Cornea

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Jacobs DS. Infiltrates Versus Ulcers: Why Words Matter. Eye Contact Lens 2020;46(5):263-264.
Jain R, Sharma N, Basu S, Iyer G, Ueta M, Sotozono C, Kannibiran C, Rathi VM, Gupta N, Kinoshita S, Gomes JAP, Chodosh J, Sangwan VS. Reply: amniotic membrane transplantation in Stevens-Johnson syndrome. Surv Ophthalmol 2017;62(2):249-250.
Jakobiec FA, Roh M, Stagner AM, Yoon MK. Caruncular dacryops. Cornea 2015;34(1):107-9.Abstract

PURPOSE: To report a case of caruncular dacryops in a 58-year-old man that was excised in its entirety and to offer an immunohistopathologic analysis. METHODS: Sections stained with hematoxylin and eosin, periodic acid-Schiff, and Grocott methenamine silver (the latter 2 for identification of mucus) were evaluated, and immunohistochemical investigations were performed using cytokeratin (CK) 7, CK14, CK17, and smooth muscle actin. RESULTS: Histopathologic examination revealed a cystic dilation of the lacrimal gland ducts containing secretory globules. The ducts were composed of double-layered cuboidal epithelium with rare scattered goblet cells and interspersed prominent lobules of lacrimal gland tissue, diagnostic of dacryops. Immunohistochemistry of cystic ducts demonstrated a CK profile identical to that of the conjunctiva including the absence of a myoepithelium. CONCLUSIONS: This is the first case of an intact caruncular lacrimal ductal cyst (dacryops). A previous report documented a spontaneously collapsed cyst with extrusion of secretory globoid bodies into extracellular space that elicited a foreign body giant cell response.

Jamali A, Hu K, Sendra VG, Blanco T, Lopez MJ, Ortiz G, Qazi Y, Zheng L, Turhan A, Harris DL, Hamrah P. Characterization of Resident Corneal Plasmacytoid Dendritic Cells and Their Pivotal Role in Herpes Simplex Keratitis. Cell Rep 2020;32(9):108099.Abstract
The presence and potential functions of resident plasmacytoid dendritic cells (pDCs) in peripheral tissues is unclear. We report that pDCs constitutively populate naïve corneas and are increased during sterile injuries or acute herpes simplex virus 1 (HSV-1) keratitis. Their local depletion leads to severe clinical disease, nerve loss, viral dissemination to the trigeminal ganglion and draining lymph nodes, and mortality, while their local adoptive transfer limits disease. pDCs are the main source of HSV-1-induced IFN-α in the corneal stroma through TLR9, and they prevent re-programming of regulatory T cells (Tregs) to effector ex-Tregs. Clinical signs of infection are observed in pDC-depleted corneas, but not in pDC-sufficient corneas, following low-dose HSV-1 inoculation, suggesting their critical role in corneal antiviral immunity. Our findings demonstrate a vital role for corneal pDCs in the control of local viral infections.
Jamali A, Harris DL, Blanco T, Lopez MJ, Hamrah P. Resident plasmacytoid dendritic cells patrol vessels in the naïve limbus and conjunctiva. Ocul Surf 2020;18(2):277-285.Abstract
Plasmacytoid dendritic cells (pDCs) constitute a unique population of bone marrow-derived cells that play a pivotal role in linking innate and adaptive immune responses. While peripheral tissues are typically devoid of pDCs during steady state, few tissues do host resident pDCs. In the current study, we aim to assess presence and distribution of pDCs in naïve murine limbus and bulbar conjunctiva. Immunofluorescence staining followed by confocal microscopy revealed that the naïve bulbar conjunctiva of wild-type mice hosts CD45 CD11c PDCA-1 pDCs. Flow cytometry confirmed the presence of resident pDCs in the bulbar conjunctiva through multiple additional markers, and showed that they express maturation markers, the T cell co-inhibitory molecules PD-L1 and B7-H3, and minor to negligible levels of T cell co-stimulatory molecules CD40, CD86, and ICAM-1. Epi-fluorescent microscopy of DPE-GFP×RAG1 transgenic mice with GFP-tagged pDCs indicated lower density of pDCs in the bulbar conjunctiva compared to the limbus. Further, intravital multiphoton microscopy revealed that resident pDCs accompany the limbal vessels and patrol the intravascular space. In vitro multiphoton microscopy showed that pDCs are attracted to human umbilical vein endothelial cells and interact with them during tube formation. In conclusion, our study shows that the limbus and bulbar conjunctiva are endowed with resident pDCs during steady state, which express maturation and classic T cell co-inhibitory molecules, engulf limbal vessels, and patrol intravascular spaces.
Jee D, Kang S, Yuan C, Cho E, Arroyo JG, of the Society ESCKO. Serum 25-Hydroxyvitamin D Levels and Dry Eye Syndrome: Differential Effects of Vitamin D on Ocular Diseases. PLoS One 2016;11(2):e0149294.Abstract

