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

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

Impacto da poluição ambiental na superfície ocular de pacientes com síndrome de Sjögren

Purpose: To evaluate the effect of air pollution on the ocular surface of patients with Sjögren's syndrome. Methods: We investigated the ocular surfaces of thirty patients with Sjögren's syndrome and thirty healthy volunteers (control group) living in the Metropolitan Area of Buenos Aires. We used nitrogen dioxide as an indicator of exposure to air pollution. An ocular symptoms questionnaire was answered by all subjects, who also underwent a complete ocular surface ophthalmic examination-including an Ocular Surface Disease Index questionnaire, biomicroscopy, tear breakup time, Schirmer 1 test, corneal and conjunctival vital staining with fluorescein and lissamine green, tear lysozyme concentration, and impression cytology. Results: In almost all ocular surface test findings, we found a positive and significant correlation between higher levels of exposure to air pollution and higher levels of ocular surface damage in both the control group and Sjögren's syndrome patients. In Sjögren's syndrome patients, the Ocular Surface Disease Index questionnaire, tear breakup time, vital staining and impression cytology showed a significant correlation between high levels of air pollution and ocular surface disease. In the control group, the Ocular Surface Disease Index questionnaire, tear breakup time, and impression cytology showed a significant correlation between high levels of air pollution and ocular surface disease. Conclusions: Here we demonstrated that in patients with dry eye syndrome associated with Sjögren, abnormalities of the ocular surface and eye irritation related to air pollution are more severe than those in the control group. We believe that measuring air quality should be not only an integral part of the evaluation of ocular surface disease but also a therapeutic consideration.Objetivo: Avaliar o efeito da poluição do ar na superfície ocular de pacientes com síndrome de Sjögren. Métodos: Foram investigadas as superfícies oculares de trinta pacientes com síndrome de Sjögren e trinta voluntários saudáveis (grupo controle) residentes na Região Metropolitana de Buenos Aires. Usamos o dióxido de nitrogênio como um indicador de exposição à poluição do ar. Um questionário de sintomas oculares foi respondido por todos os indivíduos, que também foram submetidos a um exame oftalmológico completo da superfície ocular - incluindo um questionário do Índice da Doença da Superfície Ocular, biomicroscopia, tempo de ruptura do filme lacrimal, teste de Schirmer 1, coloração da córnea e conjuntiva com fluoresceína e lissamina verde, concentração de lisozima lacrimal e citologia de impressão. Resultados: Em quase todos os achados do teste de superfície ocular, encontramos uma correlação positiva e significativa entre níveis mais altos de exposição à poluição do ar e níveis mais elevados de danos na superfície ocular tanto no grupo controle quanto nos pacientes com síndrome de Sjögren. Em pacientes com síndrome de Sjögren, o questionário do Índice da Doença da Superfície Ocular, tempo de ruptura do filme lacrimal, coloração vital e citologia de impressão mostraram uma correlação significativa entre altos níveis de poluição do ar e doença da superfície ocular. No grupo controle, o questionário do Índice de Doenças da Superfície Ocular, tempo de ruptura do filme lacrimal e citologia de impressão mostraram uma correlação significativa entre altos níveis de poluição do ar e doença da superfície ocular. Conclusões: Aqui demonstramos que, pacientes com síndrome de olho seco associada a Sjögren, as anormalidades da superfície ocular e airritação ocular relacionadas à poluição do ar são mais graves do que aquelas no grupo controle. Acreditamos que a medição da qualidade do ar não deve ser apenas uma parte integral da avaliação da doença da superfície ocular, mas também uma consideração terapêutica.Fil: Galperín, Gustavo Javier. Hospital Oftalmológico Pedro Lagleyze; ArgentinaFil: Berra, Fabio Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Oftalmológico Pedro Lagleyze; ArgentinaFil: Marquez, Maria Isabel. Bioquímica Ocular; ArgentinaFil: Mandaradoni, Mariana. Hospital Nacional Professor Dr. Alejandro Posadas; ArgentinaFil: Tau, Julia. Laboratorio de Investigaciones Oculares; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Berra, Alejandro. Laboratorio de Investigaciones Oculares; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Therapeutic Effect of Human Adipose Tissue-Derived Mesenchymal Stem Cells in Experimental Corneal Failure Due to Limbal Stem Cell Niche Damage

