Ocular Allergic Diseases Research Articles

Endoplasmic Reticulum Stress and Unfolded Protein Response in Vernal Keratoconjunctivitis.

Vernal keratoconjunctivitis (VKC) is an ocular allergic disease characterized by a type 2 inflammation, tissue remodeling, and low quality of life for the affected patients. We investigated the involvement of endoplasmic reticulum (ER) stress and unfolded protein response in VKC. Conjunctival imprints from VKC patients and normal subjects (CTs) were collected, and RNA was isolated, reverse transcribed, and analyzed with the Affymetrix microarray. Differentially expressed genes between VKC patients and CTs were evaluated. Genes related to ER stress, apoptosis, and autophagy were further considered. VKC and CT conjunctival biopsies were analyzed by immunohistochemistry (IHC) with specific antibodies against unfolded protein response (UPR), apoptosis, and inflammation. Conjunctival fibroblast and epithelial cell cultures were exposed to the conditioned medium of activated U937 monocytes and analyzed by quantitative PCR for the expression of UPR, apoptosis, autophagy, and inflammatory markers. ER chaperones HSPA5 (GRP78/BiP) and HYOU1 (GRP170) were upregulated in VKC patients compared to CTs. Genes encoding for ER transmembrane proteins, PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), ER-associated degradation (ERAD), and autophagy were upregulated, but not those related to apoptosis. Increased positive reactivity of BiP and ATF6 and unchanged expression of apoptosis markers were confirmed by IHC. Cell cultures in stress conditions showed an overexpression of UPR, proinflammatory, apoptosis, and autophagy markers. A significant overexpression of genes encoding for ER stress, UPR, and pro-inflammatory pathway components was reported for VKC. Even though these pathways may lead to ER homeostasis, apoptosis, or inflammation, ER stress in VKC may predominantly contribute to promote inflammation.

Applications of topical immunomodulators enhance clinical signs of vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC): a meta-analysis.

This meta-analysis aimed to review the safety and efficacy of topical cyclosporine A (CsA) and topical tacrolimus in allergic eye disease. A systematic search identified thirteen studies and a total of 445 patients for inclusion, making this the largest meta-analysis published on the subject. The current review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Thirteen randomized control trials were included in the meta-analysis. Eleven studies used CsA as the treatment, and two used Tacrolimus. In total, 445 participants were included, of whom 76.6% were male. The mean age of participants across the included studies was 14years. All studies reported clinical signs as evaluated by an examining clinician. Signs were usually assessed by anatomical region, with the most common regions being the conjunctiva and the cornea, and the most common signs assessed were hyperemia and papillae. Three studies accounted for more than 50% of the meta-analysis's weight. Effect size (d) ranged from - 2.37 to - 0.03, negative values favoring immunomodulators. Fixed Effect Meta-Analysis returned an SMD of - 0.81 (95% CI [- 0.98, - 0.65]). However, there was significant heterogeneity (I2 = 61%, Qw = 30.76) in the outcome measure (P = 0.0021); therefore, a random-effect meta-analysis was also completed in which the pooled SMD was - 0.98 (95% CI [- 1.26, - 0.69], τ2 = 0.16). This study affirms the current scientific community's stance that immunomodulators effectively treat clinical signs, including blepharitis, conjunctival hyperemia, edema, papillae, and corneal damage in severe ocular allergic disease.

Allergic conjunctivitis: Treatment updates and long-term monitoring

Allergic conjunctival diseases have a significant impact on the ocular surface, affecting the conjunctiva, cornea, and eyelids. Estimates indicate that approximately 35% of North Americans are affected by these diseases. Seasonal and perennial allergic conjunctivitis are the most common and mildest forms of ocular allergic disease, affecting 15–20% of the population. More severe conditions of ocular allergenic diseases include atopic keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), and giant papillary conjunctivitis (GPC). This article will review allergic conjunctivitis classifications, ocular sequelae, and a simplified treatment algorithm.

Association between keratoconus and allergic conjunctivitis in children attending a Tertiary Hospital in Nigeria.

