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The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T cell-mediated pathology in B6.Fas(lpr) mice
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 cyclin-dependent kinase inhibitor p18(INK...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2013
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3752316/ https://www.ncbi.nlm.nih.gov/pubmed/23698709 http://dx.doi.org/10.1038/gene.2013.28 |
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author | Xu, Zhiwei Croker, Byron P. Morel, Laurence |
author_facet | Xu, Zhiwei Croker, Byron P. Morel, Laurence |
author_sort | Xu, Zhiwei |
collection | PubMed |
description | 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 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 sub-loci were responsive for inducting autoimmune pathogenesis in B6.lpr mice. One of these sub-loci 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 SLE disease presentation, and represent a major step towards the identification of novel susceptibility genes involved in T-cell mediated organ damage. |
format | Online Article Text |
id | pubmed-3752316 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
record_format | MEDLINE/PubMed |
spelling | pubmed-37523162014-03-01 The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T cell-mediated pathology in B6.Fas(lpr) mice Xu, Zhiwei Croker, Byron P. Morel, Laurence Genes Immun Article 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 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 sub-loci were responsive for inducting autoimmune pathogenesis in B6.lpr mice. One of these sub-loci 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 SLE disease presentation, and represent a major step towards the identification of novel susceptibility genes involved in T-cell mediated organ damage. 2013-05-23 2013-09 /pmc/articles/PMC3752316/ /pubmed/23698709 http://dx.doi.org/10.1038/gene.2013.28 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Xu, Zhiwei Croker, Byron P. Morel, Laurence The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T cell-mediated pathology in B6.Fas(lpr) mice |
title | The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T cell-mediated pathology in B6.Fas(lpr) mice |
title_full | The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T cell-mediated pathology in B6.Fas(lpr) mice |
title_fullStr | The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T cell-mediated pathology in B6.Fas(lpr) mice |
title_full_unstemmed | The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T cell-mediated pathology in B6.Fas(lpr) mice |
title_short | The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T cell-mediated pathology in B6.Fas(lpr) mice |
title_sort | combination of two sle2 lupus-susceptibility loci and cdkn2c deficiency leads to t cell-mediated pathology in b6.fas(lpr) mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3752316/ https://www.ncbi.nlm.nih.gov/pubmed/23698709 http://dx.doi.org/10.1038/gene.2013.28 |
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