Constantly challenged by intruders such as pollens, danders, irritants and pollutants, the conjunctiva is the most immunologically active tissue of the ocular surface.1 There, mucins and other peptides with anti-infective properties are naturally produced, and conjunctival epithelial cells form a mechanical barrier to prevent entry of potential ocular interlopers.1

The junctions between conjunctival epithelial cells are connected by multi-protein complexes, which include anchoring junctions, communicating junctions and occluding junctions (tight junctions). These  junctions function in cell-cell attachment toward the apex of the epithelial surface, and they appear to play a critical role in regulating dynamics of epithelial permeability.2

Inflammatory cells involved in allergic responses (e.g., mast cells, eosinophils) reside beneath the basement membrane. When allergens infiltrate the epithelial barrier, they are taken up by antigen-presenting cells, starting a process that can incite a full-fledged allergic response. As part of this response, inflammatory cells migrate to the conjunctiva via the paracellular route that is regulated (at least in part) by the epithelial tight junctions. This migration leads to the hallmark signs of an inflammatory response: redness, itching, swelling and pain. It seems that understanding how allergens lead to increases in tight junction permeability may be a key to improving treatments for eye allergies.

The primary function of the tight junction is to maintain a barrier to entry of foreign materials. This barrier can be weakened, however, by a variety of chemical factors capable of disengaging the complexes. Allergens, irritants and pollutants do this to varying degrees and can make lasting changes to the epithelium.3 By doing so, they also facilitate easier entry for their counterparts at a later time. Major pollutants involved in urban allergy (e.g., poly-aromatic hydrocarbons) can also “open the barrier,” either directly or by activating otherwise harmless allergens.4 This is likely to explain the higher rates of allergy observed in urban populations vs. those living in more rural locations.5

Researchers have begun to unravel the responses of tight junctional complexes to allergic insult. For example, exposure to dust mite antigens caused a reduction in tight junction integrity and in the levels of two key tight junction proteins, ZO-1 and occluding.3 A study of seasonal allergy patients showed that even out of season, their epithelium is altered when compared to patients without allergies.6

A key step in the process of sensitization is the initial modulation of the conjunctival epithelium. Pollens carry proteolytic enzymes on their surfaces that are normally involved in the plant fertilization process.7 In the setting of allergy, these same enzymes can degrade components of epithelial junctions as well. When pollen “diffusates” (proteolytic breakdown products) from plants were tested for their effects on tight junctions, they elicited a rapid breakdown in junction integrity. This process continued so that within eight hours many cell-cell interfaces appeared devoid of tight junction protein staining.7

In another study, patients with allergies had a statistically significant thickening of the conjunctival epithelium during allergy season.6 Out of season, the thickening was reduced slightly, but the levels of E-cadherin and CD44 (another tight-junction marker) were significantly lower than those observed in normal patients. These results suggest that epithelia respond to the increased permeability by a generalized up-regulation leading to the observed thickening. When the stimulus is removed, there is a “rebound effect” to the generalized hypertrophy, and the expression of all epithelial components is down-regulated.

These observations highlight the complexities of epithelial cell function. Despite its redundancies, allergens and irritants can modulate the epithelial barrier and render its innate protective mechanisms ineffective. Hopefully, this enhanced understanding can provide clues to development of novel therapeutic approaches to ocular allergies.

1. Irkec M, Bozkurt B. Epithelial cells in ocular allergy. Curr Allergy Asthma Rep. 2003 Jul;3(4):352-7
2. Hingorani M, Calder VL, Buckley RJ, Lightman SL. The role of conjunctival epithelial cells in chronic ocular allergic disease. Exp Eye Res. 1998 Nov;67(5):491-500.
3.Wan H, Winton HL, Soeller C, et al. The transmembrane protein occludin of epithelial tight junctions is a functional target for serine peptidases from faecal pellets of Dermatophagoides pteronyssinus. Clin Exp Allergy. 2001 Feb;31(2):279-94.
4.Chehregani A, Majde A, Moin M, et al. Increasing allergy potency of Zinnia pollen grains in polluted areas. Ecotoxicol Environ Saf. 2004 Jun;58(2):267-72.
5. Priftis KN, Anthracopoulos MB, Nikolaou-Papanagiotou A, et al. Increased sensitization in urban vs. rural environment-rural protection or an urban living effect? Pediatr Allergy Immunol. 2007 May;18(3):209-16.
6. Hughes JL, Lackie PM, Wilson SJ, et al. Reduced structural proteins in the conjunctival epithelium in allergic eye disease. Allergy. 2006 Nov;61(11):1268-74.
7. Runswick S, Mitchell T, Davies P, Robinson C, Garrod DR. Pollen proteolytic enzymes degrade tight junctions. Respirology. 2007 Nov;12(6):834-42.