Ishida Daisuke, Su Li, Tamura Akitoshi, Katayama Yoshinori, Kawai Yohei, Wang Shu-Fang, Taniwaki Masafumi, Hamazaki Yoko, Hattori Masakazu, Minato Nagahiro
Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan.
Immunity. 2006 Apr;24(4):417-27. doi: 10.1016/j.immuni.2006.02.007.
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 Vkappa gene repertoire, including skewed Vkappa4 usage and the significant Igkappa/Iglambda 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 Vkappa4 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.
我们之前报道过，缺乏Rap1 GTP酶激活蛋白SPA-1的小鼠会出现造血干细胞紊乱。在此，我们证明SPA-1(-/-)小鼠中产生抗双链DNA抗体的B220(high) B1a细胞以及狼疮样肾炎呈现出年龄依赖性增加。SPA-1(-/-)腹膜B1细胞显示出Vkappa基因库的改变，包括Vkappa4使用偏向以及显著的Igkappa/Iglambda同种型包含，这表明存在广泛的受体编辑。Rap1GTP通过p38MAPK依赖的Creb磷酸化诱导OcaB基因激活，并且一致地，显示高Rap1GTP的SPA-1(-/-)未成熟骨髓B细胞表现出OcaB和Vkappa4基因的表达增加。SPA-1(-/-)骨髓细胞可以在Rag-2(-/-)受体中与腹膜B220(high) B1a细胞的产生相关联地转移自身免疫性。最后，一部分SPA-1(-/-)小鼠发展出伴有溶血性自身抗体的B1细胞白血病。目前的结果表明，未成熟B细胞中受调控的Rap1信号在修饰B细胞受体库和维持自身耐受性方面发挥作用。
