Impaired Pneumococcal Antibody Function and Exacerbations of Chronic Obstructive Pulmonary Disease

项目概要/摘要： 慢性阻塞性肺疾病（ECOPD）的加重是发病率的关键驱动因素， 死亡率和医疗费用。COPD患者的一个子集经历频繁的ECOPD，并且具有 尤其是预后不良。ECOPD通常是由包囊细菌感染引起的， 肺炎链球菌（肺炎球菌），越来越多的证据表明，频繁加重 适应性免疫反应受损。先前的研究已经证明了ECOPD和低血糖之间的相关性。 IgG和IgG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）和特异性IgG 2变体（同种异型）与 在原发性免疫缺陷中，包囊性细菌感染的风险增加，然而，这些因素 未在COPD中进行研究。多重调理吞噬试验（MOPA）通过杀死 肺炎双球菌的血清抗体在体外，并且是用于测量免疫应答的主要方法， 成人肺炎疫苗初步研究表明，PAF也可用于评估免疫功能， PAF在COPD中的作用，并且较低的PAF与前一年的频繁加重相关。 该建议的中心假设是PAF和IgG 2同种异型可以预测COPD亚组 COPD风险增加。为了研究这一假设，将在血液中测量PAF和IgG 2同种异型 先前从多中心SPIROMICS队列中采集的样本。本提案的目标1将决定 低基线PAF是否可预测未来ECOPD的风险。目标2的目的是确定低 PAF预测慢性支气管炎COPD表型伴嗜肺和气道优势成像参考 将使用非COPD队列的结果确定PAF水平，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 研究与低PAF相关的IgG 2同种异型是否在频繁加重者中更常见， 与非加重COPD和非COPD对照相比。 本研究的结果可以识别新的COPD亚组和急性加重的风险因素。 这项研究的发现也可能促进个性化治疗方法的发展 抗体功能低下的人。使拟议的研究和职业发展计划成为可能 通过Moon Nahm博士的指导，Moon Nahm博士是肺炎球菌免疫反应方面的国际专家， 博士Mark Dransfield是COPD临床和转化研究的领导者。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， 为了促进一个独立的研究事业，重点是免疫功能障碍的COPD。

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.