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

  • Author(s): Zhang, Fan
  • Wei, Kevin
  • Slowikowski, Kamil
  • Fonseka, Chamith Y
  • Rao, Deepak A
  • Kelly, Stephen
  • Goodman, Susan M
  • Tabechian, Darren
  • Hughes, Laura B
  • Salomon-Escoto, Karen
  • Watts, Gerald FM
  • Jonsson, A Helena
  • Rangel-Moreno, Javier
  • Meednu, Nida
  • Rozo, Cristina
  • Apruzzese, William
  • Eisenhaure, Thomas M
  • Lieb, David J
  • Boyle, David L
  • Mandelin, Arthur M
  • Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium
  • Boyce, Brendan F
  • DiCarlo, Edward
  • Gravallese, Ellen M
  • Gregersen, Peter K
  • Moreland, Larry
  • Firestein, Gary S
  • Hacohen, Nir
  • Nusbaum, Chad
  • Lederer, James A
  • Perlman, Harris
  • Pitzalis, Costantino
  • Filer, Andrew
  • Holers, V Michael
  • Bykerk, Vivian P
  • Donlin, Laura T
  • Anolik, Jennifer H
  • Brenner, Michael B
  • Raychaudhuri, Soumya
  • et al.

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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