CD8+ T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome
| Autor: | Marius Ringelstein, L. M. Yshii, Ilka Kleffner, Stephen W. Reddel, Brigitte Wildemann, Todd A. Hardy, Markus Schwaninger, Guillaume Martin-Blondel, Nicholas Schwab, Delphine Loussouarn, John Parratt, Marc Pawlitzki, Henrike Plate, Eduardo Beltrán, Catharina C. Gross, Anna R. Tröscher, Tanja Kuhlmann, Tilman Schneider-Hohendorf, Klaus Dornmair, Jan Dörr, Roland S. Liblau, Urvashi Bhatia, Hans Lassmann, Sven G. Meuth, Luisa Klotz, Sebastian Herich, Markus Kraemer, Jan Bauer, Céline Meyer, David-Axel Laplaud, Wolfgang Brück, Romana Höftberger, Michael Barnett, Michael E. Buckland, Andreas Schulte-Mecklenbeck, Heinz Wiendl |
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| Přispěvatelé: | University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Medizinische Universität Wien = Medical University of Vienna, Institute for Experimental and Clinical Pharmacology and Toxicology [Lübeck, Germany], University of Lübeck [Germany], Institute of Neuropathology [Göttingen, Germany], University Medical Center Göttingen (UMG), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service d’Anatomopathologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Royal North Shore Hospital [Sydney, Australia], Microsoft Research [Redmond], Microsoft Corporation [Redmond, Wash.], The University of Sydney, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of Heidelberg, Medical Faculty, University of Vienna [Vienna], Institute of Clinical Neuroimmunology [Munich, Germany], Ludwig-Maximilians University [Munich] (LMU), Service des maladies infectieuses et tropicales [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Le Bihan, Sylvie, MECANISMES INTEGRES DE L'INFLAMMATION - Infiltration tissulaire des macrophages et inflammation : identification d'inhibiteurs de la migration cellulaire en trois dimensions. - - MigreFlame2010 - ANR-10-MIDI-0013 - MI2 - VALID, Blanc 2013 - Migration des lymp^hocytes T CD8 T dans le système nerveux central - - T cell Mig2013 - ANR-13-BSV3-0003 - Blanc 2013 - VALID, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Ruhr University Bochum (RUB), Universitätsklinikum Knappschaftskrankenhaus = University Hospital Knappschaftskrankenhaus [Bochum], Universität zu Lübeck = University of Lübeck [Lübeck], Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Royal North Shore Hospital (RNSH), Royal Prince Alfred Hospital [Sydney, Australia], Ludwig-Maximilians-Universität München (LMU), Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Service Maladies infectieuses et tropicales [CHU Toulouse], Pôle Inflammation, infection, immunologie et loco-moteur [CHU Toulouse] (Pôle I3LM Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), ANR-10-MIDI-0013,MigreFlame,Infiltration tissulaire des macrophages et inflammation : identification d'inhibiteurs de la migration cellulaire en trois dimensions.(2010), ANR-13-BSV3-0003,T cell Mig,Migration des lymp^hocytes T CD8 T dans le système nerveux central(2013), Centre de Physiopathologie Toulouse Purpan (CPTP - U1043 INSERM - UMR5282 CNRS - UT3), University Medical Center Göttingen [Germany], Heinrich-Heine-Universität Düsseldorf [Düsseldorf], Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Service des maladies infectieuses et tropicales[Toulouse] |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
MESH: Integrin alpha4 / metabolism [SDV]Life Sciences [q-bio] Neuroimmunology General Physics and Astronomy Autoimmunity 0302 clinical medicine Natalizumab Cytotoxic T cell MESH: Animals lcsh:Science MESH: Endothelium Vascular / drug effects Multidisciplinary MESH: Central Nervous System / immunology MESH: Endothelium Vascular / pathology MESH: Microvessels / pathology 3. Good health [SDV] Life Sciences [q-bio] medicine.anatomical_structure MESH: Cell Adhesion / drug effects [SDV.IMM]Life Sciences [q-bio]/Immunology Function and Dysfunction of the Nervous System MESH: Central Nervous System / pathology medicine.drug [SDV.IMM] Life Sciences [q-bio]/Immunology MESH: Mice Transgenic Science Central nervous system General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Immune system MESH: Microvessels / immunology medicine MESH: Cell Adhesion / immunology Neuroinflammation Susac Syndrome MESH: Central Nervous System / blood suppl MESH: Humans business.industry MESH: Adult General Chemistry MESH: Integrin alpha4 / antagonists & inhibitors MESH: Male Granzyme B Susac syndrome neuro-inflammation endotheliopathy 030104 developmental biology Immunology lcsh:Q MESH: Endothelium Vascular / immunology MESH: Microvessels / drug effects MESH: Disease Models Animal business MESH: Female 030217 neurology & neurosurgery CD8 |
| Zdroj: | Nature Communications Nature Communications, Nature Publishing Group, 2019, 10 (1), pp.5779. ⟨10.1038/s41467-019-13593-5⟩ Nature Communications, 2019, 10, pp.5779. ⟨10.1038/s41467-019-13593-5⟩ Nature Communications, Vol 10, Iss 1, Pp 1-19 (2019) |
| ISSN: | 2041-1723 |
| Popis: | International audience; 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.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. |
| Databáze: | OpenAIRE |
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