Single-cell RNA sequencing of intestinal Behçet's disease identifies putative pathogenic programs and potential therapeutic targets.

Intestinal Behçet's disease is a rare, refractory subtype of systemic vasculitis, characterized by deep ileocecal ulcers and extensive clinical overlap with Crohn's disease, while the cellular and molecular mechanisms underlying its pathogenesis remain poorly characterized. This study aimed to delineate the single-cell transcriptomic landscape of intestinal Behçet's disease, characterize its putative disease-associated transcriptomic signatures, and identify potential candidates for differential diagnosis and targeted treatment. We performed single-cell RNA sequencing on paired inflamed and histologically normal terminal ileum biopsy specimens from 4 patients with active intestinal Behçet's disease, and integrated our dataset with a public single-cell dataset from 12 Crohn's disease patients and 6 healthy controls for systematic bioinformatic analysis. We thereby constructed the first single-cell transcriptomic atlas of human intestinal Behçet's disease, profiling 98,119 high-quality cells to identify 3 major cell lineages, 20 distinct cell populations, and 41 functionally defined cell subtypes. Our analysis indicated that intestinal Behçet's disease may be characterized by robust stromal compartment activation, extracellular matrix remodeling, and potentially distinct epithelial antimicrobial signatures, which showed notable differences from the prominent epithelial barrier dysfunction and interferon-driven immune activation observed in Crohn's disease in this parallel intra-disease comparison framework. We further identified predicted pathogenic crosstalk between endothelial cells and neutrophils, which may be mediated by collagen/laminin-CD44 axes. Our findings thereby characterize the potential pathogenic features of intestinal Behçet's disease, and provide hypothesis-generating clues for the clinical management of this rare disorder.