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Nat Immunol. 2019 Jul;20(7):928-942. doi: 10.1038/s41590-019-0378-1. Epub 2019 May 6.

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

Author information

1
Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA.
2
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
3
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
4
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
5
Division of Rheumatology, Immunology, Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
6
Department of Rheumatology, Barts Health NHS Trust, London, UK.
7
Division of Rheumatology, Hospital for Special Surgery, New York, NY, USA.
8
Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
9
Division of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA.
10
Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
11
Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
12
Arthritis and Tissue Degeneration, Hospital for Special Surgery, New York, NY, USA.
13
Department of Medicine, Division of Rheumatology, Allergy and Immunology, University of California, San Diego, La Jolla, CA, USA.
14
Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
15
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
16
Department of Pathology and Laboratory Medicine, Hospital for Special Surgery, New York, NY, USA.
17
Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, NY, USA.
18
Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
19
Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
20
Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, UK.
21
NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK.
22
University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
23
Division of Rheumatology, University of Colorado School of Medicine, Aurora, CO, USA.
24
Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
25
Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA. soumya@broadinstitute.org.
26
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org.
27
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org.
28
Broad Institute of MIT and Harvard, Cambridge, MA, USA. soumya@broadinstitute.org.
29
Division of Rheumatology, Immunology, Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org.
30
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK. soumya@broadinstitute.org.

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.

PMID:
31061532
PMCID:
PMC6602051
[Available on 2019-11-06]
DOI:
10.1038/s41590-019-0378-1
[Indexed for MEDLINE]

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