title: Murine lupus susceptibility locus Sle2 activates DNA-reactive B cells through two sub-loci with distinct phenotypes.
abstract: The NZM2410-derived Sle2 lupus susceptibility locus induces an abnormal B-cell differentiation, which most prominently leads to the expansion of autoreactive B1a cells. We have mapped the expansion of B1a cells to three Sle2 sub-loci, Sle2a, Sle2b and Sle2c. Sle2 also enhances the breach of B-cell tolerance to nuclear antigens in the 56R anti-DNA immunoglobulin transgenic (Tg) model. This study used the Sle2 sub-congenic strains to map the activation of 56R Tg B cells. Sle2c strongly sustained the breach of tolerance and the activation of anti-DNA B cells. The production of Tg-encoded anti-DNA antibodies was more modest in Sle2a-expressing mice, but Sle2a was responsible for the recruitment for Tg B cells to the marginal zone, a phenotype that has been found for 56R Tg B cells in mice expressing the whole Sle2 interval. In addition, Sle2a promoted the production of endogenously encoded anti-DNA antibodies. Overall, this study showed that at least two Sle2 genes are involved in the activation of anti-DNA B cells, and excluded more than two-thirds of the Sle2 interval from contributing to this phenotype. This constitutes an important step toward the identification of novel genes that have a critical role in B-cell tolerance.
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610-0275, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zeumer
authors.forename: A
authors.initials: A
authors.lastname: Sang
authors.forename: H
authors.initials: H
authors.lastname: Niu
authors.forename: L
authors.initials: L
authors.lastname: Morel
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D023061:Gene Order; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D007132:Immunoglobulin Isotypes / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D008822:Mice, Transgenic; D010641:Phenotype; D040641:Quantitative Trait Loci / Q000235:genetics*; D013154:Spleen / Q000276:immunology
chemical_list: D000974:Antibodies, Antinuclear; D007132:Immunoglobulin Isotypes