Mucosal immunity alterations in idiopathic pulmonary fibrosis : implication of the IgA-pIgR axis

Rationale: The humoral immune system has been implicated in fibrosis, however the exact role of immunoglobulin A (IgA) and its epithelial transporter, the polymeric immunoglobulin receptor (pIgR) in idiopathic pulmonary fibrosis (IPF) remains unclear. Objectives: To explore the role of the IgA-pIgR system in IPF. Methods: The different components of the IgA-pIgR system were measured in the serum and broncho-alveolar lavage (BAL) of IPF patients and controls. The local pulmonary tissue expression of the IgA-pIgR axis was evaluated by multiplex immunostaining and optical tissue clearing. Using murine models consisting of both single and repeated instillations of bleomycin, the impact of pIgR and IgA knock-out on pulmonary fibrosis was evaluated. Measurements and main results: Circulating IgA, secretory (S-)IgA and secretory component (SC) as well as BAL IgA were elevated in IPF patients. pIgR was expressed within zones of bronchiolization in the IPF lung while honeycomb- and hyperplasic type-2 alveolar cells cysts were filled with S-IgA. Repeated bleomycin instillations resulted in the dysregulation of the IgA-pIgR system in mice, with an increase in pIgR and IgA expression and the ectopic presence of pIgR within distal remodeled zones. pIgR-/- but not IgA-/- animals were protected from the development of pulmonary fibrosis and pIgR-/- mice displayed lower TGF-β1 levels in their BAL both at early and late timepoints. Conclusion: The IgA-pIgR axis is dysregulated in IPF, with an aberrant presence of its different components within the distal lung. pIgR is implicated in the fibrotic process, potentially through an interaction with TGF-β1 signaling.