Regulation of CD11c+Tbet+ B cells in lupus
Dr. Alessandra Pernis studies a unique type of B cell that has been linked to several autoimmune diseases, including lupus. These “CD11c+Tbet+” B cells have unusually high amounts of two proteins: CD11c, which hangs like a hook on the outer surface of the cell, and T-bet, a protein in the center of the cell that controls the on/off switch for some genes. CD11c+Tbet+ B cells make autoantibodies—or antibodies that mistakenly attack a person’s own tissues and, thus, trigger diseases like lupus. Dr. Pernis will use her Novel Research Grant to learn how CD11c+Tbet+ B cells are made, what molecular pathways help control the function of T-bet in the center, and how and why the cells are triggered to make autoantibodies in lupus.
What this study means for people with lupus
Dr. Pernis expects her research on CD11c+Tbet+ B cells to fill in vital pieces of the puzzle of how lupus develops. By understanding why these cells develop and how they work, she hopes to find vulnerable points that can be targeted with novel drugs that are specially designed to stop or reverse the disease process in lupus.
CD11c+Tbet+ B cells are a B cell subset with unique phenotypic and functional features. Although presence of CD11c+Tbet+ B cells has been associated with autoimmune disorders including SLE, the molecular pathways that control this subset are largely unknown. We have found that the lupus syndrome that develops in mice lacking SWEF proteins, which include Def6, a newly identified risk variant for human SLE, and its homolog SWAP-70, is accompanied by a marked accumulation of CD11c+Tbet+ B cells. CD11c+Tbet+ B cells from SWEF deficient mice produce autoantibodies and their expansion is dependent on IL-21 and SAP. CD11c+Tbet+ B cells from SWEF deficient mice exhibit a distinctive transcriptome characterized by enhanced expression of proliferative and proinflammatory pathways. Notably, chromatin accessibility profiles of CD11c+Tbet+ B cells in SWEF deficient mice revealed a unique chromatin landscape characterized by enrichment in IRF and T-bet binding motifs. In line with these findings, accumulation of CD11c+Tbet+ B cells in SWEF deficient mice is controlled by IRFs. In this proposal we will investigate the hypothesis that SWEF proteins regulate the IRF-Tbet crosstalk thus restraining the proliferation of CD11c+Tbet+ B cells and their ability to produce autoantibodies. Specifically, we will employ a number of biochemical, molecular, and genetic approaches to dissect the mechanisms that control the generation and function of CD11c+Tbet+ B cells in SLE.