Impaired Pneumococcal Antibody Function and Exacerbations of Chronic Obstructive Pulmonary Disease

项目摘要/摘要： 慢性阻塞性肺疾病(ECOPD)的恶化是发病率的关键驱动因素， 死亡率和医疗保健费用。一部分COPD患者经历频繁的ECOPD，并有 预后特别差。ECOPD通常是由被包裹的细菌感染引起的，例如 肺炎链球菌(肺炎球菌)，越来越多的证据表明，经常恶化的人 适应性免疫反应受损。先前的研究已经证明了ECOPD和LOW之间的关联 免疫球蛋白和免疫球蛋白亚类水平，以及与适应性免疫途径相关的基因下调。 肺炎球菌抗体功能受损(PAF)和特定的IgG2变异(同种异型)与 原发免疫缺陷的包膜细菌感染风险增加，然而这些因素 没有在慢性阻塞性肺疾病中进行研究。多重吞噬细胞试验(MOPA)通过杀死 肺炎球菌在体外通过血清抗体产生，是测量免疫反应的主要方法 成人肺炎球菌疫苗。初步研究表明，PAF也可用于评估免疫 在慢性阻塞性肺疾病中，低PAF与前一年的频繁恶化有关。 这一提议的中心假设是PAF和IgG2等位基因可以预测COPD亚群 增加了ECOPD的风险。为了验证这一假设，我们将测量血液中的PAF和IgG2同种异型。 之前从多中心SPIROMICS队列收集的样本。本提案的目标1将决定 较低的基线PAF是否预示着未来经社理事会的风险。目标2的目标是确定低 PAF预测慢性支气管炎COPD的表型，并伴有中性粒细胞增多和以呼吸道为主的影像表现。参考 PAF水平将使用来自非COPD队列的结果来建立，然后用于识别PAF缺陷 COPD亚组。我们将确定PAF缺乏是否与上述表型相关。目标3将 调查与低PAF相关的IgG2同种异型是否在频繁加重的患者中更常见， 与非加重COPD和非COPD对照组相比。 这项研究的结果可以确定新的COPD亚组和加重的危险因素。 这项研究的发现也可能促进个性化治疗方法的发展 对于那些抗体功能低下的人。拟议的研究和职业发展计划成为可能 通过肺炎球菌免疫反应国际专家穆恩·纳姆博士的指导，以及 马克·德兰斯菲尔德博士，临床和转化性COPD研究的领导者。该提案还包括培训 在实验室技术、生物统计学、临床和转化研究、微生物学和免疫学方面， 以培养一个独立的研究生涯，专注于COPD的免疫功能障碍。

Project Summary/Abstract: Exacerbations of chronic obstructive pulmonary disease (ECOPD) are a key driver of morbidity, mortality, and health care costs. A subset of COPD patients experience frequent ECOPD, and have a particularly poor prognosis. ECOPD are often caused by infections with encapsulated bacteria such as Streptococcus pneumoniae (pneumococcus), and there is growing evidence that frequent exacerbators have impaired adaptive immune responses. Prior studies have demonstrated associations between ECOPD and low IgG and IgG subclass levels, as well as downregulation of genes associated with adaptive immune pathways. Impaired pneumococcal antibody function (PAF) and specific IgG2 variants (allotypes) are associated with increased risk of encapsulated bacterial infections in primary immunodeficiencies, however these factors have not been studied in COPD. The multiplexed opsonophagocytosis assay (MOPA) measures PAF via killing of pneumococci by serum antibodies in vitro, and is the primary method for measuring immune responses to pneumococcal vaccines in adults. Preliminary studies indicate that PAF can also be used to evaluate immune function in COPD, and that lower PAF is associated with frequent exacerbations over the previous year. The central hypothesis for this proposal is that PAF and IgG2 allotype can predict a COPD subgroup with increased ECOPD risk. To investigate this hypothesis, PAF and IgG2 allotype will be measured in blood samples previously collected from the multicenter SPIROMICS cohort. Aim 1 of this proposal will determine whether low baseline PAF predicts risk of future ECOPD. The objective of Aim 2 is to determine whether low PAF predicts a chronic bronchitis COPD phenotype with neutrophilia and airway-dominant imaging. Reference levels for PAF will be established using results from a non-COPD cohort, then used to identify a PAF-deficient COPD subgroup. We will determine whether PAF deficiency is associated the above phenotypes. Aim 3 will investigate whether the IgG2 allotype associated with low PAF is more common among frequent exacerbators, versus non-exacerbating COPD and non-COPD controls. The results of this study could identify novel COPD subgroups and risk factors for exacerbations. Findings from this study may also promote the development of individualized therapeutic approaches tailored to those with low antibody function. The proposed research and career development plans are made possible through the mentorship of Dr. Moon Nahm, an international expert in pneumococcal immune responses, and Dr. Mark Dransfield, a leader in clinical and translational COPD research. The proposal also includes training in laboratory techniques, biostatistics, clinical and translational research, microbiology, and immunology, in order to foster an independent research career with a focus on immune dysfunction in COPD.