Decoding Immunological perturbations during Chronic Fatigue Syndrome

项目摘要/摘要 肌痛性脑脊髓炎和慢性疲劳综合征(ME/CFS)是一种令人虚弱和神秘的慢性疾病 由各种环境诱因引起的疾病。几种免疫系统成分的严重破坏 已被描述和提出为疾病发病机制和症状的驱动因素。然而，没有 就ME/CFS发展和维持的免疫学基础达成共识。面临的两大障碍 进展是患者在症状和疾病进展方面的显著异质性，结合 缺乏量化工具来对患者进行分层并探索疾病的分子免疫基础。这个 使用可靠的、临床可获得的免疫生物标记物对不同患者群体进行分层的能力 将改变临床治疗ME/CFS的努力，并从机制上研究这种疾病。 强大的多参数生物标记物集合的开发也将影响开发个性化的努力 ME/CFS患者的治疗选择。本提案概述了一种多学科的系统生物学 探讨ME/CFS的免疫机制及建立ME/CFS患者特异性免疫的途径 来自血液来源的免疫细胞的信号。指导性假设是免疫紊乱，特别是 T细胞和天然细胞(自然杀伤细胞和髓系细胞)亚群的效应器功能，参与发病 这些免疫标志物可作为预测性生物标志物。我们将解决这一问题 使用基于集成的高分辨率泛函的尖端免疫基因组学方法的假设 和转录谱分析免疫细胞亚群在血液样本中的大，临床特征 Me/CFS患者队列和健康对照。然后我们将检查相关的转录改变 在T和天然细胞亚群中的ME/CFs，重点是长的非编码RNA，因为它们的高细胞- 类型特异性及其对免疫细胞发育的影响。我们的具体目标是：1)确定 临床明确的ME/CFS患者队列中血液中免疫细胞亚群的频率；2)评估 记忆T细胞、天然T细胞的功能及幼稚T细胞的分化潜能 Me/CFS；以及3)测定T细胞和天然细胞亚群特异性基因和cRNA转录本。 我/CFS患者的血液样本。我们的目标是开发一种详细的功能和遗传免疫学 可用于i)解码ME/CFS的机制和ii)开发健壮的、定量的 用于预测疾病易感性、患者分层和指导治疗的免疫生物标志物集 战略。我们组建了一支独特的人类免疫学、临床ME/CFS生物学专家团队 定义明确的患者样本、非编码RNA、转录组学和生物信息学一起将有助于 实现这一目标所需的深厚和互补的专业知识。

PROJECT SUMMARY/ABSTRACT Myalgic Encephalomyelitis and Chronic Fatigue Syndrome (ME/CFS) is a debilitating and mysterious chronic illness caused by diverse environmental triggers. Severe disruptions in several immune system components have been described and proposed as drivers of disease pathogenesis and symptoms. However, there is no consensus on the immunological basis for ME/CFS development and sustenance. The two major barriers to progress are the significant patient heterogeneity in symptomatology and disease progression, combined with the lack of quantitative tools to stratify patients and probe the molecular immune underpinnings of disease. The ability to stratify heterogeneous patient groups using reliable, clinically accessible immunological biomarkers would transform efforts to manage ME/CFS clinically and investigate the disease mechanistically. Development of robust multi-parameter biomarker sets would also impact efforts to develop personalized treatment options for ME/CFS patients. The present proposal outlines a multi-disciplinary, systems-biology approach to investigate the immune mechanisms of ME/CFS and to develop ME/CFS-patient specific immune signatures from blood-derived immune cells. The guiding hypothesis is that immune perturbations, particularly to the effector functions of T cell and innate cell (natural killer and myeloid) subsets, contribute to pathogenesis of ME/CFS and that these immune signatures can be used as predictive biomarkers. We will address this hypothesis using a cutting-edge immunogenomics approach based on integrated, high-resolution functional and transcriptomic profiling of immune cell subsets within the blood samples of a large, clinically characterized ME/CFS patient cohort and healthy controls. We will then examine the transcriptional alterations associated with ME/CFS within T and innate cell subsets, with a focus on long non–coding RNAs, owing to their high cell- type-specificity and impact on immune cell development. Our Specific Aims are: 1) To determine the frequencies of immune cell subsets in the blood of a clinically defined ME/CFS patient cohort; 2) To assess functional capacity of memory T cells, innate cells and the differentiation potential of naive T cells during ME/CFS; and 3) To determine the T cell and innate cell subset–specific gene and lncRNA transcripts in ME/CFS patient blood samples. Our goal is to develop a detailed functional and genetic immunological framework that can be used to i) decode the mechanisms of ME/CFS and ii) to develop robust, quantitative immune-biomarker sets for predicting disease susceptibility, stratifying patients and guiding treatment strategies. We have assembled a unique team of experts in human immunology, clinical ME/CFS biology for well-defined patient samples, non-coding RNAs, transcriptomics and bioinformatics, together will contribute to the deep and complimentary expertise necessary to bring about this goal.