Endothelial neo-antigen expression initiates CD8⁺ T cell–driven CNS vasculitis amplified by peripheral immune challenge

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Abstract

Primary central nervous system (CNS) vasculitis is a rare and devastating inflammatory cerebrovascular disease for which pathogenic mechanisms remain poorly defined, largely due to limited access to human tissue and the absence of validated experimental models. Here, we present a mouse model of CNS-restricted vasculitis based on inducible, endothelial-biased neoantigen expression, termed brain endothelial ovalbumin (BrEndO). In BrEndO mice, tamoxifen-induced ovalbumin (OVA) expression in cerebral endothelial cells (ECs) elicited a controlled endogenous CD8+ T cell response at the blood–brain barrier that remained clinically restrained. In contrast, peripheral immune activation through infection with OVA-expressing Listeria monocytogenes or systemic PD-L1 immune checkpoint blockade converted this regulated response into severe, CD8+ T cell–driven CNS vasculitis with vascular injury and parenchymal infiltration. Transcriptomic profiling of inflamed cerebral microvessels and spatial transcriptomic analyses demonstrated shared inflammatory and immune activation signatures between BrEndO mice and human primary CNS vasculitis brain biopsies. These findings identify antigen-specific endothelial immune recognition as a regulated process whose breakdown precipitates CNS-restricted vasculitis and establish BrEndO as an experimentally tractable platform to investigate mechanisms and modifiers of immune-mediated cerebrovascular inflammation.

Authors

Ines Sophie Schädlich, Du Huy Nguyen, Manja Wibke Thiem, Andreas Franzelin, Marcel Seungsu Woo, Alexandros Hadjilaou, Malte Borggrewe, Jiani Jiang, Mamta Panda, Enrico Maria Costanzo, Tina Fischer, Marco Er-Lukowiak, Yinghui Duan, Anne Rissiek, Alexander Winston Veltkamp, Friederike Raczkowski, Peter Ludewig, Markus Schwaninger, Dagmar Wirth, Gisa Tiegs, Thomas G. Oertner, Danny Schreier, Maike Frye, Amirrtavarshni Sivayoganathan, Christian F. Krebs, Sonja Johann, Barbara M. Braunger, Thomas Renné, Berta Puig, Anna Wiesner, Markus Glatzel, Hans-Willi Mittrücker, Björn Rissiek, Tim Magnus