Intestinal Immune Response in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

肌痛性脑脊髓炎/慢性疲劳综合征的肠道免疫反应

• 批准号: 9021859
• 负责人: ARMIN ALAEDINI
• 金额: $ 20万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9021859
• 关键词: Affect; Age; Antibodies; Antibody Response; Antigenic Specificity; Applications Grants; Biological Markers; CD14 gene; Celiac Disease; Cereals; Chronic Fatigue Syndrome; Controlled Study; Data; Defect; Development; Diagnosis; Diet; Disease; Economic Burden; Electrophoresis; Endotoxins; Enzymes; Epitope Mapping; Epitopes; Etiology; Exhibits; Functional disorder; Gender; Gliadin; Gluten; Heterogeneity; Immune; Immune response; Immune system; Immunoblotting; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunologics; Individual; Inflammation; Intestines; Maps; Mass Spectrum Analysis; Mediating; Molecular Target; Mucosal Immune Responses; NIH Program Announcements; Pathogenesis; Patients; Pattern; Plasma; Proteins; Proteome; Proteomics; Publishing; Reporting; Request for Applications; Risk; Role; Sampling; Serum amyloid A protein; Severities; Specificity; Symptoms; Time; Treatment outcome; Wheat; Woman; cohort; disease phenotype; gastrointestinal symptom; glutenin; lipopolysaccharide-binding protein; microbial; microorganism antigen; novel; novel marker; patient subsets; public health relevance; research study; response biomarker; specific biomarkers; tandem mass spectrometry; transglutaminase 2; treatment strategy; two-dimensional

 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".

 描述（由适用提供）：更好地理解肌动脑膜炎/慢性疲劳综合征（ME/CFS）的主要障碍一直是该疾病内的异质性，并且缺乏生物标志物来表征疾病表型和分析治疗结果。虽然ME/CF的病因和发病机理知之甚少，但有证据表明，免疫系统异常与大量受影响的个体的症状有关。此外，许多ME/CFS患者还抱怨病因未知的胃肠道（GI）症状。然而，在对照研究中尚未探讨对饮食和微生物抗原的免疫反应作为胃肠道症状的根本原因或作为全身性炎症的原因。我们来自特征良好的患者和对照的研究的初步数据表明，患有ME/CFS的个体暴露于对面筋的抗体反应性显着升高，这与GI症状的严重程度相关。此外，结果表明，在ME/CFS中观察到的对面筋的免疫响应与腹腔疾病的根本不同，与转谷氨酰胺酶2酶和HLA-DQ2/DQ8分子的作用无关。该应用程序中的其他数据表明，对面筋的抗体反应性的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中对面筋的抗体反应的分子靶标是独特的，其进一步的表征可以鉴定出该病情的新生物标志物，并且这种免疫激素与ME/CFS患者子集中的微生物易位和全身性炎症有关。为了分析鉴定出的免疫反应性和评估其对ME/CFS的影响的分子靶标，我们提出了两个具体目标。在AIM 1中，我们将通过质谱辅助蛋白质组分析和表位映射来绘制ME/CFS中的面筋的抗原特异性。在AIM 2中，我们将评估ME/CFS中微生物易位和全身感染的特定标记的免疫响应与特定标记之间的关系。如果达到拟议项目的目的，则预期出现的信息会1）提供生物标志物，这些标志物可能有助于确定患者或有发展ME/CFS的患者或个人的子集，2）支持检查针对患者鉴定的识别子集的特定治疗策略的检查； 3）在近端脑膜含量的响应中，对弱点的响应进行了响应，以促进性障碍的作用。我/CFS。该赠款提案符合该计划公告（PAR-12-033）的要求，要求“检查慢性疲劳综合征的病因，诊断，病理生理学和治疗”，例如环境的识别，包括饮食，降水剂”，以及用于诊断我/CFS的新颖和客观生物学标记的开发”。