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  • Title: Alternative and classical NF-kappa B signaling retain autoreactive B cells in the splenic marginal zone and result in lupus-like disease.
    Author: Enzler T, Bonizzi G, Silverman GJ, Otero DC, Widhopf GF, Anzelon-Mills A, Rickert RC, Karin M.
    Journal: Immunity; 2006 Sep; 25(3):403-15. PubMed ID: 16973390.
    Abstract:
    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.
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