title: Systemic autoimmunity in BAFF-R-mutant A/WySnJ strain mice.
abstract: Systemic lupus erythematosis is an autoimmune disease of unknown etiology. Lupus pathology is thought to reflect autoantibody-mediated damage due to a failure of B lymphocyte tolerance. Since excessive B cell-activating factor belonging to the TNF family (BAFF) expression correlates with human and murine lupus, and BAFF signals B cell survival through BAFF-R, it is believed that excessive BAFF-R signaling can subvert B cell tolerance and facilitate lupus development. Here we report the unexpected finding that BAFF-R-mutant A/WySnJ mice develop a lupus-like syndrome. These mice carry the B cell maturation defect-1 (Bcmd-1) mutant allele of the Baffr gene. Bcmd-1 causes premature B cell death and profound B cell deficiency. Despite having 90% fewer splenic B cells than normal mice, A/WySnJ mice had an 18-fold increased frequency of splenocytes secreting IgM antibodies to dsDNA, and increased amounts of circulating IgM and IgG to dsDNA by 9 months of age. By age 11 months, most A/WySnJ mice displayed renal pathology characteristic of lupus, including proteinuria as well as periodic acid-Schiff-positive deposits and glomerular capillary bed destruction. Importantly, we genetically linked this autoimmunity to Bcmd-1, since congenic AW.Baffr(+/+) mice carrying a wild-type allele developed none of these phenotypes. Our data provide the first evidence linking altered BAFF-R signaling to the development of B cell-mediated autoimmunity.
authors.affiliation: Department of Genetics, University of Wisconsin Madison, Madison, WI 53706, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mayne
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Amanna
authors.forename: Faye E
authors.initials: FE
authors.lastname: Nashold
authors.forename: Colleen E
authors.initials: CE
authors.lastname: Hayes
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood; D001327:Autoimmune Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053264:B-Cell Activating Factor / Q000378:metabolism; D053265:B-Cell Activation Factor Receptor / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology; D002843:Chromatin / Q000276:immunology; D005260:Female; D006801:Humans; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008817:Mice, Mutant Strains; D009154:Mutation; D011828:Radiation Chimera / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D001323:Autoantibodies; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D002843:Chromatin; C486662:Tnfrsf13c protein, mouse