Accelerating Medicines Partnership-Autoimmune and Immunologic Disease Tissue Research Core Admin Supplement: Preclinical Studies in Sjogren's

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PROJECT ABSTRACT Sjögren’s syndrome (SS) is an incapacitating rheumatic disease typified by severe dry eyes and mouth, often including arthritis, debilitating fatigue, pulmonary involvement, neuropathy, vasculitis and malignant lymphoma. The personal and economic burdens ($35 billion/year in the US) are high, and there is no effective biologic therapy. Lack of understanding of basic disease processes, molecular underpinnings of patient heterogeneity, and effective diagnostic biomarkers have hindered the development of effective biologic therapies and conduct of successful clinical trials. This is especially true for patients lacking anti-Ro antibodies (Ro– SS) who require a salivary gland biopsy for classification. We are in a unique position to study the differences between Ro+ and Ro– SS. In our carefully phenotyped cohort, nearly 40% of SS patients meeting current classification criteria lack diagnostic anti-Ro autoantibodies. Our Ro– SS cases have more glandular, articular, and pulmonary involvement than Ro+ SS cases, yet these patients are often not diagnosed by rheumatologists or included in clinical trials. Herein, we leverage our multidisciplinary team of investigators with expertise in rheumatology, immunology, genomics/genetics, as well as our carefully phenotyped cohort of 668 SS cases and 925 non-SS sicca patients to address these deficiencies. The project is based on compelling preliminary data identifying common and unique features in both Ro+ and Ro– SS groups and will study a common set of 60 Ro+ SS cases, 60 Ro– SS cases, and 24 healthy controls. Aim 1 will develop and apply an autoantibody-based diagnostic test for Ro– and Ro+ SS and leverage salivary gland proteomics, spectral flow cytometry, imaging mass cytometry, and functional studies to clarify the role of T and B cell subsets in disease. Aim 2 will employ single cell RNA-seq of PBMC and sorted cells studied in Projects 1 and 2, identify chromosomal interactions in primary salivary gland epithelial cells, study functional effects of Ro+ and Ro– SS risk alleles and long non-coding RNAs using CRISPR interference or activation for enhancers, and use feature selection and machine learning to identify sources of heterogeneity between Ro+ and Ro– SS.