| 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. Conclusion 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. |
