B-1 cells contribute to increased total IgM and shape IgG autoreactivity profiles in Lyn-/- mice but are not a major source of lupus-associated pathogenic autoantibodies.

Introduction: Systemic lupus erythematosus is an autoimmune disease in which pathogenic autoantibodies targeting nucleic acid containing antigens promote inflammation and tissue damage. Recent reports suggest that deep B cell depletion will be a highly effective therapeutic strategy for lupus. However, elimination of all B cells confers susceptibility to infection. Thus, an approach which targets pathogenic B cells but spares protective ones would be ideal. The B-1 subset of B cells has been suggested to be either pathogenic or protective in lupus, depending on the study. Methods: We used several complementary approaches to define the contribution of B-1 cells to autoantibody production and immune cell activation in the Lyn-/- mouse model of lupus. We labeled activated B-1 cells to track their cellular and antibody progeny. Activated B-1 cells were also depleted or prevented from differentiating into plasma cells. Results: B-1 cells contributed significantly to the accumulation of splenic plasma cells and total IgM characteristic of Lyn-/- mice in a manner at least partially independent of the transcription factor IRF4. Unlike T-bet+ B cells, they were not a major source of pathogenic lupus-associated autoantibodies. Rather, they limited both the production of IgG against other autoantigens and the activation of CD8+ T cells. Conclusion: These studies highlight a regulatory role for B-1 cells in shaping adaptive immune tolerance in the Lyn-/- lupus model.