PURPOSE: To investigate associations between serum 25-hydroxyvitamin D levels and dry eye syndrome (DES), and to evaluate the differential effect of vitamin D on ocular diseases including age-related macular disease (AMD), diabetic retinopathy (DR), cataract, and DES. METHODS: A total of 16,396 participants aged >19 years were randomly selected from the Korean National Health and Nutrition Examination Survey. All participants participated in standardized interviews, blood 25-hydroxyvitamin D level evaluations, and comprehensive ophthalmic examinations. DES was defined by a history of clinical diagnosis of dry eyes by a physician. The association between vitamin D and DES was compared to the associations between vitamin D and AMD, DR, cataract, and DES from our previous studies. RESULTS: The odds of DES non-significantly decreased as the quintiles of serum 25-hydroxyvitamin D levels increased (quintile 5 versus 1, OR = 0.85, 95%CI: 0.55-1.30, P for trend = 0.076) after adjusting for potential confounders including age, sex, hypertension, diabetes, smoking status, and sunlight exposure times. The relative odds of DES (OR = 0.70, 95% CI: 0.30-1.64) and cataract (OR = 0.76, 95% CI: 0.59-0.99) were relatively high, while those of DR (OR = 0.37, 95% CI: 0.18-0.76) and late AMD (OR = 0.32, 95% CI: 0.12-0.81) were lower in men. CONCLUSIONS: The present study does not support an association between serum 25-hydroxyvitamin D levels and DES. The preventive effect of serum 25-hydroxyvitamin D may be more effective for DR and late AMD than it is for cataract and DES.

