Impaired Pneumococcal Antibody Function and Exacerbations of Chronic Obstructive Pulmonary Disease

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.