Goblet cell loss abrogates ocular surface immune tolerance

Ko, Byung Yi; Xiao, Yangyan; Barbosa, Flavia L.; Paiva, Cintia S. de; Pflugfelder, Stephen C.

doi:10.1172/jci.insight.98222

Cited by 45 publications

(49 citation statements)

References 24 publications

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“…It remains to be determined whether reduced conjunctival goblet cell density in SS KCS results in increased APC infiltration/maturation or whether APCs increase in the conjunctiva due to the systemic autoimmune disease and promote the Th1 immune response with increased IFN-γ expression that has been observed in human KCS. The Spdef mouse strain that lacks goblet cells has been found to have an increased number of APCs with greater production of IL-12 in their conjunctiva [ 8 ]. The findings of this study suggest that APCs are potential therapeutic targets, and therapies suppressing APC infiltration and activation may have efficacy in SS-associated KCS.…”

Section: Discussionmentioning

confidence: 99%

“…Increased expression of the T helper 1 (Th1) cytokine Interferon gamma (IFN-γ), which induces an unfolded protein response and apoptosis in (goblet cells, has been found in KCS [ 3 , 4 , 5 ]. In addition to producing mucins that lubricate and protect the ocular surface, goblet cells have also been found to produce immunomodulatory factors, including retinoic acid, transforming growth factor beta 2 (TGF-β2), and mucin 2 (MUC2), which are important for maintaining immune tolerance [ 6 , 7 , 8 , 9 , 10 ]. Conjunctival goblet cells serve as passages for ocular surface antigens to antigen-presenting cells (APCs) located in the basement membrane zone and stroma [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…Conjunctival goblet cells serve as passages for ocular surface antigens to antigen-presenting cells (APCs) located in the basement membrane zone and stroma [ 6 ]. Goblet cell mucin has been found to mix with ovalbumin (OVA) antigen as it passes through GAPs, and immune tolerance to topically applied OVA is lost in the sterile alpha motif (SAM)-pointed domain containing (E-twenty-six) ETS transcription factor (Spdef) knockout (KO) mouse strain that lacks goblet cells [ 6 , 8 ]. Goblet-cell-produced retinoic acid has been found to suppress differentiation and stimulate production of the Th1-inducing cytokine interleukin 12 (IL-12) by bone-marrow-derived APCs [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…Goblet-cell-produced retinoic acid has been found to suppress differentiation and stimulate production of the Th1-inducing cytokine interleukin 12 (IL-12) by bone-marrow-derived APCs [ 9 ]. The Spdef strain has been found to have a higher number of IL-12-producing APCs in the conjunctiva compared to the wild-type strain [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Severity of Sjögren’s Syndrome Keratoconjunctivitis Sicca Increases with Increased Percentage of Conjunctival Antigen-Presenting Cells

Pflugfelder

Bian

Gümüş

et al. 2018

IJMS

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This study investigated the relationship between clinical severity and percentage of conjunctival antigen-presenting cells (APCs) in Sjögren’s syndrome (SS)-associated keratoconjunctivitis sicca (KCS). KCS clinical severity was based on symptom severity, tear volume, tear break-up time, and ocular surface dye staining. Conjunctival goblet cell density (GCD) was measured in periodic acid Schiff (PAS)-stained membranes. Conjunctival cells obtained by impression cytology were used for flow cytometry to measure percentages of CD45+HLA-DR+ APCs and mature CD11c+CD86+ dendritic cells (DCs). Compared to normal conjunctiva, the percentages of HLA-DR+ and CD11c+CD86+ cells were higher in the conjunctiva of the KCS group (p < 0.05). The percentage of CD45+HLA-DR+ cells positively correlated with clinical severity (r = 0.71, p < 0.05) and negatively correlated with GCD (r = −0.61, p < 0.05). Clinical severity also negatively correlated with GCD (r = −0.54, p < 0.05). These findings indicate that a higher percentage of APCs and mature DCs in the conjunctiva is associated with more severe KCS in SS. These APCs may contribute to the generation of the pathogenic Th1 cells that cause goblet cell loss in KCS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Severity of Sjögren’s Syndrome Keratoconjunctivitis Sicca Increases with Increased Percentage of Conjunctival Antigen-Presenting Cells

Pflugfelder

Bian

Gümüş

et al. 2018

IJMS

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“…24 In addition, mucins protect ocular surface health through inhibiting bacterial attachment and removing contaminants and pollutants from the ocular surface. 24 Moreover, conjunctival goblet cells are essential to maintaining homeostasis and immune tolerance of the ocular surface, 25 and several studies point to decreased goblet cells as an early sign of KCS. 26,27 Although there were no significant differences in corneal staining and IL 1-β levels between cyclosporine ophthalmic solution 0.09% once and twice daily vs ciclosporin ophthalmic emulsion 0.1% once daily and cyclosporine ophthalmic solution 0.05% twice daily, cyclosporine ophthalmic solution 0.09% twice daily demonstrated numerically better corneal scores and lower levels of IL 1-β.…”

Section: Discussionmentioning

confidence: 99%

<p>Preclinical Efficacy Comparison of Cyclosporine Ophthalmic Solution 0.09% vs Cyclosporine Ophthalmic Emulsion 0.05% vs Ciclosporin Ophthalmic Emulsion 0.1% in a NOD Mouse Model of Dry Eye Disease</p>

