title: Autoreactive MZ and B-1 B-cell activation by Faslpr is coincident with an increased frequency of apoptotic lymphocytes and a defect in macrophage clearance.
abstract: Murine autoreactive anti-Smith (Sm) B cells are negatively regulated by anergy and developmental arrest, but are also positively selected into the marginal zone (MZ) and B-1 B-cell populations. Despite positive selection, anti-Sm production occurs only in autoimmune-prone mice. To investigate autoreactive B-cell activation, an anti-Sm transgene was combined with the lpr mutation, a mutation of the proapoptotic gene Fas (Fas(lpr)), on both autoimmune (MRL) and nonautoimmune backgrounds. Fas(lpr) induces a progressive and autoantigen-specific loss of anti-Sm MZ and B-1 B cells in young adult Fas(lpr) and MRL/Fas(lpr) mice that does not require that Fas(lpr) be B-cell intrinsic. This loss is accompanied by a bypass of the early pre-plasma cell (PC) tolerance checkpoint. Although the MRL bkg does not lead to a progressive loss of anti-Sm MZ or B-1 B cells, it induces a robust bypass of the early pre-PC tolerance checkpoint. Fas(lpr) mice have a high frequency of apoptotic lymphocytes in secondary lymphoid tissues and a macrophage defect in apoptotic cell phagocytosis. Since Sm is exposed on the surface of apoptotic cells, we propose that anti-Sm MZ and B-1 B-cell activation is the result of a Fas(lpr)-induced defect in apoptotic cell clearance.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, 27599, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Qian
authors.forename: Kara L
authors.initials: KL
authors.lastname: Conway
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Lu
authors.forename: Heather M
authors.initials: HM
authors.lastname: Seitz
authors.forename: Glenn K
authors.initials: GK
authors.lastname: Matsushima
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Clarke
mesh_terms: D000818:Animals; D000917:Antibody Formation; D017209:Apoptosis; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008214:Lymphocytes / Q000166:cytology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation / Q000276:immunology; D010587:Phagocytosis; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*
chemical_list: D019014:fas Receptor