Journal Article

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

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

2019

Overview

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. Susac syndrome is an inflammatory pathology of the brain endothelium. Here the authors show that the pathology is driven by CD8 T cells attacking the endothelium, and that blocking T cell-endothelial adhesion ameliorates the disease in a mouse model, and associates with improved clinical score in 4 patients.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 13/51 / 631/250/371 / 631/250/38 / 82/81 / Adult / Animals / CD8 antigen / Cell Adhesion - drug effects / Cell Adhesion - immunology / Central Nervous System - blood supply / Central Nervous System - immunology / Central Nervous System - pathology / Central Nervous System / blood suppl / Disease Models, Animal / Endothelium / Endothelium, Vascular - drug effects / Endothelium, Vascular - immunology / Endothelium, Vascular - pathology / Female / Humanities and Social Sciences / Humans / Immunology / Inflammation / Integrin alpha4 - antagonists & inhibitors / Integrin alpha4 - metabolism / Life Sciences / Lymphocytes / Lymphocytes T / Male / Mice, Transgenic / Microvessels - drug effects / Microvessels - immunology / Microvessels - pathology / Middle Aged / multidisciplinary / Natalizumab - pharmacology / Natalizumab - therapeutic use / Pathology / Science / Science (multidisciplinary) / Susac Syndrome - blood / Susac Syndrome - drug therapy / Susac Syndrome - immunology / T-Lymphocytes, Cytotoxic - immunology / Young Adult