Science

Publication list

January 2026

Eye and Vision

Anti-inflammatory and dry eye benefits of accelerated epi-off corneal cross-linking in pediatric keratoconus with allergic ocular surface disease and elevated MMP-9

Abstract

Purpose
To assess the functional and ocular surface anti-inflammatory outcomes of epithelium-off accelerated corneal cross-linking (ACXL) in adolescents with progressive keratoconus associated with allergic ocular surface disease and dry eye disease (DED) characterized by elevated tear matrix metalloproteinase-9 (MMP-9) concentrations.

Methods
Prospective interventional case series of 30 eyes from 15 patients (mean age 16.41 ± 2.36 years; Krumeich stage II) undergoing epi-off ACXL. Outcomes at baseline and 1, 3, 6, and 12 months included corrected distance visual acuity (CDVA), maximum keratometry (Kmax), minimum corneal thickness (MCT), computerized non-invasive tear break-up time (cBUT), Ocular Surface Disease Index (OSDI), and tear MMP-9 (point-of-care test). In vivo qualitative confocal microscopy (IVCM) investigation provided supportive imaging. Paired t-tests were used and results reported with 95% confidence intervals (CI).

Results
CDVA improved to 0.09 logMAR at 12 months (≈ 0.81 decimal; 95% CI: 0.10–0.08 logMAR; P < 0.001). Kmax decreased from 55.00 to 53.75 D (95% CI: 53.55–53.95 D; Δ =  − 1.25 D; P < 0.001), indicating ectasia stabilization. cBUT increased from 10.11 to 14.41 s (95% CI: 14.11–14.71; P < 0.01). OSDI decreased to 12.15 (95% CI: 11.65–12.65). Tear MMP-9 levels diminished from 64.79 to 16.15 ng/mL (P < 0.0001) and the proportion < 38.6 ng/mL reached 86.7% of the study cohort at 12 months. IVCM documented disappearance of inflammatory infiltrates. No postoperative persistent adverse events occurred.

Conclusions
Epi-off ACXL stabilized ectasia, improving visual and ocular surface outcomes, markedly lowering tear MMP-9 levels. Although exploratory, these findings are consistent with a potential ocular surface anti-inflammatory and neuromodulatory role of ACXL, meriting validation in studies involving inflammatory DED beyond keratoconus.

Link

October 2025

The Ocular Surface

Tear lymphotoxin-alpha deficiency is associated with conjunctival epitheliopathy in patients with dry eye disease

Abstract

Purpose
This study investigates the association between lymphotoxin-alpha (LTA) concentration in tear fluid and dry eye disease severity, particularly in relation to the conjunctival microenvironment, and evaluates the clinical utility of measuring LTA to guide treatment with diquafosol sodium eye drops.
Methods
In this study, 75 DED patients and 35 non-DED participants were assessed at baseline and DED patients were assessed at one month after treatment with diquafosol sodium eye drops. Clinical assessments included the OSDI, LTA concentration, TBUT, CFS, CLGS, IC, Schirmer test, and MMP-9 and MUC5Ac measurement.
Results
Among 110 participants, concordance between LTA diagnostics and clinical diagnosis reached 80.90 %. There was a strong inverse correlation between tear LTA concentration and both CLGS score (R = −0.716, p < 0.001) and IC Nelson grade (R = −0.571, p < 0.001), a positive correlation with conjunctival goblet cell count (R = 0.520, p < 0.001) and TBUT (R = 0.387, p < 0.001). DED patients were subsequently divided into two groups, based on the IC Nelson grade reflecting the degree of damages in conjunctiva. ROC curve analysis identified an optimum threshold LTA concentration of 0.11 ng/mL to distinguish between mild and severe DED. Patients in the low LTA group had higher MMP-9 and lower Muc5ac concentrations compared to the high LTA group. After one month of diquafosol treatment, patients with LTA < 0.11 ng/mL showed more significant improvements compared to those with LTA ≥ 0.11 ng/mL.
Conclusion
Tear fluid LTA concentration is strongly correlated with conjunctival damage severity. Measuring LTA concentration offers a noninvasive method for evaluating the conjunctival microenvironment and guiding DED treatment.

