Clonal associations between lymphocyte subsets and functional states in rheumatoid arthritis synovium

Garrett Dunlap, Aaron Wagner, Nida Meednu, Ruoqiao Wang, Fan Zhang, Jabea Cyril Ekabe, Anna Helena Jonsson, Kevin Wei, Saori Sakaue, Aparna Nathan, Vivian P. Bykerk, Laura T. Donlin, Susan M. Goodman, Gary S. Firestein, David L. Boyle, V. Michael Holers, Larry W. Moreland, Darren Tabechian, Costantino Pitzalis, Andrew Filer, Soumya Raychaudhuri, Michael B. Brenner, Juilee Thakar, Andrew McDavid, Deepak A. Rao () and Jennifer H. Anolik ()
Additional contact information
Garrett Dunlap: Brigham and Women’s Hospital and Harvard Medical School
Aaron Wagner: University of Rochester School of Medicine and Dentistry
Nida Meednu: University of Rochester Medical Center
Ruoqiao Wang: University of Rochester School of Medicine and Dentistry
Fan Zhang: Brigham and Women’s Hospital and Harvard Medical School
Jabea Cyril Ekabe: University of Rochester Medical Center
Anna Helena Jonsson: Brigham and Women’s Hospital and Harvard Medical School
Kevin Wei: Brigham and Women’s Hospital and Harvard Medical School
Saori Sakaue: Brigham and Women’s Hospital and Harvard Medical School
Aparna Nathan: Brigham and Women’s Hospital and Harvard Medical School
Vivian P. Bykerk: Hospital for Special Surgery
Laura T. Donlin: Hospital for Special Surgery
Susan M. Goodman: Hospital for Special Surgery
Gary S. Firestein: University of California, San Diego;
David L. Boyle: University of California, San Diego;
V. Michael Holers: University of Colorado School of Medicine
Larry W. Moreland: University of Colorado School of Medicine
Darren Tabechian: University of Rochester Medical Center
Costantino Pitzalis: Queen Mary University of London
Andrew Filer: University of Birmingham, NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital
Soumya Raychaudhuri: Brigham and Women’s Hospital and Harvard Medical School
Michael B. Brenner: Brigham and Women’s Hospital and Harvard Medical School
Juilee Thakar: University of Rochester School of Medicine and Dentistry
Andrew McDavid: University of Rochester School of Medicine and Dentistry
Deepak A. Rao: Brigham and Women’s Hospital and Harvard Medical School
Jennifer H. Anolik: University of Rochester Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49186-0

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