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We report the first case of Corynebacterium propinquum keratitis in the compromised cornea of a diabetic patient wearing therapeutic contact lenses. The strain was identified to the species level based on sequencing of the 16S rRNA gene and RNA polymerase β-subunit-encoding gene (rpoB). Ophthalmologists should be aware of nondiphtherial corynebacterial infection of compromised corneas., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Purpose: The aims of this study are to investigate the expression of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) protein in the normal human cornea and limbus and to analyze modifications of this expression under inflammatory conditions., Methods: The expression of LGR5 was evaluated in seven limbal epithelial crypts (LECs), collected from healthy cadaver donors, and five inflamed LECs obtained from enucleated eyes. Central corneal buttons were used as controls. LGR5 protein distribution was determined by immunohistochemistry staining analysis., Results: The cytoplasmic expression of LGR5 protein was observed in 100% of healthy LECs. Three out of five inflamed tissues analyzed were completely negative, while in the two remaining cases, we observed a moderate positivity in the basal cells of LECs. No relation was found between the expression of LGR5 and the grade of inflammatory cells., Conclusions: These findings demonstrate the presence of LGR5-positive cells in human LECs and their decrease in inflamed conditions, which suggests a critical role of this protein during inflammation and its possible use as a marker in normal crypts.

Importance: Recent data demonstrated somatic mutations in GJB2 that were present in affected porokeratotic eccrine ostial and dermal duct nevus (PEODDN) tissue but absent in unaffected skin. Recognizing that PEODDN lesions can also appear in individuals with keratitis-ichthyosis-deafness syndrome and finding somatic mutations in their cohort, the authors concluded that somatic GJB2 mutation may cause PEODDN. By using whole-exome sequencing, we show that somatic GJB2 mutation alone is sufficient to cause PEODDN., Observations: We performed whole-exome sequencing of paired blood and affected tissue samples isolated from a PEODDN lesion of a primary school-aged female patient with bands of hyperkeratotic-affected skin on the upper and lower extremities and trunk, and identified a single, protein-damaging p.Gly45Glu GJB2 mutation present in tissue samples but not in blood samples., Conclusion and Relevance: Our results prove that somatic GJB2 mutation is sufficient to cause PEODDN. Dominantly inherited GJB2 mutations, including the p.Gly45Glu found in our case, have been shown to cause the severe multisystem disorder keratitis-ichthyosis-deafness syndrome. GJB2 encodes connexin 26, a gap junction protein, which permits intercellular ion and macromolecule flux. Individuals with somatic mosaicism are at risk for transmitting systemic disease to their offspring, and all individuals with PEODDN lesions should be counseled regarding the risk of having a child with keratitis-ichthyosis-deafness syndrome.

The aim of the study was to report the clinical and microbiological profiles of Fusarium keratitis. In this single-centre, retrospective, non-comparative case series, 47 laboratory-confirmed cases of keratitis caused by Fusarium species treated at the L V Prasad Eye Institute, Bhubaneswar, India, between November 2006 and October 2009, were reviewed. The analysis included predisposing factors, clinical characteristics, microbiological findings, treatment and outcome. Forty-seven samples of 47 patients were included in the study. The mean age of the 47 patients was 46 ± 17 years. Twelve eyes had a history of injury. Corneal scraping could not be done in one of the cases due to large perforation. Fungal filaments were detected in corneal scraping in 41 cases, and in three cases microconidia were observed in microscopy. Fusarium solani was the most common species (44.7 %). All three cases where microconidia were present in smear were identified as F. solani in culture. The mean time to positive culture was 2.4 ± 1.5 days. Twenty-three patients underwent adjunctive surgical procedure. Visual acuity of <20/200 at presentation and final follow-up was noted in 80.9 and 51.4 % patients, respectively. One-half (23/47) of the patients had improvement in visual acuity. Fusarium keratitis may present after trauma without any satellite lesion, and the response to medical therapy is generally poor. Rapid diagnosis can be made by smear examination of corneal scrapings in a majority of the cases and confirmed by culture within 2-3 days. Presence of microconidia in smear examination may be suggestive of F. solani.

As an important immunoregulatory cell type, the role of γδ T cells in fungal keratitis (FK) is unclear. We observed the distribution of γδ T cells in infected corneas in vivo by two-photon microscopy. The γδ T cells were depleted by neutralizing antibodies. The cytokine expression profile was obtained by protein arrays to determine the cytokines regulated by γδ T cells. ICAM-1, MIP-2 and IL-17A were evaluated by ELISA assays to confirm the role of γδ T cells in FK. We counted the number of neutrophils, evaluated the volume of fungal hyphae and analyzed the manifestation of the disease. The γδ T cells increased significantly at 36 h and 72 h post fungal infection (P < 0.05) and migrated from the limbus to the infection site. The neutralizing antibodies completely depleted the γδ T cells in 24 h. The depletion of γδ T cells led to up regulation of 25 cytokines and down regulation of 3 cytokines. ICAM-1, MIP-2 and IL-17A changed significantly because of the depletion of γδ T cells (P < 0.05). However, the number of neutrophils, volume of fungal hyphae and manifestation of the disease was not affected by the depletion of γδ T cells. Our results demonstrated that γδ T cells have a role in FK via regulation of some cytokines but did not affect the manifestation of this disease, suggesting that γδ T cells are not the key regulator cells in this disease., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Corneal involvement in patients with systemic inflammatory disorders may be sight threatening, and it may be associated with a life-threatening disease. Significant systemic inflammatory diseases in this context are autoimmune connective tissue diseases, systemic autoimmune dermatological disorders, and autoimmune diseases of the lacrimal system. Keratoconjunctivitis sicca is usually the most common ocular finding in these patients. Peripheral ulcerative keratitis is a rare condition usually associated with increased ocular morbidity and also mortality, as it might act as an indicator of a more widespread vasculitis. Corneal biomechanical properties may also be altered in connective tissue diseases. Although recent studies suggest that the risk for corneal complications after ocular surgery in patients with quiescent autoimmune disease is minimal, caution is still recommended, as the knowledge about the corneal wound-healing process and the corneal biomechanical properties in these patients is not yet fully understood. This article reviews corneal abnormalities and characteristics in the setting of systemic inflammatory diseases.

