Autoimmunity to ECGF in Lyme disease and its post-infectious syndromes

莱姆病及其感染后综合征中 ECGF 的自身免疫

• 批准号: 8501754
• 负责人: ALLEN C STEERE
• 金额: $ 25.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501754
• 关键词: Accounting; Address; Antibiotic Therapy; Antibiotics; Antibody Formation; Applications Grants; Arthritis; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmunity; B-Lymphocytes; Borrelia burgdorferi; Cells; Clinical; Complement; Complication; Cytokeratin; Disease; European; Facial paralysis; Fatigue; Fibroblast Growth Factor; Freezing; Grant; Immune; Immune response; Infection; Inflammation; Integration Host Factors; Joints; Lead; Learning; Liquid substance; Location; Lyme Arthritis; Lyme Disease; Neuraxis; Neurocognitive; Order Spirochaetales; Pain; Pathogenesis; Patients; Physicians; Play; Proteomics; Publishing; Refractory; Research; Resolution; Role; Seminal; Serum; Symptoms; Syndrome; Synovitis; T-Lymphocyte; Testing; Tissue Sample; Tissues; To autoantigen; Translational Research; Work; base; candidate identification; innovation; killings; nervous system disorder; public health relevance; research clinical testing; response; translational approach

DESCRIPTION (provided by applicant): The greatest remaining clinical problem in Lyme disease (LD) is that some patients do not have complete resolution of signs or symptoms with antibiotic therapy. In recent years, we have studied this problem intensively in patients with Lyme arthritis in whom synovitis persists for months or years after spirochetal killing with antibiotics, called antibiotic-refractory arthritis. We have hypothesized that this disease course results from infection-induced autoimmunity with excessive inflammation and immune dysregulation in joints. However, until recently, identification of pathogenic autoantigens has remained elusive. Using discovery-based proteomics combined with clinical translational research, we recently identified endothelial cell growth factor (ECGF), the first known autoantigen that induces T and B cell responses in some patients with LD. In addition, we have preliminary information that the third component of complement and cytokeratin 10 may also serve as autoantigens. Our first specific aim in this grant application is to determine the clinica correlates of autoimmunity to ECGF or other candidate autoantigens across the spectrum of LD, including its post-infectious syndromes, to assess whether these responses are specific for LD, and to learn whether they occur only with U.S. B. burgdorferi (Bb) strains or also with European genospecies of the spirochete. Second, we plan to use the same proteomic and translational research approach that we employed successfully in the identification of ECGF to identify other candidate autoantigens. Third, we will determine spirochetal and host factors, including types of Bb strains and interactions with host cells, which are necessary for the induction of immune responses to ECGF of other candidate autoantigens, and we will characterize the adaptive immune response to these autoantigens in target tissues or fluids. These aims will allow us to determine whether autoimmunity to ECGF occurs as a part of a wider spectrum of Bb-induced immune responses, to ascertain the resulting clinical pictures, to identify other candidate autoantigens, and to delineate mechanisms responsible for these responses. We anticipate that a test for these antibody responses will become a part of the clinical evaluation of LD. Such information will help physicians to treat patients with LD more appropriately and effectively.

描述（由申请人提供）：莱姆病（LD）中最大的临床问题是，有些患者没有完全解决抗生素治疗的体征或症状。近年来，我们对莱姆关节炎患者进行了深入的研究，其中滑膜炎在用抗生素（称为抗生素难治性关节炎）杀死后数月或几年。我们假设该疾病病程是由于感染引起的自身免疫而引起的，关节中的炎症过多和免疫失调。然而，直到最近，病原自身抗原的鉴定仍然难以捉摸。使用基于发现的蛋白质组学与临床转化研究结合使用，我们最近确定了内皮细胞生长因子（ECGF），这是第一个诱导某些LD患者T和B细胞反应的已知自身抗原。此外，我们还有初步的信息，即补体和细胞角蛋白10的第三部分也可以用作自身抗原。我们在此赠款应用中的第一个具体目的是确定自身免疫性与ECGF的临床相关性或跨LD频谱的其他候选自动抗原的相关性，包括其感染后综合症，以评估这些反应是否针对LD，并仅针对美国B. Burgdorferi（BB）与欧洲基因相兴奋。其次，我们计划使用与我们在ECGF识别其他候选自动抗原中成功使用的相同蛋白质组学和翻译研究方法。第三，我们将确定螺旋体和宿主因素，包括BB菌株的类型以及与宿主细胞的相互作用，这对于诱导其他候选自身抗原的ECGF的免疫反应是必不可少的，我们将表征对靶组织或流体中这些自身抗原的适应性免疫反应。这些目标将使我们能够确定对ECGF的自身免疫性是否作为更广泛的BB诱导的免疫反应的一部分，以确定所得的临床图片，以识别其他候选自动抗原，并划定负责这些反应的机制。我们预计对这些抗体反应的测试将成为LD临床评估的一部分。这些信息将帮助医生更适当有效地治疗LD患者。