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

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+HLAhigh 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+HLAhigh fibroblasts and naïve B cells, and IL1B to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.
Subject Area
- Biochemistry (8820)
- Bioengineering (6523)
- Bioinformatics (23470)
- Biophysics (11798)
- Cancer Biology (9216)
- Cell Biology (13327)
- Clinical Trials (138)
- Developmental Biology (7440)
- Ecology (11417)
- Epidemiology (2066)
- Evolutionary Biology (15160)
- Genetics (10442)
- Genomics (14051)
- Immunology (9176)
- Microbiology (22170)
- Molecular Biology (8817)
- Neuroscience (47600)
- Paleontology (350)
- Pathology (1429)
- Pharmacology and Toxicology (2492)
- Physiology (3733)
- Plant Biology (8084)
- Synthetic Biology (2221)
- Systems Biology (6039)
- Zoology (1254)