Department of Bioinformatics and Computational Biology, Genentech Inc, South San Francisco, California, United States of America.
PLoS One. 2011;6(10):e25038. doi: 10.1371/journal.pone.0025038. Epub 2011 Oct 12.
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 IL23R(R381) and IL23R(Q381) 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. IL23R(Q381) 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 IL23R(Q381) positive donors. Our study shows conclusively that IL23R(Q381) 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.
全基因组关联研究（GWAS）在多个群体中表明，IL23R 基因与 IBD（克罗恩病（CD）和溃疡性结肠炎（UC））和银屑病显著相关，表明 IL-23 信号通路的失调与这些疾病的病理生理学有关。一个特定的变体，R381Q（rs11209026），强烈地保护免受 CD 的发展。我们研究了这种变体在携带 IL23R（R381）和 IL23R（Q381）单倍型的健康供体的原代 T 细胞中的作用。使用专有的抗 IL23R 抗体、ELISA、流式细胞术、磷酸化流式和实时 RT-PCR 方法，我们检查了 IL23R 表达和 STAT3 磷酸化及其对 IL-23 的反应。IL23R（Q381）与 IL-23 刺激后的 STAT3 磷酸化减少和 IL-23 反应性 T 细胞数量减少有关。我们还观察到 IL23R（Q381）阳性供体中促炎细胞因子分泌水平略有降低。我们的研究明确表明，IL23R（Q381）是一个功能丧失的等位基因，进一步加强了 GWAS 结果的暗示，即 IL-23 途径在人类疾病中是致病的。这些数据为 R381Q 在 CD 中的保护作用提供了一个解释，并可能导致开发针对 CD 等自身免疫性疾病的改良治疗方法。
