Dry eye is one of the most frequently encountered problems in ophthalmology, with highest incidence in women, especially postmenopausally where atrophy and decreased tear formation are associated with chronic inflammation. It also occurs in Sjogren's syndrome, an autoimmune disease characterized by lymphocytic infiltration and loss of lacrimal acinar cells. The hormonal milieu is a critical factor in maintenance of normal lacrimal function, and androgens and prolactin (PRL) both play important roles. We have demonstrated that lacrimal fluid production in rabbits is decreased during pregnancy, and that pregnant women experience increased symptoms of dry eye, worsening with multiple pregnancies. Our studies in rabbits demonstrate dramatic changes in the concentration and distribution of PRL and growth factors within the lacrimal gland (LG) during pregnancy and lactation, increasingly being concentrated within ductal epithelial cells. These changes are accompanied by the appearance of """"""""reactive acinar cells,"""""""" which are immunopositive for MHC Class II protein and which may also be passive sources of autoantigenic stimulation, and by a marked redistribution of T and B lymphocytes from their normal periductal location to interacinar sites. We propose a new paradigm for physiological regulation of LG function, i.e., an """"""""acinar-ductal loop."""""""" In this system, ductal epithelial cells monitor the contents of the acinar effluent, absorb and transport materials from the duct lumen to periductal immune cells, and in so doing function in transmitting immunoregulatory signals (PRL, growth factors, cytokines) that may enhance periductal immune cell activation and responses to autoantigens. We propose to approach this integrated physiological system from perspectives of endocrinology and cellular physiology, employing rabbits, and mouse models of Sjogren's syndrome to pursue the following specific aims: ? ? (1) Test the hypothesis that lacrimal acinar cells and lacrimal ductal epithelial cells represent a physiological loop, in which ductal epithelial cells monitor acinar fluid contents, absorb and transport materials from within the duct lumen, and function in local immunoregulation. (2) Test the hypothesis that artificially altering the hormonal milieu of non-pregnant rabbits will elicit responses in the LG which are identical to those observed during pregnancy and lactation. (3) Use in vitro methods to characterize the effects of pregnancy, and growth factors whose expression is increased during pregnancy, on secretory function and intracellular autoantigen traffic in lacrimal acinar cells. (4) Test the hypothesis that increased PRL, charactersitic of pregnancy and lactation, enhances activation of lymphocytes in the LG. (5) Test the hypothesis that pregnancy accelerates and exacerbates the progress of Sjogren's-like infiltration of the LG in mouse models of Sjogren's syndrome.
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