Intestinal Immune Response in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

 描述（由申请人提供）：更好地了解肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS）的主要障碍是该疾病的异质性以及缺乏表征疾病表型和分析治疗结果的生物标志物。虽然ME/CFS的病因和发病机制知之甚少，但有证据表明免疫系统异常与大量受影响个体的症状有关。此外，许多ME/CFS患者主诉病因不明的胃肠道（GI）症状。然而，尚未在对照研究中探索对饮食和微生物抗原的免疫应答作为报告的GI症状的潜在原因或作为全身性炎症的贡献者。我们的初步数据来自一项研究，充分表征的患者和对照组表明，个人与ME/CFS表现出显着升高的抗体反应面筋，这与胃肠道症状的严重程度。此外，结果表明，在ME/CFS中观察到的对麸质的免疫应答与乳糜泻中的免疫应答根本不同，独立于转氨酶2酶和HLA-DQ 2/DQ 8分子的作用。本申请中的其他数据表明，对麸质的抗体反应性增加可能与没有乳糜泻的个体中的微生物易位有关。我们假设ME/CFS中对麸质的抗体反应的分子靶点是独特的，进一步表征可能会发现该疾病的新生物标志物，并且这种免疫反应与ME/CFS患者亚组中的微生物易位和全身炎症相关。为了分析确定的免疫反应性的分子靶点，并评估其对ME/CFS的影响，我们提出了两个具体的目标。在目标1中，我们将通过质谱辅助蛋白质组分析和表位作图来绘制ME/CFS中对麸质的免疫应答的抗原特异性。在目标2中，我们将评估对麸质的免疫应答与ME/CFS中微生物易位和全身炎症的特异性标志物之间的关系。如果实现拟议项目的目标，预计将出现的信息将1）提供可能有助于识别有发生ME/CFS风险的患者或个体亚群的生物标志物，2）支持针对已识别患者亚群的特定治疗策略的检查，3）为进一步研究肠屏障缺陷和异常粘膜免疫应答在ME/CFS病理生理学中的作用提供实验支持。该拨款提案符合项目公告（PAR-12-033）对“检查慢性疲劳综合征的病因学，诊断，病理生理学和治疗”的申请的要求，例如识别“环境，包括饮食，沉淀物”和开发“用于诊断ME/CFS的新颖和客观的生物标志物”。

 DESCRIPTION (provided by applicant): A major barrier to a better understanding of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been the heterogeneity within the condition and the lack of biomarkers to characterize disease phenotypes and analyze treatment outcome. While the etiology and pathogenesis of ME/CFS are poorly understood, there is evidence that immune system abnormalities are associated with symptoms in a substantial number of affected individuals. In addition, many ME/CFS patients complain of gastrointestinal (GI) symptoms of unknown etiology. However, immune responses to dietary and microbial antigens as underlying causes of the reported GI symptoms or as contributors to systemic inflammation have not been explored in controlled studies. Our preliminary data from a study of well-characterized patients and controls demonstrate that individuals with ME/CFS exhibit significantly elevated antibody reactivity to gluten, which correlates with the severity of GI symptoms. Moreover, the results show that the observed immune response to gluten in ME/CFS is fundamentally distinct from that in celiac disease, being independent of the action of transglutaminase 2 enzyme and HLA-DQ2/DQ8 molecules. Additional data within this application indicate that increased antibody reactivity to gluten can be associated with microbial translocation in individuals without celiac disease. We hypothesize that the molecular targets of the antibody response to gluten in ME/CFS are unique, further characterization of which may identify novel biomarkers of the condition, and that this immune response is associated with microbial translocation and systemic inflammation in a subset of ME/CFS patients. To analyze the molecular targets of the identified immune reactivity and assess its implications for ME/CFS, we propose two specific aims. In Aim 1, we will map the antigenic specificity of the immune response to gluten in ME/CFS through mass spectrometry-assisted proteome analysis and epitope mapping. In Aim 2, we will assess the relationship between the immune response to gluten and specific markers of microbial translocation and systemic inflammation in ME/CFS. The information that is expected to emerge if the aims of the proposed project are achieved would 1) offer biomarkers that may be useful in identifying subsets of patients or individuals at risk of developing ME/CFS, 2) support the examination of specific treatment strategies targeted at the identified subset of patients, and 3) yield experimental support for closer examination of the role of intestinal barrier defects and aberrant mucosal immune response in the pathophysiology of ME/CFS. This grant proposal is in line with the program announcement's (PAR-12-033) request for applications that "examine the etiology, diagnosis, pathophysiology, and treatment of chronic fatigue syndrome", such as the identification "of environmental, including dietary, precipitants" and the development of "novel and objective biological markers for the diagnosis of ME/CFS".