Club cells are the primary source of pIgR in small airways

Background: Loss of secretory immunoglobulin A (SIgA) is common in COPD small airways and likely contributes to disease progression. We hypothesized loss of SIgA results from reduced numbers of cells expressing pIgR, a chaperone protein needed for SIgA transcytosis, in the COPD small airway epithelium. Methods: pIgR-expressing cells were defined and quantified at single-cell resolution in human airways using RNA in-situ hybridization, immunostaining, and single-cell RNA sequencing. Complementary studies in mice utilized immunostaining, primary murine tracheal epithelial cell (MTEC) culture, and transgenic mice with club or ciliated cell-specific knockout of pIgR. SIgA degradation by human neutrophil elastase or secreted bacterial proteases from non-typeable Haemophilus influenzae (NTHi) was evaluated in vitro. Results: Club cells are the predominant cell type responsible for pIgR expression in human and murine airways, but neither loss of pIgR-expressing club cells or reduced pIgR expression in individual cells fully explains loss of SIgA in the airways in patients with advanced COPD. In contrast, we found that neutrophil elastase and NTHi-secreted proteases degrade SIgA in vitro. Interpretation: Club cells are the dominant cell type responsible for pIgR expression and thus play a key role in the maintaining the secretory IgA immunobarrier. However, neither a loss of club cells or reduced pIgR expression within individual cells fully accounts for loss of SIgA in COPD.