The Immunological Basis of Dry Eye Disease and Current Topical Treatment Options

Abstract

Homeostasis of the lacrimal functional unit is needed to ensure a well-regulated ocular immune response comprising innate and adaptive phases. When the ocular immune system is excessively stimulated and/or immunoregulatory mechanisms are disrupted, the balance between innate and adaptive phases is dysregulated and chronic ocular surface inflammation can result, leading to chronic dry eye disease (DED). According to the Tear Film and Ocular Surface Society Dry Eye Workshop II definition, DED is a multifactorial disorder of the ocular surface characterized by impairment and loss of tear homeostasis (hyperosmolarity), ocular discomfort or pain, and neurosensory abnormalities. Dysregulated ocular immune responses result in ocular surface damage, which is a further contributing factor to DED pathology. Several therapeutics are available to break the vicious circle of DED and prevent chronic disease and progression, including immunosuppressive agents (steroids) and immunomodulators (cyclosporine and lifitegrast). Given the chronic inflammatory nature of DED, each of these agents is commonly used in clinical practice. In this study, we review the immunopathology of DED and the molecular and cellular actions of current topical DED therapeutics to inform clinical decision making.

Keywords: T cells; dry eye disease; goblet cells; immune dysregulation; immunology; inflammation; integrin protein; intercellular adhesion molecule 1 (ICAM-1); lymphocyte function-associated antigen 1 (LFA-1); ocular surface.

FIG. 1.

Ocular surface immune response. (A) A healthy system can respond to injury and invaders by mounting a response, eliminating the pathogens while limiting tissue damage, then returning to homeostasis. (B) DED is a chronic worsening spiral of immune response with loss of return to homeostasis (a vicious circle leading to damage and self-perpetuation). DED, dry eye disease.

FIG. 2.

The immunoinflammatory pathway of dry eye disease. APC, antigen-presenting cell; CCR, chemokine receptor; ERK, extracellular signal–related kinase; ICAM-1, intercellular adhesion molecule 1; IFN-γ, interferon gamma; IL-, interleukin; JNK, c-Jun N-terminal kinase; LFA-1, lymphocyte function-associated antigen 1; mAPC, mature antigen-presenting cell; MAP-K, mitogen-activated protein kinase; MMP, matrix metalloproteinase; NF-κB, nuclear factor kappa B; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor alpha; Treg, regulatory T cell. Adapted from Pflugfelder et al.

FIG. 3.

The phases of DED pathology and its processes, effectors, and actual treatments. Color-coded symbols denote specific DED treatment (corticosteroids, CsA, lifitegrast) modulation of DED effectors. APC, antigen-presenting cell; CCL, CXCL, chemokines; CCR, CXCR, chemokine receptors; CD11a, cluster of designation molecule 11a; CsA, cyclosporin A; DC, dendritic cell; DED, dry eye disease; ERK, extracellular signal–related kinase; ICAM-1, intercellular adhesion molecule 1; IFN-γ, interferon gamma; IL, interleukin; JNK, c-Jun N-terminal kinase; LFA-1, lymphocyte function-associated antigen 1; MAP-K, mitogen-activated protein kinase; mAPC, mature antigen-presenting cell; MHCII, major histocompatibility complex II; MMP, matrix metalloproteinase; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NF-κB, nuclear factor kappa B; TCR, T cell receptor; TNF-α, tumor necrosis factor alpha.

FIG. 4.

Effect of allosteric binding of lifitegrast to LFA-1 on LFA-1:ICAM-1 interactions. DED, dry eye disease; ICAM-1, intercellular adhesion molecule 1; LFA-1, lymphocyte function associated antigen 1; mAPC, mature antigen-presenting cell. Adapted from Perez et al.