Impaired expansion and selection of geminal center B cells in lupus drives autoantibody-producing cells

Abstract

Abstract Lupus is a systemic autoimmune disease characterized by the presence of autoantibodies that form immune complexes in tissues leading to the recruitment of immune cells and subsequent inflammation and organ damage. The origin of autoantibody-secreting B cells is not clear, but the germinal center (GC) is of particular interest as the B cells here undergo somatic hypermutation, which may result in the generation of autoreactive memory or long-lived plasma cells. Within the GC, B cells cycle between two major zones: the dark zone (DZ) where mutation and proliferation occur, and the light zone (LZ) where affinity-based selection occurs. We found in lupus-prone mice that as autoantibodies increased, there was a reduction in proliferation measured by EdU incorporation in conjunction with dysregulation of the GC zones as B cells here became skewed towards a LZ phenotype (CXCR4 loCD86 +). As MYC expression in LZ B cells correlates with the strength of selection, we examined MYC levels by flow cytometry and Amnis and found it and its nuclearization decreased as disease progressed. Single cell BCR sequencing of GC B cells throughout the course of disease revealed a loss in BCR repertoire diversity and mutations. Furthermore, we found that despite the accumulation of LZ B cells, there was an increase in the generation of plasma cells and memory-like CD11c +Tbet +B cells, suggesting aberrant selection and differentiation into these potentially autoantibody-secreting cells. Thus, our findings suggest that as lupus disease progresses, the ability of GC B cells in the LZ to undergo proper selection is impaired, resulting the permissive selection of autoreactive B cells and differentiation into autoantibody-secreting cells. Supported by grants from the NIH/NIAMS (R01 AR073912, R01 AR073912 - 03W1)