Jhanji V, Jacobs DS, Jeng BH. Neurotrophic Keratitis: Do Not Be Insensitive. Eye Contact Lens 2021;47(3):135.
Ji YW, Mittal SK, Hwang HS, Chang E-J, Lee JH, Seo Y, Yeo A, Noh H, Lee HS, Chauhan SK, Lee HK. Lacrimal gland-derived IL-22 regulates IL-17-mediated ocular mucosal inflammation. Mucosal Immunol 2017;10(5):1202-1210.Abstract
Inflammatory damage of mucosal surface of the eye is a hallmark of dry eye disease (DED) and, in severe cases, can lead to significant discomfort, visual impairment, and blindness. DED is a multifactorial autoimmune disorder with a largely unknown pathogenesis. Using a cross-sectional patient study and a well-characterized murine model of DED, herein we investigated the immunoregulatory function of interleukin-22 (IL-22) in the pathogenesis of DED. We found that IL-22 levels were elevated in lacrimal fluids of DED patients and inversely correlated with severity of disease. Acinar cells of the lacrimal glands (LGs), not inflammatory immune cells, are the primary source of IL-22, which suppresses inflammation in ocular surface epithelial cells upon desiccating stress. Moreover, loss of function analyses using IL-22 knockout mice demonstrated that IL-22 is essential for suppression of ocular surface infiltration of Th17 cells and inhibition of DED induction. Our novel findings elucidate immunoregulatory function of LG-derived IL-22 in inhibiting IL-17-mediated ocular surface epitheliopathy in DED thus making IL-22 a new relevant therapeutic target.
Jones L, Downie LE, Korb D, Benitez-Del-Castillo JM, Dana R, Deng SX, Dong PN, Geerling G, Hida RY, Liu Y, Seo KY, Tauber J, Wakamatsu TH, Xu J, Wolffsohn JS, Craig JP. TFOS DEWS II Management and Therapy Report. Ocul Surf 2017;15(3):575-628.Abstract
The members of the Management and Therapy Subcommittee undertook an evidence-based review of current dry eye therapies and management options. Management options reviewed in detail included treatments for tear insufficiency and lid abnormalities, as well as anti-inflammatory medications, surgical approaches, dietary modifications, environmental considerations and complementary therapies. Following this extensive review it became clear that many of the treatments available for the management of dry eye disease lack the necessary Level 1 evidence to support their recommendation, often due to a lack of appropriate masking, randomization or controls and in some cases due to issues with selection bias or inadequate sample size. Reflecting on all available evidence, a staged management algorithm was derived that presents a step-wise approach to implementing the various management and therapeutic options according to disease severity. While this exercise indicated that differentiating between aqueous-deficient and evaporative dry eye disease was critical in selecting the most appropriate management strategy, it also highlighted challenges, based on the limited evidence currently available, in predicting relative benefits of specific management options, in managing the two dry eye disease subtypes. Further evidence is required to support the introduction, and continued use, of many of the treatment options currently available to manage dry eye disease, as well as to inform appropriate treatment starting points and understand treatment specificity in relation to dry eye disease subtype.
Jowett N, Pineda R. Seeing through the evidence for corneal neurotization. Curr Opin Otolaryngol Head Neck Surg 2021;29(4):252-258.Abstract
PURPOSE OF REVIEW: Trigeminal anesthesia causes neurotrophic keratopathy, which may yield facial disfigurement and corneal blindness. RECENT FINDINGS: We summarize approaches and evidence for corneal neurotization. SUMMARY: Regional sensory nerve transfer appears safe and effective for therapeutic management of neurotrophic keratopathy. Prospective randomized clinical trials are necessary to confirm the utility of corneal neurotization.
Jowett N, Pineda Ii R. Acellular nerve allografts in corneal neurotisation: an inappropriate choice. Br J Ophthalmol 2020;104(2):149-150.
Jowett N, Pineda R. Corneal and Facial Sensory Neurotization in Trigeminal Anesthesia. Facial Plast Surg Clin North Am 2021;29(3):459-470.Abstract
Trigeminal anesthesia may yield blindness and facial disfigurement, secondary to neurotrophic keratopathy and trigeminal trophic syndrome. This article summarizes contemporary medical and emerging surgical approaches for the therapeutic management of this rare and devastating disease state.
Joyce NC. Proliferative capacity of corneal endothelial cells. Exp Eye Res 2012;95(1):16-23.Abstract
The corneal endothelial monolayer helps maintain corneal transparency through its barrier and ionic "pump" functions. This transparency function can become compromised, resulting in a critical loss in endothelial cell density (ECD), corneal edema, bullous keratopathy, and loss of visual acuity. Although penetrating keratoplasty and various forms of endothelial keratoplasty are capable of restoring corneal clarity, they can also have complications requiring re-grafting or other treatments. With the increasing worldwide shortage of donor corneas to be used for keratoplasty, there is a greater need to find new therapies to restore corneal clarity that is lost due to endothelial dysfunction. As a result, researchers have been exploring alternative approaches that could result in the in vivo induction of transient corneal endothelial cell division or the in vitro expansion of healthy endothelial cells for corneal bioengineering as treatments to increase ECD and restore visual acuity. This review presents current information regarding the ability of human corneal endothelial cells (HCEC) to divide as a basis for the development of new therapies. Information will be presented on the positive and negative regulation of the cell cycle as background for the studies to be discussed. Results of studies exploring the proliferative capacity of HCEC will be presented and specific conditions that affect the ability of HCEC to divide will be discussed. Methods that have been tested to induce transient proliferation of HCEC will also be presented. This review will discuss the effect of donor age and endothelial topography on relative proliferative capacity of HCEC, as well as explore the role of nuclear oxidative DNA damage in decreasing the relative proliferative capacity of HCEC. Finally, potential new research directions will be discussed that could take advantage of and/or improve the proliferative capacity of these physiologically important cells in order to develop new treatments to restore corneal clarity.
Jurkunas UV. Fuchs Endothelial Corneal Dystrophy Through the Prism of Oxidative Stress. Cornea 2018;37 Suppl 1:S50-S54.Abstract
The corneal endothelium (CE) is vital for maintaining the water balance and clarity of the cornea. The CE is a cell layer that is particularly susceptible to aging because of its postmitotic arrest, high metabolic activity involving pumping of ions, and lifelong exposure to ultraviolet light. Despite gradual age-related cell loss, a sufficient number of CE cells are preserved during the lifespan of an individual. However, in conditions such as Fuchs endothelial corneal dystrophy (FECD), permanent loss of CE cells leads to corneal edema and loss of vision requiring corneal transplantation. FECD is a genetic and oxidative stress disorder manifested by abnormal cell-matrix interactions and expedited cellular aging culminating in cellular death. Because the endothelium has minimal replicative capacity in vivo and an inability to replace its genome, it is particularly prone to cumulative DNA damage acquired throughout life. In FECD, the underlying genetic defects make the CE genome even more vulnerable to this damage, to the point of causing mitochondrial dysfunction, mitochondrial membrane potential loss, and excessive mitophagy activation. Endogenous and exogenous intracellular stressors alter the synthetic footprint of CE cells, leading to endothelial-mesenchymal transition and secretion of aberrant extracellular matrix (in the form of guttae), resembling scar formation in other organs. In turn, the guttae or endothelial scars contribute to a vicious cycle of FECD pathogenesis and, by further inducing endothelial-mesenchymal transition and oxidant-antioxidant imbalance, perpetuate the molecular changes of the degenerating endothelium.
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Kammerdiener LL, Speiser JL, Aquavella JV, Harissi-Dagher M, Dohlman CH, Chodosh J, Ciolino JB. Protective effect of soft contact lenses after Boston keratoprosthesis. Br J Ophthalmol 2016;100(4):549-52.Abstract

