Sodium Chloride Induced Dysregulation of CD4+CD25+ Regulatory T Cells in Patients

描述（由申请人提供）： 多发性硬化症（MS）被认为是一种自身免疫性疾病，其具有功能性CD4+FoxP3+调节性T细胞的损失，允许活化的自身反应性T细胞引发CNS损伤。自身免疫性疾病的发病率显著增加，虽然我们已经成功地阐明了MS的遗传基础的重要部分，但环境因素仍然未知。在最近的一项研究中，调查了微生物群和饮食与循环Th17细胞频率和遗传变异的关系，我们注意到“快餐”饮食的高摄入量与Th17细胞有关。这导致鉴定盐作为通过诱导致病性Th17细胞的自身免疫的可能环境触发剂。随后的初步数据表明，高盐通过一种未知的机制损害人Foxp3+调节性T细胞的抑制能力。我们的数据使我们假设，在遗传易感背景下，西方饮食中的慢性高盐摄入可能会通过解除保护性T细胞（其功能是调节免疫反应）而触发MS的发展。我们将通过首先确定在高盐条件下观察到的Treg功能丧失的机制来研究这一假设。我们将通过在正常或高盐条件下对TdR进行分子和功能分析，研究其体外效应的潜在机制。我们还将比较在体外高盐条件下从健康对照产生的TdR的RNA和基因表达特征与从MS患者的外周血离体分离的TdR，以确定在患有该疾病的患者中是否存在致病性TdR的“盐历史”。我们还将研究这些RNA和基因表达特征是否是由我们从全基因组关联扫描研究中观察到的遗传变异驱动的。这些拟议的实验结果可能揭示MS的潜在环境原因，并提供一种新的治疗策略。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is thought to be an autoimmune disease with losses of functional CD4+FoxP3+ regulatory T cells allowing activated autoreactive T cells to initiate CNS damage. There have been significant increases in the incidence of autoimmune disease and while we have been successful in elucidating a significant portion of the genetic basis of MS, the environmental contributors remain unknown. In a recent study investigating the role of microbiota and diet in relationship to frequencies of circulating Th17 cells and genetic variation, we noted high intake of a "fast food" diet was associated with Th17 cells. This led to the identification of salt as a possible environmental trigger for autoimmunity by induction of pathogenic Th17 cells. Subsequent preliminary data indicate that high salt impairs the suppressive capacity of human Foxp3+ regulatory T cells through an as yet unknown mechanism. Our data have led us to hypothesize that the chronic high salt intake in western diets, on a genetically susceptible background, may act as a trigger for developing MS by disarming protective Tregs, which function to regulate immune responses. We will investigate this hypothesis by first determining the mechanism for the loss of Treg function observed under high salt conditions. By molecular and functional analyses of Tregs under normal or high salt conditions we will investigate the underlying mechanisms of the effect in vitro. We will also compare RNA and gene expression signatures of Tregs generated under high salt conditions in vitro from healthy controls with Tregs isolated ex vivo from the peripheral blood of patients with MS to determine if there is a "salt-history" of pathogenic Tregs in patients with the disease. We will also investigate whether these RNA and gene expression signatures are driven by the genetic variation we observed from our genome wide association scan studies. The results of these proposed experiments may shed light on a potential environmental cause of MS and provide a novel treatment strategy.