系统性红斑狼疮中Th17细胞与Breg细胞的"交互"作用和机制研究

IL-17 producing CD4+ T cells (Th17) are close-related to the pathogenesis of systemic lupus erythematosus (SLE). Th17 can induce the differentiation of plasma cells and auto-antibodies production. Whereas the regulating role of Th17 on regulatory B cells (Breg), a subset of B cells with immunosuppressive function, in SLE is still unknown. Recently, we observed that the percentage of Breg were expanded in SLE patients. Based on the previous researches, we speculate that Th17 might contribute to the expansion of Breg. Here, we focus on the interaction between Th17 and Breg. Firstly, we plan to make clear the correlation between Th17 and Breg in SLE patients, and explore the role and mechanism of Th17-derived cytokines on the differentiation of Breg in vitro. The role and mechanism of Breg inhibiting Th17 are also analzyed. Secondly,the reciprocal interaction and mechanism between Th17 and Breg are further verified in vitro and in vivo of lupus-prone MRL/lpr mice.Thirdly, the therapeutic potential of induced Breg is analyzed in MRL/lpr mice，and the immunosuppressive effect of induced Breg on Th17 will be investigated in vivo. All together, our study can help to understand the pleiotropic nature of Th17, clarify the complex and close relationship between Th17 and diverse B lymphocytes,and discover new method for the differentiation of Breg. These can provide new theoretical and experimental basis for the treatment of SLE.

分泌IL-17的CD4+T细胞（Th17）与系统性红斑狼疮（SLE）发病密切相关。Th17可诱导B细胞向浆细胞分化和分泌自身抗体，但Th17对具有免疫抑制能力的调节性B细胞（Breg）的作用尚未清楚。近期我们发现SLE中Breg比例增多，基于前期的工作基础，我们推测Th17可能参与了Breg的扩增。本课题从Th17和Breg相互作用角度出发，1）首先明确SLE患者体内Th17和Breg的相关性，并从体外研究Th17通过分泌的细胞因子对Breg分化的调控作用和机制，以及Breg对Th17的抑制作用和机制；2）通过MRL/lpr狼疮鼠验证体内外Th17和Breg的交互作用和机制；3）探索体外诱导的Breg对狼疮鼠的治疗潜力和对体内Th17的抑制作用。本课题可深入认识SLE中Th17功能的多效性，进一步理清Th17和不同B细胞亚群间复杂而密切的关系，为SLE的治疗提供新的理论和实验基础。

系统性红斑狼疮（SLE）是一种常见自身免疫性疾病，但发病机制并未阐明。本课题中我们研究发现调节性B细胞（Breg）可以体外抑制分泌IL-17的CD4+T细胞(Th17)，并抑制IL-17的分泌。有趣的是，我们发现Breg在抑制Th17的同时促进了具有免疫抑制作用的Th22细胞的分化和IL-22的分泌，Breg通过分泌的TNF-α诱导T细胞中mTOR活化进而抑制Th17分化同时促进Th22的分化。体外扩增的Breg输注治疗可以抑制狼疮鼠中自身抗体分泌，减低24小时尿蛋白含量，改善狼疮肾炎的发生，并抑制体内Th17分化和促进Th22分化，抗IL-22中和抗体降低了Breg细胞对狼疮的治疗作用。提示Breg细胞可能通过促进具有免疫抑制作用的Th22加强免疫抑制作用。进一步研究发现Th17细胞可促进体内外效应性B细胞分化和抗体分泌，但对Breg的分化起到了抑制的作用。SLE中Th17扩增和氧化应急相关，并发现一组调控Th17分化的micro RNA，羟氯喹可通过抑制Th17来缓解狼疮发病。SLE中自身抗体分泌增多与泌乳素增多相关，并与扩增的滤泡辅助性T细胞（Tfh）相关，发现中药单体黄芩苷可以抑制Tfh并促进滤泡调节性T细胞（Tfr）分化，体外黄芩苷协助扩增的Tfr输注治疗可以抑制狼疮鼠体内Tfh分化、抗体分泌和缓解狼疮肾炎的发病。本课题围绕SLE中T和B细胞间的相互作用开展系列研究，揭示了Breg治疗狼疮的潜力和免疫学机制，发现了SLE中抗体增多的一系列原因，以及相应的治疗对策和方法。目前本课题共发表5篇SCI论文，1篇接收，申请3项发明专利。