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 Fasdeficient 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.

Glucose Oxidation Is Critical for CD4+ T Cell Activation in a Mouse Model of Systemic Lupus Erythematosus

“…GN was scored semi-quantitatively in a blind fashion by a renal pathologist (BPC) as previously described (25). Briefly, the type of lesion was scored by order of increasing severity: none, mesangial matrix (Mm), mesangial cellular (Mc) and proliferative global (Pg) GN and the extent of the lesions was score on a scale 1 to 4.…”

“…Briefly, the type of lesion was scored by order of increasing severity: none, mesangial matrix (Mm), mesangial cellular (Mc) and proliferative global (Pg) GN and the extent of the lesions was score on a scale 1 to 4. The glomerular deposition of C3 and IgG immune complexes was performed on frozen kidney sections as previously described (25). Glomerular size and the extent of C3 or IgG deposits were measured from sections averaging 3–6 glomeruli per sample, using Metamorph 7.5 (BioImaging Solutions).…”

Animal Models of Molecular Pathology

“…267 Renal pathology has also been associated with infiltration of IL-17-producing CD4 þ Tcells in the B6.Sle2c1.lpr strain that combined an NZM2410 susceptibility locus with the lpr mutation. 268 Moreover, the interruption of IL-23 signaling, which is essential for Th17 development and stabilization, abrogated the lupus phenotypes in B6/lpr mice with a reduction of DNT cells and their concomitant IL-17 production, showing a role of IL-23/IL-17 axis in lupus. 269 In the NZM2328 model, the disruption of TNFa signaling exacerbated lupus, which was associated with an expansion of IL-17-producing effector/memory CD4 þ T cells.…”

The Murine Pbx1-d Lupus Susceptibility Allele Accelerates Mesenchymal Stem Cell Differentiation and Impairs Their Immunosuppressive Function

“…Immune cell subset distribution and activation were analyzed by flow cytometry of splenocytes. Renal pathology was scored from H&E and periodic acidSchiff stains as previously described (31). Briefly, glomerulonephritis (GN) was scored on a semiquantitative 0-4 scale, and qualified as mesangial or proliferative.…”

“…who did not have knowledge of the treatment status. The glomerular deposition of C3 and IgG2a immune complexes was performed on frozen kidney sections and scored as previously described (31). Glomerular size and the extent of C3 deposition were measured from anti-C3-stained sections averaging four to six glomeruli per sample using the Metamorph 7.5 image analysis software (Molecular Devices, Downingtown, PA).…”