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Special Issue  |   November 2018
Inflammatory Response in Dry Eye
Author Affiliations & Notes
  • Takefumi Yamaguchi
    Department of Ophthalmology, Ichikawa General Hospital, Tokyo Dental College, Chiba, Japan
  • Correspondence: Takefumi Yamaguchi, Department of Ophthalmology, Ichikawa General Hospital, Tokyo Dental College, 5-11-13, Sugano, Ichikawa, Chiba, 272-8513, Japan;
Investigative Ophthalmology & Visual Science November 2018, Vol.59, DES192-DES199. doi:10.1167/iovs.17-23651
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      Takefumi Yamaguchi; Inflammatory Response in Dry Eye. Invest. Ophthalmol. Vis. Sci. 2018;59(14):DES192-DES199. doi: 10.1167/iovs.17-23651.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: Dry eye is a major ocular pathology worldwide. Although dry eye is a multifactorial disease, recent studies have shown that chronic immunologic processes have a pivotal role in its pathogenesis, characterized by the infiltration of immune cells in the lacrimal glands, elevated levels of tear inflammatory cytokines, and increased density of immune cells in the cornea and conjunctiva. This review describes the recent advances in understanding the relationship between dry eye and inflammation.

Methods: This narrative review is based on searches of recent international literature using terms related to the immune response in dry eye, and includes clinical trials, animal experiments, and expert reviews.

Results: Although dry eye presents clinically as tear film instability associated with corneal/conjunctival epithelial disorders, Meibomian gland dysfunction, and decreased visual function, recent laboratory and clinical studies have indicated inflammation in the lacrimal glands, Meibomian glands, conjunctiva, cornea, and aqueous tears. Furthermore, inflammation at these locations leads to conjunctival goblet cell apoptosis, corneal epithelial barrier disruption, and corneal nerve damage. These inflammatory outcomes can be exacerbated by intrinsic and extrinsic factors, such as aging, sex steroid hormone, autoimmune diseases, contact lens use, visual display terminals, and dry environment.

Conclusions: Recent advances in dry eye research have revealed the inflammatory process and its pathogenesis, which has been proposed as an “inflammatory vicious cycle” of dry eye. Comprehensive assessment of dry eye based on inflammation will improve the selection of treatments and help break the inflammatory cycle in clinical settings.

Dry eye is a prevalent ocular disorder characterized by bilateral reduced aqueous tear production and tear film instability. It is a multifactorial disease of the tear film, which affects 5% to 40% of adults older than 40 years.14 The prevalence of dry eye is higher in women than men,4 and a higher body mass index (BMI) is shown to be a preventive factor for dry eye.3 Based on a recent study, 16.4 million people were estimated to have dry eye in the United States in 2013.4 Dry eye causes eye irritation, hyperemia, glare, eye fatigue, and blurred vision. Vision impairment in dry eye is due to the increased higher-order aberrations,5,6 or superficial punctate keratitis,7 and in severe cases, such as graft-versus-host disease (GVHD) or Stevens-Johnson syndrome (SJS), blindness from corneal opacification or ulceration may result.8,9 Tear instability in dry eye is caused by a variety of conditions; aqueous deficiency due to lacrimal gland atrophy, lipid abnormalities associated with Meibomian gland dysfunction (MGD), and excessive tear evaporation. 
A variety of clinical tests currently are used in clinical practice to diagnose dry eye and assess its severity and clinical endpoints, including Schirmer's test, tear break-up time (TBUT), tear osmolarity, and vital dye staining of the cornea, such as Rose Bengal and Lissamine Green. However, to use the knowledge of dry eye mechanism in its treatment, an understanding of the pathologic processes of the disease is essential. The components of tears, such as clusterin,1012 mucin,1316 galectin,17 and lipid,1820 also are important in understanding the homeostasis of the tear film and ocular surface. Recent studies have used inflammatory parameters, such as tear cytokines or dendritic cells (DCs) density as biomarkers to assess the efficacy of treatments.21 Moreover, the number of articles on “inflammation and dry eye” has increased, especially in the last 10 years (Fig. 1), and a detailed pathogenesis of dry eye is being elucidated by immunologic research and intravital imaging technologies. The United States Food and Drug Administration recently approved two drugs, cyclosporine and lifitegrast, for the treatment of dry eye, which inhibit T-cell activation and cytokine production. These drugs represent a major advance in dry eye treatment.22 This review highlights the immune response in dry eye diseases, based on recent studies. 
Figure 1
The number of articles on “inflammation and dry eye.” The annual number of articles has increased between 1970 and 2016 when our PubMed search was conducted with the keywords of “inflammation and dry eye”.
Figure 1
The number of articles on “inflammation and dry eye.” The annual number of articles has increased between 1970 and 2016 when our PubMed search was conducted with the keywords of “inflammation and dry eye”.
Recent International Progress in Dry Eye–Associated Inflammation
Inflammatory “Vicious Cycle” in Dry Eye
Recently, dry eye was defined as “a multifactorial disease of ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities have etiologic roles” at the Dry Eye Workshop (DEWS II).23 Baudouin et al.24 proposed the concept of a “vicious cycle of inflammation” (Fig. 2) as a core driver in dry eye and breaking the cycle was reported to be an important step in the treatment of dry eye.25 The inflammatory vicious cycle includes tear film instability, tear hyperosmolarity, apoptosis of corneal/conjunctival cells, and inflammation in the ocular surface. Intrinsic and extrinsic factors cause stress to the ocular surface, which accelerates the cycle and, in turn, exacerbates dry eye. 
Figure 2
Inflammatory vicious cycle in dry eye. The inflammatory vicious cycle associated with dry eye that consists of tear instability, tear hyperosmolarity, apoptosis of the conjunctival/corneal cells, neurogenic inflammation and cytokine release (Fig. 2 is adapted from Pflugfelder et al. 2017).22 The cycle can be initiated and amplified by intrinsic and extrinsic factors.
Figure 2
Inflammatory vicious cycle in dry eye. The inflammatory vicious cycle associated with dry eye that consists of tear instability, tear hyperosmolarity, apoptosis of the conjunctival/corneal cells, neurogenic inflammation and cytokine release (Fig. 2 is adapted from Pflugfelder et al. 2017).22 The cycle can be initiated and amplified by intrinsic and extrinsic factors.
