CXCR3 ligands from different cellular sources play distinct roles in organizing lymphocytic sialadenitis in Sjögren's disease

About This Grant

Project Summary/Abstract Sjögren’s disease (SjD) is a systemic autoimmune disease in which destructive lymphocytic infiltration of the salivary (SG) and lacrimal glands leads to chronic dry eyes and mouth. It is one of the most common autoimmune diseases and causes significant disease morbidity but lacks approved disease modifying therapy. A hallmark histologic feature of SjD is dense immune infiltrate of the SG called focal lymphocytic sialadenitis (FLS). The CXCR3 chemokine signaling is an essential system for recruiting T cells to tissues and regulating their behavior. We and others show increased expression of the CXCR3 ligands, CXCL9 and CXLC10, in the SG in SjD, primarily in fibroblasts, endothelial cells, and antigen presenting cells. In this proposal, we will examine the mechanisms by which CXCR3 signaling controls the recruitment, maintenance, and activation of T cells in the SG. We hypothesize that CXCL9 and CXCL10 production by different cell types within the SG plays distinct roles in the formation and maintenance of FLS. The proposal will focus on understanding 1) which cells express CXCL9 an CXCL10 through the course of disease and 2) how different cellular sources of CXCL9 and CXCL10 influence T cell behavior and phenotype in the SG. We will perform complementary studies of human SG biopsies and mouse models of SjD to make mechanistic insights into disease-relevant immunopathogenesis. Dr. Yockey will perform the work in this K08 proposal in the Center for Immunology and Inflammatory diseases (CIID) at the Massachusetts General Hospital (MGH) under the mentorship of Dr. Andrew Luster, an expert in chemokine signaling, and Dr. Cory Perugino, an expert in human immunology. The CIID is a state-of-the-art multidisciplinary research center focused on investigating the mechanisms of immune-mediated inflammatory diseases. Dr. Yockey has developed a career development plan with four objectives to acquire: 1) Skills in tissue imaging and spatial transcriptomics, 2) Expertise in human T cell biology, 3) Knowledge of chemokine signaling and stroma-immune interactions, 4) Proficiency in histologic assessment of the salivary gland. Dr. Yockey has assembled a Training Advisory Committee and team of collaborators with unmatched and complementary expertise in key areas including SjD biology and computational biology. By completing these research and training plans, Dr Yockey will establish the intellectual and technical skills necessary to become an independent investigator. Importantly, she will develop expertise to conduct parallel studies using mouse models and patient samples to be able to ask human- relevant, fundamental questions about autoimmunity pathogenesis. She plans to use these important skills to spend the rest of her career advancing the care of patients with SjD and other autoimmune diseases by deciphering mechanisms of immune-mediated tissue damage.