Secretory Immunoglobulin A Immunity in Chronic Obstructive Respiratory Diseases

Abstract

Chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis (CF) are distinct respiratory diseases that share features such as the obstruction of small airways and disease flare-ups that are called exacerbations and are often caused by infections. Along the airway epithelium, immunoglobulin (Ig) A contributes to first line mucosal protection against inhaled particles and pathogens. Dimeric IgA produced by mucosal plasma cells is transported towards the apical pole of airway epithelial cells by the polymeric Ig receptor (pIgR), where it is released as secretory IgA. Secretory IgA mediates immune exclusion and promotes the clearance of pathogens from the airway surface by inhibiting their adherence to the epithelium. In this review, we summarize the current knowledge regarding alterations of the IgA/pIgR system observed in those major obstructive airway diseases and discuss their implication for disease pathogenesis.

Keywords: COPD; asthma; cystic fibrosis; immunoglobulin A; mucosal immunity; pIgR.

Figure 1

Schematic description of the multiple functions of IgA and the pIgR/S-IgA system at mucosal surfaces. (A) pIgR-mediated endosomal transcytosis of d-IgA, produced by submucosal B cells. (B) S-IgA-driven immune exclusion, including agglutination (1), entrapment of immune complexes (2) and clearance of trapped pathogens (3). (C) Inhibition of bacterial adherence to the mucosal epithelium. (D) Intraepithelial neutralization of penetrating viral antigens. (E) pIgR-mediated elimination of subepithelial immune complexes, after immune exclusion of pathogens by subepithelial d-IgA. (F) (1) S-IgA-induced degranulation of eosinophils resulting from binding of S-IgA to its eosinophil receptor (potentially FcαRI or another receptor such as C-type lectin), occurring possibly after epithelial barrier disruption and releasing eosinophil granule proteins. (2) IgA-induced engagement of phagocytes, enhancing clearance mechanisms.

Figure 2

Overview of the pIgR/IgA system dysregulation mechanisms in chronic respiratory diseases. (A) pIgR/IgA system in airway homeostasis, at the epithelial surface and in submucosal glands. (B) In COPD, TGF-β induces pIgR downregulation at the epithelial surface (1), while pIgR expression is preserved in the submucosal glands. The S-IgA local deficiency relates to the subsequently decreased IgA transcytosis, as well as to S-IgA proteolysis by pathogen-derived proteinases (2), favouring bacterial invasion and innate immune cell infiltration. Subepithelial IgA may accumulate as a result of decreased transepithelial transport and IL-6- and BAFF-driven IgA synthesis (3). Enhanced survival of IgA+ plasma cells around the submucosal glands could contribute to a preserved S-IgA production at this level. (C) In asthma, IL-4/IL-13 may induce pIgR downregulation, also leading to luminal S-IgA deficiency (1). (D) In CF, pIgR is conversely upregulated, along with increased production of IgA and S-IgA in airway tissues and lumen, possibly through chronic infection by Pseudomonas aeruginosa that drives pIgR upregulation through IL-17 (1).