Inflammatory Mechanism in Experimental Dry Eye Models
Experimental dry eye models have shown that the inflammatory changes associated with dry eye have an important role in its pathogenesis. First, CD4+ T cells from mice with dry eye were adoptively transferred to T-cell–deficient nude mice, which led to severe inflammation in the lacrimal glands, cornea, and conjunctiva, resulting in decreased tear production and conjunctival goblet cell loss.26 Second, topical cyclosporine, a T-cell immunomodulatory agent, was effective in inhibiting conjunctival epithelial apoptosis in an experimental dry eye model.27 Third, in mouse models, aqueous tear deficiency increased the level of IFN-γ in tear, which exacerbated goblet cell (GC) apoptosis.28 Fourth, pathologic Th17 cells resistant to regulatory T cells mediate the ocular surface autoimmunity and its blockade of IL-17 decreases the severity and suppresses the progression of experimental dry eye.29,30 Collectively, these findings from experimental research have identified the immune system as a critical factor in dry eye. 
Immune Cell Infiltration Into Multiple Locations in Dry Eye
Ocular surface inflammation sometimes can appear to be absent or subclinical, especially in patients with mild cases of dry eye. However, evidence for inflammation in dry eye has been well documented in people with various types of dry eye (such as aqueous-deficient dry eye and MGD), and includes infiltration of the conjunctiva and lacrimal glands by immune cells,3136 an increase in the density of DCs in the cornea,3639 and elevated levels of tear cytokines.21,4042 Histopathologic examination of the lacrimal glands and conjunctiva showed lymphocytic infiltrates from patients with and without Sjögren's syndrome.3335 Conjunctival cells from dry eye patients overexpressed inflammatory/apoptosis markers, such as HLA-DR (dendritic cell maturation marker), Fas (CD95, apoptosis-related marker), CD40 (costimulatory protein on antigen-presenting cell [APC]),43 IFN-γ, and TNF-α.44 Brignole et al.45 reported a reduced expression of these markers in the conjunctiva following a 6-month treatment of topical cyclosporine in patients with keratoconjunctivitis sicca. 
Among the immune cells, APCs induce T-cell activation, resulting in the inflammatory cascade in dry eye.46 Previous studies on corneal APCs showed that its density in the center cornea increased in inflammatory conditions, such as herpes simplex keratitis, corneal graft rejection, vernal keratoconjunctivitis, and bacterial keratitis, compared to normal eyes and eyes after photorefractive keratectomy.4749 Various types of immune cells, such as macrophages, monocytes, and DCs, have been demonstrated to be important in the pathogenesis of dry eye.3639 Lin et al.50 reported an increase in corneal inflammatory cells in Sjögren's syndrome (approximately 10-fold) and non-Sjögren's syndrome (approximately 3-fold), which was correlated with results from clinical dry eye diagnostic parameters, such as the Schirmer test, corneal staining score, and TBUT. Kheirkhah et al.38 evaluated morphologic parameters of corneal DCs, such as DC size, number of dendrites, and DC field (the area DCs cover) in eyes with aqueous-deficient dry eye and evaporative dry eyes using in vivo confocal microscopy (IVCM), and reported that all of these parameters were significantly increased in eyes with dry eye compared to those in normal eyes. Villani et al.51 showed that topical steroid treatment for dry eye not only improved the ocular surface conditions, but also significantly decreased corneal DC density detected by IVCM. Thus, intravital imaging of altered corneal DCs using IVCM may enable assessment of immune system activity and the inflammatory response in the cornea and, therefore, help tailor treatments through patient stratification.32 
Elevated Levels of Proinflammatory Cytokines in Dry Eye
Recent studies have suggested that proinflammatory cytokines in tears may have a key role in the pathogenesis of several corneal diseases, including dry eye disease,52 as was found in keratoconus,53,54 GVHD,55 conjunctivitis,56 as well as in the development of corneal neovascularization (NV).57 Pflugfelder et al.41,58,59 first showed elevated levels of proinflammatory cytokines in dry eye. They demonstrated increased levels of proinflammatory cytokines, such as IL-1, IL-6, and IL-8, and decreased epidermal growth factor (EGF) levels in eyes with Sjögren's syndrome.41 They also showed that the tear cytokine levels are strongly correlated with dry-eye-related clinical parameters. Hyperosmolar stress also has a direct proinflammatory effect on the ocular surface that increases the tear cytokine levels.60 Villani et al.61 reported a correlation between corneal DC density and tear inflammatory cytokines in dry eye with rheumatoid arthritis (RA) and found that IL-1 and IL-6 concentrations decreased after the systemic treatment of RA. Other studies reported reduced tear cytokine levels as an inflammatory biomarker for the effectiveness of topical steroids62 or intense pulsed light21 in treating dry eye due to MGD. In these reports,21,61,62 inflammatory cytokine levels correlated well with ocular surface parameters. 
In severe ocular surface diseases, such as SJS, chemical burns, and ocular cicatricial pemphigoid (OCP), destruction of the corneal epithelial stem cells located at the corneal limbus results in conjunctival invasion, corneal NV, chronic inflammation, and stromal scarring, leading to major impairment of vision. Such ocular surface conditions not only cause corneal epithelial damage, but also can result in severe dry eye and glaucoma.6366 Among these comorbidities, the presence of severe dry eye leads to a poor prognosis of surgical intervention, causing postoperative persistent epithelial defects and corneal melts.67 Regarding changes to tears, previous studies have shown elevated cytokine levels in tears in patients with SJS,68 trachoma,69 OCP,70 and Graves' ophthalmopathy with exposure keratitis,71 compared to normal controls. The tear cytokine levels can be improved with treatment, such as intensive steroid therapy in the acute phase of the disease,72 or mucosal membrane grafting73 in the chronic phase. In addition, ICVM revealed increased immune cell counts in the cornea and conjunctiva in severe ocular surface diseases.37,74 Vera et al.39 evaluated corneal DCs using IVCM and reported that SJS patients with dry eye had larger numbers of DCs and more severe nerve damage. 
