Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry.

Abstract

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.

• Authors: Fan Zhang, Kevin Wei, Kamil Slowikowski, Chamith Y Fonseka, Deepak A Rao, Stephen Kelly, Susan M Goodman, Darren Tabechian, Laura B Hughes, Karen Salomon-Escoto, Gerald F M Watts, A Helena Jonsson, Javier Rangel-Moreno, Nida Meednu, Cristina Rozo, William Apruzzese, Thomas M Eisenhaure, David J Lieb, David L Boyle, Arthur M Mandelin 2nd, Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium, Brendan F Boyce, Edward DiCarlo, Ellen M Gravallese, Peter K Gregersen, Larry Moreland, Gary S Firestein, Nir Hacohen, Chad Nusbaum, James A Lederer, Harris Perlman, Costantino Pitzalis, Andrew Filer, V Michael Holers, Vivian P Bykerk, Laura T Donlin, Jennifer H Anolik, Michael B Brenner, Soumya Raychaudhuri
• Journal: Nature immunology (Nat Immunol) Vol. 20 Issue 7 Pg. 928-942 (07 2019) ISSN: 1529-2916 [Electronic] United States
• PMID: 31061532 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Cytokines
• Histocompatibility Antigens Class II

Topics

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