Systemic juvenile idiopathic arthritis (sJIA) is a severe autoinflammatory disorder characterized by persistent systemic inflammation, immune dysregulation, and progressive joint destruction. Despite advances in biologic therapies targeting inflammatory cytokines, the immunopathological mechanisms driving disease initiation and progression remain incompletely understood.
In this multicenter investigation published in Genes & Diseases, researchers from Children's Hospital of Chongqing Medical University, Shenzhen Children's Hospital, Nanjing Children's Hospital, North China University of Science and Technology, and Chinese Academy of Medical Sciences comprehensively characterized peripheral immune alterations in sJIA and identified a distinct CD14+CXCL10+ monocyte subpopulation associated with inflammatory network remodeling and disease activity.
Using single-cell RNA sequencing, flow cytometry, cytokine profiling, and transcriptomic analyses across multiple clinical centers, the study systematically evaluated immune-cell heterogeneity in peripheral blood samples derived from patients with active sJIA, inactive disease, and healthy controls. The analyses revealed substantial remodeling of the peripheral immune landscape in active sJIA, marked by expansion of inflammatory myeloid populations and dysregulation of adaptive immune compartments. Among these alterations, a CD14+CXCL10+ monocyte subset emerged as a dominant inflammatory population significantly enriched in active disease states.
The transcriptomic signature of this monocyte subset is characterized by a unique enrichment of immune regulatory genes, including ETV7, HELZ2, and PNPT1, alongside regulators of innate immune signaling such as TLR7 and TRIM5. Functional enrichment analysis reveals that these cells exist in a heightened state of immune surveillance, characterized by enhanced antigen presentation, oxidative stress responses, and metabolic adaptation.
Trajectory inference models further indicate that monocytes in sJIA patients undergo a distinct proinflammatory differentiation process, transitioning from a poised state toward the highly inflammatory CD14+ CXCL10+ phenotype. This is marked by the sustained activation of the NOD-like receptor (NLR) signaling pathway and increased metabolic activity, particularly ATP biosynthesis.
Intercellular communication analysis suggests that these monocytes actively participate in a complex immune network, integrating signals from T cells and NK cells that drive their inflammatory activation. Specific ligand-receptor interactions, such as those involving CCL4, CD28, and HLA-DRA, regulate key downstream inflammatory genes in this monocyte subset, including IL1B and CXCL8.
The authors identified that UBE2D1, a gene that is selectively upregulated in sJIA and positively correlates with the expression of key cytokines, drives the inflammatory program. Validation using Ube2d1-deficient mouse models in collagen antibody-induced arthritis (CAIA) demonstrated significantly attenuated joint inflammation, reduced bone erosion, and impaired recruitment of inflammatory macrophages compared to wild-type mice. These findings suggest that UBE2D1 acts as a pivotal amplifier of the inflammatory response by modulating NLR signaling and ubiquitination-dependent pathways. Consequently, the UBE2D1-driven CD14+ CXCL10+ monocyte axis represents a promising biomarker for monitoring disease activity and a potential therapeutic target for precision intervention in sJIA.
Collectively, this study provides a comprehensive characterization of peripheral immune dysregulation in systemic juvenile idiopathic arthritis and identifies CD14+CXCL10+ monocytes as a critical inflammatory population associated with immune-network alterations. The findings expand current understanding of sJIA immunopathogenesis while highlighting potential biomarkers and therapeutic targets for precision immunomodulatory strategies in systemic inflammatory disease.
Reference
Title of the original paper: CD14+CXCL10+ monocytes are associated with peripheral immune network alterations in systemic juvenile idiopathic arthritis: From multiple centers
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101942
