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Single-cell RNA-Seq analysis reveals cell subsets and gene signatures associated with rheumatoid arthritis disease activity.
- Binvignat, Marie;
- Miao, Brenda;
- Wibrand, Camilla;
- Yang, Monica;
- Rychkov, Dmitry;
- Flynn, Emily;
- Nititham, Joanne;
- Tamaki, Whitney;
- Khan, Umair;
- Carvidi, Alexander;
- Krueger, Melissa;
- Niemi, Erene;
- Sun, Yang;
- Fragiadakis, Gabriela;
- Sellam, Jérémie;
- Mariotti-Ferrandiz, Encarnita;
- Klatzmann, David;
- Gross, Andrew;
- Ye, Chun;
- Butte, Atul;
- Criswell, Lindsey;
- Nakamura, Mary;
- Sirota, Marina
- et al.
Published Web Location
https://doi.org/10.1172/jci.insight.178499Abstract
Rheumatoid arthritis (RA) management leans toward achieving remission or low disease activity. In this study, we conducted single-cell RNA sequencing (scRNA-Seq) of peripheral blood mononuclear cells (PBMCs) from 36 individuals (18 patients with RA 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 IFN-induced transmembrane 3-overexpressing (IFITM3-overexpressing) IFN-activated monocyte subset. We observed an increase in CD4+ T effector memory cells in patients with moderate-high disease activity (DAS28-CRP ≥ 3.2) and a decrease in nonclassical 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 proinflammatory genes in the γδ T cell subset, alteration of genes associated with RA predisposition in the IFN-activated subset, and nonclassical monocytes. Additionally, we identified a gene signature associated with moderate-high disease activity, characterized by upregulation of proinflammatory genes such as TNF, JUN, EGR1, IFIT2, MAFB, and G0S2 and downregulation of genes including HLA-DQB1, HLA-DRB5, and 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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