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Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry NATURE IMMUNOLOGY Zhang, F., Wei, K., Slowikowski, K., Fonseka, C. Y., Rao, D. A., Kelly, S., Goodman, S. M., Tabechian, D., Hughes, L. B., Salomon-Escoto, K., Watts, G. M., Jonsson, A., Rangel-Moreno, J., Meednu, N., Rozo, C., Apruzzese, W., Eisenhaure, T. M., Lieb, D. J., Boyle, D. L., Mandelin, A. M., Boyce, B. F., DiCarlo, E., Gravallese, E. M., Gregersen, P. K., Moreland, L., Firestein, G. S., Hacohen, N., Nusbaum, C., Lederer, J. A., Perlman, H., Pitzalis, C., Filer, A., Holers, V., Bykerk, V. P., Donlin, L. T., Anolik, J. H., Brenner, M. B., Raychaudhuri, S., Albrecht, J., Bridges, S., Buckley, C. D., Buckner, J. H., Dolan, J., Guthridge, J. M., Gutierrez-Arcelus, M., Ivashkiv, L. B., James, E. A., James, J. A., Keegan, J., Lee, Y. C., McGeachy, M. J., McNamara, M. A., Mears, J. R., Mizoguchi, F., Nguyen, J. P., Noma, A., Orange, D. E., Rohani-Pichavant, M., Ritchlin, C., Robinson, W. H., Seshadri, A., Sutherby, D., Seifert, J., Turner, J. D., Utz, P. J., Accelerating Medicines Partnersh 2019; 20 (7): 928-+

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.

View details for DOI 10.1038/s41590-019-0378-1

View details for Web of Science ID 000471891900022

View details for PubMedID 31061532