CD8+ T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome
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Published:2019-12
Issue:1
Volume:10
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Gross Catharina C.ORCID, Meyer Céline, Bhatia UrvashiORCID, Yshii Lidia, Kleffner IlkaORCID, Bauer JanORCID, Tröscher Anna R.ORCID, Schulte-Mecklenbeck AndreasORCID, Herich SebastianORCID, Schneider-Hohendorf TilmanORCID, Plate HenrikeORCID, Kuhlmann TanjaORCID, Schwaninger Markus, Brück WolfgangORCID, Pawlitzki MarcORCID, Laplaud David-AxelORCID, Loussouarn Delphine, Parratt John, Barnett Michael, Buckland Michael E.ORCID, Hardy Todd A., Reddel Stephen W., Ringelstein MariusORCID, Dörr Jan, Wildemann Brigitte, Kraemer MarkusORCID, Lassmann HansORCID, Höftberger Romana, Beltrán EduardoORCID, Dornmair KlausORCID, Schwab NicholasORCID, Klotz LuisaORCID, Meuth Sven G.ORCID, Martin-Blondel Guillaume, Wiendl Heinz, Liblau RolandORCID
Abstract
AbstractNeuroinflammation 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference75 articles.
1. Engelhardt, B., Vajkoczy, P. & Weller, R. O. The movers and shapers in immune privilege of the CNS. Nat. Immunol. 18, 123–131 (2017). 2. Obermeier, B., Verma, A. & Ransohoff, R. M. The blood-brain barrier. Handb. Clin. Neurol. 133, 39–59 (2016). 3. Zhao, Z., Nelson, A. R., Betsholtz, C. & Zlokovic, B. V. Establishment and dysfunction of the blood-brain barrier. Cell 163, 1064–1078 (2015). 4. Ajami, B. et al. Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models. Nat. Neurosci. 21, 541–551 (2018). 5. Alvarez, J. I. et al. Focal disturbances in the blood-brain barrier are associated with formation of neuroinflammatory lesions. Neurobiol. Dis. 74, 14–24 (2015).
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