Immune dysfunction in ME/CFS

项目摘要 ME/CFS（肌痛性脑脊髓炎/慢性疲劳综合征）仍然是一种普遍、严重和不良的疾病， 这种疾病在美国影响了数百万人，他们的注意力、记忆力和睡眠都有问题。 以及肌肉骨骼疼痛。因此，迫切需要促进我们对基本的 这是一种疾病的科学-作为最终治愈的一个组成部分。尽管我们不了解 ME/CFS，大量证据表明免疫失调是根本原因或主要原因 疾病的后果。我们的工作试图系统地研究基因调控， 免疫系统，目的是确定哪些成分在ME/CFS中失调。这些研究 已经鉴定出经典的单核细胞、血小板和T细胞的某些亚群作为免疫系统的组分。 受ME/CFS影响最严重的系统。这些结果证实ME/CFS中的免疫失调 涉及免疫系统的不同组成部分。我们ME/CFS中心的项目3有三个主要目标。 首先，使用多组学方法来严格确定单核细胞中的基因调控变化， ME/CFS。为了补充这些方法，我们将进行单核细胞测定，以测试ME/CFS结果是否 单核细胞迁移和分化为巨噬细胞的能力改变， 单核细胞其次，我们将研究ME/CFS中的血小板失调，因为我们的数据确定血小板是 在ME/CFS中免疫系统最失调的组成部分中， 在经历劳力后不适的患者中明显。我们假设血小板缺陷可能导致 ME/CFS的循环系统和其他症状。在这个目标中，我们将研究血小板转录组， 检测血小板功能，并检查血小板与其他免疫细胞之间的相互作用， ME/CFS。第三，我们将系统地鉴定ME/CFS在免疫系统中信号传导的特异性改变。 系统这一目标很重要，因为识别广泛影响免疫系统的分子变化 是未来治疗发展的有吸引力的靶点。实现这些目标有可能改善 诊断，包括产生生物标志物，并将确定ME/CFS中的特定失调途径， 为今后治疗学的发展提供了基础。例如，我们的前两个目标 可能揭示ME/CFS中单核细胞和血小板之一（或两者）的相应变化，从而 建立一条通往最终治疗或治愈的合理途径。因为病人和对照组 我们将从该中心应用程序的组成部分生成协同数据， 项目特别是，我们检测单核细胞的基因组和功能测定将与 肌肉中的巨噬细胞（项目I），其来源于循环中的单核细胞。同样，项目二将 检查ME/CFS中血小板衍生的细胞外囊泡蛋白质组的改变，补充我们的研究。 血小板分析我们全面的数据将成为该领域所有研究人员的关键资源。

PROJECT SUMMARY ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) remains a prevalent, serious and poorly understood disease, impacting millions in the USA alone with problems in concentration, memory and sleep together with musculoskeletal pain. Thus, there is an urgent need to advance our understanding of the basic science of this disease – as an integral step towards an ultimate cure. Despite our lack of understanding of ME/CFS, substantial evidence implicates immune dysregulation either as an underlying cause or major consequence of the disease. Our work has sought to systematically examine gene regulation across the immune system, with the goal of determining which components are dysregulated in ME/CFS. These studies have identified classical monocytes, platelets and certain subsets of T cells as the components of the immune system most severely impacted by ME/CFS. These results establish that immune dysregulation in ME/CFS involves disparate components of the immune system. Project 3 of our ME/CFS Center has three major goals. First, to use multiomic approaches to rigorously determine the gene regulatory changes in monocytes in ME/CFS. To complement these approaches, we will perform monocyte assays to test whether ME/CFS results in alterations in the ability of monocytes to migrate and differentiate into macrophages, a critical function of monocytes. Second, we will examine platelet dysregulation in ME/CFS, as our data identifies platelets as amongst the most dysregulated component of the immune system in ME/CFS, with dysregulation particularly evident in patients undergoing post-exertional malaise. We hypothesize that platelet defects could contribute to circulatory and other symptoms in ME/CFS. In this Aim, we will examine the platelet transcriptome, perform assays to test platelet function, and examine interactions between platelets and other immune cells in ME/CFS. Third, we will systematically identify ME/CFS specific alterations in signaling across the immune system. This goal is important, as identification of molecular changes that impact the immune system broadly are attractive targets for future development of therapies. Achieving these goals has the potential to improve diagnosis, including generating biomarkers, and will identify specific dysregulated pathways in ME/CFS, providing a foundation for future development of therapeutics. For example, our first two goals have the potential to reveal consequential alterations in either (or both) monocytes and platelets in ME/CFS, thereby establishing a rational path towards eventual treatments or a cure. Because the patient and control cohorts examined are common across this Center application, we will generate synergistic data from the constituent projects. In particular, our genomic and functional assays examining monocytes will be paired with profiling of macrophages in muscle (Project I), which are derived from monocytes in circulation. Similarly, Project II will examine alterations to the platelet-derived extracellular vesicle proteome in ME/CFS, complementing our analysis of platelets. Our comprehensive data will be a key resource for all researchers in the field.