BCAP regulation of TLR7/9 signaling in Lupus

PROJECT SUMMARY Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the presenceof circulating autoantibodies to nucleic acids and to proteins with which they associate. Signaling through thenucleic acid sensing TLRs, TLR7 and TLR9, is critical in SLE pathogenesis, and dysregulated TLR signalingcan promote lupus in humans and in mouse models. Plasmacytoid dendritic cells (pDC) and B cells bothexpress these nucleic acid sensing TLR and are important in SLE pathogenesis. Autoreactive B cells producepathogenic autoantibodies in SLE, and B cell antibody production is promoted by TLR7 and TLR9 signaling.pDC use TLR7 and TLR9 to respond to nucleic acids in immune complexes resulting in the secretion of largequantities of type I IFN cytokines, which have pleiotropic effects on the immune response, including enhancingdendritic cell (DC) maturation, plasma cell formation, and T cell responses, all of which can promote a feedforward loop of immune activation. Therefore, understanding the mechanisms by which TLR7 and TLR9signaling are regulated in these two critical cell types is important for understanding the pathogenesis of SLEand in defining therapeutic targets for this disease. We have identified the signaling adapter B cell adapter forPI3-kinase (BCAP) as a key modulator of TLR signaling in multiple immune lineages. First, we found that inmacrophages BCAP inhibits TLR-induced inflammatory cytokine production via activation of PI3-kinase. Werecently showed that BCAP promotes pDC IFNα, but not IL-6, secretion. We have also begun to examine howBCAP regulates B cell TLR7/9 responses, an understudied area. Our preliminary data show that BCAP is akey regulator of B cell TLR7/9 responses in all B cell subsets, with a particularly striking decrease inproliferation and IgG secretion from splenic marginal zone B cells. Additionally, we have found that BCAP-deficiency protects the TLR7.1 mouse lupus model from disease. Together, our findings show an importantrole of BCAP in endosomal TLR signaling in pDC and B cells, both important in SLE pathogenesis. Given theimportance of TLR7 and TLR9 signaling in both B cells and pDC in SLE, the premise of this application is thatBCAP regulation of pDC and B cell TLR7/9 signaling is critical in the development of lupus-like disease.Specifically, we will 1) determine the mechanism by which BCAP regulates TLR7/9-induced IFNα production inpDCs, 2) determine the mechanism by which BCAP regulates B cell TLR7/9 responses, and 3) determine therelative contribution of BCAP in pDCs and B cells to lupus-like disease using two mouse models.