title: The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T-cell-mediated pathology in B6.Fas(lpr) mice.
abstract: The NZM2410 Sle2c1 lupus susceptibility locus is responsible for the expansion of the B1a cell compartment, and for the induction of T-cell induced renal and skin pathology on a CD95-deficient (Fas(lpr)) background. We have previously shown that deficiency in the cyclin-dependent kinase inhibitor p18(INK4c) (p18) was responsible for the B1a cell expansion but was not sufficient to account for the pathology in B6.lpr mice. This study was designed to map the additional Sle2c1 loci responsible for autoimmune pathology when co-expressed with CD95 deficiency. The production, fine-mapping and phenotypic characterization of five recombinant intervals indicated that three interacting subloci were responsive for inducting autoimmune pathogenesis in B6.lpr mice. One of these subloci corresponds most likely to p18 deficiency. Another major locus mapping to a 2-Mb region at the telomeric end of Sle2c1 is necessary to both renal and skin pathology. Finally, a third locus centromeric to p18 enhances the severity of lupus nephritis. These results provide new insights into the genetic interactions leading to systemic lupus erythematosus disease presentation, and represent a major step towards the identification of novel susceptibility genes involved in T-cell-mediated organ damage.
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610-0275, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Xu
authors.forename: B P
authors.initials: BP
authors.lastname: Croker
authors.forename: L
authors.initials: L
authors.lastname: Morel
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics* / Q000378:metabolism; D004843:Epistasis, Genetic; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D007668:Kidney / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000473:pathology; D051379:Mice; D012867:Skin / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000378:metabolism*; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
chemical_list: C493972:Cdkn2c protein, mouse; D050763:Cyclin-Dependent Kinase Inhibitor p18; C491899:Fas protein, mouse; D019014:fas Receptor