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

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      1 , , 2 , 1 , 2 , 1 , 3 , 4 , 4 , 1 , 1 , 1 , 1 , 5 , 6 , 7 , 1 , 8 , 9 , 10 , 11 , 12 , 13 , 13 , 14 , 13 , 15 , 13 , 15 , 16 , 17 , 18 , 19 , 16 , 20 , 4 , 21 , 22 , 22 , 23 , 1 , 1 , 1 , 24 , 2 , 25 , 1 , 12 , 24 , , 2 ,
      Nature Communications
      Nature Publishing Group UK
      Autoimmunity, Neuroimmunology

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          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.

          Abstract

          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.

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          Most cited references57

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          Multiple Sclerosis

          New England Journal of Medicine, 343(13), 938-952
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            Phenotypic and Functional Separation of Memory and Effector Human CD8+ T Cells

            Human CD8+ memory- and effector-type T cells are poorly defined. We show here that, next to a naive compartment, two discrete primed subpopulations can be found within the circulating human CD8+ T cell subset. First, CD45RA−CD45R0+ cells are reminiscent of memory-type T cells in that they express elevated levels of CD95 (Fas) and the integrin family members CD11a, CD18, CD29, CD49d, and CD49e, compared to naive CD8+ T cells, and are able to secrete not only interleukin (IL) 2 but also interferon γ, tumor necrosis factor α, and IL-4. This subset does not exert cytolytic activity without prior in vitro stimulation but does contain virus-specific cytotoxic T lymphocyte (CTL) precursors. A second primed population is characterized by CD45RA expression with concomitant absence of expression of the costimulatory molecules CD27 and CD28. The CD8+CD45RA+CD27− population contains T cells expressing high levels of CD11a, CD11b, CD18, and CD49d, whereas CD62L (L-selectin) is not expressed. These T cells do not secrete IL-2 or -4 but can produce IFN-γ and TNF-α. In accordance with this finding, cells contained within this subpopulation depend for proliferation on exogenous growth factors such as IL-2 and -15. Interestingly, CD8+CD45RA+CD27− cells parallel effector CTLs, as they abundantly express Fas-ligand mRNA, contain perforin and granzyme B, and have high cytolytic activity without in vitro prestimulation. Based on both phenotypic and functional properties, we conclude that memory- and effector-type T cells can be separated as distinct entities within the human CD8+ T cell subset.
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              Immunosequencing identifies signatures of cytomegalovirus exposure history and HLA-mediated effects on the T cell repertoire

              Ryan Emerson and colleagues report immunosequencing of the variable region of the TCRβ chain in 666 individuals with known cytomegalovirus (CMV) status. They show that CMV status and HLA genotype shape the T cell repertoire and demonstrate proof of principle that TCRβ sequencing can be used as a specific diagnostic of pathogen exposure.
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                Author and article information