Producción CientíficaLimbal stem cells are responsible for the continuous renewal of the corneal epithelium. The destruction or dysfunction of these stem cells or their niche induces limbal stem cell deficiency (LSCD) leading to visual loss, chronic pain, and inflammation of the ocular surface. To restore the ocular surface in cases of bilateral LSCD, an extraocular source of stem cells is needed to avoid dependence on allogeneic limbal stem cells that are difficult to obtain, isolate, and culture. The aim of this work was to test the tolerance and the efficacy of human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) to regenerate the ocular surface in two experimental models of LSCD that closely resemble the different severity grades of the human pathology. hAT-MSCs transplanted to the ocular surface of the partial and total LSCD models developed in rabbits were well tolerated, migrated to inflamed tissues, reduced inflammation, and restrained the evolution of corneal neovascularization and corneal opacity. The expression profile of the corneal epithelial cell markers CK3 and E-cadherin, and the limbal epithelial cell markers CK15 and p63 was lost in the LSCD models, but was partially recovered after hAT-MSC transplantation. For the first time, we demonstrated that hAT-MSCs improves corneal and limbal epithelial phenotypes in animal LSCD models. These results support the potential use of hAT-MSCs as a novel treatment of ocular surface failure due to LSCD. hAT-MSCs represent an available, non-immunogenic source of stem cells that may provide therapeutic benefits in addition to reduce health care expenses.This work was supported by Instituto de Salud Carlos III, CIBER‐BBN, Spain (CB06/01/003 MINECO/FEDER, EU); Regional Center for Regenerative Medicine and Cell Therapy, Castilla y León, Spain; Ministry of Science and Innovation, Spain (SAF2010–14900); Ministry of Economy and Competitiveness and European Regional Development Fund, Spain (SAF2015–63594‐R MINECO/FEDER, EU

Analysis of the pathogenic factors and management of dry eye in ocular surface disorders

The tear film represents the interface between the eye and the environment. The alteration of the delicate balance that regulates the secretion and distribution of the tear film determines the dry eye (DE) syndrome. Despite having a multifactorial origin, the main risk factors are female gender and advanced age. Likewise, morphological changes in several glands and in the chemical composition of their secretions, such as proteins, mucins, lipidics, aqueous tears, and salinity, are highly relevant factors that maintain a steady ocular surface. Another key factor of recurrence and onset of the disease is the presence of local and/or systemic inflammation that involves the ocular surface. DE syndrome is one of the most commonly encountered diseases in clinical practice, and many other causes related to daily life and the increase in average life expectancy will contribute to its onset. This review will consider the disorders of the ocular surface that give rise to such a widespread pathology. At the end, the most recent therapeutic options for the management of DE will be briefly discussed according to the specific underlying pathology

A mass and solute balance model for tear volume & osmolarity in the normal and the dry eye

Tear hyperosmolarity is thought to play a key role in the mechanism of dry eye, a common symptomatic condition accompanied by visual disturbance, tear film instability, inflammation and damage to the ocular surface. We have constructed a model for the mass and solute balance of the tears, with parameter estimation based on extensive data from the literature which permits the influence of tear evaporation, lacrimal flux and blink rate on tear osmolarity to be explored. In particular the nature of compensatory events has been estimated in aqueous-deficient (ADDE) and evaporative (EDE) dry eye.\ud \ud The model reproduces observed osmolarities of the tear meniscus for the healthy eye and predicts a higher concentration in the tear film than meniscus in normal and dry eye states. The differential is small in the normal eye, but is significantly increased in dry eye, especially for the simultaneous presence of high meniscus concentration and low meniscus radius. This may influence the interpretation of osmolarity values obtained from meniscus samples since they need not fully reflect potential damage to the ocular surface caused by tear film hyperosmolarity.\ud \ud Interrogation of the model suggests that increases in blink rate may play a limited role in compensating for a rise in tear osmolarity in ADDE but that an increase in lacrimal flux, together with an increase in blink rate, may delay the development of hyperosmolarity in EDE. Nonetheless, it is predicted that tear osmolarity may rise to much higher levels in EDE than ADDE before the onset of tear film breakup, in the absence of events at the ocular surface which would independently compromise tear film stability. Differences in the predicted responses of the pre-ocular tears in ADDE compared to EDE or hybrid disease to defined conditions suggest that no single, empirically-accessible variable can act as a surrogate for tear film concentration and the potential for ocular surface damage. This emphasises the need to measure and integrate multiple diagnostic indicators to determine outcomes and prognosis. Modelling predictions in addition show that further studies concerning the possibility of a high lacrimal flux phenotype in EDE are likely to be profitable

