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Mechanism of B cell maturaion

B细胞成熟机制

基本信息

批准号：
07457089
负责人：
TAKEMORI Toshitada
金额：
$ 1.47万
依托单位：
National Institute of Health
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07457089/
关键词：
primary follicles CD40 MAP kinase TRAF germinal center cell cycle somatic hypermutation antigen presentation 細胞周期一次免疫反応 centroblast 体細胞点変異 Bリンパ球 centrocyte 記憶Bリンパ球免疫グロブリン遺伝子

项目摘要

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.

A/WySnJ鼠标。A/J亚系，已知在B细胞成熟过程中存在缺陷。我们在本研究中观察到，与A/J相比，A/WySnJ小鼠脾初级毛囊的形成不足，这可能与B细胞中包括MAPK/ERK的信号级联缺陷有关，导致在体外对CD40和IgM刺激的反应较差。CD40刺激对B细胞的激活和分化是必不可少的，如类别转换、生发中心的形成和记忆的产生。本研究观察到CD40刺激通过Ras-Raf-1-MEK信号通路激活MAPK/ERK。CD40的胞浆尾巴与TRAF2、TRAF3、TRAF5和TRAF6相关。除TRAF3外，这些TRAF蛋白在CD40信号通路中参与了NF_KB的活化。我们的生化研究表明，TRAF3可以抑制CD40信号通路中MAPK/ERK的激活。由于TRAF3的过表达抑制了其他TRAF蛋白的功能，这一结果与尚未确定的TRAF蛋白在CD40信号中参与MAPK/ERK激活的观点是一致的。我们观察到，与发达的生发中心相反，Ig+生发中心B细胞主要处于细胞周期中。免疫后第7~8天，这些细胞以较高频率扩张并占据生发中心；而在免疫后第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细胞在体外具有强大的抗原提呈活性，提示体细胞超突变和抗原选择可能同时进行，可能是通过T细胞相互作用而激活的。