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, C. Y.; Rao, D. A.; Kelly, S.; Goodman, S. M.; Tabechian, D.; Hughes, L. B.; Salomon-Escoto, K.; Watts, G. F. M.; Apruzzese, W.; Lieb, D. J.; Boyle, D. L.; Mandelin, A. M.; Accelerating Medicines Partnership: RA Phase 1,; AMP RA/SLE,; 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. M.; Bykerk, V. P.; Donlin, L. T.; Anolik, J. H.; Brenner, M. B.; Raychaudhuri, S.

doi:10.1101/351130

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bioRxiv · 10.1101/351130

Defining Inflammatory Cell States in Rheumatoid Arthritis Joint Synovial Tissues by Integrating Single-cell Transcriptomics and Mass Cytometry

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Abstract

To define the cell populations in rheumatoid arthritis (RA) driving joint inflammation, we applied single-cell RNA-seq (scRNA-seq), mass cytometry, bulk RNA-seq, and flow cytometry to sorted T cells, B cells, monocytes, and fibroblasts from 51 synovial tissue RA and osteoarthritis (OA) patient samples. Utilizing an integrated computational strategy based on canonical correlation analysis to 5,452 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics together revealed cell states expanded in RA synovia: THY1+HLAhigh sublining fibroblasts (OR=33.8), IL1B+ pro-inflammatory monocytes (OR=7.8), CD11c+T-bet+ autoimmune-associated B cells (OR=5.7), and PD-1+Tph/Tfh (OR=3.0). We also defined CD8+ T cell subsets characterized by GZMK+, GZMB+, and GNLY+ expression. Using bulk and single-cell data, we mapped inflammatory mediators to source cell populations, for example attributing IL6 production to THY1+HLAhigh fibroblasts and naive B cells, and IL1B to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.

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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. F. M., Apruzzese, W., Lieb, D. J., Boyle, D. L., Mandelin, A. M., Accelerating Medicines Partnership: RA Phase 1,, AMP RA/SLE,, 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. M., Bykerk, V. P., Donlin, L. T., Anolik, J. H., Brenner, M. B., Raychaudhuri, S.. 2018-06-20. Defining Inflammatory Cell States in Rheumatoid Arthritis Joint Synovial Tissues by Integrating Single-cell Transcriptomics and Mass Cytometry. https://doi.org/10.1101/351130

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