Secretory 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 expression of 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 secretory 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: We found that secretory cells are the predominant cell type responsible for pIgR expression in human and murine airways. Loss of SIgA in small airways was not associated with a reduction in secretory cells but rather a reduction in pIgR protein expression despite intact PIGR mRNA expression. Neutrophil elastase and NTHi-secreted proteases are both capable of degrading SIgA in vitro and may also contribute to a deficient SIgA immunobarrier in COPD. Interpretation: Loss of the SIgA immunobarrier in small airways of patients severe COPD is complex and likely results from both pIgR-dependent defects in IgA transcytosis and SIgA degradation. Overall design: We performed single-cell RNA sequencing on distal lung parenchymal samples from the explanted lungs of 11 COPD patients undergoing lung transplantation and 10 control patients. Raw data from control samples is available under GSE135893.