PROJECT SUMMARY
Sjögren’s disease is a chronic autoimmune disease characterized by immune-mediated
destruction of salivary and lacrimal glands leading to profound dry mouth and associated oral
health complications, vision-threatening dry eye disease, and decreased quality of life. The
immunological mechanisms of Sjögren’s are poorly understood, and no disease-modifying
therapies have been identified. There is a critical need to define the early immunological
mechanisms to identify targets for earlier diagnostics and more effective therapies. Diagnosis
occurs years after initiation of the autoimmune process making the study of early mechanisms
impractical in humans. Nonobese diabetic (NOD) mice spontaneously develop salivary gland
autoimmunity with features similar to Sjögren’s in humans including the characteristic focal
lymphocytic sialadenitis that is a hallmark of Sjögren’s in humans. We have recently found that
gene-editing to disrupt the Tyk2 gene in NOD mice prevents salivary gland inflammation in a
lymphocyte-extrinsic manner. Tyk2 is a non-receptor tyrosine kinase associated with several
inflammatory cytokines, and TYK2 gene variants are associated with Sjögren’s in humans. Our
goals in this proposal are to define the specific innate immune cell subsets and the upstream
cytokines that require Tyk2-mediated signaling for the development of autoimmune salivary
gland disease. Our central hypothesis is that interleukin (IL)-12 and IL-23 signaling through
Tyk2 in antigen presenting cells within the salivary glands are required to drive the focal
lymphocytic sialadenitis. The specific aims to test this hypothesis are: (1) Identify cells that
require Tyk2 signaling for salivary gland inflammation in NOD mice; (2) Define the requirements
for IL-12 and IL-23 in the development of focal lymphocytic sialadenitis. We will use the NOD
mouse-based spontaneous disease model, genetically edited NOD strains, our adoptive transfer
model, bone marrow chimeras, in vitro cultures, and in vivo cytokine-blocking therapies to
perform these studies. The significant positive impact of completing these studies include
defining the mechanisms by which Tyk2 and associated cytokines drive salivary gland
autoimmunity, which will lead to development of early diagnostic biomarkers and identification of
immune proteins that can be targeted therapeutically in Sjögren’s. Notably, inhibitors of Tyk2
are in development, and IL-12 and IL-23 blocking therapies are already available to treat other
autoimmune diseases. Identifying the roles of Tyk2 and associated cytokines in Sjögren’s will
help guide future studies of Tyk2 and associated cytokine blocking therapies in subsets of
individuals with Sjögren’s.