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Defining Inflammatory Cell States in Rheumatoid Arthritis Joint Synovial Tissues by Integrating Single-cell Transcriptomics and Mass Cytometry

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, William Apruzzese, David J. Lieb, David L. Boyle, Arthur M. Mandelin II, Accelerating Medicines Partnership: RA Phase 1, AMP RA/SLE, 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
doi: https://doi.org/10.1101/351130
Fan Zhang
1Center for Data Sciences, Brigham and Women’s Hospital, Boston, MA 02115, USA
2Division of Rheumatology and Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
3Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115 USA
4Broad Institute of Massachusetts Institute and Technology and Harvard University, Cambridge, MA 02142, USA
5Division of Rheumatology, Immunology, Allergy, Brigham and Women’s Hospital and Harvard Medical School, MA 02115, USA
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Kevin Wei
5Division of Rheumatology, Immunology, Allergy, Brigham and Women’s Hospital and Harvard Medical School, MA 02115, USA
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Kamil Slowikowski
1Center for Data Sciences, Brigham and Women’s Hospital, Boston, MA 02115, USA
2Division of Rheumatology and Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
3Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115 USA
4Broad Institute of Massachusetts Institute and Technology and Harvard University, Cambridge, MA 02142, USA
5Division of Rheumatology, Immunology, Allergy, Brigham and Women’s Hospital and Harvard Medical School, MA 02115, USA
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Chamith Y. Fonseka
1Center for Data Sciences, Brigham and Women’s Hospital, Boston, MA 02115, USA
2Division of Rheumatology and Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
3Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115 USA
4Broad Institute of Massachusetts Institute and Technology and Harvard University, Cambridge, MA 02142, USA
5Division of Rheumatology, Immunology, Allergy, Brigham and Women’s Hospital and Harvard Medical School, MA 02115, USA
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Deepak A. Rao
5Division of Rheumatology, Immunology, Allergy, Brigham and Women’s Hospital and Harvard Medical School, MA 02115, USA
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Stephen Kelly
6Department of Rheumatology, Barts Health NHS Trust, London, E1 1BB, UK
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Susan M. Goodman
7Division of Rheumatology, Hospital for Special Surgery, New York, NY 10021, USA
8Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
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Darren Tabechian
9Division of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
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Laura B. Hughes
10Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA
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Karen Salomon-Escoto
11Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
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Gerald F. M. Watts
5Division of Rheumatology, Immunology, Allergy, Brigham and Women’s Hospital and Harvard Medical School, MA 02115, USA
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William Apruzzese
5Division of Rheumatology, Immunology, Allergy, Brigham and Women’s Hospital and Harvard Medical School, MA 02115, USA
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David J. Lieb
4Broad Institute of Massachusetts Institute and Technology and Harvard University, Cambridge, MA 02142, USA
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David L. Boyle
12Department of Medicine, Division of Rheumatology, Allergy and Immunology, University of California, San Diego, La Jolla, CA 92093 USA
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Arthur M. Mandelin II
13Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine. Chicago, IL 60611, USA
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14AMP RA Phase 1: full list of members and affiliations appears in the end of the paper
Brendan F. Boyce
15Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
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Edward DiCarlo
8Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
16Department of Pathology and Laboratory Medicine, Hospital for Special Surgery, New York, NY 10021, USA
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Ellen M. Gravallese
11Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
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Peter K. Gregersen
17Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, NY 11030, USA
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Larry Moreland
18Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 USA
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Gary S. Firestein
12Department of Medicine, Division of Rheumatology, Allergy and Immunology, University of California, San Diego, La Jolla, CA 92093 USA
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Nir Hacohen
4Broad Institute of Massachusetts Institute and Technology and Harvard University, Cambridge, MA 02142, USA
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Chad Nusbaum
4Broad Institute of Massachusetts Institute and Technology and Harvard University, Cambridge, MA 02142, USA
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James A. Lederer
19Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, MA 02115, USA
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Harris Perlman
13Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine. Chicago, IL 60611, USA
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Costantino Pitzalis
20Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute, Queen Mary University of London, E1 4NS, UK
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Andrew Filer
21Rheumatology Research Group, Institute of Inflammation and Ageing, The University of Birmingham, Birmingham, B15 2WB, UK
22University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK
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V. Michael Holers
23Division of Rheumatology, University of Colorado School of Medicine, Aurora, CO 80220, USA
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Vivian P. Bykerk
1Center for Data Sciences, Brigham and Women’s Hospital, Boston, MA 02115, USA
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Laura T. Donlin
8Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
24Arthritis and Tissue Degeneration, Hospital for Special Surgery, New York, NY 10021, USA
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Jennifer H. Anolik
9Division of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
25Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA
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Michael B. Brenner
5Division of Rheumatology, Immunology, Allergy, Brigham and Women’s Hospital and Harvard Medical School, MA 02115, USA
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Soumya Raychaudhuri
1Center for Data Sciences, Brigham and Women’s Hospital, Boston, MA 02115, USA
2Division of Rheumatology and Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
3Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115 USA
4Broad Institute of Massachusetts Institute and Technology and Harvard University, Cambridge, MA 02142, USA
5Division of Rheumatology, Immunology, Allergy, Brigham and Women’s Hospital and Harvard Medical School, MA 02115, USA
26Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK
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Abstract

To define the cell populations in rheumatoid arthritis (RA) driving joint inflammation, we applied single-cell RNA-seq (scRNA-seq), mass cytometry, bulk RNA-seq, and flow cytometry to sorted T cells, B cells, monocytes, and fibroblasts from 51 synovial tissue RA and osteoarthritis (OA) patient samples. Utilizing an integrated computational strategy based on canonical correlation analysis to 5,452 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics together revealed cell states expanded in RA synovia: THY1+HLAhigh sublining fibroblasts (OR=33.8), IL1B+ pro-inflammatory monocytes (OR=7.8), CD11c+T-bet+ autoimmune-associated B cells (OR=5.7), and PD-1+Tph/Tfh (OR=3.0). We also defined CD8+ T cell subsets characterized by GZMK+, GZMB+, and GNLY+ expression. Using bulk and single-cell data, we mapped inflammatory mediators to source cell populations, for example attributing IL6 production to THY1+HLAhigh fibroblasts and naïve B cells, and IL1B to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.

Footnotes

  • ↵^ Co-first authors

  • ↵* Co-senior authors

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Defining Inflammatory Cell States in Rheumatoid Arthritis Joint Synovial Tissues by Integrating Single-cell Transcriptomics and Mass Cytometry
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, William Apruzzese, David J. Lieb, David L. Boyle, Arthur M. Mandelin II, Accelerating Medicines Partnership: RA Phase 1, AMP RA/SLE, 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
bioRxiv 351130; doi: https://doi.org/10.1101/351130
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Defining Inflammatory Cell States in Rheumatoid Arthritis Joint Synovial Tissues by Integrating Single-cell Transcriptomics and Mass Cytometry
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, William Apruzzese, David J. Lieb, David L. Boyle, Arthur M. Mandelin II, Accelerating Medicines Partnership: RA Phase 1, AMP RA/SLE, 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
bioRxiv 351130; doi: https://doi.org/10.1101/351130

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