                Contributors
                Catharina.Gross@ukmuenster.de
                Heinz.Wiendl@ukmuenster.de
                Roland.Liblau@inserm.fr
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                18 December 2019
                18 December 2019
                2019
                : 10
                : 5779
                Affiliations
                [1 ]Department of Neurology with Institute of Translational Neurology, University Hospital Münster, University of Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany
                [2 ]Centre de Physiopathologie Toulouse-Purpan (CPTP), Université de Toulouse, CNRS, Inserm, UPS, CHU Purpan – BP 3028 – 31024, Toulouse Cedex 3, Toulouse, France
                [3 ]ISNI 0000 0004 0490 981X, GRID grid.5570.7, Department of Neurology, , University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, ; In der Schornau 23-25, 44892 Bochum, Germany
                [4 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Department of Neuroimmunology, Center for Brain Research, , Medical University of Vienna, ; Spitalgasse 4, 1090 Vienna, Austria
                [5 ]Institute of Neuropathology, University Hospital Münster, University of Münster, Pottkamp 2, 48149 Münster, Germany
                [6 ]ISNI 0000 0001 0057 2672, GRID grid.4562.5, Institute of Experimental and Clinical Pharmacology and Toxicology, , University of Lübeck, ; Ratzeburger Allee 160, 23562 Lübeck, Germany
                [7 ]ISNI 0000 0001 0482 5331, GRID grid.411984.1, Institute of Neuropathology, , University Medical Center Göttingen, ; Robert-Koch-Straße 40, 37099 Göttingen, Germany
                [8 ]GRID grid.4817.a, UMR 1064, INSERM, Centre de Recherche en Transplantation et Immunologie, , Université de Nantes, CHU Nantes - Hôtel Dieu Bd Jean Monnet, ; 44093 Nantes Cedex 01, France
                [9 ]ISNI 0000 0004 0472 0371, GRID grid.277151.7, Service Neurologie, CHU Nantes, ; Nantes, France
                [10 ]Service d’Anatomo-Pathologie, CHU Nantes, Hôtel-Dieu, rez-de-jardin, 44093 Nantes Cedex 1, France
                [11 ]ISNI 0000 0004 0587 9093, GRID grid.412703.3, Department of Neurology, , Royal North Shore Hospital, ; Sydney, Australia
                [12 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, Australia Northern Clinical School, , University of Sydney, ; Reserve Road, St Leonards, Sydney, NSW 2065 Australia
                [13 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, Brain and Mind Centre, Medical Faculty, , University of Sydney, ; Mallett Street, Camperdown, Sydney, NSW 2050 Australia
                [14 ]ISNI 0000 0004 0385 0051, GRID grid.413249.9, Department of Neuropathology, , Royal Prince Alfred Hospital, 94, ; Mallett Street, Camperdown, Sydney, NSW 2050 Australia
                [15 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, Department of Neurology, Concord Hospital, , University of Sydney, ; Sydney, NSW 2139 Australia
                [16 ]ISNI 0000 0001 2176 9917, GRID grid.411327.2, Department of Neurology, Medical Faculty, , Heinrich Heine University, ; Moorenstraße 5, 40225 Düsseldorf, Germany
                [17 ]ISNI 0000 0001 2176 9917, GRID grid.411327.2, Department of Neurology, Center of Neurology und Neuropsychiatry, , LVR-Klinikum, Heinrich Heine University Düsseldorf, ; Bergische Landstraße 2, 40629 Düsseldorf, Germany
                [18 ]Max Delbrueck Center for Molecular Medicine and Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, NeuroCure, Experimental and Clinical Research Center, Charitéplatz 1, 10117 Berlin, Germany
                [19 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, Molecular Neuroimmunology Group, Department of Neurology, , University of Heidelberg, ; Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
                [20 ]GRID grid.476313.4, Department of Neurology, , Alfried Krupp Hospital, ; Alfried-Krupp-Strasse 21, 45130 Essen, Germany
                [21 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Institute of Neurology, , Medical University of Vienna, ; Währinger Gürtel 18-20, 1090 Vienna, Austria
                [22 ]ISNI 0000 0004 0477 2585, GRID grid.411095.8, Institute of Clinical Neuroimmunology, , Biomedical Center and Hospital of the Ludwig-Maximilians-University Munich, ; Großhaderner Straße 9, Martinsried, 82152 Munich, Germany
                [23 ]GRID grid.452617.3, Munich Cluster for Systems Neurology (SyNergy), ; Munich, Germany
                [24 ]Cells in Motion (CiM), Münster, Germany
                [25 ]ISNI 0000 0001 1457 2980, GRID grid.411175.7, Department of Infectious and Tropical Diseases, , Toulouse University Hospital, ; Toulouse, France
                Author information
                http://orcid.org/0000-0002-4872-9189
                http://orcid.org/0000-0003-4923-4492
                http://orcid.org/0000-0003-3207-9684
                http://orcid.org/0000-0001-5802-8047
                http://orcid.org/0000-0003-3003-4677
                http://orcid.org/0000-0003-3855-4706
                http://orcid.org/0000-0001-8976-7811
                http://orcid.org/0000-0002-3717-5176
                http://orcid.org/0000-0003-3343-6874
                http://orcid.org/0000-0002-0174-5042
                http://orcid.org/0000-0002-6881-4479
                http://orcid.org/0000-0003-3080-2277
                http://orcid.org/0000-0001-6113-6938
                http://orcid.org/0000-0003-4755-6471
                http://orcid.org/0000-0003-3618-8407
                http://orcid.org/0000-0002-5667-3621
                http://orcid.org/0000-0001-8617-5052
                http://orcid.org/0000-0002-7266-4098
                http://orcid.org/0000-0003-0342-5373
                http://orcid.org/0000-0001-5494-9885
                http://orcid.org/0000-0001-5439-9633
                http://orcid.org/0000-0003-2571-3501
                http://orcid.org/0000-0001-5477-5475
                Article
                13593
                10.1038/s41467-019-13593-5
                6920411
                31852955
                47151959-fd8a-4a0d-a756-04c763f36778
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 3 September 2019
                : 11 November 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft (German Research Foundation);
                Award ID: GR3946_3/1
                Award ID: CRC TR128 A09
                Award ID: GR3946_3/1
                Award ID: CRC TR128 Z02
                Award ID: SCHW 416/5-2
                Award ID: CRC TR128 A05
                Award ID: CRC TR128 B01
                Award ID: SFB1009 A03
                Award ID: CRC TR128 A09
                Award ID: CRC TR128 Z02
                Award ID: SFB1009 A03
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100002347, Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research);
                Award ID: KKNMS FKZ01FI1603A
                Award ID: KKNMS FKZ01FI1603A
                Award ID: KKNMS FKZ01FI1603A
                Award Recipient :
                Funded by: Interdisciplinary Center for Clinical Studies (IZKF) grant Kl3/010/19 IMF grant KL 111421
                Funded by: Cells in Motion Bridging Fund
                Funded by: IMF grant KL 111421 European Susac Consortium (EuSaC)
                Funded by: FundRef https://doi.org/10.13039/501100002428, Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung);
                Award ID: FWF: P26936-B27
                Award ID: FWF: I3334-B27
                Award Recipient :
                Funded by: Oppenheim Research Grant MS
                Funded by: FundRef https://doi.org/10.13039/501100004718, Université de Toulouse (Toulouse University);
                Funded by: FundRef https://doi.org/10.13039/100007379, Fondation pour l'Aide à la Recherche sur la Sclérose en Plaques (Fondation ARSEP);
                Funded by: FundRef https://doi.org/10.13039/501100002915, Fondation pour la Recherche Médicale (Foundation for Medical Research in France);
                Funded by: FundRef https://doi.org/10.13039/501100004795, Institut Universitaire de France (IUF);
                Funded by: French Research Agency (ANR T-cell Mig) ERA-NET NEURON (Meltra-BBB) Inserm CNRS
                Categories
                Article
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                © The Author(s) 2019

                Uncategorized
                autoimmunity,neuroimmunology
                Uncategorized
                autoimmunity, neuroimmunology

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