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 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 up-regulation by key pro-inflammatory cytokines in psoriasis. These data pave the way for functional studies into the pathogenic role of the major psoriasis susceptibility allele.

Cell Surface Expression of HLA-Cw6 by Human Epidermal Keratinocytes: Positive Regulation by Cytokines, Lack of Correlation to a Variant Upstream of HLA-C

“…After stimulation with various cytokines, HLA-C expression was shown to be highly inducible in keratinocytes by a mix of the Th1-cytokine IFN-γ and the pro-inflammatory cytokines IL-1α and TNF-α (hereafter referred to as Th1-cytokine mix). The induction was largely dependent on IFN-γ (Figure 1a), which is in accordance with previously reported data (Hundhausen et al, 2012). In addition, we also analyzed HLA-C*06:02 mRNA presented herein may be required for to upregulate HLA-C*06:02 expression in keratinocytes.…”

Immunology of Psoriasis

“…PSORS1 lies within the class I region of the MHC, and there is consensus that HLA-C is the most likely PSORS1 gene (105). The exact functional implications of alleles at this locus are not yet fully known, although there appear to be allele-specific differences in HLA-C expression and regulation by cytokines in psoriasis (107). Given our understanding that HLA class I molecules are important for antigen presentation to CD8 + T cells, this locus links the genetics of psoriasis with the immunological basis of the disease.…”

Psoriasis

“…Nevertheless, sequence and haplotype analysis (Nair et al 2006), genome-wide association studies (GWASs) Strange et al 2010;Tsoi et al 2012), and analysis of high-density single-nucleotide polymorphism (SNP) data, further refining PSORS1 interval to a 179-kb region encompassing HLA-C (Clop et al 2013), have consistently indicated HLA-C as the most likely PSORS1 gene. SNPs within the minimal promoter region of HLA-C result in differential expression of various alleles, including HLA-Cw à 0602 (Hundhausen et al 2012). Moreover, regulatory variants in the putative HLA-C enhancer element are also likely to contribute to psoriasis susceptibility by affecting HLA-C expression (Clop et al 2013).…”