BRD2对银屑病患者初始T细胞向功能性T细胞分化及免疫特性影响的研究

Psoriasis is an autoimmune disease, which is closely related with immune. In previous study, we had found that the T cells differentiated from psoriatic bone marrow CD34+ cells were abnormal in secretion of Th1/Th2 cytokines and function of Tregs. The expression of BRD2 in peripheral blood T cell were also abnormal. Upon different enviroment, naive CD4+ T cells(Tn) differentiate into various functional T subsets. The imbalance of differentiation from Tn is related to numerous autoimmune diseases. BRD2 plays critical role in the differentiation of Tn to Th1, Tregs and Th17. With regard to these, we plan to ①interfer the expression of BRD2 in Tn, which resulted in different expression of BRD2 from no-expression to over-expression, ② test the binding of Brd2 to RUNX1 and the abundance of acetylated H4 in RUNX1, ③the expression of IL-17, IL-21 will be tested , and also to the differentiation of Th1, Th2, Tregs, Th17. The function of Tregs will also be tested, ④ T cell will also be invested as ③ isolated from lesion and normal skin. The topic will be significant to the study in differentiation of Tn and mechanism of abnormal T cells in psoriasis.

银屑病是由T细胞介导的与免疫密切相关的自身免疫性疾病。前期研究我们在国际上首先发现银屑病骨髓CD34+细胞体外定向分化的Th1、Th2及Tregs有异常，且外周血T细胞BRD2表达异常。初始CD4+T细胞（Tn）在不同环境下向不同功能T细胞分化，其优势分化与众多自身免疫性疾病相关，BRD2对Tn向Th1、Foxp3+调节性T细胞(Tregs)及Th17分化均具有重要作用。为此我们拟在前期基础上对银屑病T细胞进行如下研究：①干扰Tn中BRD2表达，使其呈自然表达/过表达/不表达状态，②检测分化2天后brd2与RUNX1的结合及RUNX1中乙酰化H4的丰度，③细胞分化成熟后，检测IL-17、IL-21等表达水平，分析Th1、Th2、Tregs及Th17分化状态，并检测Tregs对效应T细胞的抑制能力，④分离银屑病皮损及对照皮肤T细胞，检测以上指标。该课题对银屑病T细胞异常的机理研究有重要意义。

银屑病是一种以T细胞为主多种免疫细胞共同参与的慢性炎症性皮肤疾病，发病率约2%。银屑病确切的发病机理尚不清楚，银屑病发病机理及治疗手段一直是皮肤病学者研究的热点。项目对银屑病患者外周血T细胞的研究，结果显示与银屑病患者外周血T细胞共培养后，银屑病非皮损和正常皮肤增殖性相关蛋白表达和表皮通过时间均表现出银屑病的特征，而正常人外周血T细胞则不具有这样的特性。单卵双胞胎银屑病患者外周血T细胞表达谱研究结果显示，PPIL1、HSPH1、SENP3、NUP54、PABP5、PLEKHG3及SLC9A9在银屑病中表达存在差异，且明显的区别于特应性皮炎患者。采用“左旋咪唑、胸腺肽肠溶片、卡介菌多糖核酸注射、穴位注射核酪”四联免疫治疗后寻常型银屑病患者心理压力指数、皮损严重程度明显降低，该治疗方法副作用发生率较低，且复发时间延长。四联免疫治疗后，银屑病患者外周血Th1细胞比例与Th17细胞比例明显降低，而Th2型细胞和调节性T细胞比例无明显差异，T细胞组库分析结果显示，T细胞α、β链克隆数、种群多样性与物种多样性均下调。通过该项目的研究，为T细胞在银屑病发病中的重要作用提供了理论依据，且为银屑病治疗手段的研究提供了新的思路。