Journal
NATURE IMMUNOLOGY
Volume 20, Issue 7, Pages 928-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41590-019-0378-1
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Funding
- Accelerating Medicines Partnership (AMP) in Rheumatoid Arthritis and Lupus Network
- National Institutes of Health [UH2-AR067676, UH2-AR067677, UH2-AR067679, UH2-AR067681, UH2-AR067685, UH2-AR067688, UH2-AR067689, UH2-AR067690, UH2-AR067691, UH2-AR067694, UM2-AR067678]
- Ruth L. Kirschstein National Research Service Award [NIAMS F31AR070582]
- Rheumatology Research Foundation Scientist Development Award
- KL2/Catalyst Medical Research Investigator Training award (an appointed KL2 award) from Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [KL2 TR002542]
- NIAMS [1R01AR063759-01A1, K08 AR072791-01, K01 AR066063]
- Bertha and Louis Weinstein research fund
- NIAID [U19 AI111224]
- NHGRI [U01 HG009379]
- Doris Duke Charitable Foundation [2013097]
- Arthritis National Research Foundation
- Arthritis Research UK Rheumatoid Arthritis [20298]
- National Institute for Health Research (NIHR)'s Birmingham Biomedical Research Centre program
- National Institute for Health Research/Wellcome Trust Clinical Research Facility at University Hospitals Birmingham NHS Foundation Trust
- [R21 AR071670]
- MRC [G0800648, MR/S025308/1, MR/N026977/1] Funding Source: UKRI
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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 Tcells, 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-DRA(hi) sublining fibroblasts, IL1B(+) pro-inflammatory monocytes, ITGAX(+)TBX21(+) autoimmune-associated B cells and PDCD1(+) peripheral helper T (T-PH) cells and follicular helper T (T-FH) cells. We defined distinct subsets of CD8(+)Tcells characterized by GZMIK(+), GZMB(+), and GNLY(+) phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed 1L6 expression to THYl(+)HLA-DRA(hi) fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.
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