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

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

doi:10.1038/s41467-019-13593-5

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.

Highlights

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage
To gain further insights into the underlying mechanisms resulting in blood–brain barrier (BBB) dysfunction caused by lymphocytes, we investigate the pathophysiology of Susac syndrome (SuS)[6], which is considered an inflammatory endotheliopathy
Quantification showed that the majority of central nervous system (CNS) infiltrates in SuS were composed of CD3+ T cells, mainly consisting of CD8+ T cells ranging from 56% to 89% of T cells

Summary

Introduction

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Compromised function of brain ECs resulting in impaired integrity of the BBB is an early hallmark of various neurological diseases These include autoimmune inflammatory disorders, such as multiple sclerosis (MS), neuromyelitis optica, and Rasmussen encephalitis, and infections such as cerebral malaria and arbovirus-related encephalitis, as well as cerebrovascular diseases, such as ischemic stroke[3]. To gain further insights into the underlying mechanisms resulting in BBB dysfunction caused by lymphocytes, we investigate the pathophysiology of Susac syndrome (SuS)[6], which is considered an inflammatory endotheliopathy. By combining in-depth immune profiling and phenotyping of blood and cerebrospinal fluid (CSF) samples with a pathological study of brain tissue from patients with SuS6 or its differential diagnosis MS, we reveal distinct underlying mechanisms in these two chronic neuroinflammatory diseases. We demonstrate that cytotoxic CD8+ T cells (CTLs) can cause vascular CNS injury and identify CTL-mediated endotheliopathy as a targetable mechanism in SuS

Methods

Results

Conclusion