Mitochondria, cell death, and B cell tolerance.

To prevent autoimmunity, it is critical that tolerance mechanisms block autoantibody production from self-reactive B cells. B cell tolerance is maintained through mechanisms that can reversibly or irreversibly silence autoreactive B cells. Of these mechanisms, those that lead to B cell death offer the most reliable form of tolerance to prevent autoimmunity. In many cases, death of autoreactive B cells is regulated by the cell intrinsic, or mitochondrial pathway of cell death. The pro-apoptotic Bcl-2 family proteins, Bak, Bax, and Bim have been shown to be required for disruption of mitochondria and intrinsic cell death of self-reactive B cells whereas the anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1 can prevent cell death by interfering with the action of Bax and Bak. Bcl-2 and Bcl-xL have also been shown to regulate the autophagic cell death pathway that may also play a role in B cell tolerance. Even after mitochondrial disruption, mechanisms exist that may impede activation of caspases and death of autoreactive B cells. Together, understanding of cell death mechanisms and how they may affect B cell tolerance has made significant recent advances and it is now important to incorporate alternate and post-mitochondrial cell death mechanisms into B cell tolerance models.