Salivary gland dysfunction results from dietary changes, radiation therapy, aging, certain medications and viral or genetic diseases. The loss of gland function and thus saliva production results in the clinical manifestation of xerostomia or """"""""dry mouth."""""""" Some autoimmune diseases of man, for example, Sjogrens syndrome and Type 1 diabetes (IDD), show progressive lymphocytic infiltration of the salivary glands with a subsequent reduction in saliva synthesis and secretion. IDD is characterized by autoimmune destruction of insulin producing beta cells of the pancreas. Further investigations have revealed that in diabetic patients and the NOD (non-obese diabetic) mouse, lymphocytic infiltration of exocrine tissues, including the submandibular gland, is common. One metabolic complication of human autoimmune IDD is xerostomia with associated increases in caries and potential periodontal disease development. To date, development of an adequate animal model for the analysis of autoimmune induced salivary gland dysfunction would facilitate the study of xerostomia. Using the NOD mouse, we recently observed that with the progressive autoimmune reaction against beta cells, lymphocytes simultaneously infiltrated into the parotid and submandibular glands of diabetic and pre-diabetic animals. This was accompanied by a corresponding decline in stimulated flow rates and loss of specific secretory protein biosynthetic capacity. These observations suggest that salivary gland dysfunction is not due to an acute inflammatory response caused by lymphocytic infiltration and cellular destruction, but more accurately reflects changes due to the chronic lymphocytic activation present in the autoimmune pathology. Therefore, we propose here to investigate the autoimmune sialoadenitis of the NOD mouse to determine its potential as an animal model for autoimmune-induced xerostomia. Specifically, we plan to 1) Characterize the autoimmune reaction against salivary glands leading to xerostomia; 2) Determine changes in the level of membrane receptors and intracellular components of the signal transduction pathways which are commonly activated during the secretory process and 3) Characterize the role of insulin-like peptides on parotid gland function at onset of autoimmune sialoadenitis in IDD. Results from these studies should provide insights into autoimmune responses that traditionally lead to salivary gland dysfunction with obvious clinical and dental relevance. In addition, we anticipate that the NOD mouse will prove to be a useful model for developing our understanding of Sjogrens syndrome, Rheumatoid arthritis and Type 1 IDD; diseases in which the autoimmune pathology causes a loss of protective salivary secretions with the resulting patient discomfort associated with xerostomia and increased caries, periodontal disease and aggravation of oral mucosa and soft tissue.
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