Rap1 signal controls B cell receptor repertoire and generation of self-reactive B1a cells
Rap1 signal controls B cell receptor repertoire and generation of self-reactive B1a cells
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DOI：
10.1016/j.immuni.2006.02.007
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发表时间：
2006-04-01
期刊：
影响因子：
32.4
通讯作者：
Minato, N
中科院分区：
文献类型：
--
作者：
Ishida, D;Su, L;Minato, N
我们先前报道了缺乏SPA-1（Rap 1 GTP酶激活蛋白）的小鼠发生造血干细胞疾病。在这里，我们证明了SPA-1（-/-）小鼠显示出B220（高）B1 a细胞产生抗dsDNA抗体和狼疮样肾炎的年龄依赖性增加。SPA-1（-/-）腹膜B1细胞显示改变的V κ基因库，包括偏斜的V κ 4使用和显著的IG κ/IG λ同种型包含，表明广泛的受体编辑。Rap 1 GTP通过p38 MAPK依赖的CreB磷酸化诱导Oca B基因活化，并且一致地，显示高Rap 1 GTP的SPA-1（-/-）未成熟BM B细胞表现出Oca B和V κ 4基因的增强表达。SPA-1（-/-）BM细胞可在Rag-2（-/-）受体中传递与腹膜B220（高）B1 a细胞产生相关的自身免疫。最后，一部分SPA-1（-/-）小鼠发生了B1细胞白血病，并伴有溶血性自身抗体。目前的结果表明，在未成熟的B细胞中调控的Rap 1信号在修饰B细胞受体库和维持自身耐受中起作用。
We previously reported that the mice deficient for SPA-1, a Rap1 GTPase-activating protein, developed hematopoietic stem cell disorders. Here, we demonstrate that SPA-1(-/-) mice show an age-dependent increase in B220(high) B1a cells producing anti-dsDNA antibody and lupus-like nephritis. SPA-1(-/-) peritoneal B1 cells revealed the altered V kappa gene repertoire, including skewed V kappa 4 usage and the significant Ig kappa/Ig lambda isotype inclusion indicative of extensive receptor editing. Rap1GTP induced OcaB gene activation via p38MAPK-dependent Creb phosphorylation, and consistently, SPA-1(-/-) immature BM B cells showing high Rap1GTP exhibited the augmented expression of OcaB and V kappa 4 genes. SPA-1(-/-) BM cells could transfer the autoimmunity in association with the generation of peritoneal B220(high) B1a cells in Rag-2(-/-) recipients. Finally, a portion of SPA-1(-/-) mice developed B1 cell leukemia with hemolytic autoantibody. Present results suggest that the regulated Rap1 signal in the immature B cells plays a role in modifying the B cell receptor repertoire and in maintaining the self-tolerance.