Impaired Secretory IgA and Mucosal Immunity in Cystic Fibrosis: Contribution to Lung Pathology and Impaired Defence Against Bacterial Infection

Impaired secretory IgA and mucosal immunity in cystic fibrosis:

role of CFTR-related epithelial changes in the regulation of pIgR-mediated IgA transcytosis and contribution to lung pathology and impaired defence against bacterial infections.

PROJECT DESCRIPTION Cystic fibrosis (CF) represents the most common lethal autosomal recessive disorder in the white population, mainly affecting the lungs. Twenty-four years after the identification of the gene responsible for the disease, many questions remain, current treatments are symptomatic and it remains a lethal disease. It affects the Cystic Fibrosis Transmembrane Regulator (CFTR) gene, which encodes a protein expressed on the apical membrane of airway epithelial cells, where it acts as a cAMP-dependent chloride channel and regulator of other channels, including the epithelial Na+ channel (ENaC). Mutations of the CFTR (F508del, 70% of cases) either result in malfunction or complete absence of the CFTR protein at the apical membrane, due to protein misfolding and retention in the endoplasmic reticulum. It results in defects in chloride efflux and hydration of the epithelial lining fluid, resulting in abnormally viscous mucus which may obstruct the airways, the intestinal lumen and glandular ducts (e.g. in the pancreas). CFTR dysfunction also leads to pro-inflammatory activation (e.g. through NFkB) of the epithelium, resulting in CXCL8/IL8 release (Sloane et al, 2005) and impaired production of protective factors such as a-defensins. Airway colonization of the airways and lung infections are a hallmark of this disease, in particular with Pseudomonas aeruginosa (PA) that affects 70% of CF patients and is associated with poor clinical outcomes. However, the mechanisms underlying the persistence of pathogens in CF airways, remain largely unclear.

This project aims to investigate whether the production of secretory IgA (S-IgA) is impaired in the CF lung, through which mechanisms, and whether this defect contributes to the pathogenesis of CF by impairing immunoprotection against respiratory pathogens such as PA. S-IgA is a major line of mucosal defense, through so-called immune exclusion of inhaled / ingested antigens and pathogens (Norderhaug et al, 1999). Following synthesis of polymeric (mainly dimeric) IgA by subepithelial mucosal plasma cells, p-IgA is transported across the epithelium by a transcellular routing mediated by the polymeric immunoglobulin receptor (pIgR). P-IgA binds to the pIgR at the basolateral pole of the epithelium, and is transcytosed up to the apical pole, where a proteolytic cleavage releases the extracellular part of the pIgR, called secretory component (SC) which remains bound to p-IgA to form S-IgA. This transport represents the most important transcellular routing in the body (3g/day). S-IgA is mainly produced upon mucosal stimulation by microbial signals acting through Toll-like receptors on epithelial cells and B cells (MacPherson et al, 2008) while cytokines (IFN-g, IL-4, IL-1 or TNF-a) may upregulate pIgR expression and/or transcytosis (see review Pilette et al, 2001a).

A defect of pIgR expression has been identified in smoke-induced chronic obstructive pulmonary disease (COPD) (Pilette et al, 2001b). Reduced pIgR in COPD could be due to degradation by neutrophil-derived serine proteinases (Pilette et al, 2003), as well as to impaired gene transcription (Gohy & Pilette, submitted manuscript). In contrast to COPD, it remains unclear whether pIgR expression is affected in CF, through which mechanisms, and if so, with which consequences in terms of mucosal defense. Our hypothesis is that pIgR expression is reduced in CF epithelia, as a result of CFTR-related epithelial changes, and leads to impaired IgA-mediated immune exclusion of respiratory pathogens, thereby favoring chronic bacterial colonization and lung infections in CF. The specific objectives of this project are as follows: