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Allele-specific cytokine responses at the HLA-C locus: implications for psoriasis.


ABSTRACT: 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)-? (rs2524094) and IFN-? (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-? and IFN-?. Finally, we showed that HLA-Cw*0602 transcripts are not increased in psoriatic skin lesions, despite highly elevated TNF-? 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.

SUBMITTER: Hundhausen C 

PROVIDER: S-EPMC3620929 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Allele-specific cytokine responses at the HLA-C locus: implications for psoriasis.

Hundhausen Christian C   Bertoni Anna A   Mak Rose K RK   Botti Elisabetta E   Di Meglio Paola P   Clop Alex A   Laggner Ute U   Chimenti Sergio S   Hayday Adrian C AC   Barker Jonathan N JN   Trembath Richard C RC   Capon Francesca F   Nestle Frank O FO  

The Journal of investigative dermatology 20111124 3 Pt 1


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 re  ...[more]

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