Bcl-3在边缘区B细胞发育分化命运决定过程中的表观遗传调控机制

Newly formed immature B cells in bone marrow develop into transition 1 and 2 (T1, T2) and finally mature into follicular B (FOB) cells and marginal zone B (MZB) cells after entering spleen. B cells exhibit important regulatory functions in addition to secreting antibodies after differentiating into plasma cells. MZB cells constitute a first line of host defense against blood-borne pathogenes by producing TI antibodies. MZB cells including self-reactive B cells may initiate and mediate the pathogenesis of many autoimmune diseases including system lupus erythematosus. The mechanism underlying MZB cell fate decision remains unclear. B cell-fate decision depends on signaling including NF-kB signaling. Bcl-3 is an atypical member of IkB family, functions in the formation and architecture maintenance of lymphoid organs as well as germinal center formation and antibody production. Our previous data showed Bcl-3 negatively regulates the commitment to a MZB cells. Based on these findings this project will confirm this function of Bcl-3 and understand the epigenetic regulation mediated Bcl-3 in MZB cell fate decision and pathogenesis of SLE.

骨髓中新产生的不成熟B细胞进入脾脏后经过过渡期细胞（T1，T2）再分化为成熟的滤泡（FO）B细胞和边缘区（MZ）B细胞，在免疫应答过程中除了能产生抗体，还有重要的免疫调节作用。MZB细胞能迅速产生抗体，是机体抗血液中病原体的第一道防线，同时其中含有一些自身反应性B细胞启动和介导系统性红斑狼疮(SLE)等自身免疫性疾病。但对MZB细胞的分化和命运决定的机制还不甚明了。多种信号调控MZB细胞发育分化和功能，其中NF-kB信号尤为重要。Bcl-3是一IkB家族成员，有重要的免疫调节功能。我们前期研究显示Bcl-3能负向调控B细胞向MZB细胞发育分化的命运决定。本研究将证实 Bcl-3在MZB细胞发育分化的命运决定过程中的负向调控作用，研究Bcl-3介导的表观遗传调控在该过程的作用机制及Bcl-3在SLE的发病过程中作用。本项目将有助于阐明B细胞发育的命运决定和MZB细胞介导的生理病理过程的机制。

在本项目的支持下，项目组主要在Bcl-3基因敲除小鼠和B细胞特异性转基因小鼠中研究了Bcl-3对边缘区B细胞发育分化的影响，初步确定Bcl-3对边缘区B细胞发育分化中的重要功能，为以后的深入研究打下基础，完成本项目的研究内容。具体发现如下：.1. 在Bcl-3基因敲除小鼠和B细胞特异性转基因小鼠（mb-cre）中证明Bcl-3负向调控MZB细胞的发育分化，Bcl-3作用阶段可能是促进MZP细胞的发育。.2．Bcl-3调控MZB细胞发育分化是作用于B细胞本身，而非通过影响基质细胞等其它细胞起作用的。.3．Bcl-3可能通过调控BCR反应调控MZB细胞命运决定，而不是仅仅通过影响B细胞表面粘附分子表达和对BCR刺激引起的凋亡调控的。