Recent Progress on Dry Eye–Associated Inflammation Research in Japan
Inflammatory Response in Dry Eye
Regarding the inflammatory response in dry eye, Hikichi et al.33 demonstrated novel findings in the lacrimal glands, conjunctiva, cornea, and tear film, and have made important contributions to the advances of this field. They demonstrated lymphocyte infiltration in lacrimal glands in Sjögren's syndrome and Sato et al.75 later duplicated these findings using IVCM in human subjects. Recently, Fukui et al.76 found that lacrimal gland inflammation in patients with IgG4-related Mikulicz's disease caused epithelial-mesenchymal transition (EMT)-like fibrosis in the lacrimal glands. Uchino et al.77,78 showed that the oxidative stress caused multifocal inflammation and lacrimal gland fibrosis, which leads to dry eye–associated ocular symptoms using transgenic Tet-mev-1 knockout mice. Kojima et al.79 used Cu, Zu-superoxide dismutase (SOD)-1 knockout mice and also showed inflammation in the lacrimal glands, leading to decreased tear secretion. Tsubota et al.80 reported upregulation of chemokine CXCL1 in the lacrimal glands of thymectomized NFS/sld mice, leading to lymphocyte infiltration and decreased tear secretion. 
Regarding conjunctival/corneal inflammation, Tsubota et al.44 also evaluated the expression of inflammatory markers of conjunctival cells in Sjögren's syndrome. They showed that IFN-γ and TNF-α are factors for HLA-DR upregulation in conjunctival cells.44 Later, Wakamatsu et al.81 reported increased density of DCs in the conjunctiva using IVCM in patients with Sjögren's syndrome,36 which was correlated strongly with the oxidative stress markers of the ocular surface lipid in the tear film. The investigators postulated that oxidative stress can be an inciting factor in the generation of ocular surface inflammation.81 Recently, He et al.37 found an increased density of corneal DCs in patients with GVHD-induced dry eye using IVCM, which was correlated strongly with the results from a variety of dry eye assessments, such as TBUT, Schirmer's test, and ocular surface disease index (OSDI). They also found an increased density of nerve branching points and tortuosity of subbasal nerves in GVHD-induced dry eye.37 These morphologic changes have been reported in autoimmune diseases, such as rheumatic arthritis82 and Graves's ophthalmology.83 Yagi et al.72 reported a proinflammatory cytokine storm in the tears of patients with SJS, which were suppressed by therapeutic modalities, such as those using intensive steroids therapy. Their group showed that tear cytokine levels can decrease after ocular surface reconstruction by limbal stem cell transplantation in patients with SJS.68 They observed the time-course alteration of tear cytokine levels and found that tear cytokines decreased to baseline levels after the conjunctival epithelium regenerated and healed completely.72 
Regarding MGD, Matsumoto et al.84 first identified inflammatory cells in the eye lids of patients with obstructive MGD using IVCM in 2009. They also showed its reduction after anti-inflammatory treatment. Ban et al.85 also found infiltration of inflammatory cells in the Meibomian glands of patients with GVHD using IVCM, suggesting that the inflammatory response caused excessive fibrosis and atrophy of these glands. In a laboratory study, Ibrahim et al.86 reported decreased tear secretion, Meibomian gland atrophy, and increased proinflammatory cytokine levels in the tear film, leading to MGD in an experimental model of (SOD)-1 knockout mice. 
Non-Inflammatory Process of Dry Eye in Office Workers
These previous studies demonstrated the inflammatory response in humans and murine models with dry eye. The Asia Dry Eye Society (ADES) defined dry eye as “a multifactorial disease characterized by unstable tear film causing a variety of symptoms and/or visual impairment, potentially accompanied by ocular surface damage.”87 Compared to the international definition,88 the ADES definition highlight “unstable tear film” as the pivotal mechanism of dry eye.87 Uchino et al.89 reported that short tear-film break-up-time (TFBUT)-type dry eye (unstable tear film) was more prevalent than other types of dry eye in a survey among visual display terminal (VDT) workers. Therefore, their colleagues conducted basic research on dry eye in VDT workers. Nakamura et al.90 created a novel rat model of dry eye, by placing a rat on a balance swing in combination with air exposure to produce an evaporative environment as a model of VDT users. They first showed decreased tear secretion in office workers, which was dependent on the number of years of VDT use. Next, they demonstrated lacrimal gland dysfunction as a decrease in tear secretion, which recovered after cessation of the swing activity.90 Kamoi et al.91 evaluated the morphologic changes in secretary vesicles in the lacrimal glands and found no infiltration of immune cells in VDT users, whereas the number of immune cells in the lacrimal gland of Sjögren's syndrome significantly increased. From these findings, they proposed a new “non-inflammatory” mechanism for VDT work-related dry eye, in which a tear secretion disorder, probably related to a decreased blinking rate, leads to an excessive accumulation of secretary vesicles, while tear production is intact. In contrast, the mechanism of dry eye in Sjögren's syndrome is impaired tear production and secretion due to inflammation in the lacrimal gland.91 
Future Directions: Comprehensive Approach to Understanding Ocular Surface Inflammation
Corneal Nerve and Immune Homeostasis
The corneal nerve is reduced or altered in patients with ocular surface diseases.37,38 The cornea is the most innervated tissue in the body with a nerve density of 300 to 600 times that of the skin.92,93 Corneal nerves penetrate the peripheral corneal stroma and form the subbasal nerve plexus between Bowman's layer and the basal epithelium in a radial distribution.93 Corneal innervation regulates corneal sensation, provides protective and trophic functions and promotes epithelial integrity, proliferation, and wound healing.94,95 Regarding corneal nerve alteration in human subjects, specific changes occur to the corneal subbasal nerve density and morphology in dry eye,96,97 as reported in patients with keratoconus,98,99 diabetes,100 and infectious keratitis,49,101 and as a result of corneal surgery.102104 Recent studies have revealed that the peripheral nervous system (PNS) not only mediates information exchange between the central nervous system and peripheral tissues, but also regulates innate immune responses through hormonal and neuronal routes as a nonspecific response to pathogens.105,106 In contrast, dysfunction of the PNS may result in proinflammatory innate immune responses, termed “neurogenic inflammation.”107110 Further, adrenergic nerves have been identified as regulators of leukocyte recruitment to and within tissues.111,112 In the cornea, Cruzat et al.101 evaluated the density of DCs and corneal nerve loss in eyes affected by infectious keratitis, such as bacterial, fungal, and Acanthoamoeba keratitis, using in vivo confocal microscopy. They found the concomitant increase in DC density and pronounced decrease in corneal nerve density, whereas less DC infiltration occurred in eyes with moderate corneal nerve loss. They concluded that the increased density of DC was correlated with the decreased corneal nerve density, suggesting a potential interaction between the immune and nervous system in infectious keratitis.101 Their research team also found that the tear cytokine levels are positively correlated with the density of corneal immune cells and inversely correlated with the corneal nerve density in eyes with infectious keratitis,49 suggesting that tear cytokine levels can signify inflammation of the ocular surface. 