Engyodontium album is a rare and an unusual human pathogen. It is a common inhabitant of waste and moist material and frequently isolated from substrates such as paper, jute, linen and painted walls. This fungus grew within 3 days on SDA with chloramphenicol from corneal scrapping of a 70-year-old male farmer with a history of trauma by unknown vegetative matter. The fungus can be confused with Tritirachium sp and Beauveria sp.

Purpose: To investigate the role of the lipid mediator, resolvin E1 (RvE1), in corneal inflammation., Methods: The effect of RvE1 on stimulated human corneal epithelial cells (HCECs) and neutrophils, and mouse macrophage was assessed. C57BL/6 mouse corneas were abraded and treated with RvE1 either before or after stimulation with lipopolysaccharide (LPS) and antibiotic-killed Pseudomonas aeruginosa and Staphylococcus aureus. The levels of CXC chemokines in the cornea were quantified, and the presence of neutrophils in corneal infiltrates was detected by immunohistochemistry and by in vivo confocal microscopy. The effect of RvE1 on apoptosis in the corneal epithelium was assessed using the TUNEL assay., Results: RvE1 significantly inhibited cytokine production in HCECs and neutrophils, and mouse macrophages and cornea. The development of corneal infiltrates, specifically neutrophils, in response to stimulation with LPS, P. aeruginosa, and S. aureus was also significantly reduced. There was no apoptotic effect of RvE1 on mouse corneal epithelial cells., Conclusions: RvE1 inhibits corneal inflammation induced by LPS, Gram negative (P. aeruginosa) and Gram positive (S. aureus) bacteria. These findings indicate that RvE1 as a potential anti-inflammatory therapy for patients with corneal inflammation and also, when given together with antibiotics, for bacterial keratitis.

Corneal infections are frequent and potentially vision-threatening diseases, and despite the significance of the immunological response in animal models of microbial keratitis (MK), it remains unclear in humans. The aim of this study was to describe the cytokine profile of tears in patients with MK. Characteristics of ocular lesions such as size of the epithelial defect, stromal infiltration, and hypopyon were analyzed. Immunological evaluation included determination of interleukine (IL)-1β, IL-6, IL-8, IL-10, IL-12 and tumor necrosis factor (TNF)-α in tear samples obtained from infected eyes of 28 patients with MK and compared with their contralateral non-infected eyes. Additionally, frequency of CD4+, CD8+, CD19+ and CD3-CD56+ cells was also determined in peripheral blood mononuclear cells in patients with MK, and compared with 48 healthy controls. Non-significant differences were observed in the size of the epithelial defect, stromal infiltration, and hypopyon. Nevertheless, we found an immunological profile apparently related to MK etiology. IL-8 > IL-6 in patients with bacterial keratitis; IL-8 > IL-6 > IL-1β and increased frequency of circulating CD3-CD56+ NK cells in patients with gram-negative keratitis; and IL-8 = IL-6 > IL-1β in patients with fungal keratitis. Characterization of tear cytokines from patients with MK could aid our understanding of the immune pathophysiological mechanisms underlying corneal damage in humans.

Purpose: Chemical burn in cornea may cause permanent visual problem or complete blindness. In the present study, we investigated the role of microRNA 206 (miR-206) in relieving chemical burn in mouse cornea., Method: An alkali burn model was established in C57BL/6 mice to induce chemical corneal injury. Within 72 hours, the transient inflammatory responses in alkali-treated corneas were measured by opacity and corneal neovascularization (CNV) levels, and the gene expression profile of miR-206 was measured by quantitative real-time PCR (qPCR). Inhibitory oligonucleotides of miR-206, miR-206-I, were intrastromally injected into alkali-burned corneas. The possible protective effects of down-regulating miR-206 were assessed by both in vivo measurements of inflammatory responses and in vitro histochemical examinations of corneal epithelium sections. The possible binding of miR-206 on its molecular target, connexin43 (Cx43), was assessed by luciferase reporter (LR) and western blot (WB) assays. Cx43 was silenced by siRNA to examine its effect on regulating miR-206 modulation in alkali-burned cornea., Results: Opacity and CNV levels, along with gene expression of miR-206, were all transiently elevated within 72 hours of alkali-burned mouse cornea. Intrastromal injection of miR-206-I into alkali-burned cornea down-regulated miR-206 and ameliorated inflammatory responses both in vivo and in vitro. LR and WB assays confirmed that Cx43 was directly targeted by miR-206 in mouse cornea. Genetic silencing of Cx43 reversed the protective effect of miR-206 down-regulation in alkali-burned cornea., Conclusion: miR-206, associated with Cx43, is a novel molecular modulator in alkali burn in mouse cornea.

Objective: To study the clinical features, diagnosis and treatment of Thygeson's superficial punctate keratitis (TSPK)., Methods: Twenty-one cases diagnosed as TSPK between June 2010 and July 2013 were retrospectively analyzed, including clinical manifestation, characteristics of morphological changes imaged by laser confocal microscopy, treatment and therapeutic effects., Results: All the 21 cases had the same presentation. Slit lamp examination showed several rough punctate intraepithelial opacities, which were usually slightly above the niveau of the surrounding epithelium. No cases had conjunctival congestions. Eight eyes of five patients with TSPK were imaged with a laser confocal biomicroscope. Clusters of highly reflective dots were revealed in the epithelium. The number of Langerhans cells was greatly increased in the basal cell layer of the focal corneal epithelium and the Bowman's layer in ten eyes affected by TSPK. The density of the subepithelial nerve plexus decreased. Some keratocytes had highly reflective cell bodies of irregular size, orientation, and shape in the anterior stroma in the affected eyes. After treatment with low concentration steroid eye drops and antiviral drugs, punctate opacities in all 21 cases were completely absorbed, leaving no scar, and the cure rate was 100%. But TSPK recurred in four cases. All recurrent cases were cured completely after treatment., Conclusions: Thygeson's superficial punctate keratitis is a kind of chronic recurrent superficial keratitis, without conjunctivitis. Confocal microscopic images have certain specificity, help diagnose and contribute to its pathogenesis research. Local use of low concentration steroid eye drops combined with antiviral drugs is effective for TSPK. Clinicians should pay attention to recurrence of TSPK.

