Oligodendrocyte myelin glycoprotein as a novel target for pathogenic autoimmunity in the CNS
Abstract Autoimmune disorders of the central nervous system (CNS) comprise a broad spectrum of clinical entities. The stratification of patients based on the recognized autoantigen is of great importance for therapy optimization and for concepts of pathogenicity, but for most of these patients, the...
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Language: | English |
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BMC
2020-11-01
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Series: | Acta Neuropathologica Communications |
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Online Access: | https://doi.org/10.1186/s40478-020-01086-2 |
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doaj-48e9a477e7444c7f8deb69565051b888 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ramona Gerhards Lena Kristina Pfeffer Jessica Lorenz Laura Starost Luise Nowack Franziska S. Thaler Miriam Schlüter Heike Rübsamen Caterina Macrini Stephan Winklmeier Simone Mader Mattias Bronge Hans Grönlund Regina Feederle Hung-En Hsia Stefan F. Lichtenthaler Juliane Merl-Pham Stefanie M. Hauck Tanja Kuhlmann Isabel J. Bauer Eduardo Beltran Lisa Ann Gerdes Aleksandra Mezydlo Amit Bar-Or Brenda Banwell Mohsen Khademi Tomas Olsson Reinhard Hohlfeld Hans Lassmann Tania Kümpfel Naoto Kawakami Edgar Meinl |
spellingShingle |
Ramona Gerhards Lena Kristina Pfeffer Jessica Lorenz Laura Starost Luise Nowack Franziska S. Thaler Miriam Schlüter Heike Rübsamen Caterina Macrini Stephan Winklmeier Simone Mader Mattias Bronge Hans Grönlund Regina Feederle Hung-En Hsia Stefan F. Lichtenthaler Juliane Merl-Pham Stefanie M. Hauck Tanja Kuhlmann Isabel J. Bauer Eduardo Beltran Lisa Ann Gerdes Aleksandra Mezydlo Amit Bar-Or Brenda Banwell Mohsen Khademi Tomas Olsson Reinhard Hohlfeld Hans Lassmann Tania Kümpfel Naoto Kawakami Edgar Meinl Oligodendrocyte myelin glycoprotein as a novel target for pathogenic autoimmunity in the CNS Acta Neuropathologica Communications Autoantigen Multiple sclerosis Neuroinflammation Autoimmunity |
author_facet |
Ramona Gerhards Lena Kristina Pfeffer Jessica Lorenz Laura Starost Luise Nowack Franziska S. Thaler Miriam Schlüter Heike Rübsamen Caterina Macrini Stephan Winklmeier Simone Mader Mattias Bronge Hans Grönlund Regina Feederle Hung-En Hsia Stefan F. Lichtenthaler Juliane Merl-Pham Stefanie M. Hauck Tanja Kuhlmann Isabel J. Bauer Eduardo Beltran Lisa Ann Gerdes Aleksandra Mezydlo Amit Bar-Or Brenda Banwell Mohsen Khademi Tomas Olsson Reinhard Hohlfeld Hans Lassmann Tania Kümpfel Naoto Kawakami Edgar Meinl |
author_sort |
Ramona Gerhards |
title |
Oligodendrocyte myelin glycoprotein as a novel target for pathogenic autoimmunity in the CNS |
title_short |
Oligodendrocyte myelin glycoprotein as a novel target for pathogenic autoimmunity in the CNS |
title_full |
Oligodendrocyte myelin glycoprotein as a novel target for pathogenic autoimmunity in the CNS |
title_fullStr |
Oligodendrocyte myelin glycoprotein as a novel target for pathogenic autoimmunity in the CNS |
title_full_unstemmed |
Oligodendrocyte myelin glycoprotein as a novel target for pathogenic autoimmunity in the CNS |
title_sort |
oligodendrocyte myelin glycoprotein as a novel target for pathogenic autoimmunity in the cns |
publisher |
BMC |
series |
Acta Neuropathologica Communications |
issn |
2051-5960 |
publishDate |
2020-11-01 |
description |
Abstract Autoimmune disorders of the central nervous system (CNS) comprise a broad spectrum of clinical entities. The stratification of patients based on the recognized autoantigen is of great importance for therapy optimization and for concepts of pathogenicity, but for most of these patients, the actual target of their autoimmune response is unknown. Here we investigated oligodendrocyte myelin glycoprotein (OMGP) as autoimmune target, because OMGP is expressed specifically in the CNS and there on oligodendrocytes and neurons. Using a stringent cell-based assay, we detected autoantibodies to OMGP in serum of 8/352 patients with multiple sclerosis, 1/28 children with acute disseminated encephalomyelitis and unexpectedly, also in one patient with psychosis, but in none of 114 healthy controls. Since OMGP is GPI-anchored, we validated its recognition also in GPI-anchored form. The autoantibodies to OMGP were largely IgG1 with a contribution of IgG4, indicating cognate T cell help. We found high levels of soluble OMGP in human spinal fluid, presumably due to shedding of the GPI-linked OMGP. Analyzing the pathogenic relevance of autoimmunity to OMGP in an animal model, we found that OMGP-specific T cells induce a novel type of experimental autoimmune encephalomyelitis dominated by meningitis above the cortical convexities. This unusual localization may be directed by intrathecal uptake and presentation of OMGP by meningeal phagocytes. Together, OMGP-directed autoimmunity provides a new element of heterogeneity, helping to improve the stratification of patients for diagnostic and therapeutic purposes. |