Link

September 2025

International Journal of Molecular Sciences

Exploring the Diagnostic Utility of Tear IgE and Lid Wiper Epitheliopathy in Ocular Allergy Among Individuals with Hay Fever

Abstract

Allergic rhinitis (hay fever) prevalence has increased in Australia. People with hay fever often experience many eye symptoms, especially itching. This study explores clinical correlations between tear IgE levels and ocular allergy signs in hay fever sufferers, focusing also on eyelid wiper friction damage from eye rubbing. In a cross-sectional study from November 2024 to January 2025, 16 individuals with self-reported hay fever and 17 healthy controls were recruited. Participants completed demographic and allergy-related questionnaires, including symptoms and quality of life assessments. Tear samples were analyzed for IgE and MMP-9 biomarkers. Ocular surface parameters-bulbar redness, palpebral roughness, and lid wiper epitheliopathy (LWE)-were graded. Corneal and conjunctival dendritic cells were also evaluated. Elevated tear IgE significantly correlated with self-reported hay fever, QUICK score, MiniRQLQ, eye rubbing frequency, and lower LWE grade. The hay fever group showed significantly higher LWE compared to healthy controls (p < 0.001), indicating frictional eyelid damage. ROC analysis of tear IgE yielded an AUC of 0.893 (cut-off 0.03 IU/mL; sensitivity 90%, specificity 85%). Tear IgE is a useful biomarker for ocular inflammation and may indicate friction-related eyelid damage in allergy sufferers. Incorporating LWE grading into clinical assessments of ocular allergy is recommended.

Link

June 2025

Frontiers in Medicine

Correlations between tear lymphocytotoxin-α (LT-α) level and disease severity in adult keratoconus

Abstract

Purpose: This study aimed to investigate tear lymphocytotoxin-α (LT-α) levels in adult keratoconus patients and identify the correlations between LT-α and the disease severity of keratoconus.

Methods: In this cross-sectional study, tear samples from 100 keratoconus patients (KC group) and 67 healthy controls (HC group) were collected. LT-α levels were tested immediately after collection using a commercially available point-of-care test (POCT). Visual acuity, corneal tomography, anterior segment optical coherence tomography (AS-OCT), tear film parameters, including non-invasive break-up time (NI-BUT), tear meniscus height (TMH), lipid layer thickness (LLT), and meibomian glands, were also tested. Corneal topography values (K1, K2, Kmax, and astigmatism) were derived from the tomography data.

Results: The tear LT-α levels in the HC group were significantly higher than those in the KC group (p = 0.038). The NI-BUT, TMH, and LLT were significantly lower, while the meiboscore was higher in the KC group than in the HC group (p < 0.001). In the KC group, patients were further divided into preclinical stage, initial stage, and complete stage groups. Significant differences in tear LT-α levels were found among the three subgroups. Within the KC group, LT-α levels were significantly correlated with various parameters, including thinnest corneal thickness, best-corrected visual acuity (BCVA) (LogMAR), K1, K2, Kmax, and astigmatism values. However, no significant correlation was observed between the tear LT-α level and tear film parameters. Within the control group, no significant correlation was identified between the tear LT-α level and corneal topography or tear film parameters.

Conclusion: Our data demonstrated an association between tear LT-α levels and the severity of keratoconus, implying that immune-related factors may be involved in the pathogenesis and progression of the disease.

Link

January 2025

BMJ Open

Tear matrix metalloproteinases-9 and ocular surface parameters in diabetics: a cross-sectional study in Shenyang, China

Abstract

Background: Overexpression of tear matrix metalloproteinases-9 (MMP-9) on the ocular surface tissues has been reported to result in ocular surface damage. MMP-9 levels in tears have been listed as one of many tools for confirming dry eye disease (DED).

Objective: This investigation aimed to compare MMP-9 levels and ocular surface parameters in diabetic patients with and without DED.

Design: A cross-sectional study.

Setting: He Eye Specialist Hospital, Shenyang, China.

Participants: This study recruited 144 right eyes of 144 diabetic patients between November and December of 2023, and 110 patients with similar propensity scores were included in the analyses.

Main outcome measures: Non-invasive breakup time (NITBUT), tear film lipid layer (TFLL), conjunctival hyperaemia (redness score (RS)), corneoconjunctival staining (CS), corneal sensitivity and Ocular Surface Disease Index (OSDI) questionnaire were evaluated. MMP-9 was measured using an immunochromatography assay.

Results: In total, 55 patients (55 eyes) were grouped as diabetic dry eye (DDE) and 55 patients (55 eyes) as diabetic non-dry eye (DNDE). The mean MMP-9 concentrations were higher in patients with DDE than DNDE (70.63±52.06 ng/mL vs 33.98±33.93 ng/mL; p<0.001). The optimal cut-off value of MMP-9 to predict DED in diabetic patients was>52.5 ng/mL, with 58.2% sensitivity and 78.2% specificity.

Conclusions: MMP-9 concentration was higher in patients with DDE than DNDE. The MMP-9 test is a potential diagnostic tool for DDE. It may help follow-up diabetic patients with DED and guide clinicians in deciding on anti-inflammatory treatments for these patients.

Link

June 2024

Journal of Ophthalmic Inflammation and Infection

Inflammation due to ocular surface homeostasis imbalance caused by pterygia: tear lymphotoxin-alpha study and a literature review

Abstract

Objective
To estimate the pterygium ocular surface state, and compare with healthy eyes and dry eyes. To investigate the inflammation due to pterygia growth by tear Lymphotoxin-alpha (LT α) test.

