Enzler Thomas, Bonizzi Giuseppina, Silverman Gregg J, Otero Dennis C, Widhopf George F, Anzelon-Mills Amy, Rickert Robert C, Karin Michael
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
Immunity. 2006 Sep;25(3):403-15. doi: 10.1016/j.immuni.2006.07.010.
Expression of B cell-activating factor (BAFF), a critical B cell survival factor, is elevated in autoimmune and lymphoproliferative disorders. Mice overproducing BAFF develop systemic lupus erythematosus (SLE)-like disease and exhibit B cell activation of classical and alternative NF-kappaB-signaling pathways. We used a genetic approach and found that both NF-kappaB-signaling pathways contributed to disease development but act through distinct mechanisms. Whereas BAFF enhanced long-term B cell survival primarily through the alternative, but not the classical, NF-kappaB pathway, it promoted immunoglobulin class switching and generation of pathogenic antibodies through the classical pathway. Activation of the alternative NF-kappaB pathway resulted in integrin upregulation, thereby retaining autoreactive B cells in the splenic marginal zone, a compartment that contributes to their survival. Thus, both classical and alternative NF-kappaB signaling are important for development of lupus-like disease associated with BAFF overproduction. The same mechanisms may be involved in the pathogenesis of human SLE.
B细胞活化因子（BAFF）是一种关键的B细胞存活因子，在自身免疫性疾病和淋巴增殖性疾病中表达升高。过量产生BAFF的小鼠会发展出类似系统性红斑狼疮（SLE）的疾病，并表现出经典和替代NF-κB信号通路的B细胞活化。我们采用遗传学方法发现，两种NF-κB信号通路都对疾病发展有贡献，但作用机制不同。虽然BAFF主要通过替代而非经典的NF-κB途径增强B细胞的长期存活，但它通过经典途径促进免疫球蛋白类别转换和致病性抗体的产生。替代NF-κB途径的激活导致整合素上调，从而将自身反应性B细胞保留在脾边缘区，这一区域有助于它们的存活。因此，经典和替代NF-κB信号对于与BAFF过量产生相关的狼疮样疾病的发展都很重要。相同的机制可能参与人类SLE的发病过程。
