title: Elimination of germinal-center-derived self-reactive B cells is governed by the location and concentration of self-antigen.
abstract: Secondary diversification of the B cell repertoire by immunoglobulin gene somatic hypermutation in the germinal center (GC) is essential for providing the high-affinity antibody specificities required for long-term humoral immunity. While the risk to self-tolerance posed by inadvertent generation of self-reactive GC B cells has long been recognized, it has not previously been possible to identify such cells and study their fate. In the current study, self-reactive B cells generated de novo in the GC failed to survive when their target self-antigen was either expressed ubiquitously or specifically in cells proximal to the GC microenvironment. By contrast, GC B cells that recognized rare or tissue-specific self-antigens were not eliminated, and could instead undergo positive selection by cross-reactive foreign antigen and produce plasma cells secreting high-affinity autoantibodies. These findings demonstrate the incomplete nature of GC self-tolerance and may explain the frequent association of cross-reactive, organ-specific autoantibodies with postinfectious autoimmune disease.
authors.affiliation: Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Tyani D
authors.initials: TD
authors.lastname: Chan
authors.forename: Katherine
authors.initials: K
authors.lastname: Wood
authors.forename: Jana R
authors.initials: JR
authors.lastname: Hermes
authors.forename: Danyal
authors.initials: D
authors.lastname: Butt
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Jolly
authors.forename: Antony
authors.initials: A
authors.lastname: Basten
authors.forename: Robert
authors.initials: R
authors.lastname: Brink
mesh_terms: D000818:Animals; D000915:Antibody Affinity / Q000235:genetics / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D060833:Cellular Microenvironment / Q000235:genetics / Q000276:immunology; D006224:Cricetinae; D003429:Cross Reactions; D005803:Genes, Immunoglobulin; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000276:immunology
chemical_list: D001324:Autoantigens