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

项目摘要 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。 这种疾病困扰了研究人员几十年。它的不准确，但经常解雇作为一个心身 条件和缺乏认识的许多生物医学界大大阻碍了研究;作为一个 因此，对其原因知之甚少，也没有生物学诊断或批准的治疗方法。 最近的事态发展已经更清楚地定义了这种神秘的疾病，现在很清楚，它折磨多达 2.5在美国有数百万，在全世界有数百万。虽然症状表现在不同程度上， 包括神经和认知，广泛的分子和免疫异常也被 观察这与大多数患者在ME/CFS发作前报告感染一致， 尽管目前还不清楚为什么普通感染只会在一些人中成为慢性疾病的触发因素， 人尽管如此，有令人信服的证据表明ME/CFS中存在主动免疫应答， 细胞因子和杀伤性T细胞的活性，这是由细胞因子和杀伤性T细胞的信号分子水平升高引起的， 感染或自身免疫的病例。该提案旨在揭示ME/CFS的免疫学基础， 通过表征T细胞活性和可能对其有贡献的遗传因素， 这个团队发明的技术。首先，将使用单细胞免疫印迹法检测不同T细胞的活性。 DNA测序方法，将确定其激活的程度和性质，以及其调节， 基因表达。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，以及最相关的免疫学个体差异-将是 在ME/CFS患者的大队列中进行测序，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， 免疫反应将通过无细胞DNA测序来检测病原体， 识别哪些分子被激活的T细胞靶向的方法。综上所述各项 这些发现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，以及其基础是否是传染性的，自身免疫性的，或两者兼而有之。更广泛地说，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，开辟了广泛的新领域 研究、诊断和治疗的可能性。了解免疫系统的分子本质 ME/CFS的缓解可能导致临床上有价值的亚型的定义，完善的诊断，风险 预测和个性化免疫调节疗法。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，等等 这意味着这里得出的见解可能与数百万患者有关。

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.