BASAL/LATERAL--ENDOMEMBRANE TRAFFIC IN LACRIMAL ACINI

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Dry eye caused by lacrimal insufficiency is the most common form of ocular morbidity in the developed countries. It is caused by lymphocytic infiltration of the lacrimal glands in Sjogren s syndrome, which affects two million Americans, and in certain other immune system disorders. More subtle forms of lymphocytic infiltration may contribute to the secretory defect in primary lacrimal deficiency, which, like Sjogren s syndrome, occurs primarily in women. The thesis underlying this proposal is that the feature of lacrimal secretory epithelial cell function which causes them to provoke autoimmune responses is a previously little-appreciated recycling traffic between endomembrane compartments and the basal-lateral membrane (BLM), i.e., the membrane domain that contacts the interstitium. This traffic secretes immunomodulatory factors and potential auto antigens into the interstitium, and when cells have been induced to express major histocompatibility complex Class II molecules (MHC II), it allows them to present autoantigens in the same way that professional antigen presenting cells present foreign antigens. A further premise is that the normal spectra of secreted and displayed autoantigens are subject to peripheral tolerance, but that tolerance is overcome when changes in the BLM - endomembrane traffic perturb the autoantigenic spectra. Preliminary data indicate that such changes occur during sustained secretomotor stimulation, an experimental situation that may mimic the in vivo operation of the ocular surface - lacrimal gland feedback loop working to compensate for hormonally-induced glandular atrophy. Therefore, this project will combine methods of subcellular fractionation analysis that are uniquely capable of resolving compartments of the BLM -endomembrane traffic with widely used immunocytochemical methods to: 1) Delineate pathways between defined compartments of the BLM - endomembrane traffic. 2) Map the traffic of MHC II, of the La antigen, which is a prominent target of autoimmune reactions in Sjogren s syndrome, and of other potential autoantigens. 3) Investigate mechanisms responsible for stimulation-induced acceleration of BLM - endomembrane traffic. 4) Investigate mechanisms responsible for the stimulation-induced changes in targeting and/or segregation that cause Golgi and lysosomal proteins to enter the BLM pathway.