Impaired Pneumococcal Antibody Function and Exacerbations of Chronic Obstructive Pulmonary Disease

肺炎球菌抗体功能受损和慢性阻塞性肺疾病恶化

基本信息

批准号：
10370689
负责人：
David Cardy LaFon
金额：
$ 15.96万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10370689
关键词：
Adult Alleles Antibodies Antibody Response Bacteria Bacterial Infections Biological Assay Biological Markers Biometry Blood specimen Bronchiectasis Chronic Bronchitis Chronic Obstructive Pulmonary Disease Clinical Clinical Research Cohort Studies Data Defect Development Development Plans Diagnosis Disease Down-Regulation Elderly Encapsulated Evaluation Exhibits Fostering Frequencies Future Genes Goals Health Care Costs Healthcare High Prevalence IgG2 Image Immune Immune System Diseases Immune response Immunoglobulin G Immunologics Immunology Impairment In Vitro Incidence Individual Infection International Investigation Laboratories Lead Measurable Measures Mediating Mentorship Methods Microbiology Moon Morbidity - disease rate Neutrophilia Outcome Measure Participant Pathway interactions Patient Self-Report Patients Phagocytosis Phenotype Pneumococcal vaccine Population Predisposition Process Prognosis Recurrence Research Respiratory Tract Infections Risk Risk Factors Sampling Serum Severities Source Streptococcus pneumoniae Subgroup Symptoms Techniques Testing Therapeutic Therapeutic Intervention Training Translational Research Vaccines Variant adaptive immune response base career career development cohort congenital immunodeficiency disease phenotype disorder control disorder risk disorder subtype experience follow-up former smoker genetic variant immune function infection risk mortality neutrophil never smoker novel novel strategies pathogen personalized approach personalized medicine primary endpoint prospective research and development response targeted treatment tool

项目摘要

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.

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。一部分慢性阻塞性肺病 (COPD) 患者经常经历 ECOPD，并且有预后特别差。 ECOPD 通常是由包膜细菌感染引起，例如肺炎链球菌（肺炎球菌），并且越来越多的证据表明频繁的加重者已适应性免疫反应受损。先前的研究已证明 ECOPD 与低血压之间存在关联 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 (PAF) 受损和特定 IgG2 变体（同种异型）与原发性免疫缺陷患者发生荚膜细菌感染的风险增加，但是这些因素已经尚未在 COPD 中进行研究。多重调理吞噬作用测定 (MOPA) 通过杀灭 PAF 来测量 PAF 肺炎球菌通过体外血清抗体进行检测，是测量肺炎球菌免疫反应的主要方法成人肺炎球菌疫苗。初步研究表明PAF还可用于评估免疫功能慢性阻塞性肺病 (COPD) 中的功能，较低的 PAF 与前一年的频繁恶化有关。该提案的中心假设是 PAF 和 IgG2 同种异型可以预测 COPD 亚组 ECOPD 风险增加。为了研究这一假设，将测量血液中的 PAF 和 IgG2 同种异型之前从多中心 SPIROMICS 队列中收集的样本。该提案的目标 1 将确定低基线 PAF 是否可以预测未来 ECOPD 的风险。目标 2 的目标是确定是否低 PAF 可预测具有中性粒细胞增多和气道主导影像的慢性支气管炎 COPD 表型。参考将使用非 COPD 队列的结果确定 PAF 水平，然后用于识别 PAF 缺乏的患者慢性阻塞性肺病亚组。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IgG2同种异型是否在频繁的加重者中更常见，与非恶化性 COPD 和非 COPD 对照进行比较。这项研究的结果可以确定新的慢性阻塞性肺病亚组和恶化的危险因素。这项研究的结果也可能促进个体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得以实现在国际肺炎球菌免疫反应专家 Moon Nahm 博士的指导下， Mark Dransfield 博士是慢性阻塞性肺病临床和转化研究领域的领导者。该提案还包括培训实验室技术、生物统计学、临床和转化研究、微生物学和免疫学为了培养独立的研究事业，重点关注慢性阻塞性肺病的免疫功能障碍。