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, A Helena Jonsson, Javier Rangel-Moreno, Nida Meednu, Cristina Rozo, William Apruzzese, Thomas M Eisenhaure, David J Lieb, David L Boyle, Arthur M Mandelin 2nd, Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium, 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, Jennifer Albrecht, S Louis Bridges Jr, Christopher D Buckley, Jane H Buckner, James Dolan, Joel M Guthridge, Maria Gutierrez-Arcelus, Lionel B Ivashkiv, Eddie A James, Judith A James, Josh Keegan, Yvonne C Lee, Mandy J McGeachy, Michael A McNamara, Joseph R Mears, Fumitaka Mizoguchi, Jennifer P Nguyen, Akiko Noma, Dana E Orange, Mina Rohani-Pichavant, Christopher Ritchlin, William H Robinson, Anupamaa Seshadri, Danielle Sutherby, Jennifer Seifert, Jason D Turner, Paul J Utz, 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, A Helena Jonsson, Javier Rangel-Moreno, Nida Meednu, Cristina Rozo, William Apruzzese, Thomas M Eisenhaure, David J Lieb, David L Boyle, Arthur M Mandelin 2nd, Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium, 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, Jennifer Albrecht, S Louis Bridges Jr, Christopher D Buckley, Jane H Buckner, James Dolan, Joel M Guthridge, Maria Gutierrez-Arcelus, Lionel B Ivashkiv, Eddie A James, Judith A James, Josh Keegan, Yvonne C Lee, Mandy J McGeachy, Michael A McNamara, Joseph R Mears, Fumitaka Mizoguchi, Jennifer P Nguyen, Akiko Noma, Dana E Orange, Mina Rohani-Pichavant, Christopher Ritchlin, William H Robinson, Anupamaa Seshadri, Danielle Sutherby, Jennifer Seifert, Jason D Turner, Paul J Utz
Abstract
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.
Conflict of interest statement
COMPETING FINANCIAL INTERESTS
The authors declare no competing financial interests.
Figures
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Source: PubMed