Corneal nerves and their role in dry eye pathophysiology

Vereertbrugghen, Alexia; Galletti, Jeremías Gastón

doi:10.1016/j.exer.2022.109191

Cited by 34 publications

(31 citation statements)

References 137 publications

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“…Down-regulated genes in WT DED mice included: Trpm8 , Trpa1 , and Piezo2 , three cation channels involved in corneal thermo- and polymodal nociception and mechanosensation(38); Asic1 and Asic3 , acid-sensing cation channels expressed in trigeminal neurons that participate in nociception(68); Pirt , a positive regulator of transient receptor potential vanilloid-1 channel activity in nociceptive neurons(69); Kcnk18 , Scn10a , Scn4b , and several other voltage-gated potassium and sodium channels that determine sensory neuron excitability and are involved pain syndromes(70); and L1cam and Sema4f , which guide axonal growth(41). Cd74 was the only DEG that was up-regulated in both WT and Rag1 KO samples: it encodes the macrophage-inhibitory-factor receptor and its expression in the trigeminal ganglion has been mapped to macrophages and neutrophils(71).…”

Section: Resultsmentioning

confidence: 99%

“…Our current understanding of DED involves dysfunctional tear film-instigated corneal epitheliopathy and neurosensory abnormalities as defining clinical features and ocular surface inflammation as a key driver of the disease process(3,4,6). Contrasting with the numerous studies into the pathogenesis of corneal epitheliopathy in DED, the mechanisms underlying corneal nerve damage are poorly understood(38). A CD4 + T cell-driven adaptive immune response perpetuates ocular surface inflammation(8) and thus interfering with CD4 + T activation is the target of several approved therapies for DED in patients.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the number of DEGs and the fold-change in expression, the magnitude of the DED-induced transcriptomic signature in the trigeminal ganglion is smaller than those reported for other models of trigeminal nerve injury(62–64,84). However, most models involve whole nerve ligation or injection of inflammatory agents whereas DED targets the peripheral nerve endings of only 2% of trigeminal neurons(38). A combined analysis of bulk- and single-cell RNA-seq studies of dorsal root ganglia in neuropathic pain or nerve injury models showed that most gene expression changes take place in nociceptor neurons, and that the reduced magnitude of expression changes in whole ganglion studies probably relates to the diluting effect of other cell types(83).…”

Section: Discussionmentioning

confidence: 99%

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CD4⁺T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model

Vereertbrugghen,

Pizzano,

Cernutto

et al. 2024

Preprint

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Dry eye disease (DED) is a disorder characterized by a dysfunctional tear film in which the corneal epithelium and its abundant nerves are affected by ocular desiccation, inflammation, and the local immune response. Although adaptive immunity and specifically CD4+ T cells play a role in DED pathogenesis, the exact contribution of these cells to corneal epithelial and neural damage remains undetermined. To address this, we explored the progression of a surgical DED model in wild-type (WT) and T cell-deficient mice. We observed that adaptive immune-deficient mice developed all aspects of DED comparably to WT mice except for the absence of functional and morphological corneal nerve changes, nerve damage-associated transcriptomic signature in the trigeminal ganglia, and sustained tear cytokine levels. Adoptive transfer of CD4+ T cells from DED WT mice to T cell-deficient mice reproduced corneal nerve damage but not epitheliopathy. Conversely, T cell-deficient mice reconstituted solely with naive CD4+ T cells developed corneal nerve impairment and epitheliopathy upon DED induction, thus replicating the WT DED phenotype. Collectively, our data show that while corneal neuropathy is driven by CD4+ T cells in DED, corneal epithelial damage develops independently of the adaptive immune response. These findings have implications for T cell-targeting therapies currently in use for DED.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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CD4⁺T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model

Vereertbrugghen,

Pizzano,

Cernutto

et al. 2024

Preprint

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“…Dry eye disease has been associated with thalassemia [ 26 ], and this finding should not come as a surprise as corneal nerves have a central role in maintaining homeostasis of the ocular surface. Consequently, reduced corneal nerve density has a significant relationship with dry eye disease [ 27 ]. This is in line with our study, as has been discussed previously.…”

