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Review
. 2012 Jan;130(1):90-100.
doi: 10.1001/archophthalmol.2011.364.

Dry eye disease: an immune-mediated ocular surface disorder

William Stevenson  1 , Sunil K Chauhan, Reza Dana
Affiliations
Review

Dry eye disease: an immune-mediated ocular surface disorder

William Stevenson et al. Arch Ophthalmol. 2012 Jan.

Abstract

Dry eye disease is a multifactorial disorder of the tears and ocular surface characterized by symptoms of dryness and irritation. Although the pathogenesis of dry eye disease is not fully understood, it is recognized that inflammation has a prominent role in the development and propagation of this debilitating condition. Factors that adversely affect tear film stability and osmolarity can induce ocular surface damage and initiate an inflammatory cascade that generates innate and adaptive immune responses. These immunoinflammatory responses lead to further ocular surface damage and the development of a self-perpetuating inflammatory cycle. Herein, we review the fundamental links between inflammation and dry eye disease and discuss the clinical implications of inflammation in disease management.

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Figures

Figure 1
Figure 1
Immunoinflammatory pathways. Desiccating stress induces tear hyperosmolarity, activating intracellular signaling pathways that initiate the production of proinflammatory cytokines (eg, interleukin [IL] 1, tumor necrosis factor [TNF], and IL-6). This proinflammatory milieu facilitates the activation and maturation of immature antigen-presenting cells (iAPC). Mature APCs (mAPC) migrate through the afferent lymphatics to draining lymph nodes, where they induce effector helper T cell 1 (TH1) and TH17 cells that subsequently migrate through efferent blood vessels to the ocular surface. The TH17 cells antagonize regulatory T cell (Treg) functions and lead to further expansion of T effectors in the draining lymph nodes. Effector TH1-secreted interferon (IFN) γ and TH17-secreted IL-17 exert their pathogenic effects by promoting the production of proinflammatory cytokines, chemokines, matrix metalloproteinases (eg, MMP-3 and MMP-9), cell adhesion molecules (CAM), and prolymphangiogenic molecules (vascular endothelial growth factor [VEGF] D and VEGF-C) that facilitate the infiltration of pathogenic immune cells, leading to further damage of the ocular surface. IL-17R indicates IL-17 receptor; TGF, transforming growth factor.
Figure 2
Figure 2
Analysis of corneal lymphangiogenesis in normal eye (A) and in dry eye on day 6 (B), day 10 (C), and day 14 (D) (original magnification ×100). The lymphatic vessels (arrows) increased in area and caliber and progressed toward the center of the cornea with disease progression. The lymphatic vessels were unaccompanied by blood vessels (CD31 high and lymphatic endothelial marker 1 negative). L indicates limbus; C, center of the cornea. Adapted from Goyal et al.
Figure 3
Figure 3
Real-time polymerase chain reaction results showing increased relative expression of various cytokine transcripts in dry eye conjunctiva (day 10) compared with normal conjunctiva. Data are presented as the mean (SE) (error bars) (n = 18 for interleukin [IL] 1α and tumor necrosis factor [TNF] and n = 6 for the remaining cytokines). IFN-γ indicates interferon γ. Adapted from Rashid et al.
Figure 4
Figure 4
Enumeration of corneal CD11b+ monocytes. A, Representative confocal images of the center of whole-mount corneas showing CD11b+ cells (green) in untreated and vehicle-treated eyes and in eyes treated with a topical chemokine receptor 2 (CCR2) antagonist. B, Treatment with topical CCR2 antagonist significantly decreased the number of CD11b+ cells in the periphery and the center of corneas with dry eye compared with the untreated and vehicle-treated groups. Bars represent the mean values; limit lines, SEMs. Adapted from Goyal et al.
Figure 5
Figure 5
Enumeration of conjunctival T cells. A, Representative images of conjunctival cross sections immunostained for CD3 (red) and nucleus (blue) of untreated and vehicle-treated eyes and of eyes treated with a topical chemokine receptor 2 (CCR2) antagonist (T cells are marked by arrows). Ep indicates epithelial layer; St, stromal layer. B, Treatment with topical CCR2 antagonist significantly decreased the number of conjunctival T cells compared with the untreated and vehicle-treated groups. Bars represent the mean values; limit lines, SEMs. Adapted from Goyal et al.
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Comment in

  • [Pathogenesis of dry eye].
    Messmer EM. Messmer EM. Ophthalmologe. 2014 May;111(5):411. Ophthalmologe. 2014. PMID: 24959649 German. No abstract available.

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