Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry.
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 F M,Jonsson A Helena,Rangel-Moreno Javier,Meednu Nida,Rozo Cristina,Apruzzese William,Eisenhaure Thomas M,Lieb David J,Boyle David L,Mandelin Arthur M, ,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
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 sublining fibroblasts, IL1B pro-inflammatory monocytes, ITGAXTBX21 autoimmune-associated B cells and PDCD1 peripheral helper T (T) cells and follicular helper T (T) 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 THY1HLA-DRA fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.