Defining Inflammatory Cell States in Rheumatoid Arthritis Joint Synovial Tissues by Integrating Single-cell Transcriptomics and Mass Cytometry

Abstract

Abstract To define the cell populations in rheumatoid arthritis (RA) driving joint inflammation, we applied single-cell RNA-seq (scRNA-seq), mass cytometry, bulk RNA-seq, and flow cytometry to sorted T cells, B cells, monocytes, and fibroblasts from 51 synovial tissue RA and osteoarthritis (OA) patient samples. Utilizing an integrated computational strategy based on canonical correlation analysis to 5,452 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics together revealed cell states expanded in RA synovia: THY1 + HLA high sublining fibroblasts (OR=33.8), IL1B + pro-inflammatory monocytes (OR=7.8), CD11c + T-bet + autoimmune-associated B cells (OR=5.7), and PD-1 + Tph/Tfh (OR=3.0). We also defined CD8 + T cell subsets characterized by GZMK + , GZMB + , and GNLY + expression. Using bulk and single-cell data, we mapped inflammatory mediators to source cell populations, for example attributing IL6 production to THY1 + HLA high fibroblasts and naïve B cells, and IL1B to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.

Keywords

Affiliated Institutions

• Brigham and Women's Hospital US
• University of Rochester Medical Center US
• Harvard University US
• University of Pittsburgh US
• University of Massachusetts Chan Medical School US
• Feinstein Institute for Medical Research US
• University of Manchester GB
• William Harvey Research Institute GB
• Hospital for Special Surgery US
• University Hospitals Birmingham NHS Foundation Trust GB
• University of Alabama at Birmingham US
• Queen Mary University of London GB
• University of Birmingham GB
• Versus Arthritis GB
• University of Colorado Denver US
• Cornell University US
• Northwell Health US
• Broad Institute US
• Barts Health NHS Trust GB
• Genomics (United Kingdom) GB

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