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

描述（由申请人提供）：莱姆病（LD）最大的剩余临床问题是一些患者在抗生素治疗后没有完全缓解体征或症状。近年来，我们深入研究了莱姆病关节炎患者的这个问题，这些患者在用抗生素杀死螺旋体后滑膜炎持续数月或数年，称为难治性关节炎。我们推测，这种疾病的过程是由于感染诱导的自身免疫性关节过度炎症和免疫失调。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，我们最近确定了内皮细胞生长因子（ECGF），这是第一个已知的自身抗原，诱导T和B细胞反应，在一些患者与LD。此外，我们有初步的信息，补体和细胞角蛋白10的第三组分也可能作为自身抗原。我们在这项拨款申请中的第一个具体目标是确定自身免疫对ECGF或其他候选自身抗原在LD谱中的临床相关性，包括其感染后综合征，以评估这些反应是否对LD特异，并了解它们是否仅发生在美国B。burgdorferi（Bb）菌株或也与螺旋体的欧洲基因种。其次，我们计划使用相同的蛋白质组学和翻译的研究方法，我们成功地在识别ECGF，以确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，这是诱导对其他候选自身抗原的ECGF的免疫应答所必需的，我们将表征靶组织或体液中对这些自身抗原的适应性免疫应答。这些目标将使我们能够确定是否自身免疫ECGF发生作为一个更广泛的BB诱导的免疫反应的一部分，以确定由此产生的临床图片，以确定其他候选自身抗原，并描绘负责这些反应的机制。我们预计，这些抗体反应的测试将成为LD临床评价的一部分。这些信息将有助于医生更适当和有效地治疗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.