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

基本信息

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
项目类别：
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

项目摘要

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) 的某些表现不能通过抗生素治疗得到缓解。我们之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数月或数年滑膜炎，称为抗生素难治性莱姆关节炎。我们假设这种病程是由感染引起的自身免疫和关节免疫失调引起的。然而，直到最近，致病性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与临床转化研究相结合，我们最近确定内皮细胞生长因子 (ECGF) 是第一个已知的自身抗原，可诱导抗生素难治性莱姆关节炎患者的 T 和 B 细胞反应。我们在本申请中的第一个具体目标是确定整个 LD 范围内自身免疫的临床相关性，包括游走性红斑、神经疏螺旋体病、心脏炎、关节炎和感染后综合征，以评估这种反应是否是 LD 特异性的，并了解无论它仅发生在美国伯氏疏螺旋体 (Bb) 菌株中，还是也发生在欧洲螺旋体基因种中。其次，我们想要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，这对于诱导 ECGF 和 ECGF 免疫反应是必需的。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，并了解其他 LD 图片患者是否也会出现此类异常。这些目标将使我们能够扩大我们的观察范围，即 ECGF 自身免疫可能作为 Bb 诱导的免疫反应谱的一部分而发生，以确定特定的临床表现是否由此类免疫反应引起，描绘出这些反应的机制，以及描述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 是一种致病性自身抗原，我们预计这种抗体反应的测试将成为 LD 临床评估的一部分。最后，这项工作的意义超出了 LD，因为它可能为如何识别和理解其他疾病中感染诱导的自身免疫和免疫失调创造一个新的范例。