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: 10159206
• 负责人: Ronald Wayne Davis
• 金额: $ 73.78万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159206
• 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; 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.

项目总结 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、使人虚弱的疾病 这种疾病几十年来一直困扰着研究人员。它不准确，但经常被认为是一种心身疾病 生物医学界的状况和缺乏认识极大地阻碍了研究；作为 结果，对其病因(S)知之甚少，也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，它困扰着 美国有250万人，全球还有数百万人。虽然症状呈现在不同的水平， 包括神经和认知，广泛的分子和免疫异常也 观察到的。这与大多数患者在ME/CFS发病前报告感染是一致的， 尽管目前还不清楚为什么普通感染只会在某些情况下引发慢性病 人民。然而，有令人信服的证据表明，ME/CFS存在积极的免疫反应 通过被称为细胞因子的信号分子水平的升高和杀伤T细胞的活性，这是在 感染或自身免疫性病例。这项建议旨在揭示ME/CFS的免疫学基础， 通过使用尖端技术表征T细胞的活动和可能对其起作用的遗传因素 这个团队发明的技术。首先，将使用单细胞来检测不同T细胞的活性 DNA测序方法，将确定其激活的程度和性质，并通过 基因表达。其次，人类白细胞抗原(人类白细胞抗原)基因座-最具挑战性的区域 人类基因组到序列，以及与免疫学中的个体差异最相关的-将是 在一大群ME/CFS患者中进行测序，以确定人类白细胞抗原变异是否可能与 观察到的T细胞活性，和/或对疾病的易感性增加。最后，分子触发了 免疫反应将使用无细胞DNA测序来检测病原体，并通过 识别哪些分子是被激活的T细胞的靶标的方法。这些加在一起， 这些发现将有助于确定触发和/或维持ME/CFS作为一种 慢性疾病，以及其基础是传染性、自身免疫性还是两者兼而有之。更广泛地说，该项目将构建一个 作为一种分子和免疫学疾病的ME/CFS的精确框架，打开了广泛的新 研究、诊断和治疗的可能性。了解免疫的分子本质 ME/CFS的反应可能导致临床有价值的亚型的定义、精细化的诊断、风险 预测和个性化免疫调节治疗。此外，ME/CFS与其他 医学上具有挑战性的疾病，如莱姆病、多发性硬化症、海湾战争疾病、纤维肌痛等 这意味着这里得出的见解可能与数百万患者相关。