Objectives: Melting keratitis is a serious condition presenting a high risk of permanent blindness and is caused by infectious or noninfectious factors. In humans, the clinical efficacy of collagen cross-linking (CXL) has been described in the treatment of refractory infectious keratitis by arresting keratomalacia. The aim of this study was to evaluate the efficacy of accelerated CXL for the treatment of melting keratitis in cats., Animals Studied: Ten cats were treated for unilateral melting keratitis by accelerated CXL., Procedure: Corneas were irradiated by UVA (370 nm) at 30 mW/cm² irradiance for 3 min after soaking with 0.1% riboflavin in 20% dextran for 30 min (D1). Follow-up was conducted 3, 7, 14, and 30 days after treatment., Results: Pain improvement was noted for all cases at D4 examination. Epithelial healing was observed at D8 for 9 of 10 cases and at D15 for 1 of 10 cases. Resolution of cellular infiltration was observed for all cases at D8 examination. The corneal vascularization was reduced for 9 of 10 cats by D31. At D31, all cases presented a variable degree of corneal fibrosis, but all eyes had visual function. No recurrent infection was observed., Conclusion: Accelerated CXL appears to be a valuable option for the treatment of melting keratitis in cats. All the cases have reached a satisfactory outcome despite the individual differences in the conditions prior to the CXL treatment and the variable presence of infectious agents., (© 2013 American College of Veterinary Ophthalmologists.)

Background: Microorganisms of different species interact in several ecological niches, even causing infection. During the infectious process, a biofilm of single or multispecies can develop. Aspergillus fumigatus and Staphyloccocus aureus are etiologic agents that can cause infectious keratitis. We analyzed in vitro single A. fumigatus and S. aureus, and mixed A. fumigatus-S. aureus biofilms. Both isolates were from patients with infectious keratitis. Structure of the biofilms was analyzed through microscopic techniques including scanning electron microscopy (SEM), transmission electron microscopy (TEM), confocal, and fluorescence microscopy (CLSM) in mixed biofilm as compared with the single A. fumigatus biofilm., Results: To our knowledge, this is the first time that the structural characteristics of the mixed biofilm A. fumigatus-A. fumigatus were described and shown. S. aureus sharply inhibited the development of biofilm formed by A. fumigatus, regardless of the stage of biofilm formation and bacterial inoculum. Antibiosis effect of bacterium on fungus was as follows: scarce production of A. fumigatus biofilm; disorganized fungal structures; abortive hyphae; and limited hyphal growth; while conidia also were scarce, have modifications in their surface and presented lyses. Antagonist effect did not depend on bacterial concentration, which could probably be due to cell-cell contact interactions and release of bacterial products. In addition, we present images about the co-localization of polysaccharides (glucans, mannans, and chitin), and DNA that form the extracellular matrix (ECM). In contrast, single biofilms showed extremely organized structures: A. fumigatus showed abundant hyphal growth, hyphal anastomosis, and channels, as well as some conidia, and ECM. S. aureus showed microcolonies and cell-to-cell bridges and ECM., Conclusions: Herein we described the antibiosis relationship of S. aureus against A. fumigatus during in vitro biofilm formation, and report the composition of the ECM formed.

Purpose: HLA-B27 is a major histocompatibility complex class I (MHCI) allele that has been closely associated with the development of ankylosing spondylitis and acute anterior uveitis (AAU), the most common form of uveitis worldwide. We have been characterizing the phenotypes of transgenic mice carrying a human HLA-B27 allele, but that are deficient in endogenous mouse MHCI genes (H-2K(-/-) and H-2D(-/-) double knockout, or DKO) to create the HLA-B27/DKO line. In maintaining and expanding this colony, we observed a rare sporadic severe central keratitis that developed in transgenic animals, but that was not present in wild-type (WT) animals., Methods: The corneas of affected HLA-B27/DKO and DKO mice were compared to their WT counterparts by staining with standard histological methods for markers of inflammation and neovascularization. A model of experimental corneal inflammation was subsequently used to test the responses of each genotype to insult., Results: We identified a previously unreported corneal pathology in naïve HLA-B27/DKO mice, and we describe significantly prolonged CD4(+)- and CD8(+)-associated inflammation in these animals following an experimentally induced corneal injury., Conclusions: These results demonstrate an increased T-cell response in B27/DKO corneas due to the expression of the HLA-B27 allele, suggesting that low MHCI expression in WT corneas is an important contributor to immune privilege.

Background: To study the effect of topical administration of a fusion protein (PF-MC) made up of N-terminal portion of the protease inhibitor Trappin-2 (which is a substrate of transglutaminasa-2) and SLPI (protein with anti-inflammatory, anti-bacterial and anti-viral ability), in an animal model of corneal inflammation and angiogenesis., Methods: An alkali injury was produced with a filter paper of 3 mm with 1 N NaOH during 40 seconds on the right cornea of 36 male Sprague Dawley rats, under general anesthesia. Animals were divided into three groups according to treatment. Group 1 was treated with 10 ul of PF-MC (200 ug/ml; n = 12), Group 2, with 10 ul of SLPI (200 ug/ml; n = 12) and Group 3 was treated with buffer (10 ul; n = 12) topically administered four times a day for up to 7 days. Half of the animals were sacrificed at day 3 before making a re-epithelialization time analysis with fluorescein staining at 18 and 24 hours. In the remaining animals corneal opacity was studied and digital photographs were taken at day 7 before doing euthanasia. Eyes were processed for histology and immunofluorescence., Results: Corneal ulcerated area was significantly lower in PF-MC treated animals compared to SLPI and buffer-treated animals at 18 hours and 24 hours postinjury. A clear cornea and fundus red reflex was only found among PF-MC treated animals. Histological analysis revealed a stratified corneal epithelium with at least three layers in all PF-MC animals at day 7. In this group there was a reduced number of PMNs in the corneal stroma at 3 and 7 days of follow-up. Besides, corneal neovascularization was much more extended in SLPI and Buffer animals than in animals treated with PF-MC., Conclusions: The binding of SLPI with Cementoin to transglutaminase seems to be an effective strategy to treat corneal inflammation and angiogenesis.

