The eye's secretory immune system, which is primarily controlled by the lacrimal gland protects the ocular surface against viral, bacterial, parasitic and toxic challenge, and thereby plays a unique and crucial role in the maintenance of corneal integrity and the preservation of visual acuity. However, this immune function may be compromised by Sjogren's syndrome: this autoimmune disorder progressively destroys lacrimal tissue, and may lead to severe dry eye, intractable desiccation of the corneal epithelium, ulceration and perforation of the cornea, an increased incidence of infectious disease, and ultimately, pronounced visual impairment and blindness. The long-range objectives of this grant application are to advance our understanding of how neuroendocrinimmune factors enhance the secretory immune system of the eye, and suppress Sjogren's syndrome in the lacrimal gland. Experimental procedures involve rat and mouse models, molecular biological techniques, cell cultures, immunoassays, histochemical procedures and endocrine organ ablation and reconstitution experiments.
Specific aims are: (l) To determine the mechanisms involved in the endocrine, neural and immune regulation of the ocular secretory immune system. These studies include: (a) an analysis of the neuroendocrinimmune control of secretory component and IgA transcription and synthesis in lacrimal tissue; and (b) an evaluation of the endocrine, neural and immune influence on TGF-beta1 and IL-6 production by lacrimal gland epithelial cells; and (2) To determine the role of epithelial cell cytokines in the androgen-induced suppression of autoimmune disease in lacrimal glands of a mouse model of Sjogren's syndrome. This research will examine whether androgens alter the expression and/or activity of epithelial cell cytokines (i.e. TGF-beta1, IL-6, IL-1beta and TNF-alpha), thereby causing a reduction in immunopathological lesions and an enhancement of lacrimal tissue function in Sjogren's syndrome. Results from these studies should significantly advance our knowledge of the neuroendocrinimmune regulation of mucosal immunity and autoimmunity in the lacrimal gland. In addition, findings may have health relatedness for the eye, because they: (a) examine control mechanisms underlying the ocular secretory immune system; and (b) may lead to the development of specific therapies for the clinical treatment of lacrimal gland autoimmune disease in Sjogren's syndrome.
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