The Pathophysiology of Dry Eye Disease: What We Know and Future Directions for Research

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. These epithelial changes further destabilize the tear film, amplify inflammation, and create a vicious cycle. Cyclosporine and lifitegrast, the 2 US Food and Drug Administration-approved therapies, inhibit T-cell activation and cytokine production. Although 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, it is hoped, lead to further advances in diagnostic classification and treatment.

Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Dry eye inflammatory cycle that can be initiated or amplified by extrinsic and intrinsic factors that cause tear instability and tear composition changes including hyperosmolarity that activate stress signaling pathways in the ocular surface cells which triggers production of innate inflammatory mediators which can lead to recruitment and activation of CD4+ T cells which produce cytokines that cause corneal, conjunctival and lacrimal gland epithelial disease.

Figure 2

Function of the cornea, conjunctival and lacrimal gland in maintaining ocular surface homeostasis (left side of each tissue) and disease relevant mediators and pathological changes in each tissue (right side of each tissue). IL-17 = interleukin 17, IL-13 = interleukin 13, IFN-γ = interferon-gamma