Molecular and single-cell immunology of myalgic encephalomyelitis/chronic fatigue syndrome

肌痛性脑脊髓炎/慢性疲劳综合征的分子和单细胞免疫学

基本信息

批准号：
10416027
负责人：
Ronald Wayne Davis
金额：
$ 69.56万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10416027
关键词：
Adaptive Immune System Address Algorithms Alleles Antigens Autoimmune Autoimmune Diseases Autoimmune Responses Autoimmunity Automobile Driving Behavior Biological Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Chronic Chronic Disease Chronic Fatigue Syndrome Clinical Cognitive Communicable Diseases Communities Complex Cytotoxic T-Lymphocytes DNA sequencing Data Data Set Databases Development Diagnosis Diagnostic Disease Exertion Exhibits Fibromyalgia Frequencies Gene Expression Regulation Genetic HLA Antigens Heterogeneity Human Genome Immune Immune System Diseases Immune response Immunologic Factors Immunologics Immunology Individual Differences Infection Infectious Agent Inflammatory Lead Link Lyme Disease Medical Methods Molecular Molecular Abnormality Molecular Disease Multiple Sclerosis Myalgia Nature Neurologic Onset of illness Patients Peptide Library Persian Gulf Syndrome Persons Play Population Predisposition Prevalence Psychophysiologic Disorders Reporting Research Research Personnel Role Severities Severity of illness Signaling Molecule Symptoms T cell response T-Cell Antigen Receptor Specificity T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Technology Therapeutic Tuberculosis United States Variant Virus Work autoreactivity base cell free DNA cohort cytokine disabling symptom follow-up human leukocyte antigen testing immunomodulatory therapies immunoregulation improved insight novel pathogen patient stratification risk prediction single cell technology single-cell RNA sequencing transcriptional reprogramming transcriptome transcriptome sequencing treatment strategy

项目摘要

PROJECT SUMMARY Myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS), is a complex, debilitating disease that has baffled researchers for decades. Its inaccurate yet frequent dismissal as a psychosomatic condition and lack of recognition by many in the biomedical community have greatly hindered research; as a result, very little is known about its cause(s), and no biological diagnosis or approved treatments are available. Recent developments have more clearly defined this mysterious illness, and it is now clear that it afflicts up to 2.5 million in the United States and millions more worldwide. While the symptoms present at various levels, including neurological and cognitive, widespread molecular and immunological abnormalities have also been observed. This is consistent with a majority of patients reporting infection prior to the onset of ME/CFS, although it remains unclear why common infections would serve as triggers for a chronic illness only in some people. Nevertheless, there is compelling evidence for an active immune response in ME/CFS, as suggested by elevated levels of signalling molecules called cytokines and activity of killer T cells, which are triggered in cases of infection or autoimmunity. This proposal aims to uncover the immunological basis of ME/CFS, by characterizing T cell activity and genetic factors that may be contributing to it using cutting-edge technologies invented by this team. Firstly, the activity of different T cells will be examined using single-cell DNA sequencing methods that will determine the extent and nature of their activation, and its regulation by gene expression. Secondly, the human leukocyte antigen (HLA) locus – the most challenging region of the human genome to sequence, and the most relevant to individual differences in immunology – will be sequenced in a large cohort of ME/CFS patients to determine whether HLA variants may be contributing to the T cell activity observed, and/or to increased susceptibility to the disease. Finally, the molecular triggers of the immune response will be hunted using cell-free DNA sequencing to detect pathogens, and through methods to identify which molecules are being targeted by the activated T cells. Taken together, these findings will help to identify the molecular and immunological factors that trigger and/or sustain ME/CFS as a chronic illness, and whether its basis is infectious, autoimmune, or both. More broadly, this project will build a precise framework for ME/CFS as a molecular and immunological disease, opening up broad new possibilities for research, diagnosis, and treatment. Understanding the molecular nature of the immune response in ME/CFS may lead to the definition of clinically valuable subtypes, refined diagnostics, risk prediction, and personalized immunomodulatory therapies. Moreover, the similarity of ME/CFS to other medically challenging diseases like Lyme disease, multiple sclerosis, Gulf War Illness, fibromyalgia, and more means that the insights derived here could be relevant to many millions of patients.

项目概要肌痛性脑脊髓炎，也称为慢性疲劳综合征 (ME/CFS)，是一种复杂的、使人衰弱的疾病几十年来，这种疾病一直困扰着研究人员，虽然不准确，但人们经常将其视为一种心身疾病。生物医学界的状况和缺乏认可极大地阻碍了研究；结果，对其原因知之甚少，也没有可用的生物学诊断或批准的治疗方法。最近的发展更清楚地定义了这种神秘的疾病，现在很明显，它影响了多达美国有 250 万人，全球有数百万人出现不同程度的症状。包括神经学和认知学、广泛的分子和免疫学异常也已被观察到，这与大多数 ME/CFS 发病前报告感染的患者一致。尽管目前尚不清楚为什么普通感染仅在某些情况下才会成为慢性疾病的触发因素尽管如此，正如所建议的，有令人信服的证据表明 ME/CFS 存在活跃的免疫反应。被称为细胞因子的信号分子和杀伤性 T 细胞的活性水平升高，这些信号分子在该提案旨在揭示 ME/CFS 的免疫学基础，通过使用尖端技术来表征 T 细胞活性和可能对其产生影响的遗传因素首先，将使用单细胞检查不同 T 细胞的活性。 DNA 测序方法将确定其激活的程度和性质及其调节其次，人类白细胞抗原（HLA）基因座——最具挑战性的区域。人类基因组测序，以及与免疫学个体差异最相关的——将是对一大群 ME/CFS 患者进行测序，以确定 HLA 变异是否可能导致观察到的 T 细胞活性和/或对疾病的易感性增加最后是分子触发因素。将使用无细胞 DNA 测序来检测病原体，并通过总而言之，这些方法可以识别哪些分子被激活的 T 细胞靶向。研究结果将有助于确定触发和/或维持 ME/CFS 的分子和免疫因素慢性疾病，无论其基础是传染性的、自身免疫性的还是两者兼而有之，该项目将建立一个。 ME/CFS 作为一种分子和免疫疾病的精确框架，开辟了广阔的新领域了解免疫系统的分子性质。 ME/CFS 的反应可能会导致临床上有价值的亚型的定义、精确的诊断、风险此外，ME/CFS 与其他疾病的相似性。医学上具有挑战性的疾病，如莱姆病、多发性硬化症、海湾战争病、纤维肌痛等意味着这里得出的见解可能与数百万患者相关。