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To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)+HLA-DRAhi sublining fibroblasts, IL1B+ pro-inflammatory monocytes, ITGAX+TBX21+ autoimmune-associated B cells and PDCD1+ peripheral helper T (TPH) cells and follicular helper T (TFH) cells. We defined distinct subsets of CD8+ T cells characterized by GZMK+, GZMB+, and GNLY+ phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1+HLA-DRAhi fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.

Original publication

DOI

10.1038/s41590-019-0378-1

Type

Journal article

Journal

Nat Immunol

Publication Date

07/2019

Volume

20

Pages

928 - 942

Keywords

Arthritis, Rheumatoid, Autoimmunity, Biomarkers, Computational Biology, Cross-Sectional Studies, Cytokines, Fibroblasts, Flow Cytometry, Gene Expression, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Histocompatibility Antigens Class II, Humans, Leukocytes, Monocytes, Signal Transduction, Single-Cell Analysis, Synovial Membrane, T-Lymphocyte Subsets, Transcriptome, Workflow