Objective: To ascertain an association between keratoconus and allergic conjunctivitis and to know if it is necessary to investigate all patients with allergic conjunctivitis for keratoconus. Methods: A hospital-based prospective study in which the eyes of children presenting with ocular allergic diseases were examined. Social demographics and clinical data were captured in a questionnaire. All the patients underwent keratometry using the autorefractor-keratometer and the pachymeter was used to measure the central corneal thickness. Data analysis was done with IBM SPSS version 28 for Windows. Frequency and chi-square were used as descriptive statistics to determine the association between dependent and independent variables. Inferential statistics using one-way ANOVA and t-test. P - Value at <0.05 was considered statistically significant. Results: 121 children with allergic conjunctivitis were reviewed. Males were 72 and females 49. The visual acuity was 6/ 6-6/ 18 in 116, and mild visual impairment - 6/ 18-6/ 60 in 5. The most common complaint was frequent itching in 109 (90.1%). Keratometry was normal in 120 (99.5%), while probable keratoconus was found by keratometry in only one patient (0.5%). Central corneal thickness was within the normal range in 33 (27.3%) children, 43 (35.5%) had thin corneas, while 45 (37.2%) had cornea thickness of more than 560 microns. Discussion: Pediatric keratoconus tends to be more aggressive than adult keratoconus with an increased risk of corneal opacities and subsequent keratoplasty. As a result of these negative impacts, early detection and prompt treatment are mandatory. Conclusion: The prevalence of keratoconus was not found to be high in this study population, but with facts emerging between the association of allergic conjunctivitis, and increased prevalence of keratoconus, it is pertinent to integrate keratoconus screening as part of the management of allergic conjunctivitis using an appropriate tool such as video keratography and slit lamp biomicroscope. Abbreviations: KC = Keratoconus, CLEK = Collaborative Longitudinal Evaluation of Keratoconus, SAC = Seasonal Allergic Conjunctivitis, PAC = Perennial Allergic Conjunctivitis, VKC = Vernal Keratoconjunctivitis, IOP = Intraocular Pressure, CCT = Central Corneal Thickness, TNF-α = Tumor Necrosis Factor-Alpha, IL = Interleukin.

CASE REPORT DIAGNOSIS AND TREATMENT OF VERNAL KERATOCONJUNCTIVITIS

Background: Vernal keratoconjunctivitis (VKC) is a bilateral ocular allergic disease mediated by hypersensitivity reactions. VKC events occur in boys in the first decade of life and continue until puberty. Early identification and effective treatment are essential because the condition is recurrent and potentially burdensome to the patient's quality of life. This case report examines the diagnosis, management, and therapy options for patients with VKC and highlights the significance of the clinician's involvement in cases with VKC.Case Presentation: We report a case, a boy, 8 years old, came to the eye clinic at Cut Meutia Hospital with pain in both eyes, red eyes, decreased vision, and increased eye discharge. This complaint has been experienced for the past few years, and most appeared when the patient played under the sun or when the patient's allergy came. Examination showed mild conjunctival inflammation, pseudoptosis, and papillae on the limbus.Conclusion: The patient was diagnosed with VKC and received several treatments, including artificial tear and dexamethasone.

A survey‐based study on diagnosis and management of vernal keratoconjunctivitis

A survey‐based study on diagnosis and management of vernal keratoconjunctivitis

Novel Insights in the Management of Vernal Keratoconjunctivitis (VKC): European Expert Consensus Using a Modified Nominal Group Technique.

Vernal keratoconjunctivitis (VKC) is a rare, severe allergic ocular disease, typically occurring in children and adolescents, that can have a significant impact on quality of life and lead to visual impairment. Long-term treatment may be necessary to tackle chronic inflammation and topical corticosteroid dependency must be minimised due to the risk of complications. There is a need for unified clinical guidance to aid the assessment, diagnosis and management of VKC across Europe. The aim of this expert panel (the EUR-VKC Group) was to provide clear guidance for primary care physicians and general ophthalmologists involved in the diagnosis and management of VKC. An expert group of seven European ophthalmologists was convened and a modified nominal group technique used to develop key recommendations on VKC management. The recommendations were subject to up to two rounds of voting using a 5-point Likert scale to ascertain consensus and the strength of each recommendation. Consensus was set at a predetermined threshold of ≥ 75.0% of experts selecting 'Strongly agree' or 'Agree'. A total of 47 recommendations were developed relating to the assessment of key of VKC, guidance on who and when to refer, as well as treatment-escalation pathways, long-term follow-up, and supportive care and education. All recommendations reached consensus after two rounds. The group emphasise how timely diagnosis and treatment initiation that is appropriate to disease severity are crucial to benefit patients with VKC. Patients with signs ('red flags') indicating severe VKC, or persistent mild-to-moderate VKC that is non-responsive following 2-4weeks of treatment, should be referred to a sub-specialist. The EUR-VKC Group provides recommendations on the assessment, diagnosis, management, referral and follow-up of patients with VKC. It also provides a framework to facilitate collaboration between primary care physicians, general ophthalmologists and sub-specialists to improve the outcomes for patients with VKC.

