Abstract
Misguided immune reactions against self can cause autoimmunity. Although multiple factors are likely involved, a common feature is altered lymphocyte homeostasis due to dyregulated apoptosis. Here, we show that the integration of signals from the BCR and BAFF-R promotes survival of T2 cells that have passed the self-reactivity checkpoint. BCR engagement produces NF-κB2 protein, a substrate used by the BAFF-R for the activation of the alternative NF-κB pathway. In contrast, pre-checkpoint T1 cells fail to integrate BCR and BAFF-R signals and remain sensitive to BCR-mediated-apoptosis. Btk and c-Rel are critical in this signal integration and B-cell survival. Importantly, BAFF-R promotes B-cell survival by suppressing Bim, a pro-apoptotic protein of the Bcl-2 family. Because Bim suppression promotes B-cell survival, we hypothesized that Bim-dependent apoptosis of autoreactive B-cells is critical in preventing autoimmunity. To test this hypothesis, we constructed mice with B-cell-specific Bim deletion (B-Bim-/-). Loss of Bim in B-cells causes autoimmune disease characteristic of lupus and Sjögren’s Syndrome. B-Bim-/- mice develop tertiary lymphoid organs, developed glomerulonephritis and have lymphoid infiltration of salivary glands. B-cells in the B-Bim-/- mice were activated, and proliferated more robustly to BCR, BAFF-R, TLR4 and TLR9 stimulation than WT B-cells, suggesting that activated B-cells initiate and drive autoimmune pathogenesis. Deletion of Btk reduced the overall pathology in B-Bim-/- mice. Our findings demonstrate a critical role for B-cell developmental-stage-specific regulation of apoptosis and show that the loss of a physiological inducer of apoptosis in B-cells alone is sufficient to initiate generalized systemic immune dysregulation resulting autoimmune pathology.