Decoding Immunological perturbations during Chronic Fatigue Syndrome

项目总结/摘要 肌痛性脑脊髓炎和慢性疲劳综合征（ME/CFS）是一种使人衰弱和神秘的慢性 各种环境因素引起的疾病。几种免疫系统成分的严重破坏 已经被描述和提出作为疾病发病机理和症状的驱动因素。但没有 关于ME/CFS发展和维持的免疫学基础的共识。两大障碍 进展是患者在肿瘤学和疾病进展方面的显著异质性， 缺乏定量工具来对患者进行分层和探索疾病的分子免疫基础。的 使用可靠的、临床上可获得的免疫学生物标志物对异质性患者组进行分层的能力 将改变临床管理ME/CFS的努力，并从机制上研究疾病。 稳健的多参数生物标志物集的开发也将影响开发个性化生物标志物的努力。 ME/CFS患者的治疗选择。目前的建议概述了一个多学科，系统生物学 探讨ME/CFS的免疫机制，并建立ME/CFS患者特异性免疫 来自血液免疫细胞的信号指导性假设是，免疫扰动，特别是 T细胞和先天性细胞（自然杀伤细胞和骨髓细胞）亚群的效应子功能，有助于发病机制 ME/CFS的免疫特征，并且这些免疫特征可用作预测性生物标志物。我们会解决这个问题 假设使用基于集成的，高分辨率功能的尖端免疫基因组学方法， 和转录组学分析的免疫细胞亚群的血液样品中的大，临床特征 ME/CFS患者队列和健康对照。然后，我们将研究相关的转录改变， 与ME/CFS在T和先天细胞亚群，重点是长非编码RNA，由于其高细胞- 类型特异性和对免疫细胞发育的影响。我们的具体目标是：1）确定 临床定义的ME/CFS患者队列的血液中免疫细胞亚群的频率; 2）评估 记忆T细胞、先天性细胞的功能能力和幼稚T细胞的分化潜能 ME/CFS;和3）确定T细胞和先天性细胞亚群特异性基因和lncRNA转录物， ME/CFS患者血液样本。我们的目标是开发一个详细的功能和遗传免疫学 框架，可用于i）解码ME/CFS的机制和ii）开发强大的，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 战略布局我们组建了一个独特的人类免疫学、临床ME/CFS生物学专家团队， 明确定义的患者样本、非编码RNA、转录组学和生物信息学将共同有助于 实现这一目标所需的深入和互补的专业知识。

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.