ABSTRACT The Sjögren’s International Collaborative Clinical Alliance (SICCA) was established in 2003 to improve the understanding, diagnosis and treatment of patients with Sjögren’s syndrome (SS) by 1) developing/validating standardized classification criteria for SS; and 2) developing a longitudinal data and biospecimen repository that could be used by the research community for future epidemiologic, pathogenesis, and genetic studies of SS. Using rigorous study design and, standardized data/specimen collection protocols, SICCA investigators from nine leading academic research groups across the globe assembled a unique biorepository from a cohort of 3,514 participants with extremely well characterized phenotypic data (with follow-up data/specimens on 771). Multiple deliverables were achieved including 1) development and validation of classification criteria for SS provisionally approved by the American College of Rheumatology (ACR) in 2011 (followed by the development/validation of a set of classification criteria approved by ACR and EULAR in 2016); 2) a Genome-Wide Association Study that highlighted the genetic heterogeneity of SS according to ancestry, and established a unique genetic repository for SS available for public use through dbGAP; and 3) a dissemination plan, which has yielded important new findings regarding the SS phenotype. In response to FOA PAR-17-154, our proposal leverages unique NIDCR-funded resources by utilizing existing infrastructure and an expanded team, and positions us to exploit recent explosive growth in the fields of immunology, genomics and epigenetics to better understand the pathogenesis of SS and identify therapeutic pathways, and new biomarkers. Using previously collected clinical data/biospecimens, and genome-wide genotyping performed on all participants, we propose to define the transcriptomics and epigenetics of SS at the cell and tissue levels. This will enhance the SICCA registry by generating genome-wide DNA methylation and whole-genome sequencing of single-cell mRNA, bulk mRNA, and miRNA and enable high impact studies of underlying biologic pathways of SS. Given the relationship between the epigenome and gene expression, specific epigenetic modifications and transcriptomic profiles may represent novel biomarkers in autoimmune diseases. We also propose an expanded dissemination plan that can leverage these omics data sets thereby engaging SS investigators worldwide in discovery. We aim to 1) Generate transcriptome and methylation profiles in order to explore transcriptomic diversity across subsets of SICCA participants with well characterized epigenetic and genetic profiles, across cell and tissue types; 2) Explore correlations between omics profiles and signs of severe disease manifestations, including presence of germinal-center-formation (GCF) and focal lymphocytic sialadenitis with a high focus score in LSG biopsies, hypergammaglobulinemia, and hypocomplementemia; and 3) Characterize longitudinal cha...