The Pathophysiology of Dry Eye Disease

Abstract

Clinical and laboratory studies performed over the past few decades have discovered that dry eye is a chronic inflammatory disease that can be initiated by numerous extrinsic or intrinsic factors that promote an unstable and hyperosmolar tear film. These changes in tear composition, in some cases combined with systemic factors, lead to an inflammatory cycle that causes ocular surface epithelial disease and neural stimulation. Acute desiccation activates stress signaling pathways in the ocular surface epithelium and resident immune cells. This triggers production of innate inflammatory mediators that stimulate the production of matrix metalloprotease, inflammatory cell recruitment, and dendritic cell maturation. These mediators combined with exposure of autoantigens can lead to an adaptive T-cell mediated response. Cornea barrier disruption develops by protease-mediated lysis of epithelial tight junctions leading to accelerated cell death, desquamation, an irregular poorly lubricated cornea surface and exposure and sensitization of epithelial nociceptors. Conjunctival goblet cell dysfunction and death are promoted by the T helper 1 cytokine interferon gamma (IFN-γ). These epithelial changes further destabilize the tear film, amplify inflammation and create a vicious cycle. Cyclosporine and lifitegrast, the two FDA-approved therapies inhibit T cell activation and cytokine production. While these therapies represent a major advance in dry eye therapy, they are not effective in improving discomfort and corneal epithelial disease in all patients. Preclinical studies have identified other potential therapeutic targets, biomarkers and strategies to bolster endogenous immunoregulatory pathways. These discoveries will hopefully lead to further advances in diagnostic classification and treatment.

Tear Break-Up Time and Seasonal Variation in Intraocular Pressure in a Japanese Population

“…This is paradoxical since if IOP increases with worsening of DED in the cold and dry weather of winter, IOP in short BUT should be higher than in normal BUT for all seasons. A possible explanation for this seeming anomaly is cornel thinning and drug penetration facilitated by disruption of the ocular surface barrier effects in DED, as previous investigations have suggested that IOP estimated as a lower value in thin cornea and intraocular drug effects of instilled eye drops depends on the drug penetration [12,41,42]. Sleep disorder, depression, and possible decreases in melatonin secretion could also contribute to the dysregulation of IOP [21,[23][24][25] in winter when sunshine decreases and DED patients suffer more stress and worsened symptoms.…”

Blue light phototoxicity toward human corneal and conjunctival epithelial cells in basal and hyperosmolar conditions

“…On the contrary, the cornea benefits from the immune privilege (few immune cells, no blood vessels) and from the inhibition of inflammatory reactions. Thus, the conjunctiva naturally participates in the inflammation process to a much greater extent than the cornea and is therefore more responsive to phototoxic stress [46][47][48]. To better understand the pathways of occurring cellular death, we calculated the ratios between YO-PRO (apoptosis) and PI (necrosis) signals at various times after the end of illumination ( Supplementary Fig.…”

Reduced intraepithelial corneal nerve density and sensitivity accompany desiccating stress and aging in C57BL/6 mice

“…Advances in our understanding of dry eye disease have been made using both chronic and acute mouse models to study the disease and it's progression (Pflugfelder and de Paiva, 2017). Genetically engineered mice have been characterized as models for chronic forms of dry eye; these include the Aire mice (Chen et al, 2017; Yeh et al, 2009) and Langerin (CD207) deficient mice (Choi et al, 2017).…”