Brain blood vessel autoantibodies in patients with NMDA and GABAA receptor encephalitis: identification of unconventional Myosin-X as target antigen
Introduction: The antibody repertoire from CSF-derived antibody-secreting cells and memory B-cells in patients with encephalitis contains a considerable number of antibodies that do not target the disease-defining autoantigen such as the GABA or NMDA receptors. This study focuses on the functional r...
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| Format: | Article |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2023.1077204/full |
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| author | Lucie Y. Li Jakob Kreye Jakob Kreye Jakob Kreye Malgorzata Burek César Cordero-Gomez César Cordero-Gomez Paula C. Barthel Elisa Sánchez-Sendín Elisa Sánchez-Sendín Hans-Christian Kornau Hans-Christian Kornau Dietmar Schmitz Dietmar Schmitz Dietmar Schmitz Dietmar Schmitz Dietmar Schmitz Madeleine Scharf Patrick Meybohm S. Momsen Reincke S. Momsen Reincke Harald Prüss Harald Prüss Markus Höltje |
| author_facet | Lucie Y. Li Jakob Kreye Jakob Kreye Jakob Kreye Malgorzata Burek César Cordero-Gomez César Cordero-Gomez Paula C. Barthel Elisa Sánchez-Sendín Elisa Sánchez-Sendín Hans-Christian Kornau Hans-Christian Kornau Dietmar Schmitz Dietmar Schmitz Dietmar Schmitz Dietmar Schmitz Dietmar Schmitz Madeleine Scharf Patrick Meybohm S. Momsen Reincke S. Momsen Reincke Harald Prüss Harald Prüss Markus Höltje |
| author_sort | Lucie Y. Li |
| collection | DOAJ |
| description | Introduction: The antibody repertoire from CSF-derived antibody-secreting cells and memory B-cells in patients with encephalitis contains a considerable number of antibodies that do not target the disease-defining autoantigen such as the GABA or NMDA receptors. This study focuses on the functional relevance of autoantibodies to brain blood vessels in patients with GABAA and NMDA receptor encephalitis.Methods: We tested 149 human monoclonal IgG antibodies from the cerebrospinal fluid of six patients with different forms of autoimmune encephalitis on murine brain sections for reactivity to blood vessels using immunohistochemistry. Positive candidates were tested for reactivity with purified brain blood vessels, effects on transendothelial electrical resistance (TEER), and expression of tight junction proteins as well as gene regulation using human brain microvascular endothelial hCMEC/D3 cells as in vitro blood-brain barrier model. One blood-vessel reactive antibody was infused intrathecally by pump injection in mice to study in vivo binding and effects on tight junction proteins such as Occludin. Target protein identification was addressed using transfected HEK293 cells.Results: Six antibodies reacted with brain blood vessels, three were from the same patient with GABAAR encephalitis, and the other three were from different patients with NMDAR encephalitis. One antibody from an NMDAR encephalitis patient, mAb 011-138, also reacted with cerebellar Purkinje cells. In this case, treatment of hCMEC/D3 cells resulted in decreased TEER, reduced Occludin expression, and mRNA levels. Functional relevance in vivo was confirmed as Occludin downregulation was observed in mAb 011-138-infused animals. Unconventional Myosin-X was identified as a novel autoimmune target for this antibody.Discussion: We conclude that autoantibodies to blood vessels occur in autoimmune encephalitis patients and might contribute to a disruption of the blood-brain barrier thereby suggesting a potential pathophysiological relevance of these antibodies. |
| first_indexed | 2024-04-10T19:35:51Z |
| format | Article |
| id | doaj.art-b16392a720e4433bb60da4f1eeaa4644 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-04-10T19:35:51Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-b16392a720e4433bb60da4f1eeaa46442023-01-30T07:16:11ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022023-01-011710.3389/fncel.2023.10772041077204Brain blood vessel autoantibodies in patients with NMDA and GABAA receptor encephalitis: identification of unconventional Myosin-X as target antigenLucie Y. Li0Jakob Kreye1Jakob Kreye2Jakob Kreye3Malgorzata Burek4César Cordero-Gomez5César Cordero-Gomez6Paula C. Barthel7Elisa Sánchez-Sendín8Elisa Sánchez-Sendín9Hans-Christian Kornau10Hans-Christian Kornau11Dietmar Schmitz12Dietmar Schmitz13Dietmar Schmitz14Dietmar Schmitz15Dietmar Schmitz16Madeleine Scharf17Patrick Meybohm18S. Momsen Reincke19S. Momsen Reincke20Harald Prüss21Harald Prüss22Markus Höltje23Institute of Integrative Neuroanatomy Berlin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, GermanyGerman Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, GermanyDepartment of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Berlin and Berlin Institute of Health, Berlin, GermanyDepartment of Pediatric Neurology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, GermanyDepartment of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, GermanyGerman Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, GermanyDepartment of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Berlin and Berlin Institute of Health, Berlin, GermanyInstitute of Integrative Neuroanatomy Berlin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, GermanyGerman Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, GermanyDepartment