PURPOSE: To evaluate associations between preoperative diagnosis, soft contact lens (SCL) retention and complications. METHODS: A retrospective chart review was conducted of 92 adult patients (103 eyes) who received a Boston keratoprosthesis type I at the Massachusetts's Eye and Ear Infirmary or the Flaum Eye Institute. Records were reviewed for preoperative diagnosis, SCL retention and subsequent complications. Preoperative categories included 16 autoimmune (Stevens-Johnson syndrome, ocular cicatricial pemphigoid, rheumatoid arthritis and uveitis), 9 chemical injury and 67 'other' (aniridia, postoperative infection, dystrophies, keratopathies) patients. RESULTS: 50% of the lenses had been lost the first time after about a year. A subset (n=17) experienced more than 2 SCL losses per year; this group is comprised of 1 patient with autoimmune diseases, 2 patients with chemical injuries and 14 patients with 'other' diseases. The preoperative diagnosis was not predictive of contact lens retention. However, multivariate analysis demonstrated that the absence of a contact lens was an independent risk factor for postoperative complications, such as corneal melts with or without aqueous humour leak/extrusion and infections. CONCLUSIONS: Presence of a contact lens after Boston keratoprosthesis implantation decreases the risk of postoperative complications; this has been clinically experienced by ophthalmologists, but never before has the benefit of contact lens use in this patient population been statistically documented.

Kanellopoulos AJ, Asimellis G, Salvador-Culla B, Chodosh J, Ciolino JB. High-irradiance CXL combined with myopic LASIK: flap and residual stroma biomechanical properties studied ex-vivo. Br J Ophthalmol 2015;99(6):870-4.Abstract

