Molecular mechanisms for B lymphocyte selection: induction and regulation of antigen-receptor-mediated apoptosis of mature B cells in normal mice and their defect in autoimmunity-prone mice

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Abstract
Apoptosis (programmed cell death) has been suggested to be involved in clonal elimination of selfreactive lymphocytes for the normal function of the immune system. By crosslinking the antigen receptor (surface immunoglobulin; slg) on the peritoneal B cells of normal mice, we found that strong crosslinking of slg induces apoptosis of mature B cells, suggesting that interaction with membranebound self-antigens may eliminate self-reactive mature B cells by apoptosis. Antigen-receptor-mediated B cell apoptosis is blocked when a signal is transduced via the CD40 molecule on the B cell surface. Because the ligand of CD40 (CD40L) is expressed on activated T helper cells, B cells may escape from apoptosis and are activated when the immune system interacts with foreign antigens, which are normally able to activate T helper cells. Moreover, slg crosslinking fails to induce apoptosis of both bcl-2-transgenic mice and autoimmune-disease-prone New Zealand mice. In these mice, the defect in slg-mediated apoptosis of mature B cells may allow generation of self-reactive B cells, resulting in pathogenic consequences.