B cell subsets contributing to the autoreactive plasma cell pool in Lyn−/− mice

Abstract

Abstract Systemic Lupus Erythematosus (SLE) is characterized by autoantibodies (autoAbs) against nucleic acid containing antigens. These antibodies form immune complexes that promote inflammation and cause organ damage. Defining B cell subsets that give rise to these autoAbs may reveal therapeutic approaches for SLE that spare responses to foreign antigens. Mice lacking the tyrosine kinase Lyn, which limits B and myeloid cell activation, develop lupus-like autoimmune disease characterized by a large increase in autoreactive plasma cells (PCs). We used several strategies to identify the origin of these PCs. We used fate mapping to assess the contribution of T-bet+ age associated B cells (ABCs), a subset that is increased and thought to be pathogenic in both murine and human lupus. 40% of splenic PCs in Lyn−/− mice were derived from T-bet expressing cells, a significant increase compared to wild type mice that was not seen in the bone marrow PC population. Marginal zone (MZ) B cells, also implicated in some lupus models, are enriched in autoreactivity, prone to PC differentiation, and reduced in Lyn−/− mice. We hypothesized that this reduction might be due to their unchecked transit to the PC stage. However, impairing MZ B cell development in Lyn−/− mice did not reduce autoAbs. Nor did preventing PC differentiation restore MZ B cell numbers. Instead, Lyn−/− mice accumulated B1a cells when PC differentiation was impaired. B1a cells tend to be polyreactive or weakly autoreactive and are primed for terminal differentiation. Our results suggest that both ABCs and B1a cells, but not MZ B cells, contribute to the autoreactive PC pool in Lyn−/− mice. Future studies will assess the role of these subsets in the development of autoimmune disease. Supported by grants from the NIH (R21 AI161307, R21 AI137746)