We describe a 91-year-old woman who suffered from fungal keratitis after corneal transplantation. The causative organism was identified as Wickerhamomyces anomalus (formerly Pichia anomala or Hansenula anomala) on the basis of morphological characteristics and the sequence of the internal transcribed spacer region of the ribosomal RNA gene. The patient was successfully treated with topical micafungin (MCFG) only. We present the first report of a case of W. anomalus fungal keratitis that responded to topical treatment with the antifungal MCFG., (Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

A 30-year-old woman with a history of contact lens wear and exposure to swimming pool water in Thailand presented with a non-responsive, progressive corneal ulcer of the right eye. Confocal microscopy evidenced septate linear branching structures, raising suspicion of fungal keratitis. She was promptly treated with topical antibiotics and both topical and intravenous caspofungin plus voriconazole. Worsening of the clinical picture after 1 month of intensive medical therapy led to a large therapeutic penetrating keratoplasty being performed. Corneal cultures grew a mold-like organism, which was identified by sequencing as Pythium insidiosum, an aquatic oomycete. After 4 years of follow-up, the graft exhibits no infection relapse, but graft transparency has been lost after two rejection episodes. Keratoplasty combined with antifungal treatment may offer a cure to P. insidiosum keratitis, although long-term preservation of corneal transparency is difficult to obtain., (© The American Society of Tropical Medicine and Hygiene.)

Purpose: We determined the ultrastructure of mouse adenovirus keratitis, a model for human adenovirus keratitis., Methods: Adenovirus keratitis was induced in C57Bl/6j mice by intrastromal injection of human adenovirus species D type 37 (HAdV-D37) with a heat-pulled, glass, micropipette needle under compressed air. At select time points after infection, mice were euthanized and their corneas removed, fixed, and sectioned at 70-nm thickness for electron microscopy., Results: Injection of HAdV-D37 into the mouse corneal stroma placed virus predominantly in the pericellular corneal stromal matrix. Virus was seen bound to and entering stromal cells at 1 and 2 hours after infection, respectively. Cell membrane transit by virus was seen to involve two distinct structures resembling caveolae and macropinosomes. However, later during infection intracellular virus was not seen within membrane-bound organelles. By 8 hours after infection, intracellular virus had accumulated into densely packed, perinuclear arrays. Virus disassembly was not obvious at any time point after infection. Infiltrating neutrophils seen by one day after infection had engulfed degraded stromal cells by 4 days after infection., Conclusions: By transmission electron microscopy, injected HAdV-D37 readily enters stromal cells in the C57Bl/6j mouse cornea and induces stromal inflammation, as was shown previously by light microscopy. However, electron microscopy also revealed dense, static arrays of intracytoplasmic virus, suggesting a block in viral capsid disassembly and viral DNA nuclear entry. These findings may explain why human adenoviruses do not replicate in the mouse corneal stroma., (Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.)

The efficacy, tolerability and safety of the extract of Solanum tuberosum sprouts (Panavir eyedrops) have been studied on the model of ophthalmic disorder in rabbits caused by herpes simplex virus (HSV) type 1. It is established that Panavir applied via 6 instillations per day for a period of days has potent therapeutic efficacy and prevents the development of gross corneal opacity in rabbits. Instillation of Panavir eyedrops does not cause irritation, toxic and allergic effects and are well tolerated by rabbits. The fastest and most pronounced effect of Panavir eyedrops was observed in the treatment of epithelial keratitis, as well as for not prolonged persistence of HSV. The effectiveness of Panavir eyedrops is comparable with that of the reference preparation OphthalmoferonR.

Purpose: To evaluate the visualization and depth of the demarcation line with anterior segment optical coherence tomography (AS-OCT) after iontophoresis-assisted transepithelial corneal collagen cross-linking (CXL)., Methods: This prospective, consecutive, single center, non-randomized clinical study involved 15 eyes of 12 patients with keratoconus who underwent an AS-OCT scan (Spectralis; Heidelberg Engineering, Inc., Carlsbad, CA) to search for a demarcation line and its depth at 1 month after iontophoresis-assisted transepithelial CXL. AS-OCT scan measurements were performed by two independent examiners., Results: No intraoperative or postoperative complications were observed. Kappa coefficient estimation for operator agreement in demarcation line visualization (whether it was visualized) was 70.6%. The corneal stromal demarcation line was identified in 9 eyes (60%) by both examiners. Mean depth of the corneal stromal demarcation line was 246.67 ± 50.72 µm (range: 183 to 339 µm) for the first examiner and 241.89 ± 62.52 µm (range: 163 to 358 µm) for the second examiner. There were no statistically significant differences for the measurements of the paired comparisons between the two examiners (P = .61). The Pearson correlation coefficient between the measurements was 0.910., Conclusions: Iontophoresis-assisted transepithelial CXL creates a demarcation line that can be visualized with AS-OCT, which seems less easily distinguishable and shallower than in conventional CXL. However, its depth and visualization seems to be more similar to conventional CXL than transepithelial CXL., (Copyright 2015, SLACK Incorporated.)

Purpose: To compare corneal inflammation after syngeneic and allogeneic penetrating keratoplasty (PK) with miniature Keratoprosthesis (m-KPro) implantation in mice., Methods: BALB/C (syngeneic) or C57BL/6 (allogeneic) corneas were transplanted onto BALB/C host beds as part of PK or m-KPro implantation. Corneal inflammation was assessed by determining the frequencies of CD45(+) leukocytes, CD4(+) T cells, CD11b(+) cells, and Gr-1(+) granulocytes/monocytes by flow cytometry at 2, 4, and 8 weeks post transplantation. In addition, expression levels of the proinflammatory cytokines TNF-α and IL-1β were analyzed using real-time qPCR at 8 weeks post transplantation., Results: Cell frequencies in the syngeneic (syn) and allogeneic (allo) m-KPro groups were higher compared with the syngeneic and allogeneic PK groups, respectively, at all time points. However, after week 4, frequencies of all analyzed immune cells were higher in the alloPK group as compared with synKPro group. At 8 weeks, the expression of TNF-α was higher in synKPro, alloPK, and alloKPro groups compared with the naïve and synPK groups. The expression of IL-1β was significantly higher in both KPro groups as compared with PK groups., Conclusions: Although the m-KPro device augments the inflammatory response in the cornea after its implantation, allogenicity (of the carrier tissue) is also a significant contributor to corneal inflammation. These data suggest that using syngeneic or decellularized corneal tissue as a Boston-KPro carrier could reduce the postoperative inflammation response., (Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.)

