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.
Apoptosis (programmed cell death) has been suggested to be involved in clonal elimination of self-reactive lymphocytes for the normal function of the immune system. By crosslinking the antigen receptor (surface immunoglobulin; sIg) on the peritoneal B cells of normal mice, we found that strong crosslinking of sIg induces apoptosis of mature B cells, suggesting that interaction with membrane-bound 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, sIg crosslinking fails to induce apoptosis of both bcl-2-transgenic mice and autoimmune-disease-prone New Zealand mice. In these mice, the defect in sIg-mediated apoptosis of mature B cells may allow generation of self-reactive B cells, resulting in pathogenic consequences.
Tsubata
T
T
Department of Medical Chemistry, Faculty of Medicine, Kyoto University, Japan.
Murakami
M
M
Nisitani
S
S
Honjo
T
T
D000818:Animals; D000941:Antigens / Q000502:physiology*; D015703:Antigens, CD / Q000502:physiology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology; D017209:Apoptosis; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D019013:CD40 Antigens; D051379:Mice; D008810:Mice, Inbred C57BL; D011947:Receptors, Antigen, B-Cell / Q000737:chemistry / Q000502:physiology*
D000941:Antigens; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D011947:Receptors, Antigen, B-Cell