Type I interferon endotypes drive divergent clinical trajectories in childhood-onset SLE uncovered through a novel systems immunology approach.

Abstract

Childhood-onset systemic lupus erythematosus (cSLE) is a severe autoimmune disease with significant morbidity and enhanced type I interferon (IFN-I) signalling, potentially contributing to its aggressive clinical course. This study aimed to deliver the most comprehensive multiomic characterisation of IFN-I signalling in cSLE, defining its heterogeneity at transcriptomic, proteomic, and cellular levels, and linking these profiles to detailed clinical trajectories. We profiled 74 young females with cSLE and 20 matched controls using RNA-sequencing of peripheral blood mononuclear cells, single molecule array (SIMOA) for IFNα quantification, IFN-I luciferase reporter cells, spectral flow cytometry, and Olink proteomics (validated by enzyme-linked immunosorbent assay, (ELISA)). Clinical data were assessed in endotype groups based on IFN-I readouts with longitudinal trajectory analysis, and clustering reproducibility was tested in independent validation cohorts. Gene expression analysis revealed significantly upregulated genes in cSLE with strong IFN-I pathway enrichment. Patients clustered into IFN-high (65%) and IFN-low (35%) groups, independent of disease activity. IFN-high patients showed elevated IFNα, reporter cell activity, reduced lymphocyte counts, and greater in vitro response to anifrolumab. LAMP3 emerged as a stable and reproducible biomarker of IFN-high status. T cells and plasmacytoid dendritic cells were most sensitive to IFN-I ex vivo, with distinct functional marker profiles. Integrated transcriptomic, proteomic, and cellular data defined 6 IFN-driven endotypes with unique immune signatures and clinical phenotypes. Endotypes differed in IFN-I activity, organ damage, flare burden, and corticosteroid exposure with divergent longitudinal trajectories. Multilevel IFN profiling revealed an important biomarker of IFN-high patients for potential use in clinical practice, immune lineage-specific responses, and clinically meaningful endotypes, supporting systems immunology approaches and biomarker-guided personalised treatment strategies.