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

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Item Type:Article
Title:CD8(+) T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome
Creators Name:Gross, C.C. and Meyer, C. and Bhatia, U. and Yshii, L. and Kleffner, I. and Bauer, J. and Tröscher, A.R. and Schulte-Mecklenbeck, A. and Herich, S. and Schneider-Hohendorf, T. and Plate, H. and Kuhlmann, T. and Schwaninger, M. and Brück, W. and Pawlitzki, M. and Laplaud, D.A. and Loussouarn, D. and Parratt, J. and Barnett, M. and Buckland, M.E. and Hardy, T.A. and Reddel, S.W. and Ringelstein, M. and Dörr, J. and Wildemann, B. and Kraemer, M. and Lassmann, H. and Höftberger, R. and Beltrán, E. and Dornmair, K. and Schwab, N. and Klotz, L. and Meuth, S.G. and Martin-Blondel, G. and Wiendl, H. and Liblau, R.
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.
Keywords:Animal Disease Models, Cell Adhesion, Central Nervous System, Cytotoxic T-Lymphocytes, Integrin alpha4, Microvessels, Natalizumab, Susac Syndrome, Transgenic Mice, Vascular Endothelium, Animals, Mice
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:5779
Date:18 December 2019
Official Publication:https://doi.org/10.1038/s41467-019-13593-5
PubMed:View item in PubMed

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