title: 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)-α (rs2524094) and IFN-γ (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-α and IFN-γ. Finally, we showed that HLA-Cw*0602 transcripts are not increased in psoriatic skin lesions, despite highly elevated TNF-α 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.
authors: St John's Institute of Dermatology, King's College London, Guy's Hospital, London, UK.
authors: Christian
authors: C
authors: Hundhausen
authors: Anna
authors: A
authors: Bertoni
authors: Rose K
authors: RK
authors: Mak
authors: Elisabetta
authors: E
authors: Botti
authors: Paola
authors: P
authors: Di Meglio
authors: Alex
authors: A
authors: Clop
authors: Ute
authors: U
authors: Laggner
authors: Sergio
authors: S
authors: Chimenti
authors: Adrian C
authors: AC
authors: Hayday
authors: Jonathan N
authors: JN
authors: Barker
authors: Richard C
authors: RC
authors: Trembath
authors: Francesca
authors: F
authors: Capon
authors: Frank O
authors: FO
authors: Nestle
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology*; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015236:HLA-C Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D015603:Keratinocytes / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011565:Psoriasis / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D016207:Cytokines; D015236:HLA-C Antigens; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma