Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 132, Issue 3, Pages 635-641Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/jid.2011.378
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Funding
- Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award
- National Institutes of Health [RO1 AR040065]
- Wellcome Trust [GR078173MA]
- Medical Research Council [G0601387, GO700553]
- British Skin Foundation [1006]
- Dunhill Medical Trust
- Generation Trust
- Medical Research Council [MR/J006742/1, G0600698B, G0601387, G0700553] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10379] Funding Source: researchfish
- MRC [G0601387, G0700553] Funding Source: UKRI
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Psoriasis is an inflammatory skin disorder that is inherited as a complex trait. Genetic studies have repeatedly highlighted HLA-C as the major determinant for psoriasis susceptibility, with the Cw*0602 allele conferring significant disease risk in a wide range of populations. Despite the potential importance of HLA-C variation in psoriasis, either via an effect on peptide presentation or immuno-inhibitory activity, allele-specific expression patterns have not been investigated. Here, we used reporter assays to characterize two regulatory variants, which virtually abolished the response to tumor necrosis factor (TNF)-alpha (rs2524094) and IFN-gamma (rs10657191) in HLA-Cw*0602 and a cluster of related alleles. We validated these findings through the analysis of HLA-Cw*0602 expression in primary keratinocytes treated with TNF-alpha and IFN-gamma. Finally, we showed that HLA-Cw*0602 transcripts are not increased in psoriatic skin lesions, despite highly elevated TNF-alpha levels. Thus, our findings demonstrate the presence of allele-specific differences in HLA-C expression and indicate that HLA-Cw*0602 is unresponsive to upregulation by key proinflammatory cytokines in psoriasis. These data pave the way for functional studies into the pathogenic role of the major psoriasis susceptibility allele.
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