The IL23R A/Gln381 Allele Promotes IL-23 Unresponsiveness in Human Memory T-Helper 17 Cells and Impairs Th17 Responses in Psoriasis Patients

Abstract

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.

Inflammatory pathways in spondyloarthritis

“…The protective variant rs11209026 results in a R381Q substitution and functional studies in healthy individuals showed the variant to be a loss of function leading to impaired Th17 effector responses (Di Meglio et al, 2011;Pidasheva et al, 2011;Sarin et al, 2011). In concordance with these data, recent studies showed that genetic variations in genes involved in the IL-23 signalling pathway influence the effector function of Th17 and Th1 cells in patients with AS and in patients with the related skin disease psoriasis (Coffre et al, 2013;Di Meglio et al, 2013). Interestingly, SNPs in IL-23R as well as in IL-23 are also associated with PsA, a distinct phenotypic subset of SpA (Bowes et al, 2011;Filer et al, 2008).…”

Association with Genetic Variants in the IL-23 and NF-κB Pathways Discriminates between Mild and Severe Psoriasis Skin Disease

“…Several studies have previously highlighted the importance of genes and haplotypes in both the IL-23 as well as the NF-B pathways in psoriasis (Nair et al, 2009;Safrany et al, 2011;Safrany et al, 2013) as well as in many other immune-mediated diseases; PsA (Di Meglio et al, 2013;Eiris et al, 2014;Nair et al, 2010;Cargill et al, 2007;Franke et al, 2010;Strange et al, 2010;Bowes et al, 2011;Liu et al, 2008;Popa et al, 2013;Wang et al, 2012;Capon et al, 2007), Crohn's disease (Chua et al, 2012;Dinu et al, 2012;Jung et al, 2012), inflammatory bowel disease (Duerr et al, 2006;Safrany et al, 2013), ankylosing spondylitis (Safrany et al, 2009), celiac disease and multiple sclerosis (Nunez et al, 2008).…”

Regulation of Memory T Cells by Interleukin-23

“…However, IFN-γ secretion by R381Q IL23R memory T cells was not affected. Additionally, the presence of R381Q IL23R gene polymorphism has been associated with unresponsiveness to IL-23 by human memory Th17 cells, impairing the Th17 response in psoriasis patients [46]. …”