The role of apoptosis in B lymphocyte biology

Division Of Basic Sciences - Nci

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Abstract

B lymphocytes assemble the genes encoding for the antigen receptor (B cell receptor, BCR) during their development in the bone marrow. Once a diverse repertoire of naive B cells has been generated, only those B cells that can best respond to an antigenic challenge become activated, start to proliferate and some of those clones may also seed a germinal center (GC) reaction. GC B cells introduce further mutations into the BCR-encoding genes to generate and select for cells with increased antigen binding affinity. During these dynamic processes, memory B cells and high-affinity antibody producing plasma cells are also generated. Because BCR assembly in the bone marrow and BCR mutation in GCs are random processes, both can result in the production of self-reactive B cells. How these potentially dangerous cells are controlled is a long-standing question that has puzzled immunologists. Several different mechanisms have been proposed including revision of the BCR specificity, anergy and cell death. Many of these discoveries were made using transgenic mouse strains in which B cells produced a defined self-reactive BCR. However, the precise quantity, timing and role of B cell apoptosis in mice with a diverse BCR repertoire remain poorly understood. Interference with apoptosis by overexpression of Bcl-2 throughout the B cell compartment results in systemic autoimmunity, indicating the existence of at least one apoptosis-dependent checkpoint for self-reactivity. While we previously identified such a checkpoint in memory B cells and plasma cells, it remains unclear if apoptosis has additional roles in earlier stages of the B lymphocyte life span and if these contribute to the censoring of autoimmune diseases. To address these questions we have developed and are currently employing new mouse models to interrogate the role of apoptosis in mice with a normal B lymphocyte repertoire. We have also successfully developed new assays to screen for autoreactivity that will benefit this project.