Inhibition of Fas-mediated apoptosis by antigen: implications for lymphomagenesis.
Apoptotic deletion of expanded B cell populations is essential in avoidance of autoimmune disease and immune regulation of some B cell malignancies. The role of CD4+ T cells in B cell apoptosis is evident from the high incidence of B cell tumors and autoimmunity in patients with T cell diseases such as the acquired immune deficiency syndrome (AIDS). We have previously demonstrated that in Epstein-Barr Virus (EBV) negative Burkitt's lymphoma (BL), a tumor derived from proliferating centroblasts of the germinal center, the malignant lymphocytes can be induced to express Fas (CD95) by ligation of CD40 at the B cell surface. Upon CD40 engagement, BL cells are sensitized to T-cell derived death signals provided by Fas ligand (FasL, CD95L). HBL-3 is a cell line derived from an AIDS-related BL in which the tumor IgM binds the human erythrocyte "i" antigen. To determine whether Fas-mediated apoptosis of BL cells is reduced in the context of antigen to which the tumor IgM binds, we stimulated HBL-3 cells with CD40 ligand (CD40L, CD154) in the presence and absence of human erythrocytes expressing the "i" antigen, and measured Fas-mediated apoptosis upon exposure to an agonistic anti-Fas antibody. We observed that HBL-3 cells were sensitized to Fas-mediated death by exposure to CD40L. When i+ RBCs were present, Fas-mediated apoptosis in HBL-3 cells was reduced by greater than 30%. In contrast, there was no reduction in Fas-mediated apoptosis in the presence of i- (I+) RBCs. These findings demonstrate that Fas-mediated deletion of BL cells is inhibited upon surface IgM engagement by antigen for which the malignant clone has affinity.
Schattner
Elaine J
EJ
Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA. ejsch@med.cornell.edu
Friedman
Steven M
SM
Casali
Paolo
P
D017088:AIDS-Related Opportunistic Infections / Q000276:immunology; D000941:Antigens / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D002051:Burkitt Lymphoma / Q000276:immunology / Q000503:physiopathology*; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D002460:Cell Line; D004912:Erythrocytes / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology* / Q000378:metabolism
D000941:Antigens; D019013:CD40 Antigens; D019014:fas Receptor; D023201:CD40 Ligand