BACKGROUND/AIMS: To evaluate ex vivo biomechanical and enzymatic digestion resistance differences between standard myopic laser in-situ keratomileusis (LASIK) compared with LASIK+CXL, in which high-irradiance cross-linking (CXL) is added. METHODS: Eight human donor corneas were subjected to femtosecond-assisted myopic LASIK. Group A (n=4) served as a control group (no CXL). The corneas in LASIK+CXL group B were subjected to concurrent prophylactic high-irradiance CXL (n=4). Saline-diluted (0.10%) riboflavin was instilled on the stroma, subsequently irradiated with UV-A through the repositioned flap. The cornea stroma and flap specimens were separately subjected to transverse biaxial resistance measurements; biomechanical differences were assessed via stress and Young's shear modulus. Subsequently, the specimens were subjected to enzymatic degradation. RESULTS: For the corneal stroma specimen, stress at 10% strain was 128±11 kPa for control group A versus 293±20 kPa for the LASIK+CXL group B (relative difference Δ=+129%, p<0.05). The stress in group B was also increased at 20% strain by +68% (p<0.05). Shear modulus in group B was increased at 10% strain by +79%, and at 20% strain by +48% (both statistically significant, p<0.05). The enzymatic degradation time to dissolution was 157.5±15.0 min in group A versus 186.25±7.5 min in group B (Δ=+18%, p=0.014). For the flaps, both biomechanical, as well as enzymatic degradation tests showed no significant differences. CONCLUSIONS: LASIK+CXL appears to provide significant increase in underlying corneal stromal rigidity, up to +130%. Additionally, there is significant relevant enzymatic digestion resistance confirmatory to the above. LASIK flaps appear unaffected biomechanically by the LASIK+CXL procedure, suggesting effective CXL just under the flap.

Karamichos D, Hutcheon AEK, Zieske JD. Reversal of fibrosis by TGF-β3 in a 3D in vitro model. Exp Eye Res 2014;124:31-6.Abstract
Corneal scarring following moderate to severe injury is inevitable. Despite significant advancements in the field, current treatments following these types of injuries are limited, and often, the visual recovery is poor. One of the problems and limitations is that corneal wound healing is a complex process, involving corneal cells, extracellular matrix components and growth factors. Therefore, further understanding is required, along with new treatments and techniques to reduce or prevent corneal scarring following injury. Two isoforms of transforming growth factor-beta (TGF-β), TGF-β1 and -β3 (T1 and T3, respectively), are associated with corneal wound healing. T1 has been shown to drive the corneal keratocytes to differentiate into myofibroblasts; whereas, T3 has been found to inhibit fibrotic markers. In the current study, we examined whether the fibrotic characteristics expressed by human corneal fibroblasts (HCF) in our 3-dimensional (3D) construct following T1 stimulation could be reversed by introducing T3 to the in vitro system. To do this, HCF were isolated and cultured in 10% serum, and when they reached confluence, the cells were stimulated with a stable Vitamin C (VitC) derivative for 4 weeks, which allowed them to secrete a self-assembled matrix. Three conditions were tested: (1) CONTROL: 10% serum (S) only, (2) T1: 10%S + T1, or (3) Rescue: 10%S + T1 for two weeks and then switched to 10%S + T3 for another two weeks. At the end of 4 weeks, the constructs were processed for analysis by indirect-immunofluorescence (IF) and transmission electron microscopy (TEM). Different collagens that are normally present in healthy corneas in vivo, such as Type I and V, as well as Type III, which is a fibrotic indicator, were examined. In addition, we examined smooth muscle actin (SMA), a marker of myofibroblasts, and thrombospondin-1 (TSP-1), a multifunctional matrix protein known to activate the latent complex of TGF-β and appear upon wounding in vivo. Our data showed high expression of collagens type I and V under all conditions throughout the 3D constructs; however, type III and SMA expression were higher in the constructs that were stimulated with T1 and reduced to almost nothing in the Rescue samples. A similar pattern was seen with TSP-1, where TSP-1 expression following "rescue" was decreased considerably. Overall, this data is in agreement with our previous observations that T3 has a significant non-fibrotic effect on HCFs, and presents a novel model for the "rescue" of both cellular and matrix fibrotic components with a single growth factor.
Karamichos D, Hutcheon AEK, Rich CB, Trinkaus-Randall V, Asara JM, Zieske JD. In vitro model suggests oxidative stress involved in keratoconus disease. Sci Rep 2014;4:4608.Abstract
Keratoconus (KC) affects 1:2000 people and is a disorder where cornea thins and assumes a conical shape. Advanced KC requires surgery to maintain vision. The role of oxidative stress in KC remains unclear. We aimed to identify oxidative stress levels between human corneal keratocytes (HCKs), fibroblasts (HCFs) and keratoconus cells (HKCs). Cells were cultured in 2D and 3D systems. Vitamin C (VitC) and TGF-β3 (T3) were used for 4 weeks to stimulate self-assembled extracellular matrix (ECM). No T3 used as controls. Samples were analyzed using qRT-PCR and metabolomics. qRT-PCR data showed low levels of collagen I and V, as well as keratocan for HKCs, indicating differentiation to a myofibroblast phenotype. Collagen type III, a marker for fibrosis, was up regulated in HKCs. We robustly detected more than 150 metabolites of the targeted 250 by LC-MS/MS per condition and among those metabolites several were related to oxidative stress. Lactate levels, lactate/malate and lactate/pyruvate ratios were elevated in HKCs, while arginine and glutathione/oxidized glutathione ratio were reduced. Similar patterns found in both 2D and 3D. Our data shows that fibroblasts exhibit enhanced oxidative stress compared to keratocytes. Furthermore the HKC cells exhibit the greatest level suggesting they may have a myofibroblast phenotype.
Karamichos D, Zieske JD, Sejersen H, Sarker-Nag A, Asara JM, Hjortdal J. Tear metabolite changes in keratoconus. Exp Eye Res 2015;132:1-8.Abstract

