Defining Inflammatory Cell States in Rheumatoid Arthritis Joint Synovial Tissues by Integrating Single-cell Transcriptomics and Mass Cytometry
Chamith Y. Fonseka,
Susan M. Goodman,
Laura B. Hughes,
Gerald F. M. Watts,
David J. Lieb,
David L. Boyle,
Arthur M. Mandelin,
Accelerating Medicines Partnership: RA Phase 1, AMP RA/SLE,
Brendan F. Boyce,
Ellen M. Gravallese,
Solbritt Rantapää Dahlqvist,
Gary S. Firestein,
James A. Lederer,
V. Michael Holers,
Vivian P. Bykerk,
Laura T. Donlin,
Jennifer H. Anolik,
Michael B. Brenner,
Posted 20 Jun 2018
bioRxiv DOI: 10.1101/351130 (published DOI: 10.1038/s41590-019-0378-1)
Posted 20 Jun 2018
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 naive B cells, and ILB to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.
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