Mechanism of B cell maturaion

A/WySnJ小鼠。A/J的亚系，已知在B细胞成熟方面有缺陷。本研究发现，A/WySnJ小鼠脾脏初级卵泡的形成较A/J小鼠明显缺陷，这可能与B细胞中MAPK/ERK信号通路的缺陷有关，导致其对CD 40和IgM刺激的反应较差。CD 40刺激对B细胞的活化和分化是必不可少的，如类转换、生发中心的形成、和记忆的产生。本研究观察到，cd 40的刺激通过Ras-Raf-1-MEK信号通路导致MAPK/ERK的激活。CD 40的胞质尾区与TRAF 2、TRAF 3、TRAF 5和TRAF 6相关。这些TRAF蛋白除了TRAF 3之外在CD 40信号传导中的NF_κ B活化中起作用。我们的生化研究表明TRAF 3可以抑制CD 40信号通路中MAPK/ERK的激活。由于TRAF 3的过表达可以抑制其他TRAF蛋白的功能，因此这一结果与TRAF蛋白在CD 40信号通路中的MAPK/ERK激活中起作用的观点相一致，该蛋白尚未被确定。我们观察到，与发育良好的生发中心相反，IG+生发中心B细胞大多处于细胞周期中。在免疫后7-8天，这些细胞以高频率扩增并占据生殖中心，而在免疫后8-10天，这些循环B细胞迅速减少，在此期间这些细胞积累了体细胞超突变，并可被抗原选择。快速循环的IG+生发中心B细胞在体外具有有效的抗原呈递活性，这表明体细胞超变和抗原选择可能同时起作用，可能通过T细胞相互作用的活化。

A/WySnJ mouse. a subline of A/J,is known to be deficient in B cell maturation. We observed in the present study that formation of the primary follicle in the spleen is deficient in A/WySnJ mouse, as compared to A/J,which could be associated with deficiency in signal cascade including MAPK/ERK in the B cells, resulting in poor response to CD40 and IgM stimulation in vitro.CD40 stimulation is essential for B cell activation and differentiation, such as class-switch, germinal center formation, and generation of memory. We observed in the present study that cd40 stimulation resulted in activation of MAPK/ERK via Ras-Raf-1-MEK signal pathway. The cytoplasmic tail of CD40 associates with TRAF2, TRAF3, TRAF5, and TRAF6. These TRAF proteins with exception for TRAF3 play a role in NF_KB activation in CD40 signaling. Our biochemical study showed that TRAF3 could inhibit MAPK/ERK activation in CD40 signaling. As overexpression of TRAF3 is known to suppress function of other TRAF proteins, the result is compatible with the idea that the TRAF protein as yet to be defined plays a role in MAPK/ERK activation in CD40 signaling.After activation, B cells enter into the primary follicles and establish germinal center. We observed that, in contrast to well-developed germinal center, Ig+ germinal center B cells are mostly in cell cycling. There cells expand and occupy germinal center at high frequency on day 7-8 after immunization ; however, these cycling B cells rapidly reduced the number on day 8-10 postimmunization.During that time these cells accumulate somatic hypermutation and could be selected by antigen. Rapidly cycling Ig+ germinal center B cells have potent antigen-presenting activity in vitro, suggesting that somatic hypermutation and antigen selection may operate simultaneously, probable via activation through T-cell interaction.