Design
Prospective, single-center study.

Participants
400 patients, divided into 100 pterygium group, 100 mild dry eye group, 100 moderate dry eye group, and 100 age-and sex-matched normal controls.

Methods
The non-invasive break-up time (NIBUT), tear meniscus height (TMH) test, corneal fluorescein staining (CFS), meibomian gland loss score (MGs), and lipid layer thickness (LLT) were evaluated in all patients. Pterygium status and ocular status in the pterygium group were collected. The tear LT α test was conducted in the pterygium patients group.

Result
Pterygium can affect the ocular surface, leading to decreased tear film stability. The TMH, NIBUT, CFS, MGs, and lipid layer thickness can provide insights into this phenomenon. The presence of pterygium can change the structure and condition of the ocular surface. Tear LT α testing shows an abnormal decrease in LT α levels in pterygium patients. This indicates an immune-inflammation microenvironment that causes tissue repair deficiency.

Conclusion
The dry eye triggered by the growth of pterygium may originate from the tear film instability due to pterygia. As an inflammatory index, LT α in the development of pterygium and the aggravation of dry eye patients can indicate that the ocular surface is in different inflammatory states. Future tear testing in LT α may be a potential indicator to assess the inflammatory status of the dry eye.

Link

January 2024

Scientific Reports

Evaluation of lymphotoxin-alpha in pterygium and diagnostic value in active and inactive pterygium states

Abstract

To explore the correlation between tear LT-a, pterygium status, and dry eye indicators. We established a diagnostic model to evaluate active pterygium. A retrospective study was conducted between June 2021 and June 2023 on 172 patients, comprising 108 men and 64 women. The study analyzed LT-a and various ocular parameters in all participants. The data was collected using Excel software and analyzed using SPSS 25.0 statistical software and Medcalc. We made a nomogram diagnostic model to different diagnosed the state of pterygium. This study found that pterygium has progressive eye surface damage during the active state. There was no significant difference in dry eye indicators between the two groups. However, the concentration of LT-a in the active group was significantly lower than that in the inactive group (P < 0.001). We observed that increased pterygium grade corresponded to a worse ocular surface condition. In addition, LT-a was significantly positively correlated with disease duration, but negatively correlated with age, pterygium size, active pterygium state, and LLT value. The optimal intercept value for evaluating active pterygium in Lt-a was ≤ 0.49 dg/ml. We screened three variables for evaluating active pterygium through Single and Multiple regression analysis: LT-a grading, pterygium size, and congestion score. Finally, we made a reliable diagnostic nomogram model. Pterygium development triggers immune inflammation. Our model based on LT-a identifies active pterygium for personalized treatment options and new research directions.

Link

November 2023

International Journal of Ophthalmology

Role of lymphotoxin alpha as a new molecular biomarker in revolutionizing tear diagnostic testing for dry eye disease

Abstract

Dry eye disease (DED), primarily classified as multifactorial ocular surface disorder, afflicts tens of millions of individuals worldwide, adversely impacting their quality of life. Extensive research has been conducted on tear film analysis over the past decades, offering a range of tests to evaluate its volume, health, and integrity. Yet, early diagnosis and effective treatment for DED continue to pose significant challenges in clinical settings. Nevertheless, by recognizing key phenomena in DED such as ocular surface inflammation, hyperosmolarity, and tear film instability, this article provides a comprehensive overview of both traditional and recently developed methods for diagnosing and monitoring DED. The information serves as a valuable resource not only for clinical diagnosis but also for further research into DED.

Link

October 2023

Eye

Exploration of efficacy and mechanism of 0.05% cyclosporine eye drops (II) monotherapy in allergic conjunctivitis-associated dry eye

Abstract

Purpose
To explore the efficacy and relevant mechanism of 0.05% cyclosporine A (CsA) eye drops (II) monotherapy in patients with allergic conjunctivitis-associated dry eye (ACDE).

Methods
Prospective, randomized, controlled study. Fifty-three patients with mild-to-moderate ACDE were randomly assigned to two groups. The CsA group received 0.05% CsA eye drops (II) monotherapy four times daily. The control group received 0.1% olopatadine twice daily combined with 0.1% preservative-free artificial tears four times daily. Clinical symptoms and signs, tear total IgE, and lymphotoxin-α (LT-α) concentrations were assessed at pre- and post-treatment days 7, 30, and 60. And we further measured six tear cytokines levels using a microsphere-based immunoassay.

