PROJECT SUMMARY Multiple lines of evidence point to the role of adaptive immunity as response to viral infections and/or as misdirected autoimmune response in subjects with COPD and emphysema. There is support for an association between adaptive immune responses and COPD progression, but a direct link has not been made. In this proposal, we will utilize blood samples from 3,000 well-characterized subjects from the COPDGene Study, which include longitudinal follow-up and extensive available omics datasets. We will employ state of the art Phage ImmunoPrecipitation Sequencing (PhIP-Seq) technology to efficiently and comprehensively assess samples for autoantibodies and antibodies indicative of prior viral infections. Our first hypothesis is that previous infections with respiratory viruses, or differential immune responses to viral infections, are associated with more rapid progression of COPD, specifically lung function decline. The second hypothesis is that autoantibodies are associated with COPD, emphysema, and more rapid lung function decline. Aim 1: Human Virome and Lung Function Decline. We will test for associations between baseline viral antibodies and longitudinal decline in lung function at the 5 and 10-year study visits. We will also measure antiviral antibodies at the 5-year visit and test for lung function decline over the subsequent 5 years in subjects who acquire new or higher levels of specific viral antibodies, signifying interval infections. We will test whether these effects are modified by host factors including sex and HLA genotypes. Aim 2: Autoimmunity and COPD Outcomes. We will use PhIP-Seq to identify the presence of autoantibodies, we and will test for association between autoantibodies and COPD status, lung function decline, and quantitative emphysema parameters from chest CT scans. We will measure autoantibodies at the 5-year visit and test for lung function decline over the subsequent 5 years in subjects who acquire new or higher levels of autoantibodies. We will again test whether these effects are modified by host factors including sex and HLA genotypes. Aim 3: Adaptive Immunity and Chronic Inflammation Using whole blood RNA- sequencing data from the year 5 visit, we will derive gene expression scores representing antiviral and inflammatory pathways. We will test the association of these gene expression scores with viral antibodies and autoantibodies to discover novel drivers of persistent inflammation. We will validate the association of inflammatory gene expression scores with lung function and CT emphysema in a larger sample of COPDGene subjects with RNA-sequencing data. This proposal will complement the existing clinical, genetic and transcriptomic data in COPDGene by incorporating viral exposures and autoantibodies into longitudinal models of COPD progression. To accomplish this research, we have assembled a multidisciplinary team with expertise in in PhIP-Seq, COPD phenotyping, molecular immunology, genetic epidemiolo...