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

• 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
• 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

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。