topic |
Autoantigen Multiple sclerosis Neuroinflammation Autoimmunity |
url |
https://doi.org/10.1186/s40478-020-01086-2 |
work_keys_str_mv |
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doaj-48e9a477e7444c7f8deb69565051b8882020-12-06T12:32:39ZengBMCActa Neuropathologica Communications2051-59602020-11-018111710.1186/s40478-020-01086-2Oligodendrocyte myelin glycoprotein as a novel target for pathogenic autoimmunity in the CNSRamona Gerhards0Lena Kristina Pfeffer1Jessica Lorenz2Laura Starost3Luise Nowack4Franziska S. Thaler5Miriam Schlüter6Heike Rübsamen7Caterina Macrini8Stephan Winklmeier9Simone Mader10Mattias Bronge11Hans Grönlund12Regina Feederle13Hung-En Hsia14Stefan F. Lichtenthaler15Juliane Merl-Pham16Stefanie M. Hauck17Tanja Kuhlmann18Isabel J. Bauer19Eduardo Beltran20Lisa Ann Gerdes21Aleksandra Mezydlo22Amit Bar-Or23Brenda Banwell24Mohsen Khademi25Tomas Olsson26Reinhard Hohlfeld27Hans Lassmann28Tania Kümpfel29Naoto Kawakami30Edgar Meinl31Institute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität MünchenInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität MünchenInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität MünchenInstitute of Neuropathology, University Hospital MünsterInstitute of Neuropathology, University Hospital MünsterInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität MünchenInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität MünchenInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität MünchenInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität MünchenInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität MünchenInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität MünchenTherapeutic Immune Design, Department of Clinical Neuroscience, Karolinska InstitutetTherapeutic Immune Design, Department of Clinical Neuroscience, Karolinska InstitutetInstitute for Diabetes and Obesity, Monoclonal Antibody Core Facility, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH)Neuroproteomics, School of Medicine, Klinikum rechts der Isar, German Center for Neurodegenerative Diseases (DZNE), Technical University of MunichNeuroproteomics, School of Medicine, Klinikum rechts der Isar, German Center for Neurodegenerative Diseases (DZNE), Technical University of MunichResearch Unit Protein Science, Helmholtz Center MunichResearch Unit Protein Science, Helmholtz Center MunichInstitute of Neuropathology, University Hospital MünsterInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität MünchenInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität MünchenInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität MünchenInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität MünchenDepartment of Neurology, University of PennsylvaniaChildren’s Hospital of PhiladelphiaNeuroimmunology Unit, Department of Clinical Neuroscience, Karolinska InstitutetNeuroimmunology Unit, Department of Clinical Neuroscience, Karolinska InstitutetInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität MünchenCenter for Brain Research, Medical UniversityInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität MünchenInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität MünchenInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität MünchenAbstract Autoimmune disorders of the central nervous system (CNS) comprise a broad spectrum of clinical entities. The stratification of patients based on the recognized autoantigen is of great importance for therapy optimization and for concepts of pathogenicity, but for most of these patients, the actual target of their autoimmune response is unknown. Here we investigated oligodendrocyte myelin glycoprotein (OMGP) as autoimmune target, because OMGP is expressed specifically in the CNS and there on oligodendrocytes and neurons. Using a stringent cell-based assay, we detected autoantibodies to OMGP in serum of 8/352 patients with multiple sclerosis, 1/28 children with acute disseminated encephalomyelitis and unexpectedly, also in one patient with psychosis, but in none of 114 healthy controls. Since OMGP is GPI-anchored, we validated its recognition also in GPI-anchored form. The autoantibodies to OMGP were largely IgG1 with a contribution of IgG4, indicating cognate T cell help. We found high levels of soluble OMGP in human spinal fluid, presumably due to shedding of the GPI-linked OMGP. Analyzing the pathogenic relevance of autoimmunity to OMGP in an animal model, we found that OMGP-specific T cells induce a novel type of experimental autoimmune encephalomyelitis dominated by meningitis above the cortical convexities. This unusual localization may be directed by intrathecal uptake and presentation of OMGP by meningeal phagocytes. Together, OMGP-directed autoimmunity provides a new element of heterogeneity, helping to improve the stratification of patients for diagnostic and therapeutic purposes.https://doi.org/10.1186/s40478-020-01086-2AutoantigenMultiple sclerosisNeuroinflammationAutoimmunity |