Immunomics analysis of rheumatoid arthritis identified precursor dendritic cells as a key cell subset of treatment resistance

作者：Saeko Yamada, Yasuo Nagafuchi, Min Wang, Mineto Ota, Hiroaki Hatano, Yusuke Takeshima, Mai Okubo, Satomi Kobayashi, Yusuke Sugimori, M Nakano, Ryochi Yoshida, Norio Hanata, Yuichi Suwa, Yumi Tsuchida, Yukiko Iwasaki, Shuji Sumitomo, Kanae Kubo, Kenichi Shimane, Keigo Setoguchi, Takanori Azuma, Hiroko Kanda, Hirofumi Shoda, Xuan Zhang, Kazuhiko Yamamoto, Kazuyoshi Ishigaki, Tomohisa Okamura, Keishi Fujio · 发表于：Annals of the Rheumatic Diseases · 年份：2023 · DOI：10.1136/ard-2022-223645 · 被引用次数：39 · 研究领域：Rheumatoid Arthritis Research and Therapies、Immunotherapy and Immune Responses、Cancer Immunotherapy and Biomarkers

OBJECTIVES: Little is known about the immunology underlying variable treatment response in rheumatoid arthritis (RA). We performed large-scale transcriptome analyses of peripheral blood immune cell subsets to identify immune cells that predict treatment resistance. METHODS: We isolated 18 peripheral blood immune cell subsets of 55 patients with RA requiring addition of new treatment and 39 healthy controls, and performed RNA sequencing. Transcriptome changes in RA and treatment effects were systematically characterised. Association between immune cell gene modules and treatment resistance was evaluated. We validated predictive value of identified parameters for treatment resistance using quantitative PCR (qPCR) and mass cytometric analysis cohorts. We also characterised the identified population by synovial single cell RNA-sequencing analysis. RESULTS: Immune cells of patients with RA were characterised by enhanced interferon and IL6-JAK-STAT3 signalling that demonstrate partial normalisation after treatment. A gene expression module of plasmacytoid dendritic cells (pDC) reflecting the expansion of dendritic cell precursors (pre-DC) exhibited strongest association with treatment resistance. Type I interferon signalling was negatively correlated to pre-DC gene expression. qPCR and mass cytometric analysis in independent cohorts validated that the pre-DC associated gene expression and the proportion of pre-DC were significantly higher before treatment in treatment-resistant pat...