Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry
Zhang F., Wei K., Slowikowski K., Fonseka CY., Rao DA., Kelly S., Goodman SM., Tabechian D., Hughes LB., Salomon-Escoto K., Watts GFM., Jonsson AH., Rangel-Moreno J., Meednu N., Rozo C., Apruzzese W., Eisenhaure TM., Lieb DJ., Boyle DL., Mandelin AM., Albrecht J., Bridges SL., Buckley CD., Buckner JH., Dolan J., Guthridge JM., Gutierrez-Arcelus M., Ivashkiv LB., James EA., James JA., Keegan J., Lee YC., McGeachy MJ., McNamara MA., Mears JR., Mizoguchi F., Nguyen JP., Noma A., Orange DE., Rohani-Pichavant M., Ritchlin C., Robinson WH., Seshadri A., Sutherby D., Seifert J., Turner JD., Utz PJ., Boyce BF., DiCarlo E., Gravallese EM., Gregersen PK., Moreland L., Firestein GS., Hacohen N., Nusbaum C., Lederer JA., Perlman H., Pitzalis C., Filer A., Holers VM., Bykerk VP., Donlin LT., Anolik JH., Brenner MB., Raychaudhuri S.
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. 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-DRA hi sublining fibroblasts, IL1B + pro-inflammatory monocytes, ITGAX + TBX21 + autoimmune-associated B cells and PDCD1 + peripheral helper T (T PH ) cells and follicular helper T (T FH ) 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-DRA hi fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.