In the current funding period, we showed that acquired defects in mucosal immunity in small airways are a central feature of chronic obstructive pulmonary disease (COPD). We now propose to investigate mechanisms by which impairment of this first line of host defense leads to persistent activation of subsequent lines of host defense (innate and adaptive immunity), thus driving COPD progression. Although it has been clear for several years that COPD pathology begins in the small resistance airways, the mechanisms linking small airway and parenchymal pathology have been obscure. The small airway epithelium generates mucosal host defense by a variety of mechanisms, including transporting immunoglobulins to the airway surface. Down- regulation of polymeric immunoglobulin receptor (pIgR) expression, which is required for transport of dimeric IgA from the basolateral to luminal surface of the airway, is selectively reduced in COPD and impairs generation of the secretory IgA (SIgA) barrier on the airway surface. In individual small airways of COPD patients, reduced SIgA is associated with bacterial invasion into the epithelial layer, activation of NF-?B, and influx of inflammatory/immune cells. These pathogenic features can be modeled in pIgR deficient (pIgR-/-) mice, which lack SIgA on mucosal surfaces. Like COPD patients, these mice develop progressive emphysema and small airways remodeling, along with evidence of bacteria within the airway epithelial layer, epithelial NF-?B activation, and an influx of inflammatory/immune cells. Raising pIgR-/- mice in germ-free conditions, treatment with broad spectrum oral antibiotics, and neutrophil depletion reduce lung pathology. In addition, pIgR-/- mice develop lymphocyte accumulation, including increased CD4+ and Th17+ T cells, and tertiary lymphoid structures in the lungs, particularly with advanced age (similar to humans with severe COPD), along with a shift in the dendritic cell population towards increased monocyte-derived dendritic cells. Lymphocyte depletion reduces COPD-like pathology in pIgR-/- mice and treatment with broad spectrum antibiotics normalizes DC populations, reduces T cell influx, and eliminates accumulation of tertiary lymphoid structures, thus implicating both innate and adaptive immunity in the COPD-like pathology in this model. Together, available data suggests that each layer of the multi-layered airway host defense structure, which evolved to protect vulnerable mucosal surfaces, becomes dysfunctional in COPD. Therefore, we hypothesize that disruption of the SIgA immune barrier in small airways results in inflammatory signaling in epithelial cells, leading to persistent recruitment and activation of innate immune cells and pathologic activation of adaptive immunity, which synergize to drive airway remodeling and emphysema.
Specific Aims are: 1) to investigate the role of epithelial NF-?B in driving innate and adaptive immune activation in mice with mucosal immune deficiency, 2) to identify the role of T lymphocytes in development of COPD-like pathology in mice with mucosal immune deficiency, and 3) to determine whether altered dendritic cell subsets in the lungs mediate adaptive immune activation and sustained inflammation in COPD. Detailed knowledge of interactions between mucosal, innate, and adaptive immunity that drive COPD progression is required to develop new ways to limit progressive tissue injury while maintaining adequate host defense in the lungs.
Many Veterans with Chronic Obstructive Pulmonary Disease (COPD) have persistent airway inflammation and progress to end stage disease even after smoking cessation; therefore, new disease-modifying treatment approaches are needed for this disease. In this proposal, we will investigate mechanisms that account for persistent activation of the innate and adaptive immune systems in the lungs, thus leading to progressive emphysema and remodeling of small airways. If successful, our work will result in a better understanding of COPD and could lead to novel interventions to slow progression of this deadly disease.
