Single-cell analysis identifies monocyte signatures of disease activity and clinical subtypes in Behcet disease

ObjectivesBehcets disease (BD) is a multisystem inflammatory disorder with diverse phenotypes and incompletely defined immune mechanisms. This study aimed to map immune dysregulation in BD at high resolution, comparing active versus remission states and identifying pathways linked to clinical phenotypes. MethodsWe performed single-cell RNA sequencing on 247,028 peripheral blood mononuclear cells (PBMCs) from 34 BD patients and 12 healthy controls. Transcriptomic profiling, differential gene expression, pathway enrichment analyses, and phenotype-stratified comparisons were used to delineate immune cell alterations associated with disease activity and clinical subtypes. ResultsAll three monocyte subsets were markedly expanded in BD and demonstrated dominant IFN-{gamma}-associated activation, robust heat-shock responses, and enhanced antigen-presentation programs. In active disease, monocytes exhibited pronounced type II interferon signatures, which reversed in remission alongside restoration of regulatory and metabolic pathways. Remission was instead characterized by increased expression of type I interferon-regulated genes, suggesting a potentially protective IFN-I-mediated effect, and by activation of SERPIN-associated programs linked to tissue stabilization. Clinical phenotype stratification revealed distinct monocyte signatures, with vascular BD enriched for heat-shock and stress-response pathways, and ocular BD defined by TNF/NF-{kappa}B-driven inflammation. Patients without organ involvement demonstrated an increased type I interferon gene signature, further supporting a potential protective role for type I interferon responses in BD. ConclusionsThis study provides a high-resolution immune atlas of BD, identifying monocyte-driven dysregulation as a central feature. Our findings map the immune heterogeneity of BD, identify activity- and phenotype-linked monocyte states, and suggest immune pathways suitable for targeted intervention.