Secretory IgA Deficiency In Small Airways Results In COPD-Like Lung Inflammation And Remodeling

To investigate the role of secretory IgA (SIgA) deficiency in chronic obstructive pulmonary disease (COPD), we analyzed 1,104 small conducting airways from 50 former smokers with COPD and 39 healthy controls. Based on detection of IgA-immunospecific fluorescent signal on the mucosal surface, we found an increased proportion of SIgA-deficient airways in COPD patients (<5% airways in healthy controls vs. 47% airways in patients with mild-to-moderate COPD and 71% airways in patients with severe COPD). Independent of disease state, SIgA-deficient airways had thickened walls, accumulation of neutrophils and macrophages, increased susceptibility to bacterial colonization, and NF-κB pathway activation.  In contrast, airways with intact SIgA showed none of these findings.  Polyimmunoglobulin receptor (pIgR)-deficient mice, which have airway SIgA deficiency, showed bacterial invasion into the airway epithelial border, NF-κB activation, and progressive COPD-like inflammation and remodeling by 6-12 months of age.  Reconstitution of airway SIgA in pIgR^-/- mice reduced acute inflammation following bacterial challenge.  In addition, treatment of pIgR^-/- mice with the long-acting phosphodiesterase-4 inhibitor roflumilast blocked progression of the COPD-like phenotype.  Together, our findings support the concept that loss of the mucosal immune barrier in small airways and persistent activation of innate immune response contribute to COPD progression.