From inflammation to rupture: advances in the pathogenesis of pseudoaneurysm formation in Vascular Behçet's Disease

This narrative review aims to comprehensively synthesize recent advances in the immunopathological mechanisms and genetic landscape underlying pseudoaneurysm formation in Vascular Behçet's Disease (VBD). We integrate key discoveries from 2010 to 2026 regarding genetic susceptibility, immune cell dysregulation, inflammatory mediator networks, and structural deterioration of the vascular wall. Unlike previous reviews that primarily focused on clinical manifestations and descriptive observations, this article proposes a multilevel pathogenic cascade model linking genetic predisposition to full-thickness vascular wall destruction. We critically evaluate current consensus and controversies, identify unresolved knowledge gaps, and highlight potential strategies for early risk stratification and precision intervention. These insights may provide a theoretical framework for addressing the clinical challenges associated with the high rupture risk and recurrence rate of VBD-associated pseudoaneurysms.

At the genetic level, the HLA-B51/ERAP1 axis establishes a fundamental susceptibility background, while non-HLA genes, including TNFAIP3, IL10, and CCR1, contribute to fine-tuning immune regulatory thresholds. At the cellular level, excessive neutrophil NETosis, activation of THBS1^high macrophages, aberrant Th17 responses, and disruption of the Treg/effector T-cell balance collectively form a self-amplifying inflammatory network. Notably, THBS1^high macrophages have been reported to provide single-cell-level evidence linking immune activation to aneurysm development by driving vascular smooth muscle cell (VSMC) phenotypic switching; however, this finding derives from a single-center exploratory study and awaits independent replication. At the inflammatory mediator level, TNF-α functions as a central driver that cooperates with matrix metalloproteinase (MMP)-mediated extracellular matrix degradation, JAK/STAT signaling, and the IL-23/IL-17 axis to establish a highly interconnected pro-inflammatory signaling network. At the vascular structural level, inflammation propagates from the adventitial vasa vasorum toward the inner vascular layers, accompanied by medial elastic fiber disruption and VSMC phenotypic transition, ultimately resulting in pseudoaneurysm formation. The YAP/TAZ mechanotransduction pathway further reinforces a vicious cycle between vascular expansion and inflammation. Current animal models, including herpes simplex virus (HSV)-induced models and HLA-B51 transgenic models, fail to consistently reproduce vascular phenotypes, representing a major barrier to mechanistic investigation.

VBD-associated pseudoaneurysm represents a multilevel pathogenic cascade driven by the interaction of genetic susceptibility, immune cell amplification, inflammatory mediator networks, and progressive vascular wall degeneration. Integrated stratification based on immunological and genetic biomarkers may enable early identification of high-risk patients and facilitate individualized therapeutic strategies. Targeting the THBS1-macrophage axis and the NETs-IL-17A inflammatory circuit may represent a promising direction for precision intervention, although substantial translational barriers remain. Future studies should prioritize the development of vascular phenotype-relevant animal models, conduct dedicated genetic investigations focused on pseudoaneurysm susceptibility, and integrate multi-omics approaches to bridge mechanistic discoveries with clinical translation.