Dominant, hierarchical induction of peripheral tolerance during foreign antigen-driven B cell development.
We created mice expressing transgene-encoded BCRs with "dual reactivity" for the hapten Ars and nuclear autoantigens. Expression of transgene-encoded BCRs was not evident in the memory compartment despite observation of transgene-expressing B cells in germinal centers following Ars immunization. In contrast, dual reactive mAbs were readily obtained from mice with enforced expression of Bcl-2 following secondary Ars immunization. However, while these mAbs were hypermutated and displayed increased affinity for Ars, all had reduced avidity for DNA and intracellular autoantigens. Thus, Bcl-2 alters dominant-negative selection of dual reactive B cells during the Ars response, but this is restricted to those with lowered autoreactivity, demonstrating a hierarchy of peripheral tolerance during memory B cell development.
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D000915:Antibody Affinity; D000918:Antibody Specificity; D017209:Apoptosis; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002459:Cell Fusion; D002678:Chimera; D002843:Chromatin / Q000276:immunology; D017637:Clonal Deletion; D004247:DNA / Q000276:immunology; D018858:Germinal Center / Q000737:chemistry / Q000276:immunology; D006241:Haptens / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007114:Immunization; D007143:Immunoglobulin Heavy Chains / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology; D051379:Mice; D008805:Mice, Inbred A; D016513:Mice, SCID; D008822:Mice, Transgenic; D017354:Point Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology*; D027041:Somatic Hypermutation, Immunoglobulin; D019076:Transgenes; D010132:p-Azobenzenearsonate / Q000276:immunology
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D001324:Autoantigens; D002843:Chromatin; D006241:Haptens; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007519:Isoantigens; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; D010132:p-Azobenzenearsonate; D004247:DNA