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Karsten Gronert, Kyungji Min, Matthew Greenwood, Erick Lu, Jonanthan Jong, David Lin, Yuan Gao; Sex-specific Dry Eye Pathogenesis Correlates With Increased Activation of T cells and Decreased Resident PMN and Lipoxin Formation in Female Draining Lymph Nodes. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1855.
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The cause for the sex-specific prevalence of Dry Eye Disease (DED) in women is largely unknown. A protective and immune-regulatory lipid mediator circuit (lipoxin) is highly expressed in the ocular surface and markedly amplified by PMN. This lipid circuit is down regulated by estrogen and drives sex-specific differences in corneal wound healing and inflammatory responses. If the PMN-lipoxin circuit has a role in the pathogenesis of DED and lymphocyte activation in females is unknown. We investigated sex-specific difference in the pathogenesis of DED and regulation of the PMN-LXA4 circuit in the ocular surface and draining lymph nodes.
Male and female mice were subjected to the standard model of desiccating stress induced DED. Severity of DED was evaluated by Schirmer’s test and clinical fluorescence scoring. PMN and CD4+ T cells population were confirmed and quantified by using myeloperoxidase assay, fluorescence deconvolution microscopy and flow cytometry. Lipid mediator formation was quantified by LC/MS/MS-based lipidomics and gene expression quantified by qPCR.
Female mice exhibited amplified Dry Eye severity compared to males. Both males and females had a significant population of tissue PMN in the limbus prior to inducing desiccating stress. In females that PMN population decreased by 56%, while CD4+ T cells increased by 42% after inducing DED. Compared to males, females had a striking phenotype of less neutrophils and more CD4+ T cells infiltration in the corneal limbus after inducing DED. This was paralleled by a marked depression of PMN in draining lymph nodes of females, while PMN in male lymph nodes increased 7.7 fold after inducing DED. The female phenotype correlated with a marked increase in CD4+ T cells in the draining lymph nodes and a marked reduction in endogenous formation of Lipoxin A4 in both the limbus and draining lymph nodes of female mice.
These results provide the first evidence that primary innate immune cells, PMN, and the LXA4 circuit are active in draining lymph nodes, suggesting a novel regulatory role. Desiccating stress induces a striking sex-specific regulation of PMN and the lipoxin circuit in in the limbus and draining lymph nodes that correlates with increased severity of DED and activation of T cells in females.
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