Desiccating stress-induced disruption of ocular surface immune tolerance drives dry eye disease

Dry eye is an allegedly autoimmune disorder for which the initiatingmechanisms and the targeted antigens in the ocular surface are not known,yet there is extensive evidence that a localized T helper type 1 (Th1)/Th17effector T cell response is responsible for its pathogenesis. In this work, weexplore the reconciling hypothesis that desiccating stress, which is usuallyconsidered an exacerbating factor, could actually be sufficient to skew theocular surface?s mucosal response to any antigen and therefore drive thedisease. Using a mouse model of dry eye, we found that desiccating stresscauses a nuclear factor kappa B (NF-jB)- and time-dependent disruption ofthe ocular surface?s immune tolerance to exogenous ovalbumin. Thispathogenic event is mediated by increased Th1 and Th17 T cells andreduced regulatory T cells in the draining lymph nodes. Conversely, topicalNF-jB inhibitors reduced corneal epithelial damage and interleukin (IL)-1band IL-6 levels in the ocular surface of mice under desiccating stress. Theobserved effect was mediated by an augmented regulatory T cell response, afinding that highlights the role of mucosal tolerance disruption in dry eyepathogenesis. Remarkably, the NF-jB pathway is also involved in mucosaltolerance disruption in other ocular surface disorders. Together, theseresults suggest that targeting of mucosal NF-jB activation could havetherapeutic potential in dry eye.Fil: Guzman, Mauricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Keitelman, Irene Angélica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Sabbione, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Trevani, Analía Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Galletti, Jeremías Gastón. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

Effect of recombinant human nerve growth factor eye drops in patients with dry eye: a phase IIa, open label, multiple-dose study

Background: Dry eye disease (DED) affects more than 14% of the elderly population causing decrease of quality of life, high costs and vision impairment. Current treatments for DED aim at lubricating and controlling inflammation of the ocular surface. Development of novel therapies targeting different pathogenic mechanisms is sought-after. The aim of this study is to evaluate safety and efficacy of recombinant human nerve growth factor (rhNGF) eye drops in patients with DED. Methods: Forty consecutive patients with moderate to severe DED were included in a phase IIa, prospective, open label, multiple-dose, clinical trial to receive rhNGF eye drops at 20 μg/mL (Group 1: G1) or at 4 μg/mL (Group 2: G2) concentrations, two times a day in both eyes for 28 days (NCT02101281). The primary outcomes measures were treatment-emerged adverse events (AE), Symptoms Assessment in Dry Eye (SANDE) scale, ocular surface staining and Schirmer test. Results: Of 40 included patients, 39 completed the trial. Both tested rhNGF eye drop concentrations were safe and well tolerated. Twenty-nine patients experienced at least one AE (14 in G1 and 15 in G2), of which 11 had at least 1 related AE (8 in G1 and 3 in G2). Both frequency and severity of DED symptoms and ocular surface damage showed significant improvement in both groups, while tear function improved only in G1. Conclusions: The data of this study indicate that rhNGF eye drops in both doses is safe and effective in improving symptoms and signs of DED. Randomised clinical trials are ongoing to confirm the therapeutic benefit of rhNGF in DED. Trial registration number: NCT02101281