参与RA疾病进展”。本研究拟通过体内外实验从细胞和整体水平探讨IL-21通过STAT3和Akt通路调控Tfh/Tfr平衡偏移介导RA患者B细胞免疫活化及疾病进展的具体机制，为寻找新的RA诊断指标和治疗靶点提供理论及实验依据。

中文关键词： IL-21；Tfh/Tfr平衡；STAT3通路；Akt通路；类风湿关节炎

英文摘要： CD4+ T cells immune disorders and aberrant activation of B cell-mediated humoral immune are the key factors of the development of RA. Two new CD4+ T cell subsets, follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr), were confirmed to plays an important role in the regulation of B cell activation and antibody secretion. Our previous preliminary analysis found that the percentage of Tfh cells increased while that of Tfr decreased in RA patients, and the increase of Tfh was positively correlated with the anti-CCP antibody level. However, the relationship between Tfh/Tfr balance shift and the pathogenesis of RA disease has been not reported. The latest study found that, IL-21 promoted the differentiation of Tfh cells through activating STAT3, and suppressed the differentiation of Tfr cells through inhibiting phosphorylation of Akt. Combined with previous research, we propose that IL-21 mediate the Tfh/Tfr imbalance through regulating the STAT3 and Akt pathway and therefore participat in progression of RA. Through exploring the specific mechanisms of IL-21 mediating the imbalance of Tfh/Tfr through STAT3 and Akt pathway in vitro and in vivo, which result in B cell–mediated humoral immune activation in patients with RA, this study may provide the theoretical and experimental basis for seeking new diagnostic biomarkers and therapeutic targets of RA.

英文关键词： IL-21;Tfh/Tfr balance;STAT3 pathway;Akt pathway;RA