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Roderick J Fullard, Nicole M Guyette, My-Tho K Tran, John L Bradley; Correlations between non-stimulated tear levels and conjunctival gene expression of MAPK pathway-associated biomarkers in aqueous-deficient dry eye and control patients. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3683.
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Chronic hyperosmolarity at the ocular surface increases tear levels of pro-inflammatory cytokines IL-6, IL-1β, IL-8, TNF-α, and G-CSF and activates MAPK signaling pathways. Concurrent changes in conjunctival MAPK-associated gene expression are not clearly defined. The current study compares tear levels of MAPK-associated biomarkers with concurrent conjunctival gene expression of related biomarkers in aqueous-deficient dry eye (ADDE) and control patients.
Patients were allocated to three groups by Schirmer score: control > 10 mm/5min, n=16; moderate ADDE 5-10 mm, n=13; severe ADDE < 5 mm, n=14. NS tear samples were collected for BioRad 27-Plex cytokine assay. At the same patient visit, 8 conjunctival impression cytology (CIC) specimens were collected per eye, RNA extracted, and RT-qPCR conducted on TaqMan 384-well/96A low density arrays.
Severe ADDE group: tear IL-6, IL-1β, IL-8, G-CSF and IP-10 correlated significantly with expression of 11-20 conjunctival genes with inflammatory roles: primarily MAPK pathway, Th17 pathway and apoptosis. All five tear cytokines correlated with complement C3, MIP-3β, IL-10Rα, NOS2, GM-CSF, MIG, IP-10 and TNF gene expression. All other tear cytokines including TNF-α showed few correlations. Control group: MAPK tear cytokines IL-6 and G-CSF correlated with >18 conjunctival genes, the gene profile overlapping <50% with the severe ADDE group. Tear IL-1β, IL-8 and IP-10 did not correlate with any conjunctival genes in controls, while TNF-α showed 11 gene correlations. In controls, additional tear cytokines, VEGF, IL-12, IL-17 and MIP-1α showed strong conjunctival gene association patterns similar to that of tear G-CSF for this group. The most commonly correlated genes in the control group were IFN-γ, CCR1, IP-10, IL-23A, IL-6 and FAS-ligand. Patterns were conspicuously absent in the moderate ADDE group.
A clear correlation between MAPK tear cytokines and conjunctival gene expression of associated factors seen in severe ADDE patients is absent in moderate ADDE. A very different association pattern emerges in controls. The fact that only tear IL-6 and G-CSF show strong associations with conjunctival gene expression in both severe ADDE and control patients suggests key, possibly regulatory, roles for these cytokines in ADDE.
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