Single-cell RNA-seq analysis reveals cell subsets and gene signatures associated with Rheumatoid Arthritis Disease Activity

类风湿性关节炎 下调和上调 基因 细胞 外周血单个核细胞 单核细胞 T细胞 基因表达 生物 医学 遗传学 转录组 免疫学 免疫系统 体外
作者
Marie Binvignat,Brenda Miao,Camilla Wibrand,Monica M. Yang,Dmitry Rychkov,Emily Flynn,Joanne Nititham,Whitney Tamaki,Umair Khan,Alexander Carvidi,Melissa Krueger,Erene C. Niemi,Yang Sun,Gabriela K. Fragiadakis,Jérémie Sellam,Encarnita Mariotti‐Ferrandiz,David Klatzmann,Joanne Nititham,Chun Ye,Atul J. Butte,Laura Trupin,Mary C. Nakamura,Marina Sirota
出处
期刊:JCI insight [American Society for Clinical Investigation]
标识
DOI:10.1172/jci.insight.178499
摘要

Rheumatoid arthritis (RA) management lean toward achieving remission or low-disease activity. In this study, we conducted single-cell RNA sequencing (scRNAseq) of peripheral blood mononuclear cells (PBMCs) from 36 individuals (18 RA patients and 18 matched controls, accounting for age, sex, race, and ethnicity), to identify disease-relevant cell subsets and cell type-specific signatures associated with disease activity. Our analysis revealed 18 distinct PBMC subsets, including an IFITM3 overexpressing Interferon-activated (IFN-activated) monocyte subset. We observed an increase in CD4+ T effector memory cells in patients with moderate to high disease activity (DAS28-CRP ≥ 3.2), and a decrease in non-classical monocytes in patients with low disease activity or remission (DAS28-CRP < 3.2). Pseudobulk analysis by cell type identified 168 differentially expressed genes between RA and matched controls, with a downregulation of pro-inflammatory genes in the gamma-delta T cells subset, alteration of genes associated with RA predisposition in the IFN-activated subset, and non-classical monocytes. Additionally, we identified a gene signature associated with moderate-high disease activity, characterized by upregulation of pro-inflammatory genes such as TNF, JUN, EGR1, IFIT2, MAFB, G0S2, and downregulation of genes including HLA-DQB1, HLA-DRB5, TNFSF13B. Notably, cell-cell communication analysis revealed an upregulation of signaling pathways, including VISTA, in both moderate-high and remission-low disease activity contexts. Our findings provide valuable insights into the systemic cellular and molecular mechanisms underlying RA disease activity.
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