Project ? Abstract Anti-nuclear antibodies of the IgG isotype are central to the diagnosis and pathogenesis of SLE, yet fundamental questions about their origin remain. This proposal will use several novel methodologies to address some key questions. Do anti-nuclear antibodies arise because of a global defect in B cell activation leading to an increased differentiation of IgG plasma cells, or because of an antigen-specific tolerance defect? Can SLE patients be stratified based on the pathway of IgG plasma cell differentiation (i.e extrafollicular vs germinal center)? Do plasma cells activated by nuclear antigen through the B cell receptor and toll-like receptors exhibit a different transcriptional program than plasma cells activated only through the BCR? Finally, is the lupus response to vaccine antigens normal or does it stimulate antibodies cross-reactive with nuclear antigens? Addressing these questions may identify new therapeutic targets in SLE and help stratify patients for clinical trials to improve the care of SLE patients and advance precision medicine.