Dry-Eye-Associated Inflammation and the Corneal Microenvironment
Dry-eye-associated inflammation may change the corneal microenvironment. It has been well documented that the inflammation occurs in the subbasal cornea, conjunctiva, and Meibomian and lacrimal glands. Recently, Kheirkhah et al.113 reported reduced corneal endothelial cell density (CECD) and nerve density in patients with dry eye. They speculated that a lower CECD is due to the reduction of corneal nerves in dry eye, because a concomitant decrease in corneal nerve and CECD has been reported in other etiologies, such as herpetic keratitis,114,115 and Fuchs' endothelial corneal dystrophy.116 Further, Kheirkhah et al.117 showed that low corneal nerve density is associated with a higher reduction rate of CECD in patients with dry eye. We recently found elevated levels of aqueous cytokines in chronic ocular surface diseases, which suggests the existence of chronic inflammatory conditions in the anterior chamber, leading to cataract formation or reduction of CECD, if the corneal epithelial barrier function breaks down.63 Furthermore, we demonstrated a connection among iris pigment damage, elevated cytokine levels in the aqueous humor and CECD in eyes with various ocular conditions, including bullous keratopathy and post-penetrating keratoplasty,118121 providing evidence that a “chronic inflammatory” microenvironment in the anterior segment of the eye supports the pathogenesis of these conditions. With chronic inflammation, various changes occur: loss of goblet cells in the conjunctiva, limbal stem cell loss, aqueous tear deficiency, immune cell infiltration into the corneal stroma, decreased CECD, corneal nerve loss and elevated cytokine levels in the tears and aqueous humor. The cornea, lacrimal glands, tears, conjunctiva, iris and aqueous humor are anatomically close and the pathogenic alteration of one can affect another. Goblet cells, for example, maintain DCs in an immature state and modulate the local immune response.122 They also present antigens to underlying APCs via goblet cell associated antigen passages without a break in epithelial integrity.123,124 Research on the aqueous humor found that the inflammatory cytokine levels increased by a 1000-fold in some eyes, compared to those of healthy controls, which influences not only IOP, but also corneal neovascularization, tear composition, and the condition of the corneal nerves, corneal immune cells and epithelium. In other words, in normal eyes, there appears to be some mechanism for orchestrating homeostasis among tear production, nerves, and immune cells in the cornea. Although the results of these articles can be influenced by confounding factors, such as prior intraocular surgery and preexisting iris damage, future studies on their association with dry eye will be important to understand their physiologic and pathologic impacts. Because dry eye presents as tear film instability, future studies on how ocular surface inflammation changes the corneal microenvironment through its etiopathogenesis, especially in eyes with severe types of dry eye, such as SJS, OCP, or chemical burn, despite the absence of apparent and subclinical inflammation, will be valuable. 
Funding of the publication fee and administration was provided by the Dry Eye Society, Tokyo, Japan. The Dry Eye Society had no role in the contents or writing of the manuscript. 
Disclosure: T. Yamaguchi, None 
The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007; 5: 93– 107.
Stapleton F, Alves M, Bunya VY, et al. TFOS DEWS II epidemiology report. Ocul Surf. 2017; 15: 334– 365.
Uchino M, Nishiwaki Y, Michikawa T, et al. Prevalence and risk factors of dry eye disease in Japan: Koumi study. Ophthalmology. 2011; 118: 2361– 2367.
Farrand KF, Fridman M, Stillman IO, Schaumberg DA. Prevalence of diagnosed dry eye disease in the United States among adults aged 18 years and older. Am J Ophthalmol. 2017; 182: 90– 98.
Koh S. Mechanisms of visual disturbance in dry eye. Cornea. 2016; 35 (suppl 1): S83– S88.
Koh S, Maeda N, Hirohara Y, et al. Serial measurements of higher-order aberrations after blinking in patients with dry eye. Invest Ophthalmol Vis Sci. 2008; 49: 133– 138.
Koh S, Maeda N, Ikeda C, et al. Ocular forward light scattering and corneal backward light scattering in patients with dry eye. Invest Ophthalmol Vis Sci. 2014; 55: 6601– 6606.
Kaido M, Dogru M, Yamada M, et al. Functional visual acuity in Stevens-Johnson syndrome. Am J Ophthalmol. 2006; 142: 917– 922.
Kaido M, Yamada M, Sotozono C, et al. The relation between visual performance and clinical ocular manifestations in Stevens-Johnson syndrome. Am J Ophthalmol. 2012; 154: 499– 511.e1.
Bauskar A, Mack WJ, Mauris J, et al. Clusterin seals the ocular surface barrier in mouse dry eye. PLoS One. 2015; 10: e0138958.
Nakamura T, Nishida K, Dota A, Kinoshita S. Changes in conjunctival clusterin expression in severe ocular surface disease. Invest Ophthalmol Vis Sci. 2002; 43: 1702– 1707.
Jeong S, Ledee DR, Gordon GM, et al. Interaction of clusterin and matrix metalloproteinase-9 and its implication for epithelial homeostasis and inflammation. Am J Pathol. 2012; 180: 2028– 2039.
Stephens DN, McNamara NA. Altered mucin and glycoprotein expression in dry eye disease. Optom Vis Sci. 2015; 92: 931– 938.
Uchino Y, Uchino M, Yokoi N, et al. Alteration of tear mucin 5AC in office workers using visual display terminals: The Osaka Study. JAMA Ophthalmol. 2014; 132: 985– 992.