of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Berlin and Berlin Institute of Health, Berlin, GermanyGerman Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, GermanyCharité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Neuroscience Research Center, Berlin, GermanyGerman Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, GermanyCharité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Neuroscience Research Center, Berlin, GermanyMax Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, GermanyEinstein Center for Neurosciences Berlin, Berlin, GermanyBernstein Center for Computational Neuroscience Berlin, Berlin, Germany0Institute of Experimental Immunology, EUROIMMUN AG, Lübeck, GermanyDepartment of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, GermanyGerman Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, GermanyDepartment of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Berlin and Berlin Institute of Health, Berlin, GermanyGerman Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, GermanyDepartment of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Berlin and Berlin Institute of Health, Berlin, GermanyInstitute of Integrative Neuroanatomy Berlin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, GermanyIntroduction: The antibody repertoire from CSF-derived antibody-secreting cells and memory B-cells in patients with encephalitis contains a considerable number of antibodies that do not target the disease-defining autoantigen such as the GABA or NMDA receptors. This study focuses on the functional relevance of autoantibodies to brain blood vessels in patients with GABAA and NMDA receptor encephalitis.Methods: We tested 149 human monoclonal IgG antibodies from the cerebrospinal fluid of six patients with different forms of autoimmune encephalitis on murine brain sections for reactivity to blood vessels using immunohistochemistry. Positive candidates were tested for reactivity with purified brain blood vessels, effects on transendothelial electrical resistance (TEER), and expression of tight junction proteins as well as gene regulation using human brain microvascular endothelial hCMEC/D3 cells as in vitro blood-brain barrier model. One blood-vessel reactive antibody was infused intrathecally by pump injection in mice to study in vivo binding and effects on tight junction proteins such as Occludin. Target protein identification was addressed using transfected HEK293 cells.Results: Six antibodies reacted with brain blood vessels, three were from the same patient with GABAAR encephalitis, and the other three were from different patients with NMDAR encephalitis. One antibody from an NMDAR encephalitis patient, mAb 011-138, also reacted with cerebellar Purkinje cells. In this case, treatment of hCMEC/D3 cells resulted in decreased TEER, reduced Occludin expression, and mRNA levels. Functional relevance in vivo was confirmed as Occludin downregulation was observed in mAb 011-138-infused animals. Unconventional Myosin-X was identified as a novel autoimmune target for this antibody.Discussion: We conclude that autoantibodies to blood vessels occur in autoimmune encephalitis patients and might contribute to a disruption of the blood-brain barrier thereby suggesting a potential pathophysiological relevance of these antibodies.https://www.frontiersin.org/articles/10.3389/fncel.2023.1077204/fullblood-brain barrierautoimmunityencephalitisoccludinMyosin-X |
| spellingShingle | Lucie Y. Li Jakob Kreye Jakob Kreye Jakob Kreye Malgorzata Burek César Cordero-Gomez César Cordero-Gomez Paula C. Barthel Elisa Sánchez-Sendín Elisa Sánchez-Sendín Hans-Christian Kornau Hans-Christian Kornau Dietmar Schmitz Dietmar Schmitz Dietmar Schmitz Dietmar Schmitz Dietmar Schmitz Madeleine Scharf Patrick Meybohm S. Momsen Reincke S. Momsen Reincke Harald Prüss Harald Prüss Markus Höltje Brain blood vessel autoantibodies in patients with NMDA and GABAA receptor encephalitis: identification of unconventional Myosin-X as target antigen Frontiers in Cellular Neuroscience blood-brain barrier autoimmunity encephalitis occludin Myosin-X |
| title | Brain blood vessel autoantibodies in patients with NMDA and GABAA receptor encephalitis: identification of unconventional Myosin-X as target antigen |
| title_full | Brain blood vessel autoantibodies in patients with NMDA and GABAA receptor encephalitis: identification of unconventional Myosin-X as target antigen |
| title_fullStr | Brain blood vessel autoantibodies in patients with NMDA and GABAA receptor encephalitis: identification of unconventional Myosin-X as target antigen |
| title_full_unstemmed | Brain blood vessel autoantibodies in patients with NMDA and GABAA receptor encephalitis: identification of unconventional Myosin-X as target antigen |
| title_short | Brain blood vessel autoantibodies in patients with NMDA and GABAA receptor encephalitis: identification of unconventional Myosin-X as target antigen |
| title_sort | brain blood vessel autoantibodies in patients with nmda and gabaa receptor encephalitis identification of unconventional myosin x as target antigen |
| topic | blood-brain barrier autoimmunity encephalitis occludin Myosin-X |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2023.1077204/full |
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