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. Buckland, Todd 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 () and Roland Liblau ()
Additional contact information
Catharina C. Gross: University Hospital Münster, University of Münster
Céline Meyer: Université de Toulouse, CNRS, Inserm, UPS, CHU Purpan – BP 3028 – 31024
Urvashi Bhatia: University Hospital Münster, University of Münster
Lidia Yshii: Université de Toulouse, CNRS, Inserm, UPS, CHU Purpan – BP 3028 – 31024
Ilka Kleffner: University Hospital Münster, University of Münster
Jan Bauer: Medical University of Vienna
Anna R. Tröscher: Medical University of Vienna
Andreas Schulte-Mecklenbeck: University Hospital Münster, University of Münster
Sebastian Herich: University Hospital Münster, University of Münster
Tilman Schneider-Hohendorf: University Hospital Münster, University of Münster
Henrike Plate: University Hospital Münster, University of Münster
Tanja Kuhlmann: University Hospital Münster, University of Münster
Markus Schwaninger: University of Lübeck
Wolfgang Brück: University Medical Center Göttingen
Marc Pawlitzki: University Hospital Münster, University of Münster
David-Axel Laplaud: Université de Nantes, CHU Nantes - Hôtel Dieu Bd Jean Monnet
Delphine Loussouarn: CHU Nantes, Hôtel-Dieu, rez-de-jardin
John Parratt: Royal North Shore Hospital
Michael Barnett: University of Sydney
Michael E. Buckland: University of Sydney
Todd A. Hardy: University of Sydney
Stephen W. Reddel: University of Sydney
Marius Ringelstein: Heinrich Heine University
Jan Dörr: Max Delbrueck Center for Molecular Medicine and Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, NeuroCure, Experimental and Clinical Research Center
Brigitte Wildemann: University of Heidelberg
Markus Kraemer: Heinrich Heine University
Hans Lassmann: Medical University of Vienna
Romana Höftberger: Medical University of Vienna
Eduardo Beltrán: Biomedical Center and Hospital of the Ludwig-Maximilians-University Munich
Klaus Dornmair: Biomedical Center and Hospital of the Ludwig-Maximilians-University Munich
Nicholas Schwab: University Hospital Münster, University of Münster
Luisa Klotz: University Hospital Münster, University of Münster
Sven G. Meuth: University Hospital Münster, University of Münster
Guillaume Martin-Blondel: Université de Toulouse, CNRS, Inserm, UPS, CHU Purpan – BP 3028 – 31024
Heinz Wiendl: University Hospital Münster, University of Münster
Roland Liblau: Université de Toulouse, CNRS, Inserm, UPS, CHU Purpan – BP 3028 – 31024

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-13593-5

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