Clinical and Mechanistic Investigations of Salivary Gland Dysfunction

National Institute Of Dental & Craniofacial Research

Investigators

Linked publications & trials

Abstract

Summary of Accomplishments (FY2025) A national and international thought leader in Sjögren’s Disease, salivary gland biology, and pathology, the Salivary Disorders Unit (SDU) advances its mission to define the mechanisms underlying salivary gland dysfunction in autoimmune and therapy-related conditions, with the ultimate goal of identifying new therapeutic targets and strategies to restore glandular function. This work is carried out through the NIH/NIDCR Division of Intramural Research and strengthened by public–private partnerships, including the Accelerating Medicines Partnership, the Foundation for the National Institutes of Health Biomarkers Consortium, and multiple industry-sponsored cooperative research and development agreements (CRADAs) During the fiscal year, our group studied human participants with Sjogren’s Disease (an autoimmune disorder that causes salivary gland inflammation and dryness), patients who developed salivary gland dysfunction following immune checkpoint inhibitor therapy, and healthy volunteers who served as controls. Minor salivary gland biopsies, blood, saliva, and other clinical samples were collected under approved protocols to support these investigations. Significant progress was made in applying advanced genomic and spatial technologies to study human tissues. We generated and analyzed single-cell RNA sequencing (scRNA-seq) and single-cell chromatin accessibility (scATAC-seq) data to map cellular states, immune–epithelial interactions, and gene regulatory networks in salivary glands. Spatial transcriptomics using the Xenium platform enabled us to preserve tissue architecture while profiling gene expression at high resolution, providing new insights into how immune cells and glandular epithelial cells interact in disease. Bulk RNA sequencing was also used to profile gene expression patterns across large patient cohorts. Methodologically, our group integrated computational analyses, including machine learning approaches, to identify cell types and molecular pathways most affected by inflammation and fibrosis. This integration of experimental and computational biology allowed us to generate hypotheses about disease mechanisms and therapeutic opportunities. Overall, our work during this reporting period defined new cellular states in salivary gland epithelium, revealed pathogenic immune cell subsets enriched in disease, and demonstrated the feasibility of combining bulk, single-cell, and spatial genomics to better understand salivary gland dysfunction. These efforts advance our goal of developing precision medicine approaches for patients with salivary gland disorders. Important publications in the interval and their significance: 1) Stratifying Sjögren’s by JAK–STAT activity (patient endotypes → therapy targets) Perez, Yamada, Warner, et al., Annals of the Rheumatic Diseases, 2024 (Epub Aug 12, 2024). Multi-omics and tissue analyses identified distinct JAK–STAT activation patterns in Sjögren’s disease that can stratify patients and prioritize cell-type–specific targets for precision trials (e.g., JAK pathway inhibition). This provides a framework for aligning treatment to molecular endotypes rather than one-size-fits-all approaches. We used these data to initiate a human clinical trial testing tofacitinib to ameliorate glandular inflammation and restore function. 2) Bench-to-biomarker tools: flow cytometry panel for minor salivary glands Yamada, Dominick, Kulchar, Perez, Warner, et al., Frontiers in Dental Medicine, 2025 (June 12, 2025). Developed and validated a multiparameter flow cytometry workflow for ex-vivo immune profiling of minor salivary glands, including type I interferon pathway readouts. This enables standardized immune phenotyping and supports biomarker-driven stratification and response monitoring in future interventional studies. 3) Lysosome-associated mechanisms in Sjögren’s Disease/Epithelial drivers of disease: LAMP3–TLR7/type I IFN feed-forward loop Nakamura, Tanaka, Warner, Michael, Chiorini, et al., Arthritis & Rheumatology, 2024. Showed that type I interferon induces LAMP3 in salivary gland epithelium and that LAMP3 up-regulates ectopic TLR7, creating a positive feedback loop that sustains epithelial interferon signaling and contributes to Sjögren’s pathophysiology. Highlights epithelial cell–intrinsic mechanisms and nominates TLR7/LAMP3–IFN axis as a therapeutic target. Nakamura H, Tanaka T, Noguchi M, Atsumi T, Warner BM, Chiorini JA. Arthritis Rheumatology, 2025. This work highlighted the role of lysosomal pathways, specifically Lysosome-Associated Membrane Protein 3 (LAMP3), in salivary gland epithelial dysfunction and immune regulation in Sjögren’s Disease. It demonstrated that lysosomal biology contributes to disease pathophysiology and represents a promising target for novel therapeutic approaches. 4) Genetic risk and immune regulatory networks in salivary gland autoimmunity Wiley MM, Radziszewski M, Khatri B, et al., including Warner BM. Annals of the Rheumatic Diseases, 2025. In this large-scale genetics study, variants in the DDX6–CXCR5 autoimmune risk locus were shown to influence gene regulatory networks in both immune cells and salivary gland tissue. These findings link inherited susceptibility to altered immune–epithelial interactions and provide mechanistic insight into how genetic risk shapes disease pathways in Sjögren’s Disease. 5) Spatial multiomics and cell type deconvolution using TACIT Huynh KLA, Tyc KM, Matuck BF, et al., including Warner BM. Nature Communications, 2025. Collaboratively, the group applied TACIT (Transcriptome-Assisted Cell Identification Tool) to spatial transcriptomics data from human salivary glands, enabling deconvolution of cell types and states while preserving tissue architecture. This approach identified spatially restricted immune–epithelial interactions, advancing understanding of tissue niches critical to disease pathogenesis and providing a robust framework for integrating single-cell and spatial multiomics in autoimmune research. Significance: Together, these publications advance mechanistic understanding of Sjögren’s Disease by defining lysosomal and epithelial contributions to pathogenesis, mapping immune infiltration with high-resolution profiling, linking genetic risk to functional immune networks, and developing computational tools for spatial multiomic analysis. These accomplishments highlight the SDU’s focus on clinically relevant, mechanistic, and solution-oriented research, laying the foundation for novel biomarkers and targeted therapeutic strategies for salivary gland disorders.