Argueso P, Balaram M, Spurr-Michaud S, Keutmann HT, Dana MR, Gipson IK. Decreased levels of the goblet cell mucin MUC5AC in tears of patients with Sjogren syndrome. Invest Ophthalmol Vis Sci. 2002; 43: 1004– 1011.
Uchino Y, Woodward AM, Argueso P. Differential effect of rebamipide on transmembrane mucin biosynthesis in stratified ocular surface epithelial cells. Exp Eye Res. 2016; 153: 1– 7.
Uchino Y, Mauris J, Woodward AM, et al. Alteration of galectin-3 in tears of patients with dry eye disease. Am J Ophthalmol. 2015; 159: 1027– 1035.e3.
Geerling G, Baudouin C, Aragona P, et al. Emerging strategies for the diagnosis and treatment of meibomian gland dysfunction: Proceedings of the OCEAN group meeting. Ocul Surf. 2017; 15: 179– 192.
Arita R, Morishige N, Koh S, et al. Increased tear fluid production as a compensatory response to meibomian gland loss: a multicenter cross-sectional study. Ophthalmology. 2015; 122: 925– 933.
Goto E, Dogru M, Fukagawa K, et al. Successful tear lipid layer treatment for refractory dry eye in office workers by low-dose lipid application on the full-length eyelid margin. Am J Ophthalmol. 2006; 142: 264– 270.
Liu R, Rong B, Tu P, et al. Analysis of cytokine levels in tears and clinical correlations after intense pulsed light treating meibomian gland dysfunction. Am J Ophthalmol. 2017; 183: 81– 90.
Pflugfelder SC, de Paiva CS. The pathophysiology of dry eye disease: what we know and future directions for research. Ophthalmology 2017; 124: S4– S13.
Bron AJ, de Paiva CS, Chauhan SK, et al. TFOS DEWS II pathophysiology report. Ocul Surf. 2017; 15: 438– 510.
Baudouin C. A new approach for better comprehension of diseases of the ocular surface [in French]. J Fr Ophtalmol. 2007; 30: 239– 246.
Rhee MK, Mah FS. Inflammation in dry eye disease: how do we break the cycle? Ophthalmology. 2017; 124: S14– S19.
Niederkorn JY, Stern ME, Pflugfelder SC, et al. Desiccating stress induces T cell-mediated Sjogren's syndrome-like lacrimal keratoconjunctivitis. J Immunol. 2006; 176: 3950– 3957.
Strong B, Farley W, Stern ME, Pflugfelder SC. Topical cyclosporine inhibits conjunctival epithelial apoptosis in experimental murine keratoconjunctivitis sicca. Cornea. 2005; 24: 80– 85.
Zhang X, Chen W, De Paiva CS, et al. Interferon-gamma exacerbates dry eye-induced apoptosis in conjunctiva through dual apoptotic pathways. Invest Ophthalmol Vis Sci. 2011; 52: 6279– 6285.
Chauhan SK, El Annan J, Ecoiffier T, et al. Autoimmunity in dry eye is due to resistance of Th17 to Treg suppression. J Immunol. 2009; 182: 1247– 1252.
Chen Y, Chauhan SK, Shao C, Omoto M, Inomata T, Dana R. IFN-gamma-expressing Th17 cells are required for development of severe ocular surface autoimmunity. J Immunol. 2017; 199: 1163– 1169.
Pflugfelder SC, Huang AJ, Feuer W, Chuchovski PT, Pereira IC, Tseng SC. Conjunctival cytologic features of primary Sjögren's syndrome. Ophthalmology. 1990; 97: 985– 991.
Raphael M, Bellefqih S, Piette JC, Le Hoang P, Debre P, Chomette G. Conjunctival biopsy in Sjögren's syndrome: correlations between histological and immunohistochemical features. Histopathology. 1988; 13: 191– 202.
Hikichi T, Yoshida A, Tsubota K. Lymphocytic infiltration of the conjunctiva and the salivary gland in Sjogren's syndrome. Arch Ophthalmol. 1993; 111: 21– 22.
Williamson J, Gibson AA, Wilson T, Forrester JV, Whaley K, Dick WC. Histology of the lacrimal gland in keratoconjunctivitis sicca. Br J Ophthalmol. 1973; 57: 852– 858.
Belfort RJr, Mendes NF. Identification of T and B lymphocytes in the human conjunctiva and lacrimal gland in ocular diseases. Br J Ophthalmol. 1980; 64: 217– 219.
Wakamatsu TH, Sato EA, Matsumoto Y, et al. Conjunctival in vivo confocal scanning laser microscopy in patients with Sjogren syndrome. Invest Ophthalmol Vis Sci. 2010; 51: 144– 150.
He J, Ogawa Y, Mukai S, et al. In vivo confocal microscopy evaluation of ocular surface with graft-versus-host disease-related dry eye disease. Sci Rep. 2017; 7: 10720.
Kheirkhah A, Rahimi Darabad R, Cruzat A, et al. Corneal epithelial immune dendritic cell alterations in subtypes of dry eye disease: a pilot in vivo confocal microscopic study. Invest Ophthalmol Vis Sci. 2015; 56: 7179– 7185.
Vera LS, Gueudry J, Delcampe A, Roujeau JC, Brasseur G, Muraine M. In vivo confocal microscopic evaluation of corneal changes in chronic Stevens-Johnson syndrome and toxic epidermal necrolysis. Cornea. 2009; 28: 401– 407.
Jones DT, Monroy D, Ji Z, Pflugfelder SC. Alterations of ocular surface gene expression in Sjogren's syndrome. Adv Exp Med Biol. 1998; 438: 533– 536.
Pflugfelder SC, Jones D, Ji Z, Afonso A, Monroy D. Altered cytokine balance in the tear fluid and conjunctiva of patients with Sjogren's syndrome keratoconjunctivitis sicca. Curr Eye Res. 1999; 19: 201– 211.
Barton K, Monroy DC, Nava A, Pflugfelder SC. Inflammatory cytokines in the tears of patients with ocular rosacea. Ophthalmology. 1997; 104: 1868– 1874.
Brignole F, Pisella PJ, Goldschild M, De Saint Jean M, Goguel A, Baudouin C. Flow cytometric analysis of inflammatory markers in conjunctival epithelial cells of patients with dry eyes. Invest Ophthalmol Vis Sci. 2000; 41: 1356– 1363.
