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: 8543853
• 负责人: ALLEN C STEERE
• 金额: $ 60.08万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8543853
• 关键词: Accounting; Address; Antibiotic Therapy; Antibiotics; Antibody Formation; Antigen-Antibody Complex; Applications Grants; Arthritis; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Borrelia burgdorferi; Carditis; Cell Communication; Cells; Clinical; Disease; Effector Cell; Eragrostis; European; Facial paralysis; Fatigue; Fibroblast Growth Factor; Freezing; Gene Expression; Immune; Immune response; Infection; Integration Host Factors; Joints; Lead; Learning; Liquid substance; Lyme Arthritis; Lyme Disease; Neurocognitive; Neurologic; Order Spirochaetales; Pain; Pathogenesis; Patients; Phase; Phenotype; Play; Protein Binding; Proteins; Proteomics; Publishing; Reactive Arthritis; Refractory; Resistance; Resolution; Role; Seminal; Serum; Site; Surface; Symptoms; Syndrome; Synovial Fluid; Synovitis; T-Lymphocyte; Testing; Tissue Sample; Translational Research; Work; autoreactivity; base; candidate identification; cell type; erythema migrans; innovation; killings; research clinical testing; response; uptake

DESCRIPTION (provided by applicant): Certain manifestations of Lyme disease (LD) do not resolve with antibiotic therapy. We have studied this problem previously in patients with Lyme arthritis who have persistent synovitis for months or years after spirochetal killing with antibiotics, called antibiotic-refractory Lyme arthritis. We have hypothesized that this disease course results from infection-induced autoimmunity with 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) as the first known autoantigen that induces T and B cell responses in patients with antibiotic- refractory Lyme arthritis. Our first specific aim in this application is to determine the clinical correlates of autoimmunity across the spectrum of LD, including erythema migrans, neuroborreliosis, carditis, arthritis, and post-infectious syndromes, to assess whether this response is specific for LD, and to learn whether it occurs only with U.S. B. burgdorferi (Bb) strains or also with European genospecies of the spirochete. Second, we want to understand spirochetal and host cell interactions, including the types of Bb strains and host cell types, which are necessary for the induction of ECGF and ECGF immune responses. Third, we plan to characterize the phenotype, function and gene expression of immune cell subsets that lead to immune dysregulation in joints in patients with antibiotic-refractory arthriti, and to learn whether such abnormalities occur in patients with other LD pictures. These aims will allow us to expand our observation that autoimmunity to ECGF can occur as a part of the spectrum of Bb-induced immune responses, to ascertain whether specific clinical pictures result from such immune responses, to delineate mechanisms that account for these responses, and to characterize features of immune dysregulation that lead to persistent disease activity. If these studies validate ECGF as a pathogenic autoantigen, we anticipate that a test for this antibody response will become a part of the clinical evaluation of LD. Finally, this work has implications beyond LD, since it may create a new paradigm for how to identify and understand infection-induced autoimmunity with immune dysregulation in other diseases.

描述（由申请人提供）：莱姆病（LD）的某些表现不解决抗生素治疗。我们以前在患有持续性滑膜炎的莱姆关节炎患者中使用抗生素杀死后几个月或几年，称为抗生素难治性莱姆关节炎。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。我们使用基于发现的蛋白质组学与临床转化研究结合使用，我们最近将内皮细胞生长因子（ECGF）确定为诱导抗生素 - 耐耐性lyme关节炎患者T和B细胞反应的首个已知的自身抗原。 Our first specific aim in this application is to determine the clinical correlates of autoimmunity across the spectrum of LD, including erythema migrans, neuroborreliosis, carditis, arthritis, and post-infectious syndromes, to assess whether this response is specific for LD, and to learn whether it occurs only with U.S. B. burgdorferi (Bb) strains or also with European genospecies of the spirochete.其次，我们想了解螺旋体和宿主细胞相互作用，包括BB菌株和宿主细胞类型的类型，这对于诱导ECGF和ECGF免疫反应所必需。第三，我们计划表征免疫细胞亚群的表型，功能和基因表达，这些表型，抗生素难治性促性节日患者的关节免疫失调，并了解其他LD图片患者是否发生这种异常。这些目的将使我们能够扩大观察结果，即可以作为BB诱导的免疫反应的一部分进行自身免疫性，以确定是否由这种免疫反应产生的特定临床图片，以描述这些反应的机制，并导致这些反应的机制，并导致免疫失调的特征导致持续性疾病疾病的疾病。如果这些 研究将ECGF验证为病原自身抗原，我们预计该抗体反应的测试将成为LD临床评估的一部分。最后，这项工作具有超出LD的影响，因为它可能会为如何识别和理解其他疾病中的免疫失调而识别和理解感染引起的自身免疫性。