Bcl-2 obstructs negative selection of autoreactive, hypermutated antibody V regions during memory B cell development.
We analyzed the participation of a predominant B cell clonotype in the anti-arsonate immune response of mice in which Bcl-2 expression was enforced in B cells. Many of the antibodies expressed by the arsonate-induced memory compartment of these mice were "dual-reactive," displaying increased affinity acquired via V region somatic hypermutation for both arsonate and the autoantigen DNA. The hypermutated antibodies expressed by the anti-arsonate memory B cell compartment of normal mice have increased affinity for arsonate but lack measurable affinity for DNA. Thus, interference with apoptotic pathways allows developing memory B cells that have acquired autoreactivity to bypass a peripheral tolerance checkpoint. These data demonstrate that both positive and negative selection, working in concert with V gene somatic hypermutation, result in the "specificity maturation" of the antibody response.
Hande
S
S
Department of Microbiology and Immunology and The Kimmel Cancer Institute, Thomas Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Notidis
E
E
Manser
T
T
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics; D017209:Apoptosis; D015551:Autoimmunity / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology*; D002467:Cell Nucleus / Q000473:pathology; D017637:Clonal Deletion; D016384:Consensus Sequence; D004247:DNA / Q000276:immunology; D004277:DNA, Single-Stranded / Q000276:immunology; D006241:Haptens / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007156:Immunologic Memory; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D017386:Sequence Homology, Amino Acid; D013154:Spleen / Q000166:cytology / Q000276:immunology; D010132:p-Azobenzenearsonate / Q000276:immunology
D000911:Antibodies, Monoclonal; D004277:DNA, Single-Stranded; D006241:Haptens; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D019253:Proto-Oncogene Proteins c-bcl-2; D010132:p-Azobenzenearsonate; D004247:DNA