组蛋白去甲基化酶JMJD3调控系统性红斑狼疮Tfh细胞异常分化的作用及机制研究

Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease with multiple organ and system involvements. The pathogenesis of SLE remains unclear. It has been well documented that the abnormal T cells activation induced by epigenetics can promote the secretion of autoantibodies in B cells, and play an important role in the pathogenesis of SLE. The latest study suggested that a subgroup of CD4+ T cells named Tfh cells can promote the activation of B cells, and the proportion of Tfh in peripheral blood was related to the incidence of SLE. Our previous studies showed that the expression of JMJD3 is abnormally increased in Tfh cells of SLE patients; Overexpression of JMJD3 in CD4+ naïve T cells, can increase the proportion of Tfh. So we put forward a new hypothesis: JMJD3 may induce abnormal Tfh differentiation, resulting in B cell activation, and ultimately promote the occurrence and development of SLE. This project is intended to screen and identify target genes which are regulated by JMJD3 and closely related to differentiation of Tfh, and verified its effect on the Tfh differentiation regulated by JMJD3 and lupus phenotype. This project will shed new light on potential pathogenesis of SLE, and may provide a new idea to find the target of SLE treatment.

系统性红斑狼疮(SLE)是一种多器官、多系统受累的严重危害人类健康的自身免疫性疾病。其发病机制尚不明确。大量研究表明表观遗传调控介导的T细胞异常活化可促进B细胞分泌自身抗体，在SLE发病中起重要作用。最新研究发现一种命名为滤泡性辅助型T细胞(Tfh)的CD4+T亚群可促进B细胞活化，外周血Tfh比例升高与SLE发病相关。我们前期研究发现：JMJD3在SLE患者Tfh中异常高表达;在CD4+ naïve T细胞中过表达JMJD3，Tfh比例升高。为此我们提出全新假说：JMJD3可能通过诱导Tfh异常分化，导致B细胞活化，最终促进SLE发生发展。本项目拟通过筛选和鉴定Tfh分化过程中受JMJD3调控且与分化密切相关的靶基因，并通过体外、体内实验验证该基因对JMJD3调控Tfh异常分化和狼疮表型的影响。该研究将有助于进一步揭示SLE发生发展的机制，并可能为寻找SLE治疗靶点提供新思路。

系统性红斑狼疮(SLE)是一种多器官、多系统受累的严重危害人类健康的自身免疫性疾病 。其发病机制尚不明确。大量研究表明表观遗传调控介导的T细胞异常活化可促进B细胞分泌自身抗体，在SLE发病中起重要作用。最新研究发现一种命名为滤泡性辅助型T细胞(Tfh)的CD4+T 亚群可促进B细胞活化，外周血Tfh比例升高与SLE发病相关。我们后续扩大样本研究发现JMJD3在狼疮患者Tfh表达差异并不是很明显。但是在SLE患者外周血中JMJD3在CD19+B细胞中高表达，其B细胞亚群（包括Naive B,Memory B,PC）中也高表达JMJD3。特别是浆细胞中高表达最为明显。这说明，JMJD3可能参与SLE患者B细胞的异常分化。该研究将有助于进一步揭示SLE发 生发展的机制，并可能为寻找SLE治疗靶点提供新思路。