Single-cell analysis identifies monocyte signatures of disease activity and clinical subtypes in Behçet's disease

Behçet's 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 vs remission states and identifying pathways linked to clinical phenotypes.

We performed single-cell RNA sequencing on 247,028 peripheral blood mononuclear cells from 34 patients with BD 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.

All 3 monocyte subsets were markedly expanded in BD and demonstrated dominant interferon (IFN)-γ-associated activation, robust heat-shock responses, and enhanced antigen-presentation programmes. In active disease, monocytes exhibited pronounced type II IFN signatures, which reversed in remission alongside restoration of regulatory and metabolic pathways. Remission was instead characterised by increased expression of type I IFN-regulated genes and activation of serine protease inhibitor (SERPIN)-associated programmes linked to tissue stabilisation. Clinical phenotype stratification revealed distinct transcriptional signatures in peripheral blood monocytes, including enrichment of heat-shock and stress-response pathways in monocytes from patients with vascular BD and tumour necrosis factor/NF-κB-associated programmes in monocytes from patients with ocular BD. Patients without organ involvement demonstrated an increased type I IFN gene signature.

This 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 peripheral blood monocyte states, and suggest immune pathways suitable for targeted intervention.