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 的一个亚系，已知 B 细胞成熟缺陷。我们在本研究中观察到，与 A/J 小鼠相比，A/WySnJ 小鼠脾脏中初级卵泡的形成存在缺陷，这可能与 B 细胞中包括 MAPK/ERK 在内的信号级联缺陷有关，导致体外对CD40和IgM刺激的反应较差。CD40刺激对于B细胞的激活和分化至关重要，例如类别转换、生发中心形成和记忆的产生。我们在本研究中观察到 cd40 刺激通过 Ras-Raf-1-MEK 信号通路导致 MAPK/ERK 激活。 CD40 的细胞质尾部与 TRAF2、TRAF3、TRAF5 和 TRAF6 相关。除 TRAF3 外，这些 TRAF 蛋白在 CD40 信号转导中的 NF_KB 激活中发挥作用。我们的生化研究表明 TRAF3 可以抑制 CD40 信号传导中的 MAPK/ERK 激活。由于已知 TRAF3 的过表达会抑制其他 TRAF 蛋白的功能，因此该结果与尚未定义的 TRAF 蛋白在 CD40 信号传导中的 MAPK/ERK 激活中发挥作用的观点相一致。激活后，B 细胞进入初级卵泡并建立生发中心。我们观察到，与发育良好的生发中心相反，Ig+生发中心B细胞大多处于细胞循环状态。免疫后第7-8天细胞大量扩增并占据生发中心；然而，这些循环B细胞在免疫后第8-10天迅速减少数量。在此期间，这些细胞积累体细胞超突变并可以被抗原选择。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，这表明体细胞超突变和抗原选择可能同时起作用，很可能是通过 T 细胞相互作用激活的。