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

描述(申请人提供)：慢性疲劳综合症(CFS)是一种疾病，据估计在美国有80万人受到影响。受影响的人中高达80%是女性。这些人患有严重的疲劳，损害了日常活动，多年来降低了生活质量，并且没有已知的治疗方法。CFS对社会及其医疗机构来说是一种经济负担。假设CFS的启动事件包括感染、精神创伤和暴露于毒素。一组新出现的证据表明免疫系统发生了变化。免疫损伤可能导致由细胞毒性淋巴细胞控制的健康个体中潜伏病毒的间歇性激活。目前对该综合征的治疗是以症状为重点的，效果相对较差。改进的治疗方案将伴随着对该综合征潜在病理生理学的更好理解。我们的目标是提高对CFS病理生理学的理解，开发在诊断、定义亚型和治疗试验中有用的生物标记物。这项拟议研究的理论基础是基于我们和其他人的工作，这些工作表明CFS存在免疫功能障碍。在这项研究中，我们将使用纵向研究设计，在18个月的窗口内，包括两个随机时间点和两个时间点，这些时间点对应于患者对CFS相关症状相对加重和相对改善时间的感知。我们有两个具体目标。具体目标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组的免疫功能受损或免疫功能障碍模式的程度。特定目的1将在18个月的观察中确定与淋巴细胞细胞毒功能、淋巴细胞激活和炎症相关的免疫标记物与症状严重程度的关系。具体目标2将在四个时间点收集的样本上定义CFS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溶解途径的变化相关。通过在分子水平上定义免疫功能，我们将确定潜在的免疫调节疗法干预的生物标志物和靶点，以及衡量这些疗法有效性的手段。

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.