Results
The CsA group showed significant improvement in symptoms (Ocular Surface Disease Index and itching scores) and signs (conjunctival hyperaemia, conjunctival oedema, conjunctival papillae, tear break-up time (TBUT), corneal fluorescein staining, and goblet cell density) at each follow-up period compared to pre-treatment (all P < 0.050). And its improvement in itching scores (P7th < 0.001, P30th = 0.039, and P60th = 0.031) and TBUT (P7th = 0.009, P30th = 0.003, and P60th = 0.005) was more significant than the control group at all follow-up periods. The tear total IgE, interleukin (IL)-5, IL-6, periostin, eotaxin-3, and MMP-9 levels significantly decreased in the CsA group at day 60 after treatment (all P < 0.050). And the changed values in tear total IgE were positively correlated with the change in itching scores.

Conclusions
0.05% CsA eye drops (II) monotherapy can rapidly improve the symptoms and signs, especially in ocular itching and TBUT, in patients with ACDE. And its efficacy is superior to 0.1% olopatadine combined with artificial tears. Moreover, CsA downregulates the expression levels of tear inflammatory cytokines, including tear total IgE, IL-5, IL-6, periostin, eotaxin-3, and MMP-9. Among that, the reduction in tear total IgE levels may reflect the improvement of ocular itching.

Link

June 2023

IOVS

Significantly reduced level of lymphotoxin-alpha (LTA) in tears from dry eye patients with Sjogren’s syndrome or other systemic immune disease detected with a Point-of-Care LTA test

Abstract

Purpose: This study aimed to measure and compare the LTA levels in tears from dry eye disease (DED) patients with systemic immune disease (ID) and DED without, and to examine the role and clinical value of LTA in early diagnosis of DED associated with ID. LTA (also known as LTa3), the secreted soluble homotrimeric form of Lymphotoxin-alpha, is a cytokine that performs a variety of important roles in immune regulation.

Methods: An observational study consecutively enrolled moderate to severe DED patients with or without Sjogren’s syndrome (SS) or other ID at the Xi’an People’s Hospital (Xi’an, China) from March to July 2022. The Ocular Surface Disease Index (OSDI) and Ocular discomfort score (ODS), conjunctival hyperemia, eyelid margin morphology assessment (EMMA), Schirmer’s test (STT), non-invasive tear breakup time (NITBUT), tear meniscus height (NITMH), corneal fluorescein staining (CFS), and conjunctival lissamine green staining (LGS) were also conducted. The LTA levels were measured with a Point-of-Care (POC) LTA test kit on-site and compared across different DED groups. Correlations with DED clinical parameters were also examined.

Results: This study enrolled a total of 80 patients, 44 of which had SS or other ID and 36 of which did not. The DED patients with SS or ID exhibited significantly lower STT (3.61 (95% CI: 2.53-4.70), 7.58 (5.45-9.72), P<0.001), shorter NITBUT (4.57 (3.59-5.54), 9.06 (7.56-10.57) p<0.001), more conjunctival hyperemia (p<0.001), higher EMMA score (P<0.001), higher CFS (p<0.001) and LGSC (P<0.001), worse ODS (p<0.05), and worse visual acuity (p<0.01). Importantly, in the DED group with SS or ID, LTA levels in tears were significantly lower (169.82 vs. 331.13 pg/ml, p<0.01) than the DED group without. Moreover, the LTA level was significantly negatively correlated with CFS (correlation coefficient (r): -0.447, P<0.001) and EMMA score (r: -0.317, P=0.01).

Conclusions: Previously tear LTA was found reduced in DED compared with normal. Here LTA levels in DED with SS or ID were remarkably lower than in DED patients without. The level of LTA was significantly inversely correlated with the severity of ocular surface damage. Thus, a POC LTA test may have clinical value as an indicator to reflect DED severity and serve as an early diagnostic marker for SS or ID-associated dry eye.

Link

May 2023

European Journal of Ophthalmology

Management of inflammation in dry eye disease: Recommendations from a European panel of experts

Abstract

Introduction
Early initiation of anti-inflammatory therapies is recommended for dry eye disease (DED) to break the vicious cycle of pathophysiology. However, there is limited guidance on how to implement topical ciclosporin (CsA) and corticosteroid treatment into clinical practice. This expert-led consensus provides practical guidance on the management of DED, including when and how to use topical CsA.

Methods
A steering committee (SC) of seven European DED experts developed a questionnaire to gain information on the unmet needs and management of DED in clinical practice. Consensus statements on four key areas (disease severity and progression; patient management; efficacy, safety and tolerability of CsA; and patient education) were generated based on the responses. The SC and an expanded expert panel of 22 members used a nine-point scale (1  =  strongly disagree; 9  =  strongly agree) to rate statements; a consensus was reached if ≥75% of experts scored a statement ≥7.

