Enforced expression of Bcl-2 selectively perturbs negative selection of dual reactive antibodies.
We investigated the role of apoptosis in the development of B cell memory by analyzing the (p-azophenylarsonate) Ars response in a line of A strain mice in which expression of human Bcl-2 was enforced in the B cell compartment. Previous studies of the Ars immune response in these A. Bcl-2 mice, demonstrated that a large percentage of the antibodies expressed by the Ars induced memory B cell compartment had accumulated point mutations via somatic hypermutation that increased their affinity for both Ars and the autoantigen DNA ("dual reactive" antibodies). This was in sharp contrast to normal A strain mice which displayed no dual reactive B cells in their Ars induced memory B cell compartment. These data suggested that interference with apoptotic pathways regulated by Bcl-2 allows developing memory B cells that have acquired autoreactivity to bypass a peripheral tolerance checkpoint. Further studies of these mice, reported here, demonstrate that enforced expression of Bcl-2 does not alter serum antibody affinity maturation nor positive selection of B cells expressing somatically mutated antibody with an increased affinity for Ars. Moreover, the somatic hypermutation process was unaffected in A. Bcl-2 mice. Thus, enforced expression of Bcl-2 in A. Bcl-2 mice appears to selectively alter a negative selection process that operates during memory B cell differentiation.
Notidis
E
E
Department of Microbiology and Immunology and The Kimmel Cancer Institute, Thomas Jefferson Medical College, Philadelphia, PA 19107, USA.
Hande
S
S
Manser
T
T
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000974:Antibodies, Antinuclear / Q000276:immunology; D000915:Antibody Affinity; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D017637:Clonal Deletion; D004247:DNA / Q000276:immunology; D015870:Gene Expression; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007156:Immunologic Memory; D051379:Mice; D008805:Mice, Inbred A; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D027041:Somatic Hypermutation, Immunoglobulin; D013154:Spleen / Q000166:cytology / Q000276:immunology; D010132:p-Azobenzenearsonate / Q000276:immunology*
D000906:Antibodies; D000974:Antibodies, Antinuclear; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D019253:Proto-Oncogene Proteins c-bcl-2; D010132:p-Azobenzenearsonate; D004247:DNA