Macrophages under the conjunctival tissue are the first line defender cells of the corneas. Elimination of these cells would lead to aggravation of fungal keratitis. To determine how the course of fungal keratitis would be altered after the activation of these macrophages, a murine model was achieved by intrastromal instillation of latex beads before the corneas were infected with Fusarium solani. The keratitis was observed and clinically scored daily. Infected corneas were homogenized for colony counts. The levels of the IL-12, IL-4, MPO, MIF and iNOS cytokines were measured in the corneas using real-time polymerase chain reactions and enzyme-linked immunosorbent assays. CD3+, CD4+ and CD8+ lymphocytes in the corneas, submaxillary lymph nodes and peripheral blood were detected using immunohistochemistry and flow cytometry, respectively. The latex bead-treated mice exhibited aggravated keratitis. Substantially increased macrophage and polymorphonuclear leukocyte infiltration was detected in the corneas, although few colonies were observed. There was a marked increase in the IL-12, IL-4, MPO, MIF and iNOS expression in the corneas. The numbers of CD3+, CD4+ and CD8+ lymphocytes and the CD4+/CD8+ ratio were significantly enhanced in the corneas and submaxillary lymph nodes. However, the number of CD4+ lymphocytes was decreased in the peripheral blood, while the number of CD8+ lymphocytes increased. Collectively, our data demonstrate that the activation of macrophages in the cornea may cause an excessive immune response. Macrophages appear to play a critical role in regulating the immune response to corneal infections with F. solani., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Unlabelled: Despite the clinical importance of herpes simplex virus (HSV)-induced ocular disease, the underlying pathophysiology of the disease remains poorly understood, in part due to the lack of adequate virus-natural-host models in which to study the cellular and viral factors involved in acute corneal infection. We developed an air-liquid canine corneal organ culture model and evaluated its susceptibility to canine herpesvirus type 1 (CHV-1) in order to study ocular herpes in a physiologically relevant natural host model. Canine corneas were maintained in culture at an air-liquid interface for up to 25 days, and no degenerative changes were observed in the corneal epithelium during cultivation using histology for morphometric analyses, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assays, and transmission electron microscopy (TEM). Next, canine corneas were inoculated with CHV-1 for 48 h, and at that time point postinfection, viral plaques could be visualized in the corneal epithelium and viral DNA copies were detected in both the infected corneas and culture supernatants. In addition, we found that canine corneas produced proinflammatory cytokines in response to CHV-1 infection similarly to what has been described for HSV-1. This emphasizes the value of our model as a virus-natural-host model to study ocular herpesvirus infections., Importance: This study is the first to describe the establishment of an air-liquid canine corneal organ culture model as a useful model to study ocular herpesvirus infections. The advantages of this physiologically relevant model include the fact that (i) it provides a system in which ocular herpes can be studied in a virus-natural-host setting and (ii) it reduces the number of experimental animals needed. In addition, this long-term explant culture model may also facilitate research in other fields where noninfectious and infectious ocular diseases of dogs and humans are being studied., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Purpose: We investigated bilateral tear cytokine levels in patients with unilateral bacterial keratitis (BK) as associated with in vivo confocal microscopic (IVCM) alterations in corneal nerves and dendritiform immune cells (DCs)., Methods: A total of 54 (13 BK, 13 contralateral, 28 healthy controls) tear samples was collected prospectively and analyzed by multiplex microbeads assay. The IVCM of the central cornea was performed on the same day, and assessed for corneal nerve and DC alterations., Results: Interleukin-1β, IL-6, and IL-8 were significantly elevated only in affected eyes (66.6 ± 26.8, 7174 ± 2430, and 810 ± 315 ρg/mL, respectively; P = 0.04, P < 0.001, and P < 0.001, respectively), compared to healthy controls (13.0 ± 4.0, 171.8 ± 32.1, and 56.5 ± 33.8 ρg/mL). Levels of chemokine ligand 2 (CCL-2), IL-10, and IL-17a were elevated only in contralateral eyes (813 ± 478, 86.7 ± 38.3, and 3350 ± 881 ρg/mL, respectively; P = 0.02, P = 0.01, and P = 0.04, respectively), compared to controls (73.7 ± 25.3, 17.5 ± 4.9, and 1350 ± 337 ρg/mL). Triggering receptor expressed on myeloid cells (TREM)-1 was significantly elevated in affected (551 ± 231 ρg/mL, P = 0.02) and contralateral unaffected (545 ± 298 ρg/mL, P = 0.03) eyes compared to controls (31.3 ± 12.4 ρg/mL). The density of DCs was significantly increased in affected (226.9 ± 37.3 cells/mm(2), P < 0.001) and unaffected (122.3 ± 23.7 cells/mm(2), P < 0.001) eyes compared to controls (22.7 ± 5.9 cells/mm(2)). Sub-basal nerve density significantly decreased in affected (3337 ± 1615 μm/mm(2), P < 0.001) and contralateral (13,230 ± 1635 μm/mm(2), P < 0.001) eyes compared to controls (21,200 ± 545 μm/mm(2)). Levels of IL-1β, IL-6, and IL-8 were significantly correlated with DC density (R = 0.40, R = 0.55, and R = 0.31, all P < 0.02) and nerve density (R = -0.30, R = -0.53, and R = -0.39, all P < 0.01)., Conclusions: Proinflammatory tear cytokines are elevated bilaterally in patients with unilateral BK, and are correlated strongly with alterations in DCs and nerve density as detected by IVCM., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Compared with the peripheral corneal limbus, the human central cornea lacks blood vessels, which is responsible for its immunologically privileged status and high transparency. Dendritic cells (DCs) are present in the central avascular area of inflamed corneas, but the mechanisms of their migration to this location are poorly understood. Here, we investigated the contribution of vessel formation to DC migration into the central cornea, and analyzed the DC chemotactic factors produced by human corneal epithelial (HCE) cells. Using human eyes obtained from surgical procedures, we then assessed vessel formation, DC distribution, and activin A expression immunohistochemically. The results demonstrated increased numbers of vessels and DCs in the central area of inflamed corneas, and a positive correlation between the number of vessels and DCs. Activin A was expressed in the subepithelial space and the endothelium of newly formed blood vessels in the inflamed cornea. In infected corneas, DCs were present in the central area but no vascularization was observed, suggesting the presence of chemotactic factors that induced DC migration from the limbal vessels. To test this hypothesis, we assessed the migration of monocyte-derived DCs toward HCE cell supernatants with or without lipopolysaccharide (LPS) stimulation of HCE cells and inflammatory cytokines (released by HCE cells). DCs migrated toward tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and activin A, as well as LPS-stimulated HCE cell supernatants. The supernatant contained elevated TNF-α, IL-6, and activin A levels, suggesting that they were produced by HCE cells after LPS stimulation. Therefore, vessels in the central cornea might constitute a DC migration route, and activin A expressed in the endothelium of newly formed vessels might contribute to corneal vascularization. Activin A also functions as a chemotactic factor, similar to HCE-produced TNF-α and IL-6. These findings enhance our understanding of the pathophysiology of corneal inflammation during infection.

