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

Catharina Gross 1, 2 Céline Meyer 3 Urvashi Bhatia 1, 2 Lidia Yshii 3 Ilka Kleffner 1, 4, 5, 2 Jan Bauer 6 Anna Tröscher 6 Andreas Schulte-Mecklenbeck 1, 2 Sebastian Herich 1, 2 Tilman Schneider-Hohendorf 1, 2 Henrike Plate 1, 2 Tanja Kuhlmann 1, 2 Markus Schwaninger 7 Wolfgang Bruck 8 Marc Pawlitzki 1, 2 David-Axel Laplaud 9, 10 Delphine Loussouarn 11 John Parratt 12, 13 Michael Barnett 14 Michael Buckland 13, 15 Todd Hardy 13 Stephen Reddel 13 Marius Ringelstein 16 Jan Dörr 17 Brigitte Wildemann 18 Markus Kraemer 16 Hans P Lassmann 6 Romana Höftberger 6 Eduardo Beltrán 19 Klaus Dornmair 19, 20 Nicholas Schwab 1, 2 Luisa Klotz 1, 2 Sven G Meuth 1, 2 Guillaume Martin-Blondel 21, 3 Heinz Wiendl 1, 14, 2 Roland Liblau 3, 22 
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. 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.
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Catharina Gross, Céline Meyer, Urvashi Bhatia, Lidia Yshii, Ilka Kleffner, et al.. CD8+ T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome. Nature Communications, Nature Publishing Group, 2019, 10, pp.5779. ⟨10.1038/s41467-019-13593-5⟩. ⟨inserm-02448919⟩

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