Section: Discussionmentioning

confidence: 99%

Peripheral Neuropathy in Beta-Thalassemia: Corneal Confocal Microscopy-Based Study

Khan¹,

Naqvi²,

Saeed³

et al. 2022

Cureus

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BackgroundPeripheral neuropathy is a controversial but serious complication of beta-thalassemia (β-Th). Although few studies have reported no relationship between neuropathy and thalassemia, many have linked it with increasing age, iron overload, and iron chelator toxicity. This study aims to investigate the presence of neuropathy in β-Th using corneal nerve fibers. MethodologyA cross-sectional study was conducted using corneal confocal microscopy on individuals with intermediate and major β-Th who were compared to healthy individuals. The main outcome variables were corneal main nerve and branch nerve densities which were calculated using Image J software. The comparison between groups was done using the independent-samples F-test and Bonferroni post-hoc analysis. ResultsThere was reduced corneal main nerve and branch nerve density in β-Th intermediate and major patients compared to the control group, and the results were statistically significant (p-value <0.05). However, a significant correlation was not observed between serum ferritin levels and corneal nerve parameters. ConclusionsThe reduction in corneal nerve parameters in β-Th patients compared to healthy controls can be an indication of peripheral neuropathy in β-Th. Further work is needed to confirm these findings.

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“…These factors stimulate epithelial growth, proliferation and differentiation [ 3 , 8 , 9 ]. The ensuing corneal nerve dysfunction contributes to dry eye progression, ocular pain and discomfort, and other neuropathic symptoms [ 10 ]. Their study location focused on the center of the cornea, while due to the less observed range and on positioning function, each measurement was conducted in a different position, notably increased variability, poor reproducibility and decreased comparability.…”

Section: Introductionmentioning

confidence: 99%

Change Patterns in Corneal Intrinsic Aberrations and Nerve Density after Cataract Surgery in Patients with Dry Eye Disease

Jing

Jiang

Ren

et al. 2022

JCM

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This study aimed to evaluate the change patterns in corneal intrinsic aberrations and nerve density after cataract surgery in dry eye disease. The preoperative, 1- and 3-month postoperative dry eye-related parameters were obtained by the Oculus keratograph and the ocular surface disease index questionnaire. The corneal intrinsic aberrations were measured using the Pentacam HR system. In vivo confocal microscopy was performed to observe the vortical and peripheral corneal nerves. An artificial intelligence technique run by the deep learning model generated the corneal nerve parameters. Corneal aberrations on the anterior and total corneal surfaces were significantly increased at 1 month compared with the baseline (p < 0.05) but gradually returned to the baseline by 3 months (p > 0.05). However, the change in posterior corneal aberration lasted up to 3 months (p < 0.05). There was a significant decrease in the corneal vortical nerve maximum length and average density after the operation (p < 0.05), and this damage lasted approximately 3 months. The corneal vortical nerve maximum length and average density were negatively correlated with the anterior corneal surface aberrations before and 1 month after the operation (correlation coefficients, CC = −0.26, −0.25, −0.28; all p < 0.05). Corneal vortex provided a unique site to observe long-term corneal nerve injury related to eye dryness. The continuous damage to the corneal vortical nerve may be due to the continuous dry eye state.

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Corneal nerves and their role in dry eye pathophysiology

Cited by 34 publications

References 137 publications

CD4⁺T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model

CD4⁺T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model

Peripheral Neuropathy in Beta-Thalassemia: Corneal Confocal Microscopy-Based Study

Change Patterns in Corneal Intrinsic Aberrations and Nerve Density after Cataract Surgery in Patients with Dry Eye Disease

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Corneal nerves and their role in dry eye pathophysiology

Cited by 34 publications

References 137 publications

CD4+T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model

CD4+T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model

Peripheral Neuropathy in Beta-Thalassemia: Corneal Confocal Microscopy-Based Study

Change Patterns in Corneal Intrinsic Aberrations and Nerve Density after Cataract Surgery in Patients with Dry Eye Disease

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CD4⁺T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model

CD4⁺T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model