Lesley Robin, Xu Ying, Kalled Susan L, Hess Donna M, Schwab Susan R, Shu Hong-Bing, Cyster Jason G
Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 USA.
Immunity. 2004 Apr;20(4):441-53. doi: 10.1016/s1074-7613(04)00079-2.
Peripheral autoantigen binding B cells are poorly competitive with naive B cells for survival and undergo rapid cell death. However, in monoclonal Ig-transgenic mice lacking competitor B cells, autoantigen binding B cells can survive for extended periods. The basis for competitive elimination of autoantigen binding B cells has been unknown. Here we demonstrate that autoantigen binding B cells have increased dependence on BAFF for survival. In monoclonal Ig-transgenic mice, each autoantigen binding B cell receives elevated amounts of BAFF, exhibiting increased levels of NFkappaB p52 and of the prosurvival kinase Pim2. When placed in a diverse B cell compartment, BAFF receptor engagement and signaling are reduced and the autoantigen binding cells are unable to protect themselves from Bim and possibly other death-promoting factors induced by chronic BCR signaling. These findings indicate that under conditions where BAFF levels are elevated, autoantigen-engaged cells will be rescued from rapid competitive elimination, predisposing to the development of autoimmune disease.
外周自身抗原结合B细胞在与幼稚B细胞竞争存活时竞争力较弱，并会迅速发生细胞死亡。然而，在缺乏竞争B细胞的单克隆Ig转基因小鼠中，自身抗原结合B细胞能够长期存活。自身抗原结合B细胞被竞争性清除的基础一直不明。在此我们证明，自身抗原结合B细胞对BAFF的存活依赖性增加。在单克隆Ig转基因小鼠中，每个自身抗原结合B细胞接收到的BAFF量增加，表现出NFκB p52和促生存激酶Pim2水平升高。当置于多样化的B细胞区室中时，BAFF受体的结合和信号传导会减少，自身抗原结合细胞无法保护自身免受慢性BCR信号传导诱导的Bim及可能其他促死亡因子的影响。这些发现表明，在BAFF水平升高的情况下，自身抗原结合细胞将从快速的竞争性清除中被挽救，从而易患自身免疫性疾病。
