The IL23R A/Gln381 allele promotes IL-23 unresponsiveness in human memory T-helper 17 cells and impairs Th17 responses in psoriasis patients.

We and others have shown that the minor, nonconserved allele Gln381 of the Arg381Gln single-nucleotide polymorphism (rs11209026G>A) of the IL-23 receptor gene (IL23R) protects against psoriasis. Moreover, we have recently shown impaired IL-23-induced IL-17A production and STAT-3 phosphorylation in Th17 cells generated in vitro from healthy individuals heterozygous for the protective A allele (GA). However, the biological effect of this variant has not been determined in homozygous carriers of the protective A allele (AA), nor in psoriatic patients. Here we expand our functional investigation of the IL23R Arg381Gln gene variant to include AA homozygous individuals. By using isolated memory CD4+ T cells, we found attenuated IL-23-induced Th17 response in heterozygous individuals. Moreover, we found that AA homozygous individuals were strikingly unresponsive to IL-23, with minimal or no IL-17A and IL-17F production and failure of human memory Th17 cell survival/expansion. Finally, IL-23-induced Th17 response was also attenuated in age- and sex-matched GA versus GG psoriatic patients undergoing systemic treatment. Taken together, our data provide evidence for an allele-dosage effect for IL-23R Gln381 and indicate that common gene alleles associated with complex diseases might have biological effects of considerable magnitude in homozygous carriers.

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

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.

Lower incidence of sesquiterpene lactone sensitivity in a population in Asia versus a population in Europe: an effect of chrysanthemum tea?

Sesquiterpene lactones (SLs) (Fig. 1) are an important cause of allergic plant contact dermatitis but are uncommon in the Far East. They belong to the Compositae family of plants. Sensitivity to SL may be airborne or via the topical route [topical herbal remedies, cosmetic products, and in many occupations such as gardeners and florists].

Oral tolerance to contact allergens: a common occurrence? A review.

Experimental and clinical oral tolerance to contact allergens has been reported sporadically, most notably in respect of nickel, and is generally assumed to be an uncommon phenomenon. There has recently been increased understanding of the immunological mechanisms inducing and maintaining oral tolerance. There are several contact allergens, including fragrance, antioxidant, and preservative chemicals, to which subjects are exposed through both cutaneous and oral routes. We examine the possibility that oral tolerance to contact allergens may be more common than previously thought. Animal models of oral tolerance to contact allergens indicate that cutaneous exposure to small, subsensitizing doses of contact allergens might negate any subsequent attempts to induce tolerance by oral administration. Extrapolating these observations to common human practises raises the possibility that application of contact allergens (fragrances, preservatives and antioxidants) in consumer products used by children could prevent or inhibit the later acquisition of specific tolerance resulting from 'natural' dietary exposure after weaning. Existing data on formaldehyde may conflict with this theory, though this could be explained by allergen specificity. We propose that further work in this area is needed.