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

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解决。我们以前曾在莱姆病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，称为难治性莱姆病关节炎。我们推测，这种疾病的过程是由于感染诱导的自身免疫与免疫失调的关节。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结合临床转化研究，我们最近鉴定了内皮细胞生长因子（ECGF）作为第一个已知的在患有抗生素难治性莱姆病关节炎的患者中诱导T和B细胞应答的自身抗原。我们在本申请中的第一个具体目标是确定LD谱中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对LD特异，并了解它是否仅发生在美国B。burgdorferi（Bb）菌株或也与螺旋体的欧洲基因种。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免疫应答所必需的。第三，我们计划表征免疫细胞亚群的表型、功能和基因表达，这些免疫细胞亚群导致难治性关节炎患者关节中的免疫失调，并了解此类异常是否发生在其他LD图片的患者中。这些目标将使我们能够扩大我们的观察，自身免疫ECGF可以发生作为一个频谱的BB诱导的免疫反应的一部分，以确定是否特定的临床图片从这种免疫反应的结果，描绘这些反应的机制，并表征功能的免疫失调，导致持续的疾病活动。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检测将成为LD临床评价的一部分。最后，这项工作的影响超出了LD，因为它可能会为如何识别和理解感染诱导的自身免疫与其他疾病的免疫失调创造一个新的范例。

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.