Dataset Information

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.

SUBMITTER: Xu Z

PROVIDER: S-EPMC3752316 | biostudies-other | 2013 Sep

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T-cell-mediated pathology in B6.Fas(lpr) mice.

Xu Z Z Croker B P BP Morel L L

Genes and immunity 20130523 6

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 ...[more]

PMID: 23698709

Similar Datasets

Project description:Previous studies showed that loss of tumor necrosis factor ? (TNF?) signaling delayed fracture healing by delaying chondrocyte apoptosis and cartilage resorption. Mechanistic studies showed that TNF? induced Fas expression within chondrocytes; however, the degree to which chondrocyte apoptosis is mediated by TNF? alone or dependent on the induction of Fas is unclear. This question was addressed by assessing fracture healing in Fas-deficient B6.MRL/Fas(lpr) /J mice. Loss of Fas delayed cartilage resorption but also lowered bone fraction in the calluses. The reduced bone fraction was related to elevated rates of coupled bone turnover in the B6.MRL/Fas(lpr) /J calluses, as evidenced by higher osteoclast numbers and increased osteogenesis. Analysis of the apoptotic marker caspase 3 showed fewer positive chondrocytes and osteoclasts in calluses of B6.MRL/Fas(lpr) /J mice. To determine if an active autoimmune state contributed to increased bone turnover, the levels of activated T cells and Treg cells were assessed. B6.MRL/Fas(lpr) /J mice had elevated Treg cells in both spleens and bones of B6.MRL/Fas(lpr) /J but decreased percentage of activated T cells in bone tissues. Fracture led to ?30% to 60% systemic increase in Treg cells in both wild-type and B6.MRL/Fas(lpr) /J bone tissues during the period of cartilage formation and resorption but either decreased (wild type) or left unchanged (B6.MRL/Fas(lpr) /J) the numbers of activated T cells in bone. These results show that an active autoimmune state is inhibited during the period of cartilage resorption and suggest that iTreg cells play a functional role in this process. These data show that loss of Fas activity specifically in chondrocytes prolonged the life span of chondrocytes and that Fas synergized with TNF? signaling to mediate chondrocyte apoptosis. Conversely, loss of Fas systemically led to increased osteoclast numbers during later periods of fracture healing and increased osteogenesis. These findings suggest that retention of viable chondrocytes locally inhibits osteoclast activity or matrix proteolysis during cartilage resorption.

Project description:Previous studies have reported that deletion of the transcription factor, early growth response protein 2 (EGR2), in normal C57BL/6 (B6) resulted in the development of lupus-like autoimmune disease. However, increased EGR2 expression has been noted in human and murine lupus, which challenges the notion of the autoimmune suppressive role of EGR2 in B6 mice. In this study, we derived both conditional EGR2-/-B6/lpr and EGR2-/-B6 mice to elucidate the immune and autoimmune regulatory roles of EGR2 in autoinflammation (B6/lpr) versus physiologically normal (B6) conditions. We found that conditional EGR2 deletion increased spleen weight, enhanced T cell activation and IFNγ production, and promoted germinal center B cells and LAG3+ regulatory T cells development in both B6/lpr and B6 mice. Nevertheless, EGR2 deletion also showed strikingly differential effects in these two strains on T lymphocyte subsets profile, Foxp3+ Tregs and plasma cell differentiation, anti-dsDNA autoantibodies and immunoglobulins production, and on the induction of IL-17 in in vitro activated splenocytes. Specifically, EGR2 deletion in B6/lpr mice significantly decreased serum levels of anti-dsDNA autoantibodies, total IgG, IgM, IgG1, and IgG2a with reduced plasma cells differentiation. Furthermore, EGR2 deletion in B6/lpr mice had no obvious effect on IgG immunocomplex deposition, medium caliber vessel, and glomeruli inflammation but increased complement C3 immunocomplex deposition and large caliber vessel inflammation in the kidneys. Importantly, we demonstrated that EGR2 deletion in B6/lpr mice significantly reduced pathogenic CD4-CD8-CD3+B220+ double negative T cells, which correlated with the reduced anti-dsDNA autoantibodies in serum and decreased IL-17 production in splenocytes of EGR2-/-B6/lpr mice. Together, our data strongly suggest that the role of EGR2 is complex. The immunoregulatory role of EGR2 varies at normal or autoinflammation conditions and should not be generalized in differential experimental settings.

Dataset Information

The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T-cell-mediated pathology in B6.Fas(lpr) mice.

Publications

The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T-cell-mediated pathology in B6.Fas(lpr) mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets