Loss of the proapoptotic protein, Bim, breaks B cell anergy

Abstract

Although B cells that respond with high avidity to self-antigen are eliminated early in their development, many autoreactive B cells escape elimination and are tolerized later in their lives via anergy. Anergic B cells are unresponsive to antigen and die prematurely. It has been suggested that the proapoptotic protein, Bim, controls the fate of anergic B cells. To test this idea, mice lacking Bim were crossed with mice that express soluble hen egg lysozyme and whose B cells bear receptors specific for the protein. In Bim+/+ mice these B cells are anergic and die rapidly. If the mice lack Bim, however, the B cells live longer, are more mature, respond to antigen, and secrete anti–hen egg lysozyme antibodies. This break of tolerance is not due to expression of endogenous B cell receptors, nor is it dependent on T cells. Rather, it appears to be due to a reduced requirement for the cytokine BAFF. Normal B cells require BAFF both for differentiation and survival. Bim−/− B cells, on the other hand, require BAFF only for differentiation. Therefore, autoreactive B cells are allowed to survive if they lack Bim and thus accumulate sufficient signals from differentiating factors to drive their maturation and production of autoantibodies.