Functional Studies on the IBD Susceptibility Gene IL23R Implicate Reduced Receptor Function in the Protective Genetic Variant R381Q

Abstract

Genome-wide association studies (GWAS) in several populations have demonstrated significant association of the IL23R gene with IBD (Crohn's disease (CD) and ulcerative colitis (UC)) and psoriasis, suggesting that perturbation of the IL-23 signaling pathway is relevant to the pathophysiology of these diseases. One particular variant, R381Q (rs11209026), confers strong protection against development of CD. We investigated the effects of this variant in primary T cells from healthy donors carrying IL23RR381 and IL23RQ381 haplotypes. Using a proprietary anti-IL23R antibody, ELISA, flow cytometry, phosphoflow and real-time RT-PCR methods, we examined IL23R expression and STAT3 phosphorylation and activation in response to IL-23. IL23RQ381 was associated with reduced STAT3 phosphorylation upon stimulation with IL-23 and decreased number of IL-23 responsive T-cells. We also observed slightly reduced levels of proinflammatory cytokine secretion in IL23RQ381 positive donors. Our study shows conclusively that IL23RQ381 is a loss-of-function allele, further strengthening the implication from GWAS results that the IL-23 pathway is pathogenic in human disease. This data provides an explanation for the protective role of R381Q in CD and may lead to the development of improved therapeutics for autoimmune disorders like CD.

Protective role of R381Q (rs11209026) polymorphism in IL-23R gene in immune-mediated diseases: A comprehensive review

“…suggested that IL-23R RQ381 exerted its protective effects by attenuation of IL-23-induced T H 17 functions (IL-17A production) without interfering with T H 17 differentiation (Pidasheva et al 2011). Further, Sarin et al (2011) showed that CD4 + CD45RO…”

“…On activation by IL-23, IL23R signals through a JAK/STAT pathway. IL23R associates constitutively with JAK2 (Pidasheva et al 2011). JAK proteins generally associate through their 4.1, ezrin, radixin, moesin (FERM) domains with membrane proximal regions of cytokine receptors.…”

“…Recent studies have shown that untransformed polyclonal IL-23 RQ381 + T-cell lines had a decreased number of IL-23R + cells and, thus, reduced responsiveness to IL-23 as compared to IL-23R R381 T-cell lines (Pidasheva et al 2011). A allele of the IL-23R R381Q gene variant suggested that its protective effect against autoimmune disease was driven by an impairment of T H 17 cell effector functions, i.e.…”

Association between lower frequency of R381Q variant (rs11209026) in IL-23 receptor gene and increased risk of recurrent spontaneous abortion (RSA)

“…JAK2 then phosphorylates STAT3 which then homodimerizes and translocates to the nucleus and triggers expression of cytokines, including IL-17A and IL-17F in T H 17 cells. Thus, IL-23 acts as a mediator of T H 17 cytokine production (Pidasheva et al, 2011;Safrany et al, 2013 (Guan et al, 2012). Some studies have indicated that R381Q variants confer protection from inflammatory diseases, including ankylosing spondylitis, psoriasis, and inflammatory bowel disease (Liu et al, 2010;Pidasheva et al, 2011).…”

“…Thus, IL-23 acts as a mediator of T H 17 cytokine production (Pidasheva et al, 2011;Safrany et al, 2013 (Guan et al, 2012). Some studies have indicated that R381Q variants confer protection from inflammatory diseases, including ankylosing spondylitis, psoriasis, and inflammatory bowel disease (Liu et al, 2010;Pidasheva et al, 2011). With this regards, because RSA is related to inflammatory factors (IL-17 and IL-23) and T H 17 cells and the R381Q SNP can act as a regulator of inflammation, it occurred to us that there could be a relationship between expression of this SNP and the incidence of RSA in women.…”