Tsubota K, Fukagawa K, Fujihara T, et al. Regulation of human leukocyte antigen expression in human conjunctival epithelium. Invest Ophthalmol Vis Sci. 1999; 40: 28– 34.
Brignole F, Pisella PJ, De Saint Jean M, Goldschild M, Goguel A, Baudouin C. Flow cytometric analysis of inflammatory markers in KCS: 6-month treatment with topical cyclosporin A. Invest Ophthalmol Vis Sci. 2001; 42: 90– 95.
Perez VL, Pflugfelder SC, Zhang S, Shojaei A, Haque R. Lifitegrast, a novel integrin antagonist for treatment of dry eye disease. Ocul Surf. 2016; 14: 207– 215.
Mastropasqua L, Nubile M, Lanzini M, et al. Epithelial dendritic cell distribution in normal and inflamed human cornea: in vivo confocal microscopy study. Am J Ophthalmol. 2006; 142: 736– 744.
Villani E, Baudouin C, Efron N, et al. In vivo confocal microscopy of the ocular surface: from bench to bedside. Curr Eye Res. 2014; 39: 213– 231.
Yamaguchi T, Calvacanti BM, Cruzat A, et al. Correlation between human tear cytokine levels and cellular corneal changes in patients with bacterial keratitis by in vivo confocal microscopy. Invest Ophthalmol Vis Sci. 2014; 55: 7457– 7466.
Lin H, Li W, Dong N, et al. Changes in corneal epithelial layer inflammatory cells in aqueous tear-deficient dry eye. Invest Ophthalmol Vis Sci. 2010; 51: 122– 128.
Villani E, Garoli E, Termine V, Pichi F, Ratiglia R, Nucci P. Corneal confocal microscopy in dry eye treated with corticosteroids. Optom Vis Sci. 2015; 92: e290– e295.
VanDerMeid KR, Su SP, Krenzer KL, Ward KW, Zhang JZ. A method to extract cytokines and matrix metalloproteinases from Schirmer strips and analyze using Luminex. Mol Vis. 2011; 17: 1056– 1063.
Jun AS, Cope L, Speck C, et al. Subnormal cytokine profile in the tear fluid of keratoconus patients. PLoS One. 2011; 6: e16437.
Lema I, Duran JA. Inflammatory molecules in the tears of patients with keratoconus. Ophthalmology. 2005; 112: 654– 659.
Riemens A, Stoyanova E, Rothova A, Kuiper J. Cytokines in tear fluid of patients with ocular graft-versus-host disease after allogeneic stem cell transplantation. Mol Vis. 2012; 18: 797– 802.
Leonardi A, Curnow SJ, Zhan H, Calder VL. Multiple cytokines in human tear specimens in seasonal and chronic allergic eye disease and in conjunctival fibroblast cultures. Clin Exp Allergy. 2006; 36: 777– 784.
Zakaria N, Van Grasdorff S, Wouters K, et al. Human tears reveal insights into corneal neovascularization. PLoS One. 2012; 7: e36451.
Lam H, Bleiden L, de Paiva CS, Farley W, Stern ME, Pflugfelder SC. Tear cytokine profiles in dysfunctional tear syndrome. Am J Ophthalmol. 2009; 147: 198– 205.e1.
Solomon A, Dursun D, Liu Z, Xie Y, Macri A, Pflugfelder SC. Pro- and anti-inflammatory forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disease. Invest Ophthalmol Vis Sci. 2001; 42: 2283– 2292.
Luo L, Li DQ, Corrales RM, Pflugfelder SC. Hyperosmolar saline is a proinflammatory stress on the mouse ocular surface. Eye Contact Lens. 2005; 31: 186– 193.
Villani E, Galimberti D, Del Papa N, Nucci P, Ratiglia R. Inflammation in dry eye associated with rheumatoid arthritis: cytokine and in vivo confocal microscopy study. Innate Immun. 2013; 19: 420– 427.
Lee H, Chung B, Kim KS, Seo KY, Choi BJ, Kim TI. Effects of topical loteprednol etabonate on tear cytokines and clinical outcomes in moderate and severe meibomian gland dysfunction: randomized clinical trial. Am J Ophthalmol. 2014; 158: 1172– 1183.e1.
Aketa N, Yamaguchi T, Asato T, et al. Elevated aqueous cytokine levels in eyes with ocular surface diseases. Am J Ophthalmol. 2017; 184: 42– 51.
Khanal S, Tomlinson A. Tear physiology in dry eye associated with chronic GVHD. Bone Marrow Transplant. 2012; 47: 115– 119.
Yuki K, Shimmura S, Shiba D, Tsubota K. End-stage glaucoma in Stevens-Johnson syndrome. Jpn J Ophthalmol. 2009; 53: 68– 70.
Tsai JH, Derby E, Holland EJ, Khatana AK. Incidence and prevalence of glaucoma in severe ocular surface disease. Cornea. 2006; 25: 530– 532.
Shimazaki J, Shimmura S, Fujishima H, Tsubota K. Association of preoperative tear function with surgical outcome in severe Stevens-Johnson syndrome. Ophthalmology. 2000; 107: 1518– 1523.
Ang LP, Sotozono C, Koizumi N, Suzuki T, Inatomi T, Kinoshita S. A comparison between cultivated and conventional limbal stem cell transplantation for Stevens-Johnson syndrome. Am J Ophthalmol. 2007; 143: 178– 180.
Satici A, Guzey M, Dogan Z, Kilic A. Relationship between Tear TNF-alpha, TGF-beta1, and EGF levels and severity of conjunctival cicatrization in patients with inactive trachoma. Ophthalmic Res. 2003; 35: 301– 305.
Chan MF, Sack R, Quigley DA, et al. Membrane array analysis of tear proteins in ocular cicatricial pemphigoid. Optom Vis Sci. 2011; 88: 1005– 1009.
Huang D, Xu N, Song Y, Wang P, Yang H. Inflammatory cytokine profiles in the tears of thyroid-associated ophthalmopathy. Graefes Arch Clin Exp Ophthalmol. 2012; 250: 619– 625.