Burade

Zalawadia

Patel

et al. 2020

OPTH

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Introduction: Cyclosporine ophthalmic solution 0.09% (CsA 0.09% sol) is approved to increase tear production in patients with keratoconjunctivitis sicca. This study evaluated the efficacy of CsA 0.09% sol vs cyclosporine ophthalmic emulsion 0.05% (CsA 0.05% eml) vs ciclosporin ophthalmic emulsion 0.1% (CsA 0.1% eml) in a NOD mice model. Methods: Mice were randomized and administered placebo, CsA 0.09% sol twice daily, CsA 0.05% eml twice daily, CsA 0.09% sol once daily, or CsA 0.1% eml once daily in the conjunctival sac of both eyes for 60 days. Tear volume was measured with phenol red threads at baseline and 4 hours after treatment every 15 days. On day 58, the corneal surface was observed under a slit-lamp after staining with 3% lissamine green administered into the inferior lateral conjunctival sac. On day 61, mice were euthanized, globes excised, sliced into 4 µm sections in 3 areas per section, and stained. Total number of stained goblet cell/µm was counted, and the sum per eye was averaged. Lacrimal gland tissues were removed and interleukin (IL) 1-β cytokine levels estimated. Results: Groups comprised 11 mice each, including an untreated normal and untreated diseased control group (7 groups total). CsA 0.09% sol twice daily significantly increased tear volume on day 30, 45, and 60 vs CsA 0.05% eml (P<0.05, <0.001, <0.001, respectively) and vs CsA 0.1% eml on day 60 (P<0.05); CsA 0.09% sol once daily significantly increased tear volume on day 45 vs CsA 0.05% eml (P<0.05). Goblet cell density significantly increased with CsA 0.09% sol twice daily vs placebo and NOD control (P<0.01 both). There was no significant difference in corneal staining and IL-1β levels with CsA 0.09% sol. Conclusion: Sixty-day treatment with CsA 0.09% sol showed comparatively improved preclinical results vs CsA 0.05% eml and CsA 0.1% eml.

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Sociodemographic and Clinical Predictors of Prolonged Length of Corneal Ulcer Hospitalizations

Akosman,

Li,

Kwon

et al. 2024

JAMA Ophthalmol

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ImportanceThe length of stay (LOS) of hospitalizations may be a useful indicator of the burden of disease of corneal ulcers. Identifying variables associated with longer LOS may help to enhance delivery of care for high-risk patients.ObjectiveTo investigate the sociodemographic, social, and clinical factors associated with LOS in hospitalizations for corneal ulcers in the US.Design, Setting, and ParticipantsThis was a retrospective cross-sectional study of adult patients (aged &gt;18 years) admitted with a primary diagnosis of corneal ulcer between quarter 4 of 2015 through 2020 and conducted using data from the National Inpatient Sample (NIS). Patients were stratified into 2 even cohorts based on LOS: LOS of 4 days or less and LOS greater than 4 days. Individual-level sociodemographic, social risk factors, and medical comorbidities associated with longer LOS were examined by multivariable regression. Data were analyzed from October 2015 to December 2020.ExposurePotential sociodemographics or medical comorbidities at hospital admission.Main Outcome and MeasureThe primary outcome of interest was factors associated with extended length of stay. The hypothesis being tested was formulated during data collection.ResultsA total of 1187 patients (mean [SD] age, 53.5 [20.9] years; 602 female [50.7%]) were included for analysis. The cohort with LOS greater than 4 days had higher total charges than the cohort with LOS of 4 days or less (mean [SD] charges, $79 504 [$86 719] vs $26 474 [$20 743]; P &lt; .001). Sociodemographic variables associated with LOS greater than 4 days were Black race (adjusted odds ratio [aOR], 1.41; 95% CI, 1.03-1.92; P = .03), Medicare insurance (aOR, 1.42; 95% CI, 1.09-1.85; P = .009), and housing insecurity (aOR, 1.99; 95% CI, 1.29-3.06; P = .002). Medical comorbidities associated with LOS greater than 4 days were alcohol use (aOR, 1.50; 95% CI, 1.00-2.26; P = .05), dementia (aOR, 2.35; 95% CI, 1.36-4.07; P = .002), complicated diabetes (aOR, 1.75; 95% CI, 1.21-2.53; P = .003), uncomplicated diabetes (aOR, 1.57; 95% CI, 1.02-2.42; P = .04), drug misuse (aOR, 1.66; 95% CI, 1.08-2.57; P = .02), and legal blindness (aOR, 3.42; 95% CI, 1.19-9.82; P = .02). Based on NIS national estimates, corneal ulcers were estimated to have a direct annual health care expenditure of $35 819 590 in the US.Conclusion and RelevanceCorneal ulcer hospitalizations represent a significant burden of disease for patients and health care systems. This study highlights sociodemographic and clinical factors that may help clinicians identify high-risk patients vulnerable to complications and morbidity due to corneal ulcers.

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Goblet cell loss abrogates ocular surface immune tolerance

Cited by 45 publications

References 24 publications

Severity of Sjögren’s Syndrome Keratoconjunctivitis Sicca Increases with Increased Percentage of Conjunctival Antigen-Presenting Cells

Severity of Sjögren’s Syndrome Keratoconjunctivitis Sicca Increases with Increased Percentage of Conjunctival Antigen-Presenting Cells

<p>Preclinical Efficacy Comparison of Cyclosporine Ophthalmic Solution 0.09% vs Cyclosporine Ophthalmic Emulsion 0.05% vs Ciclosporin Ophthalmic Emulsion 0.1% in a NOD Mouse Model of Dry Eye Disease</p>

Sociodemographic and Clinical Predictors of Prolonged Length of Corneal Ulcer Hospitalizations

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