title: The NZM2410-derived lupus susceptibility locus Sle2c1 increases Th17 polarization and induces nephritis in fas-deficient mice.
abstract: OBJECTIVE
  Sle2 is a lupus susceptibility locus that has been linked to glomerulonephritis in the NZM2410 mouse. By itself, Sle2 does not induce any autoimmune pathology but results in the accumulation of B-1a cells. This study was designed to assess the contribution of Sle2 to the pathogenesis of autoimmunity.
  
  
  METHODS
  Sle2 or its subcongenic intervals (Sle2a, Sle2b, and Sle2c1) were bred to Fas-deficient B6.lpr mice. Lymphoid phenotypes, which were focused on T cells, were assessed by flow cytometry, and histopathologic changes were compared between cohorts of B6.Sle2.lpr congenic mice and B6.lpr mice of ages up to 6 months.
  
  
  RESULTS
  Sle2 synergized with lpr, resulting in a greatly accelerated lymphadenopathy that largely targeted T cells and mapped to the Sle2c1 locus. This locus has been identified as the main contributor to B-1a cell expansion. Further analyses showed that Sle2c1 expression skewed the differentiation and polarization of Fas-deficient T cells, with a reduction of the CD4+CD25+FoxP3+ regulatory T cell subset and an expansion of the Th17 cells. This was associated with a high number of T cell infiltrates that promoted severe nephritis and dermatitis in the B6.Sle2c1.lpr mice.
  
  
  CONCLUSIONS
  These results show that Sle2c1 contributes to lupus pathogenesis by affecting T cell differentiation in combination with other susceptibility loci, such as lpr. The significance of the cosegregation of this phenotype and B-1a cell expansion in Sle2c1-expressing mice in relation to the pathogenesis of lupus is discussed.
authors.affiliation: University of Florida, Gainesville, FL 32610-0275, USA.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Xu
authors.forename: Carla M
authors.initials: CM
authors.lastname: Cuda
authors.forename: Byron P
authors.initials: BP
authors.lastname: Croker
authors.forename: Laurence
authors.initials: L
authors.lastname: Morel
mesh_terms: D000818:Animals; D016764:Cell Polarity / Q000276:immunology*; D003872:Dermatitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D008206:Lymphatic Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D019463:Mice, Inbred MRL lpr; D008814:Mice, Inbred NZB; D008822:Mice, Transgenic; D013154:Spleen / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D019014:fas Receptor / Q000235:genetics*
chemical_list: D019014:fas Receptor