HERV-K18 as a Risk Factor for CFIDS

描述(申请人提供)：慢性疲劳综合征(CFS)的病因还远未被了解，可能是由于多种遗传因素造成的。EB病毒感染和干扰素-α的治疗与发病有关。我们的实验室已经证明，EBV感染和外源性干扰素-α？激活了人类内源性逆转录病毒HERV-K18的env基因的转录。这种前病毒通常是沉默的，但当被诱导时，它会编码一种超抗原(SAG)，这是一类能够解除免疫系统调节的蛋白质。HERV-K18包膜蛋白的三个等位基因K18.1、K18.2、K18.3已被证实，它们的基因产物具有SAG活性，但预测在生化和功能上存在差异。我们的工作假设是HERV-K18是CFS的危险因素。在一项初步研究中，比较了不同组CFS患者和健康对照组HERV-K18 env基因的等位基因和基因型分布。虽然在不同的队列中只有有限数量的样本可用，但获得的优势比在统计学上具有显著意义。对这些数据最耐人寻味的解释是，它们为至少一组CFS患者的独特病因提供了遗传学证据。因此，根据患者的临床病史来划分不同的CFS亚型是可能的。现在建议使用一个更大的与EBV相关的400名CFS患者的队列来证实这些试验结果，这一队列是由共同研究员Renee Taylor博士组装的。获得儿科和儿科传染病认证的本·卡茨博士将对患者队列进行临床评估，遗传流行病学家和生物统计学家英加·彼得博士将负责统计分析。此外，还将测量HERV-K18 SAG在疾病活动期和间歇期的表达模式。此外，在疾病过程中患者外周血淋巴细胞上表达的这种SAG的T细胞刺激活性将使用我们实验室开发的T细胞杂交瘤报告试验进行体外测试。由于SAG激活的T细胞产生大量的趋化因子、淋巴因子和神经因子，因此Herv-K18 SAG的表达不仅可以影响免疫系统，还可以影响其他器官。CFS与HERV-K18等位基因或表达模式的正相关将为这种慢性疾病的临床治疗开辟新的途径。慢性疲劳综合征是一种影响世界各地相当数量的人的疾病，但其发病的潜在机制(S)仍不清楚。疱疹病毒EBV和干扰素-a被认为与CFS有关，尽管这些概念还远未被接受。我们提出了EBV/CFS相关性的一个新的遗传学方面，即某些HERV-K18等位基因的存在，这些等位基因的超抗原活性不同。

DESCRIPTION (provided by applicant): The etiology of Chronic Fatigue Syndrome (CFS) is far from understood and is likely due to multiple genetic components. Infection with EBV and treatment with IFN-a have been implicated in the pathogenesis. Our laboratory has shown that EBV-infection, and exogenous IFN-a?, activate transcription of the env gene of a Human Endogenous Retrovirus, HERV-K18. This provirus is normally silent, but when induced it encodes a superantigen (SAg), which is a class of proteins that is capable of deregulating the immune system. Three alleles of HERV-K18 env have been documented, K18.1, K18.2, K18.3, whose gene products have SAg activity, but are predicted to differ biochemically and functionally. Our working hypothesis is that HERV-K18 is a risk factor for CFS. In a pilot study, the allele and genotype distributions of the HERV-K18 env gene were compared between various groups of CFS patients and healthy controls. Although only a limited number of samples were available in the various cohorts, the odds ratios that were obtained were statistically significant. The most intriguing interpretation of these data are that they provide genetic evidence for the unique etiology of at least one group of CFS patients. Thus, it may be possible to delineate different subtypes of CFS, depending on the clinical history of the patients. It is now proposed to substantiate these pilot results, using a much larger cohort of 400 CFS patients associated with EBV that has been assembled by the co-investigator, Dr. Renee Taylor. Dr. Ben Katz, board certified in both Pediatrics and Pediatric Infectious Diseases, will clinically evaluate the patient cohort, and Dr. Inga Peter, a genetic epidemiologist and biostatistician, will oversee the statistical analyses. In addition, the expression pattern of the HERV-K18 SAg during active disease versus intermission will be measured. Furthermore, T cell stimulatory activity of this SAg, expressed on peripheral blood lymphocytes of patients during the course of the disease, will be tested ex vivo, using a T cell hybridoma reporter assay that has been developed in our lab. Since SAg-activated T cells produce massive quantities of chemokines, lymphokines and neurokines, the expression of the HERV-K18 SAg could influence not only the immune system, but other organs as well. A positive association between CFS and either HERV-K18 alleles or expression patterns would open new avenues for the development of clinical treatments of this chronic disease. CFS is a disease that affects a significant number of people worldwide, yet the underlying mechanism(s) of pathogenesis remains unclear. The herpesvirus EBV and IFN-a have been suggested to be associated with CFS, although these concepts are far from accepted. We propose a novel genetic aspect in the EBV/ CFS association, namely the presence of certain HERV-K18 alleles that differ in their superantigen activity.