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)的某些症状不能通过抗生素治疗解决。我们以前曾在莱姆关节炎患者中研究过这个问题，这些患者在用抗生素杀死螺旋体后持续滑膜炎数月或数年，称为抗生素难治性莱姆关节炎。我们假设这种疾病的病程是由感染诱导的自身免疫和关节的免疫失调所致。然而，直到最近，对致病自身抗原的鉴定仍然难以捉摸。利用基于发现的蛋白质组学和临床翻译研究相结合的方法，我们最近发现内皮细胞生长因子(ECGF)是第一个已知的诱导抗生素难治性莱姆关节炎患者T和B细胞反应的自身抗原。我们在这项应用中的第一个具体目标是确定各种LD的自身免疫的临床相关性，包括红斑迁徙、神经疏螺旋体病、心脏炎、关节炎和感染后综合征，评估这种反应是否是LD特有的，并了解它是仅发生在美国伯氏杆菌(BB)菌株还是也发生在欧洲的螺旋体基因种。其次，我们想了解螺旋体和宿主细胞的相互作用，包括BB菌株的类型和宿主细胞类型，这是诱导ECGF和ECGF免疫反应所必需的。第三，我们计划表征导致抗生素难治性关节炎患者关节免疫失调的免疫细胞亚群的表型、功能和基因表达，并了解这种异常是否发生在其他LD照片的患者中。这些目的将使我们能够扩大我们的观察，即对ECGF的自身免疫可以作为BB诱导的免疫反应的一部分来发生，以确定这种免疫反应是否产生特定的临床表现，描述解释这些反应的机制，并表征导致持续疾病活动的免疫失调的特征。如果这些 研究证实ECGF是一种致病的自身抗原，我们预计这种抗体反应的检测将成为LD临床评估的一部分。最后，这项工作具有超越LD的意义，因为它可能为如何识别和理解感染诱导的自身免疫以及其他疾病中的免疫失调创造了一个新的范式。