The autoimmune disease-associated SNP rs917997 of IL18RAP controls IFNγ production by PBMC.
The autoimmune disease-associated SNP rs917997 of IL18RAP controls IFNγ production by PBMC.
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DOI：
10.1016/j.jaut.2013.06.001
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发表时间：
2013-08
影响因子：
12.8
通讯作者：
Atkinson MA
中科院分区：
文献类型：
--
作者：
Myhr CB;Hulme MA;Wasserfall CH;Hong PJ;Lakshmi PS;Schatz DA;Haller MJ;Brusko TM;Atkinson MA
1型糖尿病（T1D）是一种以异常T细胞反应为特征的自身免疫性疾病。先天免疫激活缺陷可能促进T辅助1 （Th1）表型。细胞因子IL-18与IL-12协同诱导IFNγ产生和Th1分化。IL-18R亚基（IL18RAP） SNP rs917997与IL18RAP基因表达降低有关。先前的报道将rs917997等位基因A与T1D的保护联系起来，相反地与乳糜泻的易感性联系起来。然而，很少有研究研究IL-18在T1D中的通路。在本研究中，我们分析了T1D对IL-18的响应性，以及rs917997基因型对激活后IL18RAP基因表达的影响。在IL-12和IL-18处理后，携带rs917997易感等位基因的受试者外周血单个核细胞产生的IFNγ水平高于具有保护性基因型的受试者。此外，该SNP修饰了NK细胞和活化T细胞中IL18RAP表面蛋白的表达。综上所述，这些数据表明疾病相关的rs917997等位基因G允许对IL-18的高反应性，为T1D的治疗干预提供了新的靶点。
Type 1 Diabetes (T1D) is an autoimmune disorder characterized by aberrant T cell responses. Innate immune activation defects may facilitate a T helper 1 (Th1) phenotype. The cytokine IL-18 synergizes with IL-12 to induce IFNγ production and Th1 differentiation. The IL-18R subunit (IL18RAP) SNP rs917997 has been linked to decreased IL18RAP gene expression. Prior reports link rs917997 allele A with protection from T1D, and conversely with susceptibility to Celiac disease. However, few studies have investigated the IL-18 pathway in T1D. In this study, we analyzed responsiveness to IL-18 in T1D, and the effect of rs917997 genotype on IL18RAP gene expression post-activation. Upon IL-12 and IL-18 treatment, peripheral blood mononuclear cells from subjects carrying susceptibility alleles at rs917997 produced higher levels of IFNγ than those with protective genotypes. Additionally, the SNP modified IL18RAP surface protein expression by NK cells and gene expression in activated T cells. Taken together, these data suggest that the disease-associated rs917997 allele G permits hyperresponsiveness to IL-18, providing a novel target for therapeutic intervention in T1D.