Immunologic Mechanisms, Biomarkers and Subsets in Chronic Fatigue Syndrome (CFS)

描述（由申请人提供）：慢性疲劳综合征（CFS）是一种疾病，据估计在美国有80万人受到影响。受影响的患者中多达80%是女性。这些人患有严重的疲劳，影响了日常活动，降低了多年的生活质量，并且没有已知的治疗方法。慢性疲劳综合症是社会及其卫生保健机构的经济负担。慢性疲劳综合症的假设起始事件包括感染、精神创伤和接触毒素。越来越多的证据表明免疫系统发生了变化。免疫损伤可导致潜伏病毒的偶发性激活，潜伏病毒在健康个体中被细胞毒性淋巴细胞抑制。目前对该综合征的治疗以症状为重点，效果相对较差。随着对该综合征潜在病理生理学的更好理解，治疗方案也会得到改善。我们的目标是提高对CFS病理生理学的理解，并开发在诊断、定义亚群和治疗试验中有用的生物标志物。提出这项研究的基本原理是基于我们的工作和其他人的工作，这些工作表明CFS存在免疫功能障碍。在本研究中，我们将采用纵向研究设计，在18个月的窗口内，纳入两个随机时间点和两个时间点，对应于患者对CFS相关症状相对增强和相对改善次数的感知。我们有两个具体目标。特异性目标1将确定与健康、久坐的对照组相比，符合CFS病例定义的患者或患者亚群存在免疫损伤或免疫功能障碍模式的程度。特异性目的1将在18个月的观察中确定与淋巴细胞细胞毒性功能、淋巴细胞活化和炎症相关的免疫标记物与症状严重程度的关系。特异性目标2将定义在四个时间点收集的CFS样本中免疫功能受损的分子生物学，并使我们能够确定疾病严重程度的变化是否与细胞免疫裂解途径的变化相关。通过在分子水平上定义免疫功能，我们将确定免疫调节疗法干预的潜在生物标志物和靶标，以及测量这些疗法疗效的手段。

DESCRIPTION (provided by applicant): Chronic Fatigue Syndrome (CFS) is an illness that has been estimated to affect 800,000 people in the United States. Up to 80% of those affected are women. These individuals suffer from severe fatigue that impairs daily activity, diminishes quality of life for years and has no known cure. CFS represents an economic burden for society and its healthcare institutions. Hypothetical initiating events for CFS include infections, psychiatric trauma and exposure to toxins. An emerging body of evidence demonstrates alterations in the immune system. Immunologic impairment may lead to episodic activation of latent viruses -held in check in healthy individuals by cytotoxic lymphocytes. Current treatments for the syndrome are symptom-focused and relatively ineffective. Improved treatment options will come with a better understanding of the underlying pathophysiology of the syndrome. Our goal is to improve the understanding of CFS pathophysiology and to develop biomarkers useful in diagnosis, in defining subsets and in therapeutic trials. The rationale for the proposed research is based on our work and that of others that suggests immune dysfunction in CFS. In this study, we will use a longitudinal study design that incorporates, within an 18-month window, two random time points and two time points corresponding to the patient perception of times of relative intensification and relative amelioration of CFS related symptoms. We have two Specific Aims. Specific Aim 1 will determine the extent to which patients, or subset of patients who meet the CFS case definition have immune impairment, or patterns of immune dysfunction, as compared to healthy, sedentary controls. Specific Aim 1 will determine the relationship of immune markers related to lymphocyte cytotoxic function, lymphocyte activation and inflammation to symptom severity over the 18 months of observation. Specific Aim 2 will define the molecular biology of impaired immune function in CFS on samples collected at the four time points and allow us to determine if changes in disease severity correlate with changes in the lytic pathway of cellular immunity. By defining immune function at the molecular level, we will identify potential biomarkers and targets for intervention with immuno-modulatory therapies and the means to measure the efficacy of these therapies.