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

Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium

doi:10.1038/s41590-019-0378-1

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

Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium

Medicine, Rheumatology Division

Research output: Contribution to journal › Article › peer-review

835 Scopus citations

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-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⁺ 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-DRA^hi fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.

Original language	English (US)
Pages (from-to)	928-942
Number of pages	15
Journal	Nature Immunology
Volume	20
Issue number	7
DOIs	https://doi.org/10.1038/s41590-019-0378-1
State	Published - Jul 1 2019

Funding

This work was supported by the Accelerating Medicines Partnership (AMP) in Rheumatoid Arthritis and Lupus Network. AMP is a public-private partnership (AbbVie Inc., Arthritis Foundation, Bristol-Myers Squibb Company, Lupus Foundation of America, Lupus Research Alliance, Merck Sharp & Dohme Corp., National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Pfizer Inc., Rheumatology Research Foundation, Sanofi and Takeda Pharmaceuticals International, Inc.) created to develop new ways of identifying and validating promising biological targets for diagnostics and drug development. Funding was provided through grants from the National Institutes of Health (UH2-AR067676, UH2-AR067677, UH2-AR067679, UH2-AR067681, UH2-AR067685, UH2-AR067688, UH2-AR067689, UH2-AR067690, UH2-AR067691, UH2-AR067694, and UM2-AR067678). K.S. is supported by the Ruth L. Kirschstein National Research Service Award (NIAMS F31AR070582). K.W. is supported by a Rheumatology Research Foundation Scientist Development Award, and 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 Award KL2 TR002542). D.A.R. is supported by NIAMS K08 AR072791-01. L.T.D. is supported by NIAMS K01 AR066063. J.H.A. is supported by R21 AR071670, and the Bertha and Louis Weinstein research fund. S.R. is supported by NIAMS 1R01AR063759-01A1, NIAID U19 AI111224, NHGRI U01 HG009379, and Doris Duke Charitable Foundation Grant #2013097. A.H.J. is supported by an Arthritis National Research Foundation Grant. A.F., C.D.B. and J.D.T. were supported by the Arthritis Research UK Rheumatoid Arthritis (#20298), and by the National Institute for Health Research (NIHR)’s Birmingham Biomedical Research Centre program, supported by the National Institute for Health Research/ Wellcome Trust Clinical Research Facility at University Hospitals Birmingham NHS Foundation Trust.

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41590-019-0378-1

Cite this

@article{c607abe55e1548189c74ca4dca1678f8,

title = "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.",

author = "{Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium} and Fan Zhang and Kevin Wei and Kamil Slowikowski and Fonseka, {Chamith Y.} and Rao, {Deepak A.} and Stephen Kelly and Goodman, {Susan M.} and Darren Tabechian and Hughes, {Laura B.} and Karen Salomon-Escoto and Watts, {Gerald F.M.} and Jonsson, {A. Helena} and Javier Rangel-Moreno and Nida Meednu and Cristina Rozo and William Apruzzese and Eisenhaure, {Thomas M.} and Lieb, {David J.} and Boyle, {David L.} and Mandelin, {Arthur M.} and Jennifer Albrecht and Bridges, {S. Louis} and Buckley, {Christopher D.} and Buckner, {Jane H.} and James Dolan and Guthridge, {Joel M.} and Maria Gutierrez-Arcelus and Ivashkiv, {Lionel B.} and James, {Eddie A.} and James, {Judith A.} and Josh Keegan and Lee, {Yvonne C.} and McGeachy, {Mandy J.} and McNamara, {Michael A.} and Mears, {Joseph R.} and Fumitaka Mizoguchi and Nguyen, {Jennifer P.} and Akiko Noma and Orange, {Dana E.} and Mina Rohani-Pichavant and Christopher Ritchlin and Robinson, {William H.} and Anupamaa Seshadri and Danielle Sutherby and Jennifer Seifert and Turner, {Jason D.} and Utz, {Paul J.} and Boyce, {Brendan F.} and Edward DiCarlo and Harris Perlman",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

month = jul,

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doi = "10.1038/s41590-019-0378-1",

language = "English (US)",

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Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. / Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium.
In: Nature Immunology, Vol. 20, No. 7, 01.07.2019, p. 928-942.

Research output: Contribution to journal › Article › peer-review

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

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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