CD14⁺CXCL10⁺ monocytes are associated with peripheral immune network alterations in systemic juvenile idiopathic...

Systemic juvenile idiopathic arthritis (sJIA) is an autoinflammatory disorder characterized by systemic immune dysregulation, yet reliable biomarkers to predict its unpredictable disease course are lacking. Identifying immune cell subsets and molecular drivers of disease progression is essential for improving prognosis and developing targeted therapies. Here, we performed comprehensive immunophenotypic profiling of PBMCs from sJIA patients across five clinical centers. We identified an unrecognized CD14⁺CXCL10⁺ monocyte subset in sJIA distinguished by a unique transcriptomic signature enriched in immune regulatory genes. Deconvolution analysis with longitudinal follow-up in the Chongqing cohort revealed a previously unrecognized CD14⁺CXCL10⁺ monocyte subset that was markedly expanded during active sJIA and diminished during remission, correlating strongly with disease activity. Flow cytometry confirmed its dynamic changes, and in vitro inflammatory stimulation promoted the differentiation of monocytes into the CXCL10 phenotype. To validate these observations in vivo, we used Ube2d1 knockout mice, which exhibit impaired CXCL10 induction and attenuated arthritis severity, highlighting the pivotal role of Ube2d1 in driving this inflammatory program. Furthermore, a cross-disease single-cell reference atlas demonstrated that this monocyte subset displayed a distinct expression profile in sJIA compared with other JIA subtypes and inflammation-related diseases. Collectively, our findings indicate that UBE2D1-driven CD14⁺CXCL10⁺ monocytes are central to sJIA pathogenesis and may represent both a biomarker and a therapeutic target for disease monitoring and intervention.