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

描述(申请人提供)：莱姆病(LD)最大的临床遗留问题是，一些患者使用抗生素治疗后，症状或体征没有完全消失。近年来，我们在莱姆关节炎患者中深入研究了这个问题，这些患者在使用抗生素杀死螺旋体后滑膜炎症持续数月或数年，称为抗生素难治性关节炎。我们假设这种疾病的病程是由感染诱导的自身免疫引起的，关节过度炎症和免疫失调。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，我们最近发现了内皮细胞生长因子(ECGF)，这是已知的第一个在一些LD患者中诱导T和B细胞反应的自身抗原。此外，我们有初步信息，补体的第三组分和细胞角蛋白10也可能作为自身抗原。我们在这项赠款申请中的第一个具体目标是确定临床上对整个LD谱系的ECGF或其他候选自身抗原的免疫相关性，包括其感染后综合征，评估这些反应是否是LD所特有的，并了解它们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，我们计划使用我们在ECGF鉴定中成功使用的相同的蛋白质组学和翻译研究方法来鉴定其他候选自身抗原。第三，我们将确定螺旋体和宿主因素，包括BB菌株的类型和与宿主细胞的相互作用，这些因素是诱导其他候选自身抗原对ECGF的免疫反应所必需的，我们将表征靶组织或液体中对这些自身抗原的适应性免疫反应。这些目的将使我们能够确定对ECGF的自身免疫是否作为BB诱导的更广泛免疫反应的一部分发生，以确定由此产生的临床图像，识别其他候选自身抗原，并描述这些反应的机制。我们预计，对这些抗体反应的检测将成为LD临床评估的一部分。这些信息将有助于医生更恰当、更有效地治疗LD患者。

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.