Immune dysfunction in ME/CFS

项目总结 肌痛性脑脊髓炎/慢性疲劳综合征(ME/CFS)仍然是一种流行、严重和糟糕的疾病 了解疾病，仅在美国就影响了数百万人的注意力、记忆力和睡眠问题 同时伴有肌肉骨骼疼痛。因此，迫切需要提高我们对基本原则的理解 这种疾病的科学--作为走向最终治愈的不可或缺的一步。尽管我们对此缺乏了解 ME/CFS，大量证据表明免疫失调是潜在原因或主要原因 这种疾病的后果。我们的工作试图系统地检查整个 免疫系统，目的是确定ME/CFS中哪些成分调节失调。这些研究 已经确定经典的单核细胞、血小板和某些T细胞亚群是免疫的组成部分 受ME/CFS影响最严重的系统。这些结果证实了ME/CFS的免疫失调。 涉及免疫系统的不同组成部分。我们的ME/CFS中心的项目3有三个主要目标。 首先，使用多组学方法严格确定单核细胞中基因调控的变化。 我/CFS。为了补充这些方法，我们将进行单核细胞分析，以测试ME/CFS结果 在单核细胞迁移和分化为巨噬细胞的能力变化中， 单核细胞。第二，我们将检查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中免疫系统中调节最失调的成分之一，尤其是调节失调 在经历劳后不适的患者中表现得尤为明显。我们推测，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，我们将检查血小板转录组，执行 测试血小板功能，并检查血小板与其他免疫细胞之间的相互作用 我/CFS。第三，我们将系统地确定ME/CFS在整个免疫系统中信号的特定变化 系统。这一目标很重要，因为确定了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。实现这些目标有改进的潜力。 诊断，包括产生生物标记物，并将确定ME/CFS中特定的失调通路， 为今后治疗学的发展奠定了基础。例如，我们的前两个目标有 可能揭示ME/CFS中的一个(或两个)单核细胞和血小板的相应变化，从而 建立一条通向最终治疗或治愈的合理道路。因为患者和对照人群 所检查的数据在此中心应用程序中是常见的，我们将从成分中生成协同数据 项目。特别是，我们检查单核细胞的基因组和功能分析将与 肌肉中的巨噬细胞(项目I)，来自循环中的单核细胞。同样，项目二将 检查ME/CFS中血小板衍生的胞外囊泡蛋白质组的变化，补充我们的 对血小板的分析。我们的全面数据将是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.