We previously showed that topical flagellin induces profound mucosal innate protection in the cornea against microbial infection, a response involving multiple genes and cell types. In this study, we used a Candida albicans (CA)-C57BL/6 mouse keratitis model to delineate the contribution of CXCL10- and CXCR3-expressing cells in flagellin-induced protection. Flagellin pretreatment markedly enhanced CXCL10 expression at 6 h post CA infection (hpi), but significantly dampened CXCL10 expression at 24 hpi. At the cellular level, CXCL10 was expressed in the epithelia at 6 hpi in flagellin-pretreated corneas, and concentrated at lesion sites 24 hpi. CXCR3-expressing cells were detected in great numbers at 24 hpi, organized within clusters at the lesion sites in CA-infected corneas. CXCL10 or CXCR3 neutralization increased keratitis severity and dampened flagellin-induced protection. CXCR3-positive cells were identified as NK cells, the depletion of which resulted in severe CA keratitis. Contributions from NK T-cells were excluded by finding no change in flagellin-induced protection in Rag1 KO mice. Recombinant CXCL10 inhibited CA growth in vitro and accelerated fungal clearance and inflammation resolution in vivo. Taken together, our data indicate that epithelium-expressed CXCL10 plays a critical role in fungal clearance and that CXCR3-expressing NK cells contribute to CA eradication in mouse corneas., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: To compare the efficacy of combined intrastromal injection and topical natamycin 5% to standard topical therapy alone in an experimental rabbit model of Fusarium keratitis., Methods: Fungal keratitis was induced in the right eyes of 12 New Zealand rabbits by stromal injection of Fusarium solani spore suspension into the cornea. Four days after inoculation, animals were randomly assigned to 2 different treatment groups (n=6 in each group). The study group received intrastromal injections of natamycin 5% on treatment day 1 and 4, combined with topical natamycin 5% eye drops given hourly between 8:00 and 20:00 for the first 2 days, followed by 4 times daily on days 3-11. The control group received only topical natamycin 5% at identical intervals. Eyes were examined clinically on days 1, 4, 7, and 11 for status of corneal healing, corneal vascularization, and hypopyon. Animals were sacrificed on day 11, and corneas were subjected to histopathological examination., Results: Both groups showed significant improvement in terms of conjunctival hyperemia, size and density of corneal infiltrate, corneal edema, and total clinical score. In the study group, there was a significant improvement in the height of hypopyon in the anterior chamber, while there was also an increased amount of vascularization., Conclusions: This study showed that intrastromal injection of natamycin 5% combined with topical treatment has little beneficial effect over topical therapy in a Fusarium keratitis rabbit model. The addition of intrastromal injection should be reserved to the most severe or recalcitrant cases.

Purpose: Urokinase-type plasminogen activator (u-PA) plays an important role in corneal wound healing, yet its role in corneal inflammation remains poorly understood. We investigated the role of u-PA in a murine model of lipopolysaccharide (LPS)-induced corneal inflammation., Methods: The corneal epithelium was scraped and LPS was applied to u-PA wild-type (u-PA(+/+)) and u-PA-deficient (u-PA(-/-)) mice. Corneal re-epithelialization and opacity were measured by stereomicroscopy. Fibrin zymography was performed to detect plasminogen activators in corneas from u-PA(+/+) and u-PA(-/-) mice. Neutrophil, macrophage, and u-PA receptor (u-PAR) expression were determined by immunohistochemistry. Gene expression of corneal macrophage chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-2 was assessed with reverse transcription-polymerase chain reaction. The in vitro effects of endogenous u-PA on MCP-1, MIP-2, matrix metalloproteinase (MMP)-2, and MMP-9 expression, and macrophage migration activity in mouse ocular fibroblasts stimulated by LPS, were examined., Results: The u-PA(+/+) mice showed enhanced corneal inflammation as compared with u-PA(-/-) mice. The u-PA expression was increased by LPS stimulation. Immunohistochemical analyses indicated that more neutrophils and macrophages were present in corneas from u-PA(+/+) mice than u-PA(-/-) mice. The u-PAR expression was detected in inflammatory cells and in the leading edges of the epithelial migrating cells. Enhanced mRNA expression of MCP-1 and MIP-2 was observed in corneas from u-PA(+/+) mice compared to u-PA(-/-) mice. Macrophage chemoattractant protein-1, MIP-2, and MMP-9, but not MMP-2, significantly increased in corneal fibroblasts from u-PA(+/+) mice compared with u-PA(-/-) mice., Conclusions: These data indicate that u-PA promotes LPS-induced leukocyte infiltration in cornea and that u-PA is an important component in LPS-induced corneal inflammatory responses., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

This study was undertaken to evaluate the clinico-demographical profile of keratomycosis. (January 2004 to January 2012). The corneal scrapings were processed by direct microscopic methods and standard culture techniques. Of 209 cases of keratitis studied, culture yielded growth in 80 cases (38.3%). Out of these 80 cases of growth, fungi were isolated in 77.5% and bacteria in 22.5%. The spectrum of keratomycosis was Aspergillus flavus (22.5%), Fusarium solani (16.1%), A. fumigatus (11.3%), Candida albicans (6.4%), etc., Routine surveillance of fungal keratitis is necessary to know the existing and emerging pattern of pathogens and to prevent use of un-warranted anti-microbial therapy.

