title: Colocalization of expansion of the splenic marginal zone population with abnormal B cell activation and autoantibody production in B6 mice with an introgressed New Zealand Black chromosome 13 interval.
abstract: Polyclonal B cell activation is a prominent feature of the lupus-prone New Zealand Black (NZB) mouse strain. We have previously demonstrated linkage between a region on NZB chromosome 13 and increased costimulatory molecule expression on B cells. In this study we have produced C57BL/6 congenic mice with an introgressed homozygous NZB interval extending from approximately 24 to 73 cM on chromosome 13 (denoted B6.NZBc13). We show that B6.NZBc13 female mice not only have enhanced B cell activation but also share many other B cell phenotypic characteristics with NZB mice, including expansion of marginal zone and CD5+ B cell populations, increased numbers of IgM ELISPOTs, and increased serum levels of total IgM and IgM autoantibodies. In addition these mice have increased T cell activation, increased numbers of germinal centers, mild glomerulonephritis, and produce high-titer IgM and IgG anti-chromatin Abs. Male B6.NZBc13 mice have a less pronounced cellular phenotype, lacking expansion of the marginal zone B cell population and IgG anti-chromatin Ab production, indicating the presence of gender dimorphism for this locus. Thus, we have identified a genetic locus that recapitulates with fidelity the B cell phenotypic abnormalities in NZB mice, and we demonstrate that this locus is sufficient to induce an autoimmune phenotype. The data provide further support to the contention that immune abnormalities leading to altered B cell activation and selection contribute to the development of autoimmunity in NZB mice.
authors.affiliation: Arthritis Centre of Excellence, Toronto Western Research Institute, Toronto, Ontario, Canada. jwither@uhnres.utoronto.ca
authors.forename: Joan E
authors.initials: JE
authors.lastname: Wither
authors.forename: Christina
authors.initials: C
authors.lastname: Loh
authors.forename: Ginette
authors.initials: G
authors.lastname: Lajoie
authors.forename: Svinda
authors.initials: S
authors.lastname: Heinrichs
authors.forename: Yong-Chun
authors.initials: YC
authors.lastname: Cai
authors.forename: Gabriel
authors.initials: G
authors.lastname: Bonventi
authors.forename: Ralph
authors.initials: R
authors.lastname: MacLeod
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002874:Chromosome Mapping; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D020297:Mice, Congenic; D008814:Mice, Inbred NZB; D013154:Spleen / Q000166:cytology / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D001323:Autoantibodies