Susac syndrome (SuS) as a paradigm of a CD8 T-cell mediated endotheliopathy
Immunology
Clinical Neurology; Neurosurgery and Neuroradiology
Final Report Abstract
CD8 T cells are a driving force in the pathophysiology of distinct neuro-immunological diseases, in which they attack different target structures of the central nervous system (CNS). We deciphered Susac syndrome (SuS) – an orphan disease affecting the microvessels of the brain, retina, and inner ear – as a CD8 T cell-mediated endotheliopathy. Analysis of human biomaterial from discrete compartments (blood, cerebrospinal fluid, and brain biopsies) revealed that in SuS an unknown antigenic stimulus leads to clonal expansion and differentiation of naïve CD8 T cells into granzyme B (GrB) and perforin expressing CD8 TEMRA cells (CTLs). CTLs accumulate in microvessels, where they adhere to HLA class I expressing endothelial cells (ECs) resulting in EC apoptosis most likely in a GrB/perforin-dependent manner. The causality between CTL-mediated apoptosis of ECs and the main neuropathological features of SuS was confirmed in a reverse translational approach using a newly developed SuS-like pre-clinical model. CTL-mediated apoptosis of ECs prompted vascular leakage resulting in small ischemic lesions and gliosis predominantly in the corpus callosum, cerebellum, and inner ear. Our hypothesis of CTLs as a driving force in the pathophysiology of SuS was further corroborated in the pre-clinical model and in a small proofof-concept study by demonstrating disease amelioration through blocking of adhesion and trafficking of CTLs by anti-alpha 4 beta 1 integrin mAb. Moreover, reduced clinical and paraclinical activity including reduced number of relapses under natalizumab (recombinant humanized anti-alpha 4-integrin antibody) treatment suggested a more targeted and effective treatment-regimen in addition to current treatment recommendations in SuS. Overall, our study deciphered SuS as an HLA class I-restricted CD8-mediated endotheliopathy; thus, indicating novel therapeutic options.
Publications
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CD8+ T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome. Nature Communications, 10(1).
Gross, Catharina C.; Meyer, Céline; Bhatia, Urvashi; Yshii, Lidia; Kleffner, Ilka; Bauer, Jan; Tröscher, Anna R.; Schulte-Mecklenbeck, Andreas; Herich, Sebastian; Schneider-Hohendorf, Tilman; Plate, Henrike; Kuhlmann, Tanja; Schwaninger, Markus; Brück, Wolfgang; Pawlitzki, Marc; Laplaud, David-Axel; Loussouarn, Delphine; Parratt, John; Barnett, Michael; ... & Liblau, Roland
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Generation of a Model to Predict Differentiation and Migration of Lymphocyte Subsets under Homeostatic and CNS Autoinflammatory Conditions. International Journal of Molecular Sciences, 21(6), 2046.
Gross, Catharina C.; Pawlitzki, Marc; Schulte-Mecklenbeck, Andreas; Rolfes, Leoni; Ruck, Tobias; Hundehege, Petra; Wiendl, Heinz; Herty, Michael & Meuth, Sven G.
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Classification of neurological diseases using multi-dimensional CSF analysis. Brain, 144(9), 2625-2634.
Gross, Catharina C.; Schulte-Mecklenbeck, Andreas; Madireddy, Lohith; Pawlitzki, Marc; Strippel, Christine; Räuber, Saskia; Krämer, Julia; Rolfes, Leoni; Ruck, Tobias; Beuker, Carolin; Schmidt-Pogoda, Antje; Lohmann, Lisa; Schneider-Hohendorf, Tilman; Hahn, Tim; Schwab, Nicholas; Minnerup, Jens; Melzer, Nico; Klotz, Luisa; Meuth, Sven G.; ... & Wiendl, Heinz
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Classification of Neurological or Psychiatric Disease Manifestations using Multi-Dimensional Cerebrospinal Fluid Analysis, EP: UKM17184EP, US: 63168114. (filed at EPA under EP21166177.2 and at USPTO under 42325631)
H. Wiendl, G. Meyer zu Hörste, C.C. Gross, S.E. Baranzini, A. Schulte-Mecklenbeck & L. Madireddy
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Fundamental mechanistic insights from rare but paradigmatic neuroimmunological diseases. Nature Reviews Neurology, 17(7), 433-447.
Wiendl, Heinz; Gross, Catharina C.; Bauer, Jan; Merkler, Doron; Prat, Alexandre & Liblau, Roland