Results
A stepwise approach to DED management is required in patients presenting with moderate corneal staining. Early topical CsA initiation, alone or with corticosteroids, should be considered in patients with clinical risk factors for severe DED. Patient education is required before and during treatment to manage expectations regarding efficacy and tolerability in order to optimise adherence. Follow-up visits are required, ideally at Month 1 and every 3 months thereafter. Topical CsA may be continued indefinitely, especially when surgery is required.

Conclusion
This consensus fills some of the knowledge gaps in previous recommendations regarding the use of topical corticosteroids and CsA in patients with DED.

Link

2023

Journal of Ocular Pharmacology and Therapeutics

Effects of Diquafosol Sodium Ophthalmic Solution on Tear Film Matrix Metallopeptidase-9 and Corneal Nerve Density in Patients with Type 2 Diabetic Dry Eye

Abstract

Purpose: Diabetes mellitus has been associated with increased dry eye disease (DED) and exacerbates DED’s pathology. This preliminary short-term study aimed to evaluate the effects of 3% Diquafosol Sodium ophthalmic solution (DQS) on ocular surface inflammation and corneal nerve density in diabetic dry eye (DDE) patients.
Methods: In this perspective, participants used 1 drop of 3% DQS (Diquas; Santen Pharmaceutical Co., Ltd., Osaka, Japan) 6 times daily for 8 weeks. Non-invasive tear breakup time (NITBUT), tear film lipid layer (TFLL), conjunctival hyperemia [redness score (RS)], corneoconjunctival staining (CFS), corneal sensitivity (CS), Meibomian gland quality (MGQ) and Meibomian gland expressibility (MGEx), corneal nerve fiber density (CNFD), and Standard Patient Evaluation Eye Dryness (SPEED) questionnaire were assessed at baseline, at weeks 4, and up to 8 weeks. Matrix metalloproteinase-9 (MMP-9) of tear samples was measured at baseline and weeks 8.
Results: The mean age was 61.27 ± 11.68 years. At baseline NITBUT = 5.89 ± 2.81 s, tear meniscus height = 0.17 ± 0.05 mm, TFLL = 2.74 ± 0.51, CFS = 4.35 ± 0.68, CS = 53.83 ± 9.63 mm, MMP-9 = 49.10 ± 10.42 ng/mL, RS = 1.65 ± 0.44, MGEx = 1.85 ± 0.72, MGQ = 2.65 ± 0.50, CNFD = 20.36 ± 8.20 no./mm2, and SPEED = 12.62 ± 3.91. At week 4, significant improvements were found in all parameters except RS (1.59 ± 0.46, P = 0.172) and CNFD (21.46 ± 8.41, P = 0.163). Finally, at week 8, all parameters had significant improvements.
Conclusion: Preliminary short-term findings suggest that treatment of DDE patients with DQS was found to be safe and efficacious in improving dry eye parameters. In addition, inflammatory marker and corneal nerve density were significantly improved. This study was registered with ClinicalTrials.gov (NCT05193331).

Link

October 2022

Allergology International

Executive summary: Japanese guidelines for allergic conjunctival diseases 2021

Abstract

Allergic conjunctival disease (ACD) is an inflammatory disease of the conjunctiva that is mainly caused by type I hypersensitivity response to allergens and accompanied by subjective symptoms and other findings induced by antigens. ACD is classified as allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis. This article summarizes the third edition of the Japanese guidelines for allergic conjunctival diseases published in 2021 and outlines the diagnosis, pathogenesis, and treatment of ACD.
Since the introduction of immunosuppressive eye drops, the treatment strategies for severe ACDs have significantly changed. To clarify the recommended standard treatment protocols for ACD, the advantages and disadvantages of these treatments were assessed using clinical questions, with a focus on the use of steroids and immunosuppressive drugs. This knowledge will assist healthcare providers and patients in taking an active role in medical decision making.

Link

August 2022

Frontiers in Medicine

Diagnosis, Management, and Treatment of Vernal Keratoconjunctivitis in Asia: Recommendations From the Management of Vernal Keratoconjunctivitis in Asia Expert Working Group

Abstract

Vernal keratoconjunctivitis (VKC) is an underdiagnosed and underrecognized ocular surface disease with limited epidemiological data in Asia. It is more prevalent in warm, dry, and windy climates, and often has a substantial impact on a patient’s quality of life. In rare cases, VKC can be associated with vision loss, either through corticosteroid overuse or inadequate treatment of persistent inflammation. As a potentially severe and complex disease, there is variability with how VKC is managed across Asia and among the various allergic eye diseases. Diagnosis and treatment of patients with VKC is a challenge for many ophthalmologists, since no precise diagnostic criteria have been established, the pathogenesis of the disease is unclear, and anti-allergic treatments are often ineffective in patients with moderate or severe disease. In addition, the choice of treatment and management strategies used for patients varies greatly from country to country and physician to physician. This may be because of a lack of well-defined, standardized guidelines. In response, the Management of Vernal Keratoconjunctivitis in Asia (MOVIA) Expert Working Group (13 experts) completed a consensus program to evaluate, review, and develop best-practice recommendations for the assessment, diagnosis, and management of VKC in Asia. The expert-led recommendations are summarized in this article and based on the currently available evidence alongside the clinical expertise of ophthalmologists from across Asia with specialism and interest in the ocular surface, VKC, and pediatric ophthalmology.

