Epithelial barrier dysfunction in ocular allergy

Abstract

The epithelial barrier is the first line of defense that forms a protective barrier against pathogens, pollutants, and allergens. Epithelial barrier dysfunction has been recently implicated in the development of allergic diseases such as asthma, atopic dermatitis, food allergy, and rhinitis. However, there is limited knowledge on epithelial barrier dysfunction in ocular allergy (OA). Since the ocular surface is directly exposed to the environment, it is important to understand the role of ocular epithelia and their dysfunction in OA. Impaired epithelial barrier enhances allergen uptake, which lead to activation of immune responses and development of chronic inflammation as seen in allergies. Abnormal expression of tight junction proteins that helps to maintain epithelial integrity has been reported in OA but sufficient data not available in chronic atopic (AKC) and vernal keratoconjunctivitis (VKC), the pathophysiology of which is not just complex, but also the current treatments are not completely effective. This review provides an overview of studies, which indicates the role of barrier dysfunction in OA, and highlights how ocular barrier dysfunction possibly contributes to the disease pathogenesis. The review also explores the potential of ocular epithelial barrier repair strategies as preventive and therapeutic approach.

Keywords: allergic conjunctivitis; epithelial barrier; glycocalyx; ocular allergy; tight junctions; vernal keratoconjunctivitis.

FIGURE 1

Schematic illustration representing the structure of the epithelial barriers in normal ocular surface epithelium. Adjacent epithelial cells, covered by the glycocalyx made up of membrane‐associated mucins (MAMs) and galectin‐3, adhere to each other through a network of transmembrane proteins: tight junctions (TJs), reside in the apical lateral side and consist of the anchoring proteins, occludin, claudins, and junctional adhesion molecules (JAMs). JAMs are connected to the cytoskeleton through the zonula occludens (ZO)‐1, ZO‐2, and ZO‐3. Adherens junctions (AJs), located more basally than TJs, include a series of cadherin proteins of which E‐cadherin are highly expressed. Desmosomes and gap junctions seal the intercellular space at the most basolateral side of the cells. Environmental factors may disrupt cell‐to‐cell adhesion causing a “barrier dysfunction”

FIGURE 2

Schematic illustration of conjunctival and corneal structure. (A) The conjunctiva comprises of a superficial epithelial layer and a highly vascularized connective tissue containing accessory lacrimal glands, mast cells (MC), the components of the conjunctival associated lymphatic tissue (CALT) T‐ and B‐lymphocytes and antigen‐presenting cells (APC) cells within the matrix. (B) The corneal epithelium is a 5–6 cell layer thick, flat and transparent, stratified squamous epithelium lacking goblet cells, covering the avascular corneal stroma made up of an orderly, tightly packed collagen network which ensures transparency, and contain keratocytes and few APC. Apical cells of the stratified epithelium of both corneal and conjunctival epithelium express membrane‐associated mucins, which forms the thick glycocalyx at the epithelium‐tear film interface. Apical cells are sealed through tight junctions, adherens junctions and desmosomes while hemidesmosomes in the basal layers provide structural integrity and anchoring support by connecting the cytoskeletons of adjoining cells to the underlying substrate. Gap junctions are present at the basal layers. Please note that the proportions of the different components and the different tear film and tissue layers and are not respectful of the anatomical picture

FIGURE 3

The role of the epithelial barrier and epithelial‐mesenchymal trophic unit (EMTU) as a central player in development, repair and homeostasis of the ocular surface. Reciprocal interactions and modulation between epithelial cells, fibroblasts, immune cells, extracellular matrix (ECM), protease‐antiprotease imbalance contribute to the EMTU function. Dysregulation of EMTU favored by genetic factors and exposome may lead to barrier dysfunction, inflammation and tissue remodeling and the vicious circle of ocular allergy

FIGURE 4

Factors affecting epithelial barrier function. Barrier dysregulation can be induced by loss or defects in major TJs and adhesion proteins, disruption of barrier by exposome (proteases, pollutants, chemical injury, trauma), inflammatory responses (barrier disrupting Th2 cytokines) and endogenous mechanisms such as altered metabolism, microbiome or imbalance of hormones regulating epithelial homeostasis