New Strategies to Decipher the Pathophysiology of Chronic Fatigue Syndrome

描述(申请人提供)：慢性疲劳综合症(CFS)是一种复杂的疾病，估计在西方世界影响0.5%-2%的人口。其发病机制被认为涉及遗传和环境(包括病毒)成分，就像其他慢性炎症性疾病，如多发性硬化症、类风湿性关节炎和动脉粥样硬化。与这种慢性炎症背景相一致，众所周知，CFS患者的寿命较短，并有发生淋巴瘤的风险。我们推测，在易感宿主的遗传背景上，多种病毒的活跃和反复感染所产生的慢性炎症刺激导致了以CFS为特征的发病机制。这项研究项目的总体目标是在欧洲和美国的CFS患者队列中确定这些病毒和宿主参数，这些参数与不同的疾病表型相关，包括美国队列中一个亚组的套细胞淋巴瘤(MCL)的发展。在目标1中，我们将在欧洲和美国的CFS患者队列中识别和确认新的病毒感染。1.1)我们将使用两种互补的方法来检测新的病毒mRNA：大规模并行签名测序(MPSS)和定制的DNA微阵列。1.2)定量聚合酶链式反应Q-PCR用于病毒基因表达的确认。1.3)将开发永生化细胞系来分离病毒并阐明病毒与宿主细胞基因表达之间的联系。在第二个目标中，我们将阐明易感的遗传因素和寄主防御系统的失调。具体地说，我们将确定：2.1)之前被证实在CFs中差异表达的88个人类基因的PBMC基因表达2.2)在Luminex平台上使用多重悬浮抗体阵列的血清趋化因子和细胞因子谱2.3)人类白细胞抗原、KIR基因型和全基因组SNP谱2.4)I型干扰素信号通路中的缺陷。在每个子目标中，这两个队列都将与正常和疾病对照组进行比较，使用从单个患者的多个时间点采集的血清和PBMC样本，并从我们独特的和广泛的样本库中获取。这项研究将为针对不同亚群的CFS患者制定治疗和诊断策略提供必要的信息，并可能识别新的病毒相关性、遗传特征和生物标记物，这些可以预测MCL的发展，从而使预防性治疗成为可能。公共卫生相关性：拟议的研究将为慢性疲劳综合征的疾病机制提供重要的洞察力，因此可以开发准确的测试和特定的治疗方法，以治愈疾病和预防危及生命的并发症。

DESCRIPTION (provided by applicant): Chronic Fatigue Syndrome (CFS) is a complex disease estimated to affect between 0.5%-2% of the population in the Western world. Its pathogenesis is thought to involve both inherited and environmental (including viral) components, as with other chronic inflammatory diseases such as, multiple sclerosis, rheumatoid arthritis, and atherosclerosis. Consistent with this chronic inflammatory context, CFS patients are known to have a shortened life-span and are at risk for developing lymphoma. We hypothesize that chronic inflammatory stimulation from active and recurrent infections of multiple viruses on a susceptible host genetic background leads to the pathogenesis characterized by CFS. The overall goal of this research project is to define these viral and host parameters in European and American cohorts of CFS patients that correlate with distinct disease phenotypes, including the development of mantle cell lymphoma (MCL) in a subgroup of the American cohort. In Aim 1) we will identify and confirm novel viral infections in European and American CFS patient cohorts. 1.1) we will use two complementary methods for detection of novel virus mRNA: massive parallel signature sequencing (MPSS) and a custom DNA microarray. 1.2) Quantitative polymerase chain reaction Q-PCR will be used for confirmation of virus gene expression. 1.3) immortalized cell lines will be developed to isolate virus and elucidate links between virus and host cell gene expression. In Aim 2), we will elucidate genetic factors of susceptibility and the dysregulation of the host defense system. Specifically, we will determine: 2.1) PBMC gene expression of 88 human genes previously confirmed as being differentially expressed in CFS 2.2) serum chemokine and cytokine profiles using multiplex suspension antibody arrays on a Luminex platform 2.3) HLA, KIR genotypes and whole genome SNP profiles 2.4) Defects in the type I Interferon signaling pathway. In each subaim both cohorts will be compared to normal and disease controls using specimens of serum and PBMC taken at multiple time-points from individual patients and taken from our unique and extensive sample repository. This study will provide information necessary for development of treatment and diagnostic strategies for distinct subgroups of CFS patients, and may identify novel virus associations, genetic signatures and biomarkers, which can predict the development of MCL, thus enabling use of preventive therapeutics. PUBLIC HEALTH RELEVANCE: The proposed research will provide significant insight into the disease mechanisms of Chronic Fatigue Syndrome so accurate testing and specific treatments can be developed with a goal of curing the disease and preventing life-threatening complications.