Abstract

Rheumatoid arthritis (RA) is an autoimmune disease involving antigen-specific T and B cells. Here, we perform single-cell RNA and repertoire sequencing on paired synovial tissue and blood samples from 12 seropositive RA patients. We identify clonally expanded CD4 + T cells, including CCL5+ cells and T peripheral helper (Tph) cells, which show a prominent transcriptomic signature of recent activation and effector function. CD8 + T cells show higher oligoclonality than CD4 + T cells, with the largest synovial clones enriched in GZMK+ cells. CD8 + T cells with possibly virus-reactive TCRs are distributed across transcriptomic clusters. In the B cell compartment, NR4A1+ activated B cells, and plasma cells are enriched in the synovium and demonstrate substantial clonal expansion. We identify synovial plasma cells that share BCRs with synovial ABC, memory, and activated B cells. Receptor-ligand analysis predicted IFNG and TNFRSF members as mediators of synovial Tph-B cell interactions. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate the synovium of patients with RA.

Activated B cells and T cells accumulate within joints of patients with rheumatoid arthritis. Here, the authors use single-cell transcriptome and repertoire profiling to identify clonally expanded synovial B cells and T cells and define their phenotypes and predicted cell-cell interactions.

Details

Title
Clonal associations between lymphocyte subsets and functional states in rheumatoid arthritis synovium
Author
Dunlap, Garrett 1   VIAFID ORCID Logo  ; Wagner, Aaron 2 ; Meednu, Nida 3   VIAFID ORCID Logo  ; Wang, Ruoqiao 4   VIAFID ORCID Logo  ; Zhang, Fan 5   VIAFID ORCID Logo  ; Ekabe, Jabea Cyril 3 ; Jonsson, Anna Helena 1   VIAFID ORCID Logo  ; Wei, Kevin 1   VIAFID ORCID Logo  ; Sakaue, Saori 6   VIAFID ORCID Logo  ; Nathan, Aparna 6   VIAFID ORCID Logo  ; Albrecht, Jennifer 3 ; Apruzzese, William 7 ; Barnas, Jennifer L. 3 ; Bathon, Joan M. 8 ; Ben-Artzi, Ami 9 ; Boyce, Brendan F. 10 ; Bridges, S. Louis 11 ; Campbell, Debbie 3 ; Carr, Hayley L. 12 ; Ceponis, Arnold 13 ; Chicoine, Adam 1 ; Cordle, Andrew 14 ; Curtis, Michelle 6 ; Deane, Kevin D. 15 ; DiCarlo, Edward 16 ; Dunn, Patrick 17 ; Forbess, Lindsy 9 ; Geraldino-Pardilla, Laura 8 ; Gravallese, Ellen M. 1 ; Gregersen, Peter K. 18 ; Guthridge, Joel M. 19 ; Horowitz, Diane 18 ; Hughes, Laura B. 20 ; Ishigaki, Kazuyoshi 21 ; Ivashkiv, Lionel B. 11 ; James, Judith A. 19 ; Kang, Joyce B. 6 ; Keras, Gregory 1 ; Korsunsky, Ilya 6 ; Lakhanpal, Amit 11 ; Lederer, James A. 22 ; Li, Yuhong 1 ; Li, Zhihan J. 1 ; Liao, Katherine P. 23 ; Maecker, Holden 24 ; Mandelin, Arthur M. 25 ; Mantel, Ian 11 ; Maybury, Mark 26 ; McGeachy, Mandy J. 27 ; Mears, Joseph 6 ; Nerviani, Alessandra 28 ; Orange, Dana E. 29 ; Perlman, Harris 25 ; Rangel-Moreno, Javier 3 ; Raza, Karim 26 ; Reshef, Yakir 6 ; Ritchlin, Christopher 3 ; Rivellese, Felice 28 ; Robinson, William H. 30 ; Rumker, Laurie 6 ; Sahbudin, Ilfita 26 ; Salomon-Escoto, Karen 31 ; Scheel-Toellner, Dagmar 26 ; Seifert, Jennifer A. 15 ; Singaraju, Anvita 11 ; Smith, Melanie H. 32 ; Utz, Paul J. 30 ; Weinand, Kathryn 6 ; Weisenfeld, Dana 1 ; Weisman, Michael H. 33 ; Xiao, Qian 6 ; Zhu, Zhu 1 ; Bykerk, Vivian P. 11 ; Donlin, Laura T. 11   VIAFID ORCID Logo  ; Goodman, Susan M. 11   VIAFID ORCID Logo  ; Firestein, Gary S. 13 ; Boyle, David L. 13 ; Holers, V. Michael 15   VIAFID ORCID Logo  ; Moreland, Larry W. 34 ; Tabechian, Darren 3 ; Pitzalis, Costantino 35   VIAFID ORCID Logo  ; Filer, Andrew 36   VIAFID ORCID Logo  ; Raychaudhuri, Soumya 6   VIAFID ORCID Logo  ; Brenner, Michael B. 1   VIAFID ORCID Logo  ; Thakar, Juilee 37   VIAFID ORCID Logo  ; McDavid, Andrew 2 ; Rao, Deepak A. 1   VIAFID ORCID Logo  ; Anolik, Jennifer H. 38   VIAFID ORCID Logo 

