title: Activation-induced cytidine deaminase mediates central tolerance in B cells.
abstract: The Aicda gene product, activation-induced cytidine deaminase (AID), initiates somatic hypermutation, class-switch recombination, and gene conversion of Ig genes by the deamination of deoxycytidine, followed by error-prone mismatch- or base-excision DNA repair. These processes are crucial for the generation of genetically diverse, high affinity antibody and robust humoral immunity, but exact significant genetic damage and promote cell death. In mice, physiologically significant AID expression was thought to be restricted to antigen-activated, mature B cells in germinal centers. We now demonstrate that low levels of AID in bone marrow immature and transitional B cells suppress the development of autoreactivity. Aicda(-/-) mice exhibit significantly increased serum autoantibody and reduced capacity to purge autoreactive immature and transitional B cells. In vitro, AID deficient immature/transitional B cells are significantly more resistant to anti-IgM-induced apoptosis than their normal counterparts. Thus, early AID expression plays a fundamental and unanticipated role in purging self-reactive immature and transitional B cells during their maturation in the bone marrow.
authors.affiliation: Department of Immunology, Duke University, Durham, NC 27710, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kuraoka
authors.forename: T Matt
authors.initials: TM
authors.lastname: Holl
authors.forename: Dongmei
authors.initials: D
authors.lastname: Liao
authors.forename: Mandy
authors.initials: M
authors.lastname: Womble
authors.forename: Derek W
authors.initials: DW
authors.lastname: Cain
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Reynolds
authors.forename: Garnett
authors.initials: G
authors.lastname: Kelsoe
mesh_terms: D000818:Animals; D017209:Apoptosis; D001323:Autoantibodies / Q000097:blood; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D023201:CD40 Ligand / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation; D003564:Cytidine Deaminase / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D005260:Female; D050438:Genes, Immunoglobulin Heavy Chain; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D027041:Somatic Hypermutation, Immunoglobulin; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D001323:Autoantibodies; D011947:Receptors, Antigen, B-Cell; D023201:CD40 Ligand; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase