BAFF-BR3信号途径对Tfh细胞分化的调控作用和机理研究及其在狼疮中价值

The differentiation abnormalities of immune cells are associated with the pathogenesis and progress of a broad array of autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). However, the underlying mechanisms behind the differentiation abnormalities of immune cells are currently unclear. Given the therapeutic effect on autoimmune diseases is not satisfactory so far, it is important to elucidate the mechanisms of immune cells differentiation, which will significantly promote the development of new potential therapeutics. Our group has first reported that BAFF promotes T helper 17 (Th17) cells and aggravates experimental autoimmune encephalomyelitis. It implicates BAFF might promote autoimmune diseases such as SLE through regulating the differentiation and function of T helper cells. Our preliminary data have identified that BAFF boosts the T follicular helper (Tfh) cells and germinal center formation through BR3 in KLH immunized mice. To test the hypothesis that BAFF promotes lupus through regulating the Tfh differentiation and function, we plan to develop a series of BAFF and its receptors knockout and transgene mice, and use B6. Sle1b lupus mice to systemically study the mechanisms thereby BAFF-BR3 signal facilitates Tfh cells, GC formation and lupus development. The expected results will take a further insight into the mechanisms of Tfh differentiation and development, autoantibodies and autoimmune disease development. This novel pathway may be targeted for future pharmacological intervention to treat SLE and other autoimmune diseases.

免疫细胞分化异常和机体许多自身免疫性疾病的发病和发展有密切关系，但免疫细胞分化异常的机理至今未明，因此阐明其机理对发掘新的治疗方法具有重要意义。本课题组在国际上首先报道了BAFF能够影响Th17细胞的分化和功能，提示了BAFF信号在促进自身免疫性疾病发展中可能也调控T辅助细胞的分化和功能。在最近的预实验中，进一步观察到BAFF能够通过BR3参与调控Tfh细胞的分化，影响生发中心的形成和抗体的产生。而自身抗体的产生是狼疮的主要特征之一。为验证假设：BAFF-BR3信号通路通过调控Tfh细胞的分化和功能进而影响狼疮的发生和发展，我们计划采用BAFF KO、BAFF Tg、BR3 KO.B6.sle1b等一系列小鼠进行体内外实验。项目的成功将帮助加深对Tfh细胞分化和发育调控机制的认识，深入理解自身抗体产生和自身免疫性疾病发生发展机制，对自身免疫性疾病的诊疗有重要的临床指导价值。

免疫细胞分化异常和机体许多自身免疫性疾病的发病和发展有密切关系，但免疫细胞分化异常的机理至今未明，因此，阐明其机理，并发掘新的治疗方法具有重要意义。本课题组在国际上首先报道了BAFF能够调控Th17细胞的分化和功能，提示了BAFF信号可能通过调控T辅助细胞的分化和功能，影响自身免疫性疾病的发生和发展。我们利用KLH免疫模型来探讨BAFF对Tfh细胞体内分化的影响。研究结果显示，BAFF-/-小鼠中Tfh细胞发育和分化异常，而BAFF同家族蛋白APRIL-/-小鼠中的Tfh细胞则不受影响。我们进一步发现，BAFF-/-小鼠的生发中心发育异常，其血清抗体水平显著低于野生小鼠。BAFF还能够激活T细胞NF-kb信号通路，促进Bcl-6的表达，调控Tfh发育和分化，以及向生发中心迁移。在SLE病人中，BAFF的表达显著增加，并与疾病进展呈正相关。为了进一步探明BAFF对Tfh细胞的调控机理，我们分别构建BAFF受体（BCMA，TACI和BR3）敲除小鼠模型，结果显示，BCMA-/-、TACI-/-小鼠中Tfh细胞分化正常，而BR3-/-小鼠中Tfh细胞分化受到抑制，并减少抗体的产生。综上，BAFF-BR3信号促进Tfh细胞的发育和分化，以及生发中心B细胞成熟和抗体产生。此外，我们还初步探讨了Pkcδ调控B细胞分化的机制。借助体外生发中心B细胞（Germinal Center B cell, GCB）分化诱导手段，我们发现Pkcδ的缺失促进GCB细胞的分化。通过体外激活B细胞，分析发现Pkcδ缺失的GCB细胞中STAT3的磷酸化水平升高，以及B细胞重要转录因子IRF4表达增加，这些结果表明Pkcδ可能通过IRF-4和p-STAT3参与调控B细胞的分化，进而调控Tfh细胞的分化。进一步明确狼疮等自身免疫性疾病的发生发展机制对探索发展这些疾病的新的诊疗方法意义重大。