CD8+ T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome

Catharina C. Gross*, Céline Meyer, Urvashi Bhatia, Lidia Yshii, Ilka Kleffner, Jan Bauer, Anna R. Tröscher, Andreas Schulte-Mecklenbeck, Sebastian Herich, Tilman Schneider-Hohendorf, Henrike Plate, Tanja Kuhlmann, Markus Schwaninger, Wolfgang Brück, Marc Pawlitzki, David Axel Laplaud, Delphine Loussouarn, John Parratt, Michael Barnett, Michael E. BucklandTodd A. Hardy, Stephen W. Reddel, Marius Ringelstein, Jan Dörr, Brigitte Wildemann, Markus Kraemer, Hans Lassmann, Romana Höftberger, Eduardo Beltrán, Klaus Dornmair, Nicholas Schwab, Luisa Klotz, Sven G. Meuth, Guillaume Martin-Blondel, Heinz Wiendl, Roland Liblau

*Corresponding author for this work
11 Citations (Scopus)


Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8+ T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8+ T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities.

Original languageEnglish
Article number5779
JournalNature Communications
Issue number1
Publication statusPublished - 01.12.2019

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)


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