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Harumitsu Hirata, Thirugnana Vijmasi, Mark I Rosenblatt, Nancy A McNamara; Autoimmune regulator (Aire) gene deficient mice, a model of autoimmune-mediated, aqueous-deficient dry eye, exhibit functional alteration of a recently demonstrated, special type of corneal nerves involved in basal tearing, referred to as the dry-sensitive corneal afferents.. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3666.
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Many of the symptoms and signs of aqueous deficient dry eye, such as reduced tearing and ocular neuropathy, are manifested in, Aire-knockout (KO) mice. To investigate the contribution of dry-sensitive neurons to the pathogenesis of dry eye disease (DED), we examined the response characteristics of these corneal neurons to a variety of ocular stimuli important in basal tear production.
In ketamine/xylazine (supplemented with isoflurane)-anesthetized mice, single extracellular recordings were made from trigeminal ganglion cells innervating the cornea while the cornea was stimulated with ocular dryness, menthol solutions and temperature changes. The corneal neurons excited by drying of the cornea (dry-sensitive corneal afferents) were studied in wild type (WT) and Aire-KO mice.
In WT mice, the dry-sensitive corneal afferents were found within 30 min - 2 hrs after the start of the electrophysiological recordings. In line with our previous studies of corneal neurons in rats, the dry-sensitive neurons in WT mice showed vigorous discharges to drying of the cornea (and quieted by wetting), menthol and cooling stimuli applied to the ocular surface. By contrast, thus far, we have not been able to find the dry-sensitive corneal afferents in Aire-KO mice even after 3 hrs of recording and after demonstrating the presence of mechanoreceptors innervating the upper eyelids which lie in close proximity to dry-sensitive neurons. We are currently treating the Aire-KO mice with dexamethsone to attempt to reverse the effect of the deleterious ocular inflammation. We predict the presence of dry-sensitive neurons in the corneas of KO mice following anti-inflammatory therapy.
Our results demonstrate that the corneas of Aire-KO mice may be devoid of afferents whose activation is critical in maintaining ocular homeostasis by basal tear production, suggesting functional denervation of corneal nerves. We hypothesize that the neuronal loss in these mice with autoimmune disease is the direct result of chronic inflammation mediated by CD4+ T cells. Unraveling the mechanisms of how autoimmunity is associated with inflammation and corneal denervation, may provide a new avenue of treatments for DED.
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