B lineage-specific deletion of Bim leads to lymphoproliferative and autoimmune disease (159.23)

Abstract

Abstract Autoreactive B cells are known to contribute to the onset and progression of a variety of autoimmune diseases including systemic lupus erythematosus (SLE). To prevent this, the B cell receptor (BCR) exerts specificity-based quality control and B cell activating factor receptor (BAFF-R) maintains homeostasis primarily through controlling apoptosis. An appropriate balance in the levels of the pro- and anti-apoptotic members of the Bcl-2 family is central to this process. Using mice with B lineage-specific deletion of the pro-apoptotic gene Bim (B-bim-/-), we showed that B cell autonomous dysregulation of apoptosis is sufficient to cause systemic autoimmune disease with lymphoproliferation. B-bim-/- mice display progressive splenomegally and lymphoadenopathy with a significant increase in B cells as well as an overall increase in innate and T cells which display markers of activation. B-bim-/- mice had higher serum levels of autoantibodies and proinflammatory cytokines. These mice also displayed increased lymphocyte proliferation and infiltration of the salivary gland, lung and liver. Furthermore, accumulation of lymphocytes in the B-bim-/- mice results in the formation of tertiary lymphoid structures. These results suggest that apoptosis resistant B-bim-/- B cells can acquire an activated phenotype and become pathogenic, culminating in the activation of T cells and the generation of a pro-inflammatory microenvironment leading to systemic autoimmunity. In addition, massive lymphoproliferation and inflammation may predispose B-bim-/- mice to B cell and other hematopoietic malignancies.