Altered CD4+ T cell function in relation to the AHI1 MS locus

项目总结/摘要 多发性硬化症（MS）是一种炎症性和神经退行性疾病，其具有遗传性和神经变性。 环境因素对易感性的影响。应用全基因组无偏遗传算法鉴定易感基因座 关联研究（GWAS）是多发性硬化症（MS）的一个重要进展，但我们还不了解 等位基因变异如何影响免疫功能。这一过渡仍然是联合国面临的一个重大挑战。 了解MS和其他人类自身免疫性疾病。越来越多的证据表明， 自身反应性CD 4 + T细胞在MS病理生理学中起中心作用。我们对110个经验证的MS的评价 一个使用健康基因型成人队列的易感性基因座鉴定了改变邻近基因的MS变体， 在幼稚的CD 4 + T细胞中表达。我们很快将注意力集中在rs6908428单核苷酸上， 位于Abelson辅助整合位点1（AHI 1）转录起始位点附近的SNP 基因，因为（i）该基因座与MS易感性强相关（p=1.8 x 10-20），（ii） 与可能包含因果变异的最高SNP处于强连锁不平衡（LD）的SNP很小 （n=11），（iii）易感性等位基因rs6908428 A对AHI 1的RNA表达具有强烈影响（1.12 × 10-107） 而不是在CD 4 + T细胞中的相邻基因上（不是巧合的重叠），（iv）AHI 1表达在CD 4 + T细胞中被诱导， 致病性白细胞介素（IL）-17A-产生T细胞（Th 17）参与MS发病机制， （v）我们发现Ahi 1/AHI 1与磷脂酶C（PLC）γ1结合 药理学抑制PLCγ1抑制人Th 17细胞增殖， 女士最后，在MS患者中，与对照组相比，来自MS患者的CD 4 + T细胞中AHI 1 RNA表达升高。 健康受试者以及疾病活动性较高的MS患者的PBMC中。 本课题的主要目标是：（1）鉴定和体外、离体研究 验证参与调节CD 4 + T细胞中AHI 1转录的致病变体，（2）分析 Ahi 1在小鼠CD 4 + T细胞中的功能及其对MS小鼠模型中致脑炎性的影响，和（3） 分析AHI 1对基因分型的健康受试者（n=100）中人Th 17细胞中基因网络的影响，以及 醋酸格拉替雷治疗的MS患者（n=100）。因此，我们提出了一种多方面的方法， 遗传和人类功能免疫学实验，以了解易感基因座如何改变状态 激活致病性Th 17以调节对MS的易感性并加重疾病的严重程度。

Project Summary/Abstract Multiple sclerosis (MS) is both an inflammatory and neurodegenerative disease that has genetic and environmental components to susceptibility. The identification of susceptibility loci by unbiased genome-wide association studies (GWAS) is a major step forward in multiple sclerosis (MS), but we do not yet understand how allelic variation influences immune function. This transition remains a major challenge in the understanding of MS and of other human autoimmune diseases. Increasing evidence suggests that autoreactive CD4+ T cells play a central role in MS pathophysiology. Our evaluation of the 110 validated MS susceptibility loci using a cohort of healthy genotyped adults identified MS variants that alter nearby gene expression in naïve CD4+ T cells. We quickly focused our attention on the rs6908428 single nucleotide polymorphism (SNP) located near the transcription start site of the Abelson helper Integration site 1 (AHI1) gene because (i) this locus is robustly associated with MS susceptibility (p=1.8 x 10-20), (ii) the “credible set” of SNPs in strong linkage disequilibrium (LD) with the top SNP that may contain the causal variant is small (n=11), (iii) the susceptibility allele rs6908428A has a strong effect on RNA expression of AHI1 (1.12 x 10-107) but not on neighboring genes in CD4+ T cells (not a coincidental overlap), (iv) AHI1 expression is induced in pathogenic interleukin (IL)-17A-producing T cells (Th17) that are implicated in MS pathogenesis and are well characterized in the laboratory and (v) we have discovered that Ahi1/AHI1 binds phospholipase C (PLC)γ1 and that pharmacological inhibition of PLCγ1 suppresses human Th17 cell proliferation and a mouse model of MS. Finally, in MS patients, AHI1 RNA expression is elevated in CD4+ T cells from MS patients compared to healthy subjects, as well as in PBMCs of MS patients with a higher disease activity. The principal goals of the proposed project are: (1) Identification as well as in vitro and ex vivo validation of causal variant(s) involved in the regulation of AHI1 transcription in CD4+ T cells, (2) analysis of Ahi1 function in murine CD4+ T cells and its influence on encephalitogenicity in a mouse model of MS, and (3) analysis of AHI1's influence on gene networks in human Th17 cells in genotyped healthy subjects (n=100), and glatiramer acetate-treated MS patients (n=100). We thus propose a multifaceted approach integrating human genetic and human functional immunology experiments to understand how the susceptibility loci alter the state of activation in pathogenic Th17 to modulate susceptibility to MS and aggravate disease severity.