Mitochondria connects the antigen receptor to effector caspases during B cell receptor-induced apoptosis in normal human B cells

We have previously reported that CD40 stimulation sensitizes human memory B cells to undergo apoptosis upon subsequent B cell receptor (BCR) ligation, We have proposed that activation stimuli connect the BCR to an apoptotic p athway in mature B cells and that BCR-induced apoptosis of activated B cell s could serve a similar function as activation-induced cell death in the ma ture T cell compartment, Although it has been reported that caspases are ac tivated during this process, the early molecular events that link the Ag re ceptor to these apoptosis effecters are largely unknown. In this study, we report that acquisition of susceptibility to BCR-induced :apoptosis require s entry of memory B cells into the S phase of the cell cycle. We also show that transduction of the death signal via the BCR sequentially proceeds thr ough a caspase-independent and a Caspase-dependent phase, which take place upstream and downstream of the mitochondria, respectively. Furthermore, bur data indicate that the BCR-induced alterations of the mitochondrial functi ons are involved in activation of the caspase cascade, We have found both c aspases-3 and -9,but not caspase-8, to he involved in the BCR apoptotic pat hway, thus supporting the notion that initiation of the caspase cascade cou ld be under the control of the caspase-9/Apaf-1/cytochrome c multimolecular complex, Altogether, our findings establish the mitochondria as the connec tion point through which the Ag receptor can trigger the executioners of ap optotic cell death in mature B lymphocytes.