Editorial introductions.

Editorial introductions.

Ayurvedic management of allergic conjunctivitis in 30 years old patient

Allergic Conjunctivitis is a common clinical condition faced by practitioners. About 5-22% percent of the world population suffer from some sort of allergic ocular disease. In Ayurveda it can be correlated with Vataja Abhishyanda on the basis of symptoms like Toda (Pricking pain), Sangharsha (foreign body sensation), Achchasruta (watering), Alpa Shopha (mild chemosis), Vishushka Bhava (feeling of dryness), Parushya (dryness), Alpa Dushika (discharge), Kandu (itching) etc. Vata is the chief culprit and other Doshas are associated with it. In these studies, Ksheer Saindhav Pariseka was used as treatment.This treatment modalities showed highly significant results in relieving the signs and symptoms of disease with no adverse reaction.

Role of Damage-Associated Molecular Patterns (DAMPs/Alarmins) in Severe Ocular Allergic Diseases.

Severe ocular allergic diseases, such as atopic keratoconjunctivitis and vernal keratoconjunctivitis, cause severe allergic inflammation in the conjunctiva and corneal epithelial damage, resulting in visual disturbances. The involvement of damage (danger)-associated molecular patterns (DAMPs/alarmins) in the pathogenesis of these diseases has been recognized. Alarmins released from damaged corneal epithelial cells or eosinophils play a critical role in the induction of corneal lesions, vicious loop of corneal injury, and exacerbation of conjunctival allergic inflammation. Alarmins in the conjunctiva also play an essential role in the development of both allergic inflammation, based on the acquired immune system, and type 2 inflammation by innate immune responses in the ocular surface. Therefore, alarmins may be a potentially important therapeutic target in severe refractory ocular allergic diseases.

Ocular Allergic Surface Disease Symptoms Associated with Atopic Keratoconjunctivitis (AKC) Alleviated With Dupilumab

Dupilumab is a monoclonal antibody approved for the treatment of atopic dermatitis (AD) and asthma. However, adverse ocular surface reactions often arise as side effects– conjunctivitis has been reported in 16% of patients. We report the use of dupilumab in a patient with AD, asthma and atopic keratoconjunctivitis (AKC) resulting in improvement in all three conditions.

Therapeutic potential of the interleukin-4/interleukin-13 inhibitor dupilumab for treating IgG4-related disease.

Dear Editor, IgG4-related disease (IgG4-RD) is a chronic fibroinflammatory condition with diffuse or focal organ mass formation and shows storiform fibrosis with the infiltration of IgG4-positive plasma cells [1]. Corticosteroids as first-line treatment are effective against IgG4-RD; however, their long-term use may cause serious adverse effects. Dupilumab, a human monoclonal antibody against the IL-4 receptor α-subunit (IL-4Rα), inhibits the signal transduction of IL-4 and IL-13. Thus, dupilumab has been recently approved for treating type 2 inflammatory diseases, such as chronic rhinosinusitis, asthma and atopic dermatitis. We have also recently reported the successful treatment by dupilumab in two cases with severe atopic keratoconjunctivitis, suggesting dupilumab may be a potential alternative agent for another type 2 inflammatory disease—severe ocular allergic disease [2]. Although the pathogenetic mechanisms of IgG4-RD have not been fully uncovered, both innate and adaptive immune responses may be involved in IgG4-RD immunopathogenesis. IL-4 and...

A calcium channel blocker, manoalide exerts an anti-allergic inflammatory effect through attenuating NF-κB activity