Yagi T, Sotozono C, Tanaka M, et al. Cytokine storm arising on the ocular surface in a patient with Stevens-Johnson syndrome. Br J Ophthalmol. 2011; 95: 1030– 1031.
Gurumurthy S, Iyer G, Srinivasan B, Agarwal S, Angayarkanni N. Ocular surface cytokine profile in chronic Stevens-Johnson syndrome and its response to mucous membrane grafting for lid margin keratinisation. Br J Ophthalmol. 2017; 102: 169– 176.
Kheirkhah A, Qazi Y, Arnoldner MA, Suri K, Dana R. In vivo confocal microscopy in dry eye disease associated with chronic graft-versus-host disease. Invest Ophthalmol Vis Sci. 2016; 57: 4686– 4691.
Sato EA, Matsumoto Y, Dogru M, et al. Lacrimal gland in Sjogren's syndrome. Ophthalmology. 2010; 117: 1055– 1055.e3.
Fukui M, Ogawa Y, Shimmura S, et al. Possible involvement of epithelial-mesenchymal transition in fibrosis associated with IgG4-related Mikulicz's disease. Mod Rheumatol. 2015; 25: 737– 743.
Uchino Y, Kawakita T, Ishii T, Ishii N, Tsubota K. A new mouse model of dry eye disease: oxidative stress affects functional decline in the lacrimal gland. Cornea. 2012; 31 (suppl 1): S63– S67.
Uchino Y, Kawakita T, Miyazawa M, et al. Oxidative stress induced inflammation initiates functional decline of tear production. PLoS One. 2012; 7: e45805.
Kojima T, Wakamatsu TH, Dogru M, et al. Age-related dysfunction of the lacrimal gland and oxidative stress: evidence from the Cu,Zn-superoxide dismutase-1 (Sod1) knockout mice. Am J Pathol. 2012; 180: 1879– 1896.
Tsubota K, Nishiyama T, Mishima K, et al. The role of fractalkine as an accelerating factor on the autoimmune exocrinopathy in mice. Invest Ophthalmol Vis Sci. 2009; 50: 4753– 4760.
Wakamatsu TH, Dogru M, Matsumoto Y, et al. Evaluation of lipid oxidative stress status in Sjogren syndrome patients. Invest Ophthalmol Vis Sci. 2013; 54: 201– 210.
Villani E, Galimberti D, Viola F, Mapelli C, Del Papa N, Ratiglia R. Corneal involvement in rheumatoid arthritis: an in vivo confocal study. Invest Ophthalmol Vis Sci. 2008; 49: 560– 564.
Villani E, Viola F, Sala R, et al. Corneal involvement in Graves' orbitopathy: an in vivo confocal study. Invest Ophthalmol Vis Sci. 2010; 51: 4574– 4578.
Matsumoto Y, Shigeno Y, Sato EA, et al. The evaluation of the treatment response in obstructive meibomian gland disease by in vivo laser confocal microscopy. Graefes Arch Clin Exp Ophthalmol. 2009; 247: 821– 829.
Ban Y, Ogawa Y, Ibrahim OM, et al. Morphologic evaluation of meibomian glands in chronic graft-versus-host disease using in vivo laser confocal microscopy. Mol Vis. 2011; 17: 2533– 2543.
Ibrahim OM, Dogru M, Matsumoto Y, et al. Oxidative stress induced age dependent meibomian gland dysfunction in Cu, Zn-superoxide dismutase-1 (Sod1) knockout mice. PLoS One. 2014; 9: e99328.
Tsubota K, Yokoi N, Shimazaki J, et al. New perspectives on dry eye definition and diagnosis: a consensus report by the Asia Dry Eye Society. Ocul Surf. 2017; 15: 65– 76.
Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II definition and classification report. Ocul Surf. 2017; 15: 276– 283.
Uchino M, Yokoi N, Uchino Y, et al. Prevalence of dry eye disease and its risk factors in visual display terminal users: the Osaka study. Am J Ophthalmol. 2013; 156: 759– 766.
Nakamura S, Kinoshita S, Yokoi N, et al. Lacrimal hypofunction as a new mechanism of dry eye in visual display terminal users. PLoS One. 2010; 5: e11119.
Kamoi M, Ogawa Y, Nakamura S, et al. Accumulation of secretory vesicles in the lacrimal gland epithelia is related to non-Sjogren's type dry eye in visual display terminal users. PLoS One. 2012; 7: e43688.
Rozsa AJ, Beuerman RW. Density and organization of free nerve endings in the corneal epithelium of the rabbit. Pain. 1982; 14: 105– 120.
Muller LJ, Marfurt CF, Kruse F, Tervo TM. Corneal nerves: structure, contents and function. Exp Eye Res. 2003; 76: 521– 542.
Garcia-Hirschfeld J, Lopez-Briones LG, Belmonte C. Neurotrophic influences on corneal epithelial cells. Exp Eye Res. 1994; 59: 597– 605.
Belmonte C, Giraldez F. Responses of cat corneal sensory receptors to mechanical and thermal stimulation. J Physiol. 1981; 321: 355– 368.
Kheirkhah A, Dohlman TH, Amparo F, et al. Effects of corneal nerve density on the response to treatment in dry eye disease. Ophthalmology. 2015; 122: 662– 668.
Labbe A, Alalwani H, Van Went C, Brasnu E, Georgescu D, Baudouin C. The relationship between subbasal nerve morphology and corneal sensation in ocular surface disease. Invest Ophthalmol Vis Sci. 2012; 53: 4926– 4931.
Pahuja NK, Shetty R, Nuijts RM, et al. An in vivo confocal microscopic study of corneal nerve morphology in unilateral keratoconus. Biomed Res Int. 2016; 2016: 5067853.
Niederer RL, Perumal D, Sherwin T, McGhee CN. Laser scanning in vivo confocal microscopy reveals reduced innervation and reduction in cell density in all layers of the keratoconic cornea. Invest Ophthalmol Vis Sci. 2008; 49: 2964– 2970.
Tavakoli M, Boulton AJ, Efron N, Malik RA. Increased Langerhan cell density and corneal nerve damage in diabetic patients: role of immune mechanisms in human diabetic neuropathy. Cont Lens Anterior Eye. 2011; 34: 7– 11.