Link

March 2022

Clin Transl Allergy

Total IgE in tears accurately reflects the severity and predicts the prognosis of seasonal allergic conjunctivitis

Abstract

Background: Although immunoglobulin E (IgE) increases significantly in tears and serum during seasonal allergic conjunctivitis (SAC), it is unclear whether tear total IgE can reflect the severity and prognosis of SAC more accurately than serum total IgE. We aimed to investigate the usefulness of measuring the total IgE in tears to evaluate the severity and determine the treatment of SAC.

Methods: This prospective, nonrandomized study involved 55 patients with SAC and 10 age- and sex-matched healthy controls. Serum and tears were collected before and after treatment to analyze the total IgE. SAC patients received the same topical anti-allergy treatment and were followed-up every 2 weeks for 1 month. The relationship of tear and serum total IgE concentrations with pollen concentrations and symptom severity before and after treatment was assessed.

Results: The total IgE concentration in tears was higher in SAC patients than in healthy participants with significant correlations between tear and serum total IgE concentrations. The total IgE concentration in tears, but not in serum, correlated with the pollen concentration and severity of ocular symptoms and reactions in SAC. Treatment-associated improvements in symptoms and reactions in SAC correlated with decreased concentrations of the tear total IgE. Patients with disease recurrence following treatment demonstrated significantly higher tear total IgE concentrations than patients with no recurrence.

Conclusion: The total tear IgE level can indicate the severity and predict the prognosis of SAC more accurately than the serum total IgE.

Link

January 2022

BMC Ophthalmology

Ophthalmic manifestations are associated with reduced tear lymphotoxin-α levels in chronic ocular graft-versus-host disease

Abstract

Purpose
To determine the role tear lymphotoxin-α (LT-α) in chronic ocular graft-versus-host disease (oGVHD).

Methods
Twenty-two chronic oGVHD and 17 control tear samples were collected, and commercial test strips were used to detect LT-α concentrations. Concentration differences between patients with and without oGVHD were determined via Mann-Whitney U test. The correlation between LT-α levels and ophthalmic parameters was analyzed using Spearman’s test.

Results
The concentration of LT-α was significantly lower in oGVHD patients than in controls. LT-α levels were significantly correlated with OSDI, NIH eye score, T-BUT, and CFS among all participants. ROC analysis revealed that the area under the curve of LT-α was 0.847, and the cutoff value for chronic oGVHD diagnosis was 0.203 ng/mL.

Conclusion
Our study revealed the significant decrease of tear LT-α in oGVHD, and suggested LT-α as a promising marker for chronic oGVHD diagnosis.

Link

September 2020

American Journal of Ophthalmology

Evaluation of Tear Protein Markers in Dry Eye Disease with Different Lymphotoxin-Alpha Expression Levels

Abstract

Purpose
To compare tear protein markers between normal subjects and patients with dry eye (DE) and high and low lymphotoxin-alpha (LT-α) levels.
Design
Prospective cross-sectional study.
Methods
Patients with DE were divided into low (≤700 pg/mL) and high (>700 pg/mL) LT-α groups. Twelve protein markers were measured by microsphere-based immunoassay and ocular surface parameters were determined in right eyes (33 high LT-α DE, 27 low LT-α DE, and 20 control eyes) and left eyes (21 high LT-α DE, 39 low LT-α DE, and 20 control eyes).
Results
In both eyes, tumor necrosis factor–α (TNF-α), interleukin (IL)-10, IL-1β, IL-1 receptor antagonist (IL-1Ra), IL-17A, and IL-12/23 p40 levels in high LT-α DE were significantly higher (P < .01) than in low LT-α DE. Significant correlations identified in high LT-α DE were: Standard Patient Evaluation Eye Dryness with IL-10 (R = 0.43, P = .013), IL-1β (R = 0.48, P = .005), and IL-12/23 p40 (R = 0.50, P = .003), IL-12/23 p40 with ocular surface disease index (R = 0.35, P = .049), and epidermal growth factor with corneal fluorescein staining score (R = −0.36, P = .038). Significant correlations in low LT-α DE were: Standard Patient Evaluation Eye Dryness with IL-10 (R = −0.39, P = .046), TNF-α (R = −0.39, P = .047), and IL-17A (R = −0.48, P = .013), ocular surface disease index with TNF-α (R = −0.47, P = .017) and IL-17A (R = −0.46, P = .018), and IL-6 with tear breakup time (R = −0.40, P = .044). Lastly, IL-1Ra levels significantly increased in DE patients, positively correlated with temporal conjunctival hyperemia index, and negatively correlated with Schirmer I test (P < .05).
Conclusions
Our study identified tear IL-1Ra level as a potential biomarker to replace the Schirmer I test. Multiple tear protein marker levels increased in high LT-α DE, indicating that high LT-α DE might have a different pathogenesis.