Purpose: Dry eye disease is becoming recognized as an immune-inflammation mediated disorder. Surgical insults such as corneal incision or suture can aggravate dry eye. We sought to determine whether underlying dry eye aggravates corneal inflammatory infiltration, hemangiogenesis, and lymphangiogenesis (LY) induced by surgical injury in a murine model., Methods: We used treatment arms; one, normal eye (non-dry eye) and the other, a scopolamine-induced dry eye model. We first compared the corneas of both groups on which no surgery was performed with confocal and fluorescent microscopy. In subgroups of each treatment arm, we made a corneal incision followed by 2 corneal sutures to approximate the wound. After harvesting the cornea on postoperative day 9 and immunohistochemical staining, we compared corneal neovascularization (NV), LY, and CD11b inflammatory cell infiltration between non-dry eye and dry eye groups., Results: In corneas in which no surgery was performed, the dry eye group showed more CD11b cell infiltration than did the non-dry eye group (P < 0.05). With respect to corneas after injury, there was significantly more hemangiogenesis, LY, and inflammatory infiltration in the dry eye group than in the non-dry eye group (all P < 0.05)., Conclusions: The underlying status of the cornea, whether it is dry or not, plays a significant role in the development of NV, LY, and inflammation after corneal injury. Dry eye can aggravate post-injury NV, LY, and inflammation.

Purpose: To demonstrate that ultraviolet-A (UV-A) and voriconazole combination therapy is more effective than voriconazole single treatment for fungal keratitis., Methods: The in vitro UV-A (375 nm) fungicidal effect was evaluated on Fusarium solani solutions. Each fungal solution was irradiated with different UV-A irradiation doses. Also, a fungal solution containing voriconazole was also irradiated with UV-A. The in vivo therapeutic effect of UV-A and voriconazole treatment was studied in a rabbit keratitis model. Fungi were injected intrastromally into the cornea of 16 rabbits. Each treatment was initiated 3 days after fungal injection and continued up to 8 days for the following groups: Group 1, control; Group 2, treated with UV-A once a day; Group 3, treated with voriconazole 3 times a day; Group 4, treated with voriconazole 3 times a day and UV-A once a day. On the last day, the sclera-cornea buttons were extracted and microbiological and histological evaluations were performed., Results: The colony-forming units (CFUs) of fungal solutions in culture significantly decreased with UV-A irradiation. The CFUs of fungal solutions containing voriconazole also decreased with UV-A irradiation. In vivo, clinical scores of Group 3 (P=0.03) and Group 4 (P=0.02) 5 days after treatment were significantly lower compared to that of Group 1. The clinical score of Group 4 (P=0.03) 5 days after treatment was significantly lower compared to that of Group 3. The histopathological scores 5 days after treatment were significantly lower in Group 4 compared to those of Group 1 (P<0.01) and Group 3 (P=0.02). Based on our CFU analysis, only Group 4 showed significantly lower CFUs compared to Group 1 (P=0.04)., Conclusions: UV-A and voriconazole combination treatment could be a safe and effective alternative to voriconazole single treatment for fungal keratitis.

The purposes of this study were to establish a rabbit multidrug-resistant Pseudomonas aeruginosa (MDRP) keratitis model, and test the efficacy of levofloxacin, colistin methanesulfate (CL-M), colistin sulfate (CL-S) and polymyxin B (PL-B) against MDRP infection. In a rabbit eye, making a 2-mm circular corneal excision, and MDRP strain #601 or representative P. aeruginosa strain IID1210 were instilled into the corneal concavity. IID1210 was used to confirm this model developed P. aeruginosa keratitis. After MDRP keratitis developed, we treated the eyes with levofloxacin, CL-M, CL-S or PL-B eye drops. The infected eyes were evaluated by clinical score, histopathological examination and viable bacterial count (CFU). Rabbits developed MDRP keratitis reproducibly after instilled the bacteria into the corneal lesion. MDRP produced severe keratitis similarly with IID1210, as shown by slit lamp examination and clinical score. In MDRP keratitis models, clinical scores and viable bacterial counts were significantly lower in levofloxacin- and CL-M-treated groups compared with PBS-treated group, but the magnitudes of reduction were not remarkable. However, clinical scores were dramatically lowered in CL-S- and PL-B-treated groups compared with PBS-treated group. CL-S- and PL-B-treated group were kept corneal translucency and little influx of polymorphonuclear neutrophils in histopathological examination. In addition, both CL-S- and PL-B-treated groups were not detected viable bacteria in infected cornea. Using our MDRP keratitis model, we showed that topical levofloxacin and CL-M are not adequately effective, while CL-S and PL-B are efficacious in controlling MDRP keratitis. Especially, PL-B, which is commercially available eye drop, might be most effective against MDRP., (Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Purpose: To produce in guinea pigs a UV-induced keratitis, to analyze the effects of this pathology on corneal nerve activity., Methods: In anesthetized animals, one eye was exposed to 254 nm UV-C radiation (500-1000 mJ/cm(2)), excised 24 to 48 hours later and superfused in vitro. Nerve impulse activity was recorded in ciliary nerve filaments or in corneal sensory terminals of intact and UV-irradiated eyes. Impulse activity in response to mechanical (von Frey hairs), chemical (98.5% CO2 gas jets), and thermal stimulation (cooling from 34°C to 20°C; heating to 50°C) was analyzed. Duration of eyelid closure and blinking and tearing rates were evaluated in control and in UV-irradiated eyes, before and after application of TRPV1, TRPA1, and TRPM8 agonists (100 μM capsaicin; 10 mM AITC, and 200 μM menthol, respectively)., Results: After irradiation, mechanical threshold of mechano-nociceptor corneo-scleral fibers was reduced (0.59 ± 0.4 vs. 0.27 ± 0.07 mN; P < 0.05) while polymodal nociceptors increased their response to chemical stimulation (1.7 ± 0.2 vs. 3.4 ± 0.5 imps/s; P < 0.05). In contrast, cold thermoreceptors showed a significantly lower ongoing activity at 34°C (8.6 ± 0.5 vs. 6.1 ± 0.9 imp/s; P < 0.05) and a reduced responsiveness to cooling pulses (peak frequency = 29.8 ± 1.3 vs. 18.9 ± 1.8 imp/s; P < 0.001). Blinking but not tearing rate was significantly higher; behavioral responses to topical capsaicin and AITC, but not to menthol were enhanced in UV-irradiated animals., Conclusions: Sensitization of nociceptor and depression of cold thermoreceptor activity following UV radiation appear to result from an action of inflammatory mediators on TRP channels selectively expressed by sensory nerve terminals. Changes in nerve activity possibly underlie discomfort sensations associated with corneo-conjunctival inflammation induced by UV exposure., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

A case of traumatic blepharectomy secondary to a rat bite in a 13 day old neonate. Infants should not be kept in an isolated place in a rat endemic area. This case suggests an existence of a relationship between poverty and rat bite.

