Murine Cytomegalovirus-Induced Salivary Gland Disease

Sjögren's Syndrome (SS) is a complex autoimmune disease with unknown etiology. The hallmarks of SS are focal inflammation and dysfunction of the exocrine glands, tissues that secrete saliva and tears. To investigate disease pathogenesis, spontaneous mouse models have been studied which recapitulate certain human disease features. For example, the non-obese diabetic mouse has been helpful in the identification of autoantibodies as one cause of salivary gland hypofunction. However, the genetic and environmental factors contributing to SS are not understood. Viruses which infect the glands have long been suspected to initiate disease. Indeed, human viruses HCV or HIV can lead to a sicca syndrome resembling SS. In this dissertation, the ability of murine cytomegalovirus (MCMV) to induce SS disease features was characterized in the autoimmune mouse strain, NZM2328. MCMV persisted in the salivary gland for many weeks and was associated with a strong inflammatory response within the gland. After viral latency was established, severe focal inflammation in the salivary and lacrimal glands was observed in females. Focal inflammation induced by MCMV depended on genetic factors, since B6 mice were protected. MCMV infection of NZM2328 mice led to production of autoantibodies reactive with salivary and lacrimal gland proteins. In addition, secretory function was progressively lost in a subset of females. Therefore, MCMV infection of NZM2328 female mice led to many of the disease manifestations of SS. Xerostomia, or chronic dry mouth, is a complication of SS as well as certain human viral infections. Further studies showed that MCMV impaired saliva secretion within the first few days of infection. Remarkably, secretory dysfunction early after infection did not depend on viral load in the gland or require lymphocytes or inflammatory monocytes which suggested that a soluble factor was responsible. NK cells, beyond their recognized antiviral role in MCMV infection, were critical in protecting the host from damaging inflammatory responses and functional loss of the salivary gland.

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