Lung immunoglobulin A immunity dysregulation in cystic fibrosis

Abstract

Background In cystic fibrosis (CF), recurrent infections suggest impaired mucosal immunity but whether production of secretory immunoglobulin A (S-IgA) is impaired remains elusive. S-IgA is generated following polymeric immunoglobulin receptor (pIgR)-mediated transepithelial transport of dimeric (d-)IgA and represents a major defence through neutralisation of inhaled pathogens like Pseudomonas aeruginosa ( Pa ). Methods Human lung tissue (n = 74), human sputum (n = 118), primary human bronchial epithelial cells (HBEC) (cultured in air-liquid interface) (n = 19) and mouse lung tissue and bronchoalveolar lavage were studied for pIgR expression, IgA secretion and regulation. Findings Increased epithelial pIgR immunostaining was observed in CF lung explants, associated with more IgA-producing plasma cells, sputum and serum IgA, especially Pa -specific IgA. In contrast, pIgR and IgA transport were downregulated in F508del mice, CFTR-inhibited HBEC, and CF HBEC. Moreover, the unfolded protein response (UPR) due to F508del mutation, inhibited IgA transport in Calu-3 cells. Conversely, pIgR expression and IgA secretion were strongly upregulated following Pa lung infection in control and F508del mice, through an inflammatory host response involving interleukin-17. Interpretation A complex regulation of IgA secretion occurs in the CF lung, UPR induced by CFTR mutation/dysfunction inhibiting d-IgA transcytosis, and Pa infection unexpectedly unleashing this secretory defence mechanism. Funding This work was supported by the Forton's grant of the King Baudouin's Foundation, Belgium, the Fondazione Ricerca Fibrosi Cistica, Italy, and the Fonds National de la Recherche Scientifique, Belgium.

Mucosal humoral immunity in cystic fibrosis - a tangled web of failed proteostasis, infection and adaptive immunity

“…First, Collin et al utilized explanted end-stage lung tissue as well as sputum and serum from clinically stable CF patients, classified by Pa infection status, and controls to demonstrate increased lymphoid aggregates, IgA plasmacytes, epithelial polymeric immunoglobulin receptor (pIgR; necessary for IgA transcytosis into the airway lumen) and IgA, in adults with CF. Serum and sputum IgA were increased, while sIgA and secretory component (SC) were also present in sputum [4]. This validates studies demonstrating an intact and activated systemic and mucosal adaptive humoral immunity in CF.…”

“…Second, transmission electron microscopy showed enlarged ER cavities in CFderived HBECs. Third, in Calu-3 epithelial cells, which stably express high levels of pIgR, UPR activation in vitro (as shown by increased XPB1s as well as phosphorylated stress-induced eukaryotic initiation factor 2a) demonstrated reduced pIgR protein, IgA transcytosis and SC release [4].…”

“…However, studies of sIgA are surprisingly sparse in the otherwise voluminous literature on respiratory host defense in relation to underlying genetic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and resulting functional defects in CFTR protein. In their EBioMedicine paper, Collin et al have endeavored to address this gap with a multifaceted approach evaluating the sIgA system in CF spanning cellular, murine model and clinical components, with emphasis on sIgA antibody response to Pa [4]. Three main groups of findings emerge, the first of which is confirmatory of prior work, but the second and third offer some surprising and provocative results that bring a new perspective and raise unanswered questions to pursue.…”

“…In HBEC cultures this down-regulation was mimicked with CFTR inhibitors. Downregulation was not observed in lung homogenates, a finding the investigators attribute to dilutional effects in the whole lung milieu [4].…”

“…In support of this hypothesis Collin et al examined the CF UPR closely. They found, first, both CF-derived HBECs and F508del mice had increased levels of spliced X-box binding protein 1 (XPB1s) [4], a target of UPR activation via inositol-requiring transmembrane kinase/endonuclease a, one of several known pathways of UPR activation [5]. Second, transmission electron microscopy showed enlarged ER cavities in CFderived HBECs.…”