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 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. What is the key question? This study addresses whether loss of SIgA in the small airways of COPD patients is due to reduced numbers of pIgR-expressing cells or reduced pIgR expression per cell. What is the bottom line? pIgR is expressed primarily by club cells in human and murine airways, but neither loss of these cells or reduced pIgR expression per cell fully explains loss of SIgA in COPD small airways. Why read on? SIgA levels on the surface of small airways are determined by rates of production, transcytosis across the airway epithelium, and degradation. This study suggests pIgR-independent defects in SIgA transcytosis or SIgA degradation may be more important determinants of airway SIgA levels than previously appreciated. ### Competing Interest Statement The authors have declared no competing interest.