Determinants of Post-Treatment Phenotypes in Lyme Disease

项目总结/摘要 目前尚不清楚为什么有些患者在适当治疗莱姆病后恢复了病前的健康状况 而另一些进展为治疗后莱姆病（PTLD）。重要的先前出版和 初步数据表明，感染开始时临床、免疫和代谢因素的变异性 和B在一起Burgdorferi有助于发展不同的治疗后结果，包括PTLD。在这 在这项研究中，我们将利用明确定义的PTLD患者的独特队列，没有PTLD病史的健康对照， 莱姆病和早期莱姆病患者在治疗结束后纵向随访长达1年。 治疗结合先进的，创新的统计和实验室方法，这项赠款的目标是 确定这些因素，并检查它们如何与患者的潜在症状表型相关， PTLD。为了实现这一目标，我们将确定与治疗后相关的临床相关风险因素。 随着时间的推移，莱姆病的结果。这些因素将用于制定评估分数，以确定 在临床环境中发生PTLD风险增加的患者（AIM 1）。一个纵向的，多元的，交叉的- 这类领域分析的目标是将研究结果直接转化为临床实践， PTLD的基本疾病途径以前没有进行过。我们还将确定新的汽车- 通过蛋白质阵列检测与PTLD相关的抗体，并检查它们与潜在的PTLD的关系。 临床表型（AIM 2）。虽然自身免疫过程被怀疑是糖尿病发病机制的基础， PTLD，至少对某些个体来说，对自身抗原的适应性免疫识别才刚刚开始。 介绍了PTLD中自身抗体的发现可能揭示以特定临床特征为标志的患者亚群， 例如主要肌肉骨骼疼痛或神经症状，并识别其疾病 由自身免疫过程驱动最后，我们将研究慢性乙型肝炎患者的纵向免疫代谢特征。 不同的临床结果，使用一种新的，高维流式细胞术的方法，并假设， 体外干扰途径的药理学操作可能能够使PTLD相关的 代谢特征（AIM 3）。免疫代谢在全球范围内报告急性细胞毒性的能力 环境表明，在未来发展PTLD的个体中询问免疫细胞代谢可能 为疾病机制提供了基本的见解。总的来说，我们的研究代表了一种严格的方法， 揭示与PTLD结局及其基础临床相关的决定因素 表型。该项目的长期目标是产生基础知识， 创新的治疗策略以及新的干预措施，以防止或减少往往显着的 PTLD的症状负担和功能影响。

PROJECT SUMMARY/ABSTRACT It is unknown why some patients regain their pre-morbid health following appropriate treatment for Lyme disease while others progress to develop post-treatment Lyme disease (PTLD). Significant prior published and preliminary data suggest that variability in clinical, immunologic, and metabolic factors at the onset of infection with B. burgdorferi contribute to the development of divergent post-treatment outcomes, including PTLD. In this study, we will draw upon unique cohorts of patients with well-defined PTLD, healthy controls without a history of Lyme disease, and patients with early Lyme disease followed longitudinally up to 1 year after the end of treatment. Combining advanced, innovative statistical and laboratory methods, the objective of this grant is to identify these factors and examine how they relate to underlying symptom phenotypes among patients with PTLD. To accomplish this goal, we will identify clinically-relevant risk factors associated with post-treatment outcomes in Lyme disease over time. These factors will then be used to develop an assessment score to identify patients at increased risk of developing PTLD in the clinical setting (AIM 1). A longitudinal, multivariate, cross- domain analysis of this sort with the goal of direct translation of findings to clinical practice and the study of fundamental disease pathways in PTLD has not previously been performed. We will also identify novel auto- antibodies that are associated with PTLD through protein array, and examine their relationship with underlying clinical phenotypes (AIM 2). While an autoimmune process has been suspected to underlie the pathogenesis of PTLD, at least for some individuals, adaptive immune recognition of self-antigens is only beginning to be described. Discovery of autoantibodies in PTLD may reveal patient subsets marked by specific clinical features, such as predominant musculoskeletal pain or neurologic symptoms, and identify individuals whose disease is driven by an autoimmune process. Finally, we will study the longitudinal immunometabolic profile of patients with differing clinical outcomes using a novel, high-dimensional flow cytometry approach, and hypothesize that pharmacologic manipulation of perturbed pathways in vitro may be able to normalize a PTLD-associated metabolic signature (AIM 3). The ability of immunometabolism to globally report on the acute cellular environment suggests that interrogating immune cell metabolism in individuals develop PTLD in the future could provide fundamental insights into disease mechanism. Collectively, our studies represent a rigorous approach towards uncovering determinants that are associated with the outcome of PTLD and its underlying clinical phenotypes. The long-term goal of this project is to generate fundamental knowledge to inform the development of innovative therapeutic strategies as well as novel interventions to prevent or reduce the often significant symptom burden and functional impact of PTLD.