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

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

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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.

项目摘要肌脑脊髓炎，也称为慢性疲劳综合征（ME/CFS），是一种复杂的，令人衰弱的几十年来一直困扰着研究人员的疾病。它不准确但经常被视为心身许多人在生物医学界的状况和缺乏认可极大地阻碍了研究。作为结果，对其原因知之甚少，没有生物学诊断或批准的治疗方法。最近的事态发展更清楚地定义了这种神秘的疾病，现在很明显，它遭受了在美国250万，全球数百万。虽然符号在各个层面上都存在，但包括神经系统和认知，宽度分子和免疫异常，也已经存在观察到。这与ME/CFS发作之前报告感染的大多数患者一致，尽管尚不清楚为什么只有在某些人中，常见感染才能成为慢性疾病的触发因素人们。然而，如建议的通过称为细胞因子的信号分子水平升高和杀伤T细胞的活性，这些细胞触发。感染或自身免疫的病例。该建议旨在揭示ME/CFS的免疫学基础，通过表征T细胞活性和遗传因素，可能会使用尖端该团队发明的技术。首先，将使用单细胞检查不同T细胞的活性 DNA测序方法将决定其激活的程度和性质，并通过基因表达。其次，人类白细胞抗原（HLA）基因座 - 最具挑战性的地区人类基因组至顺序，与免疫学的个体差异最相关 - 将是在大量的ME/CFS患者中测序，以确定HLA变体是否可能有助于观察到的T细胞活性和/或增加了对疾病的敏感性。最后，分子触发器免疫反应将使用无细胞的DNA测序来寻找病原体，并通过识别激活的T细胞靶向哪些分子的方法。总的来说，这些调查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，以及它的基础是传染性，自身免疫性还是两者兼而有之。更广泛地，这个项目将建立一个我/CFS作为分子和免疫疾病的精确框架，开辟了广泛的新的研究，诊断和治疗的可能性。了解免疫的分子性质 ME/CFS的反应可能导致临床上有价值的亚型，精致诊断，风险的定义预测和个性化免疫调节疗法。而且，我/CFS与其他的相似性诸如莱姆病，多发性硬化症，海湾战争疾病，纤维肌痛等的医学挑战性疾病意味着这里得出的见解可能与数百万患者有关。