1  Brigham and Women’s Hospital and Harvard Medical School, Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294) 
2  University of Rochester School of Medicine and Dentistry, Department of Biostatistics and Computational Biology, Rochester, USA (GRID:grid.16416.34) (ISNI:0000 0004 1936 9174) 
3  University of Rochester Medical Center, Division of Allergy, Immunology and Rheumatology, Rochester, USA (GRID:grid.412750.5) (ISNI:0000 0004 1936 9166) 
4  University of Rochester School of Medicine and Dentistry, Department of Microbiology and Immunology, Rochester, USA (GRID:grid.16416.34) (ISNI:0000 0004 1936 9174) 
5  Brigham and Women’s Hospital and Harvard Medical School, Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294); Brigham and Women’s Hospital, Center for Data Sciences, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294); Department of Medicine, Brigham and Women’s Hospital, Division of Genetics, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294); Harvard Medical School, Department of Biomedical Informatics, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623); University of Colorado School of Medicine, Division of Rheumatology and the Center for Health Artificial Intelligence, Aurora, USA (GRID:grid.499234.1) (ISNI:0000 0004 0433 9255) 
6  Brigham and Women’s Hospital and Harvard Medical School, Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294); Brigham and Women’s Hospital, Center for Data Sciences, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294); Department of Medicine, Brigham and Women’s Hospital, Division of Genetics, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294); Harvard Medical School, Department of Biomedical Informatics, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623) 
7  Accelerating Medicines Partnership Program: Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network, Bethesda, USA (GRID:grid.412750.5) 
8  Columbia University College of Physicians and Surgeons, Division of Rheumatology, New York, USA (GRID:grid.21729.3f) (ISNI:0000 0004 1936 8729) 
9  Cedars-Sinai Medical Center, Division of Rheumatology, Los Angeles, USA (GRID:grid.50956.3f) (ISNI:0000 0001 2152 9905) 
10  University of Rochester Medical Center, Department of Pathology and Laboratory Medicine, Rochester, USA (GRID:grid.412750.5) (ISNI:0000 0004 1936 9166) 
11  Hospital for Special Surgery, New York, USA (GRID:grid.239915.5) (ISNI:0000 0001 2285 8823); Weill Cornell Medicine, New York, USA (GRID:grid.471410.7) (ISNI:0000 0001 2179 7643) 
12  University of Birmingham, NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital, Rheumatology Research Group, Institute for Inflammation and Ageing, Birmingham, UK (GRID:grid.6572.6) (ISNI:0000 0004 1936 7486) 
13  University of California, San Diego;, Division of Rheumatology, Allergy and Immunology, La Jolla, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046) 
14  University of Pittsburgh Medical Center, Department of Radiology, Pittsburgh, USA (GRID:grid.412689.0) (ISNI:0000 0001 0650 7433) 
15  University of Colorado School of Medicine, Division of Rheumatology, Aurora, USA (GRID:grid.499234.1) (ISNI:0000 0004 0433 9255) 
16  Hospital for Special Surgery, Department of Pathology and Laboratory Medicine, New York, USA (GRID:grid.239915.5) (ISNI:0000 0001 2285 8823) 
17  National Institute of Allergy and Infectious Diseases, National Institutes of Health, Division of Allergy, Immunology, and Transplantation, Bethesda, USA (GRID:grid.419681.3) (ISNI:0000 0001 2164 9667); Northrop Grumman Health Solutions, Rockville, USA (GRID:grid.421350.1) (ISNI:0000 0004 0634 4349) 
18  Northwell Health, Manhasset, Feinstein Institute for Medical Research, New York, USA (GRID:grid.416477.7) (ISNI:0000 0001 2168 3646) 
19  Oklahoma Medical Research Foundation, Department of Arthritis and Clinical Immunology, Oklahoma City, USA (GRID:grid.274264.1) (ISNI:0000 0000 8527 6890) 
20  University of Alabama at Birmingham, Division of Clinical Immunology and Rheumatology, Department of Medicine, Birmingham, USA (GRID:grid.265892.2) (ISNI:0000 0001 0634 4187) 
21  Brigham and Women’s Hospital and Harvard Medical School, Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294); Brigham and Women’s Hospital, Center for Data Sciences, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294); Department of Medicine, Brigham and Women’s Hospital, Division of Genetics, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294); Harvard Medical School, Department of Biomedical Informatics, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623); RIKEN Center for Integrative Medical Sciences, Laboratory for Human Immunogenetics, Yokohama, Japan (GRID:grid.509459.4) (ISNI:0000 0004 0472 0267) 
