title: Specificity-based negative selection of autoreactive B cells during memory formation.
abstract: Autoreactive B cells are not completely purged from the primary B cell repertoire, and whether they can be prevented from maturation into memory B cells has been uncertain. We show here that a population of B cells that dominates primary immune responses of BALB/c mice to influenza virus A/PR/8/34 hemagglutinin (HA) are negatively selected in transgenic mice expressing PR8 HA as an abundant membrane-bound Ag (HACII mice). However, a separate population of B cells that contains precursors of memory B cells is activated by PR8 virus immunization and is subsequently negatively selected during the formation of the memory response. Negative selection of PR8 HA-specific B cells altered the specificity of the memory B cell response to a mutant virus containing a single amino acid substitution in a B cell epitope. Strikingly, this skewed reactivity resulted from an increase in the formation of memory B cells directed to non-self-epitopes on the mutant virus, which increased 8-fold in HACII mice relative to nontransgenic mice and precisely compensated for the absence of autoreactive PR8 HA-specific memory B cells. Negative selection of PR8 HA-specific B cells was a dominant process, since B cells from HACII mice could induce negative selection of PR8 HA-specific B cells from BALB/c mice. Lastly, HA-specific memory responses were unaffected by self-tolerance in another lineage of HA-transgenic mice (HA104 mice), indicating that the amount and/or cell type in which self-Ags are expressed can determine their ability to prevent autoreactive memory B cell formation.
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Heath M
authors.initials: HM
authors.lastname: Guay
authors.forename: Laura
authors.initials: L
authors.lastname: Panarey
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Reed
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Caton
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D000921:Antibody-Producing Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000821:virology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002999:Clone Cells; D018985:Epitopes, B-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015322:Gene Rearrangement, B-Lymphocyte; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D007156:Immunologic Memory / Q000235:genetics; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008822:Mice, Transgenic
chemical_list: D000914:Antibodies, Viral; D001323:Autoantibodies; D001324:Autoantigens; D018985:Epitopes, B-Lymphocyte; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D016056:Immunodominant Epitopes; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007252:Influenza Vaccines