Innate immune responses have a critical role in regulating sight-threatening ocular surface (OcS) inflammation. While glucocorticoids (GCs) are frequently used to limit tissue damage, the role of intracrine GC (cortisol) bioavailability via 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in OcS defense, remains unresolved. We found that primary human corneal epithelial cells (PHCEC), fibroblasts (PHKF) and allogeneic macrophages (M1, GM-CSF; M2, M-CSF) were capable of generating cortisol (M1>PHKF>M2>PHCEC) but in corneal cells, this was independent of Toll-like receptor (TLR) activation. While PolyI∶C induced maximal cytokine and chemokine production from both PHCEC (IFNγ, CCL2, CCL3, and (CCL4), IL6, CXCL10, CCL5, TNFα) and PHKF (CCL2, IL-6, CXCL10, CCL5), only PHKF cytokines were inhibited by GCs. Both Poly I∶C and LPS challenged-corneal cells induced M1 chemotaxis (greatest LPS-PHKF (250%), but down-regulated M1 11β-HSD1 activity (30 and 40% respectively). These data were supported by clinical studies demonstrating reduced human tear film cortisol∶cortisone ratios (a biomarker of local 11β-HSD1 activity) in pseudomonas keratitis (1∶2.9) versus healthy controls (1∶1.3; p<0.05). This contrasted with putative TLR3-mediated OcS disease (Stevens-Johnson Syndrome, Mucous membrane pemphigoid) where an increase in cortisol∶cortisone ratio was observed (113.8∶1; p<0.05). In summary, cortisol biosynthesis in human corneal cells is independent of TLR activation and is likely to afford immunoprotection under physiological conditions. Contribution to ocular mucosal innate responses is dependent on the aetiology of immunological challenge.

Purpose: To evaluate a novel bioengineered corneal endothelial cell sheet that fits the curvature of the posterior corneal surface., Methods: A spherically curved gelatin hydrogel sheet (SCGS) was prepared by the dehydrothermal cross-linking method, and its permeability to water and protein was tested. Monkey corneal endothelial cells (MCECs) were seeded onto these hydrogel sheets, and the cells were examined by immunohistochemistry. Then MCEC-SCGS constructs were transplanted in monkeys with bullous keratopathy to assess the efficacy of the hydrogel sheets as a scaffold., Results: The hydrogel sheets showed similar permeability to water and protein as that of atelocollagen and vitrigel sheets. After transplantation, the SCGS did not show wrinkling and adhered tightly to the posterior corneal surface, whereas the flat sheets developed wrinkles that inhibited tight adhesion. Monkey corneal endothelial cells grown on hydrogel sheets expressed anti-zonula occludens-1 (ZO-1), N-cadherin, and sodium, potassium, and adenosine triphosphatase (Na,K-ATPase) along the plasma membrane. In a monkey model of bullous keratopathy, transplanted MCEC-SCGS constructs showed good adhesion to the posterior corneal surface, with subsequent improvement of corneal edema and transparency., Conclusions: A novel MCEC-SCGS construct was effective in a monkey model of bullous keratopathy. The SCGS achieves close adhesion to the posterior corneal surface without wrinkling and may contribute to clinical transplantation of corneal endothelial cell sheets.

Purpose: To determine whether rapamycin altered corneal growth factor levels to impact severity of Pseudomonas aeruginosa keratitis., Methods: BALB/c mice were injected intraperitoneally with rapamycin or PBS and infected with P. aeruginosa. Corneas were harvested and mRNA levels of growth factors (EGF, HGF, FGF-7/KGF), receptors (EGFR, c-met, FGFR-2), and signaling molecules (PI3K, Akt, S6K1, and IGF-1R) tested. ELISA determined HGF/c-met, IGF-1, and Substance P (SP) protein levels. Corneal application of recombinant (r)HGF was assessed by clinical score, photography with a slit lamp, real-time RT-PCR (mRNA for mT0R, IL-10, IL-12, IL-18, PI3KCα, Akt), and ELISA (total and phosphorylated [p]c-met); rIGF-1 effects also were tested by ELISA. In vitro, RAW cells and peritoneal macrophages were stimulated with LPS ± rHGF ± c-met inhibitor (CI) and mTOR mRNA levels tested., Results: Rapamycin disparately regulated infected corneal mRNA levels of EGF/EGFR and FGF-7/FGFR-2, but HGF/c-met mRNA levels both increased. ELISA confirmed elevated HGF protein. Rapamycin did not change PI3KCα or Akt signaling molecule expression, downregulated S6K1, but upregulated IGF-1R mRNA levels; IGF-1 and SP proteins also were upregulated. After infection, topical rHGF versus PBS increased mRNA levels of IL-12p40, IL-18, PI3KCα, and Akt; mTOR and IL-10 mRNA were downregulated; rIGF-1 increased HGF protein. In vitro, rHGF and LPS lowered RAW cell and macrophage mTOR levels; CI addition restored them., Conclusions: Collectively, these data provide evidence that enhanced corneal HGF levels increase signaling through the c-met receptor, decrease mTOR levels, and enhance proinflammatory cytokines, while decreasing anti-inflammatory cytokines, and that HGF signaling is central to disease outcome.

Dendritic cells (DCs) are highly potent stimulators of the immune system, and their contribution as such to the pathogenesis of corneal and ocular surface inflammatory disease has been well established. These vigorous antigen-presenting cells are reliant upon their effective migration from peripheral tissues (e.g., those of the ocular surface) to the lymphoid organs, where immune responses are triggered and can then cause disease. The chemokine receptor CCR7 expressed on DCs has emerged as the master mediator of this highly complex migratory process, and thus it is important in causing corneal and ocular surface inflammation. Furthermore, CCR7 has received considerable attention as a potential therapeutic target, as topically instilled antagonists of this receptor are quite effective therapeutically in a mouse model of ocular allergy. These findings and more are reviewed in the current article. In addition, the understanding regarding CCR7 function in mice and humans, and the biology of DCs that populate the ocular surface are also detailed herein. The involvement of DCs and their expression of CCR7 in corneal and ocular surface diseases such as in ocular allergy, dry eye disease, immune rejection and more, are also reviewed here., (Copyright © 2014 Elsevier Inc. All rights reserved.)