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A comprehensive transcriptomic analysis of alternate interferon signaling pathways in peripheral blood mononuclear cells in rheumatoid arthritis.

ABSTRACT: Interferon (IFN) signaling pathways play crucial roles in the pathogenesis of rheumatoid arthritis (RA). Prior studies have mainly studied mixed alterations in the IFN signaling pathway in RA, but these studies have not been sufficient to elucidate how imbalanced IFN signaling subtly influences immune cells. Single-cell RNA (scRNA) sequencing makes it possible to better understand the alternations in the interferon signaling pathways in RA. In the present study, we found that IFN signaling pathways were activated in natural killer (NK) cells, monocytes, T cells, B cells, and most immune cell subclasses in RA. We then explored and analyzed the connections between abnormal IFN signaling pathways and cellular functional changes in RA. Single-Cell rEgulatory Network Inference and Clustering (SCENIC) analysis and gene regulatory network (GRN) construction were also performed to identify key transcription factors in RA. Finally, we also investigated altered IFN signaling pathways in multiple RA peripheral blood samples, which indicated that abnormal IFN signaling pathways were universally observed in RA. Our study contributes to a better understanding of the delicate and precise regulation of IFN signaling in the immune system in RA. Furthermore, common alternations in IFN signaling pathway-related transcription factors could help to identify novel therapeutic targets for RA treatment.

SUBMITTER: Han L

PROVIDER: S-EPMC8436925 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The factors responsible for radiographic severity in African American patients with rheumatoid arthritis (RA) are poorly understood. We sought to identify genes whose expression in peripheral blood mononuclear cells is associated with radiographic severity in RA.In the first phase of the study, we performed real-time quantitative polymerase chain reaction to analyze the expression of 182 candidate genes in 40 African American RA patients with extremes of radiographic damage (low versus high radiographic scores) and disease duration (?2 years versus >2 years) and 20 healthy African American control subjects; the genes were selected based on plausible immune pathways. In the second phase, we analyzed the expression of the genes that were shown to be significantly associated with radiographic scores in 576 African American patients with RA and 51 African American control subjects who had not been studied previously, accounting for autoantibody status and disease duration.We observed significant differences in IFNGR1 expression between patients with RA and control subjects (adjusted P [P(adj)]?=?6 × 10(-14)) and in IFNGR2 expression between RA patients with erosions and those with no erosions (P(adj) =?0.01 by Wilcoxon's rank sum test). We also observed significant correlations between IFNGR2 expression and radiographic scores (P(adj) =?0.03 for erosions, P(adj) =?0.04 for joint space narrowing, and P(adj) =?0.03 for total radiographic score [zero-inflated negative binomial regression model]) and annualized progression rate (P(adj) =?0.0024 by Spearman's correlation analysis).These findings have important implications with respect to the role of interferon-? (IFN?) in the pathogenesis of RA and may lead to identification of a biomarker for radiographic damage. Additional studies are needed to define the cell subsets responsible for the association of IFN? receptor gene expression with radiographic findings, which downstream mechanisms are involved, and generalizability to other RA populations.

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A comprehensive transcriptomic analysis of alternate interferon signaling pathways in peripheral blood mononuclear cells in rheumatoid arthritis.

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