While efforts have been made over the years, the exact cause of keratoconus (KC) remains unknown. The aim of this study was to identify alterations in endogenous metabolites in the tears of KC patients compared with age-matched healthy subjects. Three groups were tested: 1) Age-matched controls with no eye disease (N = 15), 2) KC - patients wearing Rigid Gas permeable lenses (N = 16), and 3) KC - No Correction (N = 14). All samples were processed for metabolomics analysis using LC-MS/MS. We identified a total of 296 different metabolites of which >40 were significantly regulated between groups. Glycolysis and gluconeogenesis had significant changes, such as 3-phosphoglycerate and 1,3 diphosphateglycerate. As a result the citric acid cycle (TCA) was also affected with notable changes in Isocitrate, aconitate, malate, and acetylphosphate, up regulated in Group 2 and/or 3. Urea cycle was also affected, especially in Group 3 where ornithine and aspartate were up-regulated by at least 3 fold. The oxidation state was also severely affected. Groups 2 and 3 were under severe oxidative stress causing multiple metabolites to be regulated when compared to Group 1. Group 2 and 3, both showed significant down regulation in GSH-to-GSSG ratio when compared to Group 1. Another indicator of oxidative stress, the ratio of lactate - pyruvate was also affected with Groups 2 and 3 showing at least a 2-fold up regulation. Overall, our data indicate that levels of metabolites related to urea cycle, TCA cycle and oxidative stress are highly altered in KC patients.

Karamichos D, Funderburgh ML, Hutcheon AEK, Zieske JD, Du Y, Wu J, Funderburgh JL. A role for topographic cues in the organization of collagenous matrix by corneal fibroblasts and stem cells. PLoS One 2014;9(1):e86260.Abstract
Human corneal fibroblasts (HCF) and corneal stromal stem cells (CSSC) each secrete and organize a thick stroma-like extracellular matrix in response to different substrata, but neither cell type organizes matrix on tissue-culture polystyrene. This study compared cell differentiation and extracellular matrix secreted by these two cell types when they were cultured on identical substrata, polycarbonate Transwell filters. After 4 weeks in culture, both cell types upregulated expression of genes marking differentiated keratocytes (KERA, CHST6, AQP1, B3GNT7). Absolute expression levels of these genes and secretion of keratan sulfate proteoglycans were significantly greater in CSSC than HCF. Both cultures produced extensive extracellular matrix of aligned collagen fibrils types I and V, exhibiting cornea-like lamellar structure. Unlike HCF, CSSC produced little matrix in the presence of serum. Construct thickness and collagen organization was enhanced by TGF-ß3. Scanning electron microscopic examination of the polycarbonate membrane revealed shallow parallel grooves with spacing of 200-300 nm, similar to the topography of aligned nanofiber substratum which we previously showed to induce matrix organization by CSSC. These results demonstrate that both corneal fibroblasts and stromal stem cells respond to a specific pattern of topographical cues by secreting highly organized extracellular matrix typical of corneal stroma. The data also suggest that the potential for matrix secretion and organization may not be directly related to the expression of molecular markers used to identify differentiated keratocytes.

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