Link

June 2020

IOVS

Large Scale, Prospective, Multicenter, Clinical Evaluation of Point-of-Care Lymphotoxin alpha (LTA) Test in Dry Eye Disease

Abstract

Purpose: To evaluate the diagnostic value of a point-of-care (POC) Lymph toxin alpha (LTA-POC) test in dry eye disease (DED).

Methods: Participants were assessed using the Ocular Surface Disease Index(OSDI) ocular symptom sub-scale. Tear fluid were collected and LTA-POC test was performed to measure LTA, before conducting the following tests: tear break-up time (TBUT), and corneal fluorescein staining (CFS), and Schirmer’s test. The receiver operating characteristic (ROC) curve was used to evaluate LTA as a biomarker for dry eye diagnosis.

Results: The study enrolled 1088 subjects: 782 patients with clinical signs and symptoms of dry eye and 306 non-dry eye controls. LTA level in dry eye group (0.64±1.35, ng/mL) was significantly lower than control group (2.05±2.92, ng/mL) (P<0.001). LTA level correlated positively with Schirmer test and TBUT, and correlated negatively with OSDI score, CFS and conjunctival hyperemia (all of them P<0.001) . Kappa value was 0.496 (95%CI: 0.438~0.553)（P<0.001）. With ROC curve analysis, area under the curve (AUC) was 0.765 (95% CI: 0.731~0.800).

Conclusions: Findings from this large prospective clinical study support LTA as a biomarker for dry eye digsnosis. They also support the intended use of LTA-POC tear test as a point of care immunoassay to be used in facilitating diagnosis of dry eye.

Link

May 2019

JCRS

An algorithm for the preoperative diagnosis and treatment of ocular surface disorders

Abstract

Any ocular surface disease (OSD), but most commonly, dry-eye disease (DED), can reduce visual quality and quantity and adversely affect refractive measurements before keratorefractive and phacorefractive surgeries. In addition, ocular surgery can exacerbate or induce OSD, leading to worsened vision, increased symptoms, and overall dissatisfaction postoperatively. Although most respondents of the recent annual American Society of Cataract and Refractive Surgery (ASCRS) Clinical Survey recognized the importance of DED on surgical outcomes, many were unaware of the current guidelines and most were not using modern diagnostic tests and advanced treatments. To address these educational gaps, the ASCRS Cornea Clinical Committee developed a new consensus-based practical diagnostic OSD algorithm to aid surgeons in efficiently diagnosing and treating visually significant OSD before any form of refractive surgery is performed. By treating OSD preoperatively, postoperative visual outcomes and patient satisfaction can be significantly improved.

Link

August 2018

Scientific Reports

TNFR2 ligation in human T regulatory cells enhances IL2-induced cell proliferation through the non-canonical NF-κB pathway.

Abstract

Human T regulatory cells (T regs) express high levels of TNF receptor 2 (TNFR2). Ligation of TNFR2 with TNF, which can recognise both TNFR1 and TNFR2, or with a TNFR2-selective binding molecule, DARPin 18 (D18) activates canonical NF-κB signalling, assessed by IκBα degradation, and the magnitude of the response correlates with the level of TNFR2 expression. RNA-seq analysis of TNF- or D18-treated human T regs revealed that TNFR2 ligation induces transcription of NFKB2 and RELB, encoding proteins that form the non-canonical NF-κB transcription factor. In combination with IL2, D18 treatment is specific for T regs in (1) stabilising NF-κB-inducing kinase protein, the activator of non-canonical NF-κB signalling, (2) inducing translocation of RelB from cytosol to nucleus, (3) increasing cell cycle entry, and (4) increasing cell numbers. However, the regulatory function of the expanded T regs is unaltered. Inhibition of RelB nuclear translocation blocks the proliferative response. We conclude that ligation of TNFR2 by D18 enhances IL2-induced T regs proliferation and expansion in cell number through the non-canonical NF-κB pathway.

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October 2017

The Ocular Surface

Review: The function of regulatory T cells at the ocular surface

Abstract

Regulatory T cells (Tregs) are critical modulators of immune homeostasis. Tregs maintain peripheral tolerance to self-antigens, thereby preventing autoimmune disease. Furthermore, Tregs suppress excessive immune responses deleterious to the host. Recent research has deepened our understanding of how Tregs function at the ocular surface. This manuscript describes the classification, the immunosuppressive mechanisms, and the phenotypic plasticity of Tregs. We review the contribution of Tregs to ocular surface autoimmune disease, as well as the function of Tregs in allergy and infection at the ocular surface. Finally, we review the role of Tregs in promoting allotolerance in corneal transplantation.

