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Discordant Dry Eye Disease (An American Ophthalmological Society Thesis).

ABSTRACT: To improve understanding of dry eye disease and highlight a subgroup of patients who have a component of central sensitization and neuropathic pain contributing to their condition.Prospective, cross-sectional, IRB-approved study comparing isolated dry eye disease (n=48) to fibromyalgia (positive control; n=23) and healthy (negative control; n=26) individuals with ocular surface examination, corneal confocal microscopy, quantitative sensory testing, and self-reported ocular symptoms and systemic associations. A subset of patients also underwent skin biopsy and/or brain neuroimaging. Dry eye patients were split into concordant (ie, those with dry eyes on examination) and discordant (ie, those with dry eye symptoms but normal examination) subgroups for further analysis. We hypothesized that on the systemic measures included, concordant patients would resemble healthy controls, whereas discordant patients would show evidence of centralized mechanisms similar to fibromyalgia.Schirmer test and Ocular Surface Disease Index (OSDI) scores indicated significant decreases in tear production (Schirmer: healthy, 18.5±8.2 mm; dry, 11.2±5.4 mm; fibromyalgia, 14.4±7.5; P<.001) and increases in self-reported dry eye symptoms (OSDI: healthy, 1.9±3.0; dry, 20.3±17.7; fibromyalgia, 20.3±17.1; P<.001) in the dry eye and fibromyalgia patients, compared to controls. The discordant subgroup had decreased corneal nerve density and decreased visual quality-of-life scores, similar to patients with fibromyalgia. Concordant patients were more similar to healthy controls on these measures.Individuals with discordant dry eye may have a central pathophysiologic mechanism leading to their eye pain symptoms, which could be an important factor to consider in treatment of chronic idiopathic dry eye.

SUBMITTER: Shtein RM

PROVIDER: S-EPMC5189926 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Discordant Dry Eye Disease (An American Ophthalmological Society Thesis).

Shtein Roni M RM Harper Daniel E DE Pallazola Vincent V Harte Steven E SE Hussain Munira M Sugar Alan A Williams David A DA Clauw Daniel J DJ

Transactions of the American Ophthalmological Society 20160801

<h4>Purpose</h4>To improve understanding of dry eye disease and highlight a subgroup of patients who have a component of central sensitization and neuropathic pain contributing to their condition.<h4>Methods</h4>Prospective, cross-sectional, IRB-approved study comparing isolated dry eye disease (n=48) to fibromyalgia (positive control; n=23) and healthy (negative control; n=26) individuals with ocular surface examination, corneal confocal microscopy, quantitative sensory testing, and self-report ...[more]

PMID: 28050051

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Project description:PurposeMutations of keratoepithelin (KE) and myocilin (MYOC) have been linked to certain types of inherited corneal stromal dystrophy and open-angle glaucoma, respectively. In this study, the feasibility of using small interfering RNAs (siRNAs) to suppress the expression of keratoepithelin and myocilin and their capabilities to reduce the related cytotoxic effects caused by mutant myocilins were investigated.MethodscDNAs of human KE gene and myocilin gene were amplified by polymerase chain reaction and subcloned into pEGFP-N1 to construct respective plasmids, KEpEGFP and MYOCpEGFP, to produce fluorescence-generating fusion proteins. Short hairpin RNAs (shRNAs) were generated from an RNA polymerase III promoter-driven vector (pH1-RNA). Transformed HEK293 and trabecular meshwork (TM) cells were cotransfected via liposomes with either KEpEGFP or MYOCpEGFP and respective shRNA-generating plasmids to evaluate the suppression efficacy of shRNAs. Suppression of KE-EGFP by KE-specific shRNAs was evaluated by fluorescence microscopy and Western blotting. Suppression of MYOC-EGFP by myocilin-specific shRNAs was quantified with UN-SCAN-IT software on digitized protein bands of Western blots. A BiP promoter-driven luciferase reporter assay was used to evaluate the stress response of TM cells induced by misfolded mutant myocilins.ResultsTwo KE-specific shRNAs that effectively suppressed the expression of KE-EGFP in HEK293 cells were identified. One shRNA (targeting the coding sequence starting at 1528bp of KE) reduced the expression of KE-EGFP approximately by 50%, whereas the other shRNA (targeting the 3'-UTR region of KE) suppressed greater than 80% of the expression. Cotransfection of MYOCpEGFP and various shRNA-generating plasmids targeting different regions of myocilin (containing amino acid residues R76, E352, K423, or N480 associated with inherited glaucoma) showed effective reduction of MYOC-EGFP, ranging from 78% to 90% on average. The activation of BiP gene (as a stress response induced by mutant myocilins) in transformed TM cells was significantly reduced when mutant myocilin proteins were suppressed by myocilin-specific shRNAs.ConclusionsKE- or myocilin-specific shRNAs could effectively suppress the expression of recombinant KE or myocilin proteins and the related cytotoxicity of mutant myocilins. RNA interference may have future therapeutic implications in suppressing these genes.

Dataset Information

Discordant Dry Eye Disease (An American Ophthalmological Society Thesis).

Publications

Discordant Dry Eye Disease (An American Ophthalmological Society Thesis).

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