Background Many people are troubled by allergic inflammation including ocular allergic diseases, anaphylaxis, allergic rhinitis, atopic dermatitis, and eczema. Consequently, finding medications for use in allergic inflammation therapy is crucial in human health. Manoalide, a marine natural product isolated as an anti-bacterial metabolite from Luffariella variabilis, is a calcium channel blocker. However, its latent ability as an anti-allergic inflammatory agent has not yet been reported. Our research aimed to elucidate whether manoalide exerts an anti-allergic inflammatory effect in the human mast cell line, HMC-1. Methods Herein, we investigated the immunoregulatory effects and molecular mechanisms of manoalide in HMC-1 cells. Results Manoalide significantly alleviated secretion of the inflammatory cytokines interleukin (IL)-1β, thymic stromal lymphopoietin, tumor necrosis factor-α, IL-6, and IL-8 via blockage of caspase-1 without cytotoxicity in activated HMC-1 cells. Activation of nuclear factor-κB increased by mast cell stimulation was attenuated by treatment with manoalide. In addition, we demonstrated that manoalide treatment remarkably attenuated the activation of mitogen-activated protein kinases in activated-HMC-1 cells. Conclusions Taken together, our findings indicate manoalide has an anti-allergic inflammatory role, and we propose that manoalide might have potential as a novel anti-allergic inflammatory agent.

Editorial introductions.

Editorial introductions.

Understanding Vernal Keratoconjunctivitis: Beyond Allergic Mechanisms.

Vernal keratoconjunctivitis (VKC) is a chronic, recurrent, inflammatory disease of the cornea and conjunctiva mostly affecting boys in prepubertal age. VKC recurrence is characterized by intense symptoms of itching, redness, and photophobia associated with corneal damage, impairment of visual function, and quality of life. The pathogenesis of VKC has not yet been completely understood, and it is still controversial. In fact, VKC is considered an ocular allergic disease due to the involvement of immunoglobulin E, eosinophils, and mast cells, and of a lymphocyte T-helper type 2 reaction. However, approximately half of VKC patients have negative allergological history and testing, suggesting that other pathogenic mechanisms participate in VKC development and severity. Specifically, evidence suggests that genetic, endocrine, neuronal factors and an imbalance of innate immunity are involved in the pathogenesis of VKC. The purpose of this review is to summarize evidence on the pathogenic role of innate immunity, neuroimmune reaction, and hormonal changes in VKC. Increasing understanding of the pathogenic mechanisms behind VKC may lead to the identification of novel biomarkers for diagnosis and/or potential therapeutic targets in order to improve the management of this challenging condition.

Elevated levels of prostaglandin E2 in the tears of patients with severe allergic conjunctivitis and primary cultured conjunctival cells are suppressed by ketotifen and dexamethasone

ObjectiveWe examined the production of prostaglandin E2 (PGE2), which is the key prostaglandin involved in inflammatory disorders of the ocular surface. Tears and conjunctival fibroblasts were evaluated in order to...

Increased Expression of TLR4 in Circulating CD4+T Cells in Patients with Allergic Conjunctivitis and In Vitro Attenuation of Th2 Inflammatory Response by Alpha-MSH.

Ocular allergic diseases are frequently seen in ophthalmological clinical practice. Immunological damage is mediated by a local Th2 inflammatory microenvironment, accompanied by changes in circulating cell subsets, with more effector cells and fewer T regulatory cells (Tregs). This study aimed to evaluate the involvement of toll-like receptor 4 (TLR4) and α-melanocyte stimulating hormone (α-MSH) in the immune regulation associated with perennial allergic conjunctivitis (PAC). We performed an Ag-specific stimulation during 72 h of culturing with or without lipopolysaccharide (LPS) or α-MSH in peripheral blood mononuclear cells (PBMC), analyzing the cell subsets and cytokines induced by the stimuli. We also determined α-MSH in tear samples from healthy donors (HD) or PAC patients. Our findings demonstrate an immunological dysregulation characterized by an increased frequency of CD4+TLR4+ in the PBMC of patients with PAC, compared to HD. Most of these CD4+TLR4+ cells were also CD25+, and when α-MSH was added to the culture, the percentage of CD4+CD25+FoxP3+ increased significantly, while the percentage of CD69+ cells and cytokines IL-4 and IL-6 were significantly decreased. In tears, we found an increased concentration of α-MSH in PAC patients, compared with HD. These findings indicate a novel mechanism involved in controlling ocular allergic diseases, in which α-MSH diminishes the concentration of IL-6 and IL-4, restoring the frequency of Tregs and down-regulating CD4 activation. Moreover, we demonstrated the involvement of CD4+TLR4+ cells as an effector cell subset in ocular allergy.