22  Brigham and Women’s Hospital and Harvard Medical School, Department of Surgery, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294) 
23  Brigham and Women’s Hospital and Harvard Medical School, Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294); Harvard Medical School, Department of Biomedical Informatics, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
24  Stanford University, Human Immune Monitoring Center, Stanford, USA (GRID:grid.168010.e) (ISNI:0000 0004 1936 8956) 
25  Northwestern University Feinberg School of Medicine, Division of Rheumatology, Department of Medicine, Chicago, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507) 
26  University of Birmingham, NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital, Rheumatology Research Group, Institute for Inflammation and Ageing, Birmingham, UK (GRID:grid.6572.6) (ISNI:0000 0004 1936 7486); University of Birmingham, Queen Elizabeth Hospital, NIHR Birmingham Biomedical Research Center and Clinical Research Facility, Birmingham, UK (GRID:grid.6572.6) (ISNI:0000 0004 1936 7486) 
27  University of Pittsburgh School of Medicine, Division of Rheumatology and Clinical Immunology, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
28  Queen Mary University of London, Centre for Experimental Medicine & Rheumatology, EULAR Centre of Excellence, William Harvey Research Institute, London, UK (GRID:grid.4868.2) (ISNI:0000 0001 2171 1133); National Institute for Health and Care Research (NIHR), Barts Health NHS Trust, Barts Biomedical Research Centre (BRC), London, UK (GRID:grid.139534.9) (ISNI:0000 0001 0372 5777) 
29  Hospital for Special Surgery, New York, USA (GRID:grid.239915.5) (ISNI:0000 0001 2285 8823); The Rockefeller University, Laboratory of Molecular Neuro-Oncology, New York, USA (GRID:grid.134907.8) (ISNI:0000 0001 2166 1519) 
30  Stanford University School of Medicine, Division of Immunology and Rheumatology, Institute for Immunity, Transplantation and Infection, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
31  University of Massachusetts Chan Medical School, Division of Rheumatology, Department of Medicine, Worcester, USA (GRID:grid.168645.8) (ISNI:0000 0001 0742 0364) 
32  Hospital for Special Surgery, New York, USA (GRID:grid.239915.5) (ISNI:0000 0001 2285 8823) 
33  Cedars-Sinai Medical Center, Division of Rheumatology, Los Angeles, USA (GRID:grid.50956.3f) (ISNI:0000 0001 2152 9905); Stanford University School of Medicine, Division of Immunology and Rheumatology, Institute for Immunity, Transplantation and Infection, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
34  University of Colorado School of Medicine, Division of Rheumatology, Aurora, USA (GRID:grid.499234.1) (ISNI:0000 0004 0433 9255); University of Pittsburgh School of Medicine, Division of Rheumatology and Clinical Immunology, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
35  Queen Mary University of London, Centre for Experimental Medicine & Rheumatology, EULAR Centre of Excellence, William Harvey Research Institute, London, UK (GRID:grid.4868.2) (ISNI:0000 0001 2171 1133); National Institute for Health and Care Research (NIHR), Barts Health NHS Trust, Barts Biomedical Research Centre (BRC), London, UK (GRID:grid.139534.9) (ISNI:0000 0001 0372 5777); Humanitas University and Humanitas Research Hospital, Department of Biomedical Sciences, Milan, Italy (GRID:grid.452490.e) (ISNI:0000 0004 4908 9368) 
36  University of Birmingham, NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital, Rheumatology Research Group, Institute for Inflammation and Ageing, Birmingham, UK (GRID:grid.6572.6) (ISNI:0000 0004 1936 7486); University of Birmingham, Birmingham Tissue Analytics, Institute of Translational Medicine, Birmingham, UK (GRID:grid.6572.6) (ISNI:0000 0004 1936 7486); University of Birmingham, Queen Elizabeth Hospital, NIHR Birmingham Biomedical Research Center and Clinical Research Facility, Birmingham, UK (GRID:grid.6572.6) (ISNI:0000 0004 1936 7486) 
37  University of Rochester School of Medicine and Dentistry, Department of Biostatistics and Computational Biology, Rochester, USA (GRID:grid.16416.34) (ISNI:0000 0004 1936 9174); University of Rochester School of Medicine and Dentistry, Department of Microbiology and Immunology, Rochester, USA (GRID:grid.16416.34) (ISNI:0000 0004 1936 9174) 
38  University of Rochester Medical Center, Division of Allergy, Immunology and Rheumatology, Rochester, USA (GRID:grid.412750.5) (ISNI:0000 0004 1936 9166); University of Rochester School of Medicine and Dentistry, Department of Microbiology and Immunology, Rochester, USA (GRID:grid.16416.34) (ISNI:0000 0004 1936 9174) 
Pages
4991
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-024-49186-0
ProQuest document ID
3066598783
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.