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Signal Regulation Mechanisms for B Cell Development and Self-Tolerance Establishment.

B 细胞发育和自我耐受建立的信号调节机制。

基本信息

批准号：
14207015
负责人：
KITAMURA Daisuke
金额：
$ 31.53万
依托单位：
Tokyo University of Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14207015/
关键词：
B cells antigen receptor adaptor proteins BASH BLNK receptor editing B cell development self tolerance

项目摘要

Pre-B cell receptor (pre-BCR) signaling induces proliferative expansion of large pre-B cells and the following differentiation into small pre-B cells (pre-B cell transition), and inhibits V_H to DJ_H rearrangement of IgH locus (IgH allelic exclusion), the latter also accounting for counter-selection of pro-B cells expressing Dμ protein (Dμ selection). We have previously shown that a B-cell specific adaptor protein, BASH (or BLNK/SLP-65), which is critical for B-cell antigen receptor(BCR) signaling, is important, but not essential, for pre-B cell transition. In this study we have discovered a buck-up role in the pre-BCR signaling for CD19, a B-cell specific co-receptor for BCR. The pre-B cell transition was completely abolished and accumulation of large non-cycling, pre-BCR-expressing cells was augmented in BASH/CD19 double-mutant mice. However, IgH allelic exclusion was intact even in the double-mutant mice, while Dμ selection was abolished in BASH- and the double-mutant mice. Thus, di … More stinct signals are required for these events. In addition, these mice succumbed to pre-B cell leukemia, indicating BASH (and CD19) contributes to tumor suppression.We also found that editing of self-binding antigen receptors is significantly dependent on BASH, through examining anti-DNA-antibody knock-in mice deficient for BASH. Thus contribution of the receptor editing in the establishment of self-tolerance is clearly documented. In addition, BASH has turned out to be unnecessary for T-independent secondary and memory response, as well as affinity maturation of antibodies.BASH interacts with signaling molecules such as Btk, PLCγ, Vav, Grb2, HPK1, and the significance of such interactions in BCR signal transduction has been shown. We have identified novel proteins that bind to a conserved N-terminal domain of BASH, and termed them BNAS1 and BNAS2. They are both presumed to be a 4-times membrane-span protein and localize at endoplasmic reticulum, Golgi apparatus and peri-nuclear region. Functional studies utilizing gene targeting methodology are currently underway. Less

前 B 细胞受体 (pre-BCR) 信号传导诱导大前 B 细胞增殖扩张，并随后分化为小前 B 细胞（前 B 细胞转变），并抑制 IgH 基因座的 V_H 到 DJ_H 重排（IgH 等位基因排除），后者还导致表达 Dμ 蛋白的前 B 细胞的反选择（Dμ 选择）。我们之前已经证明，B 细胞特异性衔接蛋白 BASH（或 BLNK/SLP-65）对于 B 细胞抗原受体 (BCR) 信号转导至关重要，对于前 B 细胞转变很重要，但不是必需的。在这项研究中，我们发现 CD19（BCR 的 B 细胞特异性共受体）在 BCR 前信号转导中具有增强作用。在 BASH/CD19 双突变小鼠中，前 B 细胞转变被完全消除，并且大的非循环、前 BCR 表达细胞的积累增加。然而，即使在双突变小鼠中，IgH 等位基因排除也是完整的，而 BASH 和双突变小鼠中 Dμ 选择被取消。因此，这些事件需要明确的信号。此外，这些小鼠死于前B细胞白血病，表明BASH（和CD19）有助于肿瘤抑制。通过检查BASH缺陷的抗DNA抗体敲入小鼠，我们还发现自结合抗原受体的编辑显着依赖于BASH。因此，受体编辑在建立自我耐受性中的贡献被清楚地记录下来。此外，BASH 已被证明对于 T 依赖性次级反应和记忆反应以及抗体的亲和力成熟来说是不必要的。BASH 与 Btk、PLCγ、Vav、Grb2、HPK1 等信号分子相互作用，并且这种相互作用在 BCR 信号转导中的重要性已被证明。我们已经鉴定出与 BASH 保守 N 末端结构域结合的新型蛋白质，并将它们命名为 BNAS1 和 BNAS2。推测它们都是 4 倍膜跨度蛋白，定位于内质网、高尔基体和核周区域。目前正在进行利用基因靶向方法的功能研究。较少的