Conjunctival transcriptome analysis reveals the overexpression of multiple pattern recognition receptors in vernal keratoconjunctivitis

BackgroundVernal keratoconjunctivitis (VKC) is a chronic, potentially blinding ocular allergic disease affecting children with uncertain pathogenic mechanisms. ObjectiveTo identify differences in gene expression between VKC and normal subjects (CT) and to evaluate the expression of pattern recognition receptors (PRRs). MethodsConjunctival cells were collected by impression cytology device from 25 VKC patients and 10 CT. Isolated RNA was assayed with the NanoString human immunology codeset to evaluate the expression levels of immunology-related genes. ResultsOf the 579 genes, 398 were detected and 58 were significantly differently expressed in VKC compared to CT. The number of significantly differentially expressed genes (DEG) in the 3 different phenotypes vs CT were 149 in tarsal, 17 in limbal and 68 in the mixed form of VKC.The list of the most overexpressed genes included several chemokines (CCL24, CCL18, CCL22, CXCL1), proinflammatory cytokines (IL-1β, IL-6, IL-8, TGFβ-1) and genes related to Th2- and Th17-signaling families. Toll like receptors (TLR)4 and TLR8, Dectin-1/CLEC7A, mincle/CLEC4E, MCR1, NOD2 and NLRP3 and several of their pathway-related genes were significantly overexpressed in VKC. The number of DEG increased with the disease severity either in IgE+ or IgE- patients. Immunohistochemistry analysis of VKC conjunctival tissues confirmed an increased expression of these molecules at protein level. ConclusionsThe increased expression of several chemotactic factors and co-stimulatory signals required for T-cell activation, confirms that VKC is mostly cell-mediated with local eosinophilia. The multiple expression of PRRs suggests a role of host-pathogens interaction in VKC development.

Reduced steroid-induced intraocular pressure elevation in tacrolimus-treated refractory allergic ocular diseases.

To determine whether topical tacrolimus can lessen steroid-induced intraocular pressure (IOP) elevation. Open cohort post hoc analysis study. Five hundred eleven patients with vernal keratoconjunctivitis or atopic keratoconjunctivitis (mean age 17.0 ± 9.2years) were studied. All 511 patients were treated with topical tacrolimus with or without topical steroids, and the changes in IOP were measured monthly for 3months. The elevation in IOP induced by use of topical steroids was calculated using mixed linear regression analyses. The relationship between the elevation in IOP within 4weeks and the use or nonuse of tacrolimus reported in published data was analyzed using metaregression analysis to estimate the effects of tacrolimus on the IOP in eyes treated with topical steroids. The mean topical steroid-induced IOP elevation in tacrolimus-treated eyes was lower, by 5.2mmHg (P = 0.04), than that in earlier published data without tacrolimus as the control. In the tacrolimus-treated eyes, the mean betamethasone-induced IOP elevation was 1.3mmHg without discontinuation of the steroid. Metaregression analysis indicated that glaucoma history and younger age had significant effects on topical steroid-induced IOP elevation, by 4.0mmHg (P = 0.002) and 3.9mmHg (P = 0.01), respectively. In tacrolimus-treated eyes, the most significant effect on the IOP was associated with glaucoma history or medication; however, its effect on the IOP was limited to 1.7mmHg elevation (P = 0.006). Topical tacrolimus may lessen the steroid-induced elevation in IOP in younger individuals and may be a good adjunctive therapy to avoid IOP elevation in refractory cases.

Corneal fibroblasts: Function and markers

Corneal stromal keratocytes contribute to the maintenance of corneal transparency and shape by synthesizing and degrading extracellular matrix. They are quiescent in the healthy cornea, but they become activated in response to insults from the external environment that breach the corneal epithelium, with such activation being associated with phenotypic transformation into fibroblasts. Corneal fibroblasts (activated keratocytes) act as sentinel cells to sense various external stimuli—including damage-associated molecular patterns derived from injured cells, pathogen-associated molecular patterns of infectious microorganisms, and inflammatory mediators such as cytokines—under pathological conditions such as trauma, infection, and allergy. The expression of various chemokines and adhesion molecules by corneal fibroblasts determines the selective recruitment and activation of inflammatory cells in a manner dependent on the type of insult. In infectious keratitis, the interaction of corneal fibroblasts with various components of microbes and with cytokines derived from infiltrated inflammatory cells results in excessive degradation of stromal collagen and consequent corneal ulceration. Corneal fibroblasts distinguish between type 1 and type 2 inflammation through recognition of corresponding cytokines, with their activation by type 2 cytokines contributing to the pathogenesis of corneal lesions in severe ocular allergic diseases. Pharmacological targeting of corneal fibroblast function is thus a potential novel therapeutic approach to prevention of excessive corneal stromal inflammation, damage, and scarring.