Salivary gland response to innate immune mediators dictates Sjogren's syndrome development

Project Summary Sjögren's syndrome (SS) is a systemic autoimmune disorder affecting multiple organ systems. A dysregulated immune response targeting the exocrine salivary and lacrimal glands reduces fluid secretion, which manifests into the dry mouth and dry eye symptoms of SS. Recent evidence in the literature suggests that innate immune activation is a prominent etiologic factor. Nevertheless, how a systemic or localized innate immune response transitions into an adaptive autoimmune response and targets the exocrine glands remains unclear. This issue is also highly relevant in the context of the ongoing COVID-19 pandemic. In genetically susceptible individuals, the systemic cytokine storm elicited by the SARS-CoV-2 infection and the salivary gland tropism of this virus may heighten the risk for developing SS or worsening its severity. The presence of lymphocytic infiltrates in exocrine glands is a significant feature of SS. These infiltrates are predominantly peri-ductal, suggesting that ductal cells are involved in initiating inflammatory cell infiltration into the salivary glands. By using the innovative collaborative cross mice and poly(I:C) as a surrogate for viral infection, this proposal will investigate how the genetic regulation of innate immunity in salivary gland epithelial cells (SGEC) influences SS development. We will test the overall hypothesis that in genetically susceptible individuals, the SGEC response to innate immune stimuli dictates lymphocytic infiltration into the salivary glands and SS development. To test this hypothesis, in Aim 1, we will investigate whether the hierarchy of systemic IFN responses in collaborative cross mice influences lymphocytic infiltration within the salivary glands. In Aim 2, we will investigate whether the genetic makeup of SGECs dictates the magnitude of their response to innate immune mediators. The successful completion of this proposal will help decipher the influence of a differential gradient of innate immune responsiveness in SS pathogenesis. Further, SS development in any of the collaborative cross mice used in this proposal will provide the SS research community a more patient-relevant model system to investigate gene-environment interaction(s) in the disease.