Epithelial barrier function: at the frontline of asthma immunology and allergic airway inflammation

Airway epithelial cells are an important part of the innate immune system in the lung. Not only do they establish mucociliary clearance, epithelial cells produce anti-microbial peptides, chemokines, and cytokines that recruit and activate other cell types and promote pathogen clearance. Recent studies emphasize the importance of epithelial derived cytokines in the promotion of Th2 immune responses, at least in part by conditioning local dendritic cells (DCs). Epithelial cells also from a barrier to the outside world comprised of airway surface liquids, mucus, and apical junctional complexes (AJC) that form between neighboring cells. In their recent review, Georas and Rezaee discuss why defective epithelial barrier function may be linked to Th2 polarization in asthma, and propose a rheostat model of barrier dysfunction that implicates the size of inhaled allergen particles as an important factor influencing adaptive immunity (J Allergy Clin Immunol 2014; 134(3): 509-520). 

Increasing evidence indicates that defective epithelial barrier function is a feature of airway inflammation in asthma. A challenge in this area is that barrier function and junctional integrity are difficult to study in the intact lung, but innovative approaches are providing new knowledge in this area. The authors review the structure and function of epithelial apical junctional complexes, emphasizing how regulation of the epithelial barrier impacts innate and adaptive immunity. They propose that epithelial barrier dysfunction is not “all or none”, but rather a graded phenomenon with consequences for allergen uptake and processing that may impact subsequent adaptive immune responses. For example, inducible barrier dysfunction caused by environmental exposures can vary in severity and will affect the penetration of fate of inhaled particles, depending on their size and other physical characteristics. While inhaled allergens alone may be capable of promoting transient barrier disruption, sustained dysfunction is more likely to follow inhalation of toxic air pollutants and respiratory viral infections. In fact, inducible barrier dysfunction is a strategy used by viruses to promote their replication, but likely represents a risk factor for allergen sensitization. 

This review goes into great detail about the complexity of the epithelial barrier function and how it relates to the involvement of allergic diseases of the airway. The understanding of the basic structure and function of apical junctional complexes is necessary to determine the mechanisms involved in allergic disease, as is the understanding of epithelial permeability which is a hallmark of mucosal inflammation. Future studies of the mechanisms and consequences of airway epithelial barrier dysfunction in asthma should enhance our understanding of asthma heterogeneity as well as the pathogenesis of allergic diseases. 

Questions for the authors: The importance of the epithelial barrier function is relatively new to the study of allergic diseases. What do you think are likely implications of these findings in regards to prevention of allergic diseases? For example, does research suggest that barrier dysfunction could be prevented, thus preventing the cascade of events that causes allergy?

This is a very important question in an area where we need more research.  For example, we do not know the relationship between airway epithelial barrier dysfunction and whether this precedes sensitization to aeroallergens.  Emerging data indicate that alterations in lung development either in utero or early in life are a risk factor for asthma, and may even precede allergic inflammation.  It will be interesting to determine whether altered epithelial barrier integrity is a feature of these alterations in lung development, which will require non-invasive assays that are safe in infants.  Although certain therapeutic agents have been shown to have barrier protective / restorative effects on epithelial monolayers in vitro, we have limited understanding of how most commonly used therapies affect airway epithelial integrity and tight junction expression / function in vivo.  This is another area that is ripe for future research.