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. By directly cloning BCRs from live and apoptotic GC B cells that we could distinguish and isolate using a novel apoptosis indicator mouse, we found that self-reactivity is quite rare among GC B cells and not significantly enriched in dying cells. In line with these findings, a newly generated mouse strain with GC-restricted Bcl-2 expression remained healthy when aged. In contrast, age-matched mice that expressed Bcl-2 in GC B cells, memory B cells and plasma cells developed high titers of anti-nuclear autoantibodies, kidney inflammation, as well as B cell lymphoma. These results indicate that self-reactive B cells which escape deletion in the GC need to be controlled by apoptosis in a post-GC checkpoint. The results also highlight that irreversible Bcl-2 overexpression at the GC B cell stage is required for the malignant transformation of B cells in the mouse models used. Overall, this research provided insights into immune tolerance and diseases resulting from a breakdown of immune regulatory circuits. The findings have a particular relevance for the human autoimmune disease systemic lupus erythematosus.