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January 2017

The Ocular Surface

New Perspectives on Dry Eye Definition and Diagnosis: A Consensus Report by the Asia Dry Eye Society

Abstract

For the last 20 years, a great amount of evidence has accumulated through epidemiological studies that most of the dry eye disease encountered in daily life, especially in video display terminal (VDT) workers, involves short tear film breakup time (TFBUT) type dry eye, a category characterized by severe symptoms but minimal clinical signs other than short TFBUT. An unstable tear film also affects the visual function, possibly due to the increase of higher order aberrations. Based on the change in the understanding of the types, symptoms, and signs of dry eye disease, the Asia Dry Eye Society agreed to the following definition of dry eye: “Dry eye is a multifactorial disease characterized by unstable tear film causing a variety of symptoms and/or visual impairment, potentially accompanied by ocular surface damage.” The definition stresses instability of the tear film as well as the importance of visual impairment, highlighting an essential role for TFBUT assessment. This paper discusses the concept of Tear Film Oriented Therapy (TFOT), which evolved from the definition of dry eye, emphasizing the importance of a stable tear film.

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2015

J Investig Allergol Clin Immunol

Consensus Document on Allergic Conjunctivitis (DECA)

Abstract

Allergic conjunctivitis (AC) is an inflammatory disease of the conjunctiva caused mainly by an IgE-mediated mechanism. It is the most common type of ocular allergy. Despite being the most benign form of conjunctivitis, AC has a considerable effect on patient quality of life, reduces work productivity, and increases health care costs. No consensus has been reached on its classification, diagnosis, or treatment. Consequently, the literature provides little information on its natural history, epidemiological data are scarce, and it is often difficult to ascertain its true morbidity. The main objective of the Consensus Document on Allergic Conjunctivitis (Documento dE Consenso sobre Conjuntivitis Alérgica [DECA]), which was drafted by an expert panel from the Spanish Society of Allergology and Spanish Society of Ophthalmology, was to reach agreement on basic criteria that could prove useful for both specialists and primary care physicians and facilitate the diagnosis, classification, and treatment of AC. This document is the first of its kind to describe and analyze aspects of AC that could make it possible to control symptoms.

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July 2012

IOVS

Evaluation of Tear protein markers in Dry Eye Disease: Repeatability of measurement and Correlation with Disease

Abstract

Purpose: We characterized tear protein markers in dry eye disease (DED).

Methods: In this prospective study, based on the ocular surface disease index (OSDI) and corneal staining (CS), 95 DED patients (OSDI ≥13) with increasing CS were enrolled into 3 severity groups: DE1 (CS <4), DE2 (CS 4–7), and DE3 (CS >7), while 25 asymptomatic subjects with no CS were enrolled into the control group (OSDI <13 and CS = 0). Tear fluid was collected at day 0 and day 7 visits, and concentrations of 43 protein markers were measured by multiplexed immunoassay.

Results: We analyzed 22 control and 80 DED subjects. Among 33 markers detectable, good inter-visit repeatability was observed with 25 markers, with intraclass correlation coefficients (ICC) ranging from 0.85–0.60; ICCs were <0.60 in the other 8. Correlation with clinical measures was found with two markers, with absolute partial correlation coefficients >0.40: Interleukin-1 receptor antagonist (IL-1Ra) and IL-8. IL-1Ra and IL-8 correlated with conjunctival staining (0.43, P < 0.001 and 0.35, P < 0.01, respectively), and with Schirmer test (−0.58 and −0.42, P < 0.001). IL-1Ra and IL-8 in DE3 were 4.4- and 2.1-fold higher than in DE1 (P = 0.0001 and 0.0007), and 1.9- and 1.6-fold higher than in DE2 (P = 0.022 and 0.017). IL-1Ra in DE2 was 2.3-fold higher than in DE1 (P = 0.038).

Conclusions: Tear levels of many immune mediators were highly repeatable between visits in DED. Among them, IL-1Ra and IL-8 were associated with clinical signs and disease severity defined by corneal staining.

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May 2008

Cell

Regulatory T cells and immune tolerance

Abstract

Regulatory T cells (Tregs) play an indispensable role in maintaining immunological unresponsiveness to self-antigens and in suppressing excessive immune responses deleterious to the host. Tregs are produced in the thymus as a functionally mature subpopulation of T cells and can also be induced from naive T cells in the periphery. Recent research reveals the cellular and molecular basis of Treg development and function and implicates dysregulation of Tregs in immunological disease.

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