Cruzat A, Witkin D, Baniasadi N, et al. Inflammation and the nervous system: the connection in the cornea in patients with infectious keratitis. Invest Ophthalmol Vis Sci. 2011; 52: 5136– 5143.
Mohamed-Noriega K, Riau AK, Lwin NC, Chaurasia SS, Tan DT, Mehta JS. Early corneal nerve damage and recovery following small incision lenticule extraction (SMILE) and laser in situ keratomileusis (LASIK). Invest Ophthalmol Vis Sci. 2014; 55: 1823– 1834.
Patel SV, Erie JC, McLaren JW, Bourne WM. Keratocyte density and recovery of subbasal nerves after penetrating keratoplasty and in late endothelial failure. Arch Ophthalmol. 2007; 125: 1693– 1698.
Vestergaard AH, Gronbech KT, Grauslund J, Ivarsen AR, Hjortdal JO. Subbasal nerve morphology, corneal sensation, and tear film evaluation after refractive femtosecond laser lenticule extraction. Graefes Arch Clin Exp Ophthalmol. 2013; 251: 2591– 2600.
Tracey KJ. Reflex control of immunity. Nat Rev Immunol. 2009; 9: 418– 428.
Ordovas-Montanes J, Rakoff-Nahoum S, Huang S, Riol-Blanco L, Barreiro O, von Andrian UH. The regulation of immunological processes by peripheral neurons in homeostasis and disease. Trends Immunol. 2015; 36: 578– 604.
Chiu IM, von Hehn CA, Woolf CJ. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nature Neuroscience. 2012; 15: 1063– 1067.
Scholz J, Woolf CJ. The neuropathic pain triad: neurons, immune cells and glia. Nature Neuroscience. 2007; 10: 1361– 1368.
Tracey KJ. The inflammatory reflex. Nature. 2002; 420: 853– 859.
Riol-Blanco L, Ordovas-Montanes J, Perro M, et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature. 2014; 510: 157– 161.
Straub RH, Mayer M, Kreutz M, Leeb S, Scholmerich J, Falk W. Neurotransmitters of the sympathetic nerve terminal are powerful chemoattractants for monocytes. J Leukoc Biol. 2000; 67: 553– 558.
Nakai A, Hayano Y, Furuta F, Noda M, Suzuki K. Control of lymphocyte egress from lymph nodes through beta2-adrenergic receptors. J Exp Med. 2014; 211: 2583– 2598.
Kheirkhah A, Saboo US, Abud TB, et al. Reduced corneal endothelial cell density in patients with dry eye disease. Am J Ophthalmol. 2015; 159: 1022– 1026.e2.
Cavalcanti BM, Cruzat A, Sahin A, Pavan-Langston D, Samayoa E, Hamrah P. In vivo confocal microscopy detects bilateral changes of corneal immune cells and nerves in unilateral herpes zoster ophthalmicus. Ocul Surf. 2017; 16: 101– 111.
Muller RT, Pourmirzaie R, Pavan-Langston D, et al. In vivo confocal microscopy demonstrates bilateral loss of endothelial cells in unilateral herpes simplex keratitis. Invest Ophthalmol Vis Sci. 2015; 56: 4899– 4906.
Schrems-Hoesl LM, Schrems WA, Cruzat A, et al. Cellular and subbasal nerve alterations in early stage Fuchs' endothelial corneal dystrophy: an in vivo confocal microscopy study. Eye (Lond). 2013; 27: 42– 49.
Kheirkhah A, Satitpitakul V, Hamrah P, Dana R. Patients with dry eye disease and low subbasal nerve density are at high risk for accelerated corneal endothelial cell loss. Cornea. 2017; 36: 196– 201.
Yamaguchi T, Higa K, Suzuki T, et al. Elevated cytokine levels in the aqueous humor of eyes with bullous keratopathy and low endothelial cell density. Invest Ophthalmol Vis Sci. 2016; 57: 5954– 5962.
Yagi-Yaguchi Y, Yamaguchi T, Higa K, et al. Association between corneal endothelial cell densities and elevated cytokine levels in the aqueous humor. Sci Rep. 2017; 7: 13603.
Yagi-Yaguchi Y, Yamaguchi T, Higa K, et al. Preoperative aqueous cytokine levels are associated with a rapid reduction in endothelial cells after penetrating keratoplasty. Am J Ophthalmol. 2017; 181: 166– 173.
Aketa N, Yamaguchi T, Suzuki T, et al. Iris damage is associated with elevated cytokine levels in aqueous humor. Invest Ophthalmol Vis Sci. 2017; 58: BIO42– BIO51.
Contreras-Ruiz L, Masli S. Immunomodulatory cross-talk between conjunctival goblet cells and dendritic cells. PLoS One. 2015; 10: e0120284.
Knoop KA, McDonald KG, McCrate S, McDole JR, Newberry RD. Microbial sensing by goblet cells controls immune surveillance of luminal antigens in the colon. Mucosal Immunol. 2015; 8: 198– 210.
McDole JR, Wheeler LW, McDonald KG, et al. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature. 2012; 483: 345– 349.
Figure 1
The number of articles on “inflammation and dry eye.” The annual number of articles has increased between 1970 and 2016 when our PubMed search was conducted with the keywords of “inflammation and dry eye”.
Figure 1
The number of articles on “inflammation and dry eye.” The annual number of articles has increased between 1970 and 2016 when our PubMed search was conducted with the keywords of “inflammation and dry eye”.
Figure 2
Inflammatory vicious cycle in dry eye. The inflammatory vicious cycle associated with dry eye that consists of tear instability, tear hyperosmolarity, apoptosis of the conjunctival/corneal cells, neurogenic inflammation and cytokine release (Fig. 2 is adapted from Pflugfelder et al. 2017).22 The cycle can be initiated and amplified by intrinsic and extrinsic factors.
Figure 2
Inflammatory vicious cycle in dry eye. The inflammatory vicious cycle associated with dry eye that consists of tear instability, tear hyperosmolarity, apoptosis of the conjunctival/corneal cells, neurogenic inflammation and cytokine release (Fig. 2 is adapted from Pflugfelder et al. 2017).22 The cycle can be initiated and amplified by intrinsic and extrinsic factors.

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