title: Enforced expression of the apoptosis inhibitor Bcl-2 ablates tolerance induction in DNA-reactive B cells through a novel mechanism.
abstract: How self tolerance is maintained during B cell development in the bone marrow has been a focal area of study in immunology. Receptor editing, anergy and clonal deletion all play important roles in the regulation of autoimmunity in the immature population. The mechanisms of tolerance induction in the periphery, however, are less well characterized. Overexpression of the apoptosis inhibitor Bcl-2 rescues autoreactive B cells from deletion and can contribute to the development of autoimmune disease in certain genetic backgrounds. Using a peptide-induced autoimmunity model, we recently identified a peripheral tolerance checkpoint in antigen-activated B cells that have undergone class switching and somatic hypermutation. At this checkpoint, receptor editing, induced by antigen engagement, dampened the autoantibody response. In this study, we show that receptor editing fails to be induced in antigen-activated DNA-reactive B cells that overexpress Bcl-2 (Bcl-2 Tg). The failure to induce RAG and receptor editing is likely due, at least partially, to the lack of self antigen. First, the levels of circulating DNA and of apoptotic bodies in the spleen of Bcl-2 Tg mice are significantly lower than in control mice. Second, in Bcl-2 Tg mice, RAG can be induced in a population of antigen-activated B cells by providing exogenous soluble antigen. These data suggest that, in addition to its anti-apoptotic activity, Bcl-2 may indirectly inhibit tolerance induction in B cells acquiring anti-nuclear antigen reactivity after peripheral activation by limiting the availability of self antigen.
authors: The Center for Autoimmune and Musculoskeletal Disease, The Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, USA.
authors: Ying-Hua
authors: YH
authors: Wang
authors: Yi
authors: Y
authors: Yan
authors: Jeffrey S
authors: JS
authors: Rice
authors: Bruce T
authors: BT
authors: Volpe
authors: Betty
authors: B
authors: Diamond
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood / Q000276:immunology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D004247:DNA / Q000097:blood / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics*; D007114:Immunization; D007156:Immunologic Memory / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D018716:Molecular Mimicry / Q000276:immunology; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000276:immunology
chemical_list: D000974:Antibodies, Antinuclear; D001324:Autoantigens; D004268:DNA-Binding Proteins; D000939:Epitopes; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; C064655:V(D)J recombination activating protein 2; D004247:DNA