Oligodendrocyte myelin glycoprotein as a novel target for pathogenic autoimmunity in the CNS
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RESEARCH
Oligodendrocyte myelin glycoprotein as a novel target for pathogenic autoimmunity in the CNS Ramona Gerhards1 , Lena Kristina Pfeffer1, Jessica Lorenz1, Laura Starost2, Luise Nowack2, Franziska S. Thaler1, Miriam Schlüter1, Heike Rübsamen1, Caterina Macrini1, Stephan Winklmeier1, Simone Mader1, Mattias Bronge3, Hans Grönlund3, Regina Feederle4, Hung‑En Hsia5, Stefan F. Lichtenthaler5,11, Juliane Merl‑Pham6, Stefanie M. Hauck6, Tanja Kuhlmann2, Isabel J. Bauer1, Eduardo Beltran1, Lisa Ann Gerdes1, Aleksandra Mezydlo1, Amit Bar‑Or7, Brenda Banwell8, Mohsen Khademi9, Tomas Olsson9, Reinhard Hohlfeld1,11, Hans Lassmann10, Tania Kümpfel1, Naoto Kawakami1† and Edgar Meinl1*†
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 rel‑ evance 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. Keywords: Autoantigen, Multiple sclerosis, Neuroinflammation, Autoimmunity
*Correspondence: [email protected]‑muenchen.de † Naoto Kawakami and Edgar Meinl contributed equally to this work 1 Institute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität München, Großhaderner Str. 9, 82152 Planegg‑Martinsried, Germany Full list of author information is available at the end of the article
Introduction Inflammatory diseases of the CNS comprise a broad spectrum of disorders, multiple sclerosis is the most abundant one. A misguided immune response to autoantigens expressed in the CNS is expected to drive the disease in these patients [21, 51, 52, 68] and multiple targets of the auto
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