Tertiary Lymphoid Structures and CXCL13 as Targets in Intracranial Aneurysm

BACKGROUND: Intracranial aneurysms (IAs) are localized dilations of cerebral arteries that pose a significant threat of rupture, leading to fatal subarachnoid hemorrhage. The inflammation driven by immune cell infiltration is believed to be a key driver for the pathogenesis of IAs; however, the detailed immune cell landscape and spatial composition of immune cells remain unclear. METHODS: In this study, we employed an integrated multi-omics approach using human IA tissues, including single‑cell RNA sequencing, spatial transcriptomics, microarray data, and multiplex immunofluorescence, to construct a comprehensive immune cell atlas of IAs, providing a systematic characterization of their immune composition and spatial architecture. Findings were further validated in a mouse model of IA. RESULTS: We identified, for the first time, tertiary lymphoid structures within the aneurysm wall and demonstrated that their presence strongly correlates with rupture. Furthermore, we observed a significant expansion of a specific T-cell subset, CXCL13 + T-follicular helper cells. These cells were critical for B-cell recruitment and the structural organization of the tertiary lymphoid structures. In the IA mouse model, CXCL13 neutralization effectively suppressed both aneurysm formation and rupture. CONCLUSIONS: Our finding establishes tertiary lymphoid structures and CXCL13 + T follicular helper cells as central elements in IA progression and highlight the CXCL13 signaling axis as a promising therapeutic target for preventing aneurysm advancement.