TY - JOUR
T1 - Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry
AU - Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium
AU - Zhang, Fan
AU - Wei, Kevin
AU - Slowikowski, Kamil
AU - Fonseka, Chamith Y.
AU - Rao, Deepak A.
AU - Kelly, Stephen
AU - Goodman, Susan M.
AU - Tabechian, Darren
AU - Hughes, Laura B.
AU - Salomon-Escoto, Karen
AU - Watts, Gerald F.M.
AU - Jonsson, A. Helena
AU - Rangel-Moreno, Javier
AU - Meednu, Nida
AU - Rozo, Cristina
AU - Apruzzese, William
AU - Eisenhaure, Thomas M.
AU - Lieb, David J.
AU - Boyle, David L.
AU - Mandelin, Arthur M.
AU - Albrecht, Jennifer
AU - Bridges, S. Louis
AU - Buckley, Christopher D.
AU - Buckner, Jane H.
AU - Dolan, James
AU - Guthridge, Joel M.
AU - Gutierrez-Arcelus, Maria
AU - Ivashkiv, Lionel B.
AU - James, Eddie A.
AU - James, Judith A.
AU - Keegan, Josh
AU - Lee, Yvonne C.
AU - McGeachy, Mandy J.
AU - McNamara, Michael A.
AU - Mears, Joseph R.
AU - Mizoguchi, Fumitaka
AU - Nguyen, Jennifer P.
AU - Noma, Akiko
AU - Orange, Dana E.
AU - Rohani-Pichavant, Mina
AU - Ritchlin, Christopher
AU - Robinson, William H.
AU - Seshadri, Anupamaa
AU - Sutherby, Danielle
AU - Seifert, Jennifer
AU - Turner, Jason D.
AU - Utz, Paul J.
AU - Boyce, Brendan F.
AU - DiCarlo, Edward
AU - Perlman, Harris
N1 - Funding Information:
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.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/7/1
Y1 - 2019/7/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41590-019-0378-1
DO - 10.1038/s41590-019-0378-1
M3 - Article
C2 - 31061532
AN - SCOPUS:85065310005
SN - 1529-2908
VL - 20
SP - 928
EP - 942
JO - Nature Immunology
JF - Nature Immunology
IS - 7
ER -