title: All naturally occurring autoantibodies against the NMDA receptor subunit NR1 have pathogenic potential irrespective of epitope and immunoglobulin class.
abstract: Autoantibodies of the IgG class against N-methyl-d-aspartate-receptor subunit NR1 (NMDAR1) were first described in anti-NMDAR encephalitis and seen as disease indicators. Recent work on together over 5000 individuals challenged this exclusive view by showing age-dependently up to >20% NMDAR1-autoantibody seroprevalence with comparable immunoglobulin class and titer distribution across health and disease. The key question therefore is to understand the properties of these autoantibodies, also in healthy carriers, in order to assess secondary complications and possible contributions to neuropsychiatric disease. Here, we believe we provide for human NMDAR1-autoantibodies the first comprehensive analysis of their target epitopes and functionality. We selected sera of representative carriers, healthy or diagnosed with very diverse conditions, that is, schizophrenia, age-related disorders like hypertension and diabetes, or anti-NMDAR encephalitis. We show that all positive sera investigated, regardless of source (ill or healthy donor) and immunoglobulin class, provoked NMDAR1 internalization in human-induced pluripotent stem cell-derived neurons and reduction of glutamate-evoked currents in NR1-1b/NR2A-expressing Xenopus oocytes. They displayed frequently polyclonal/polyspecific epitope recognition in the extracellular or intracellular NMDAR1 domains and some additionally in NR2A. We conclude that all circulating NMDAR1-autoantibodies have pathogenic potential regarding the whole spectrum of neuronal NMDAR-mediated effects upon access to the brain in situations of increased blood-brain-barrier permeability.
authors: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors: E
authors: E
authors: Castillo-Gómez
authors: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors: B
authors: B
authors: Oliveira
authors: Department of Biochemistry I - Receptor Biochemistry, Ruhr University, Bochum, Germany.
authors: D
authors: D
authors: Tapken
authors: HiQscreen, Geneva, Switzerland.
authors: S
authors: S
authors: Bertrand
authors: Department of Biochemistry I - Receptor Biochemistry, Ruhr University, Bochum, Germany.
authors: C
authors: C
authors: Klein-Schmidt
authors: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors: H
authors: H
authors: Pan
authors: Institute of Pharmacology and Toxicology, University Medical Center, Göttingen, Germany.
authors: P
authors: P
authors: Zafeiriou
authors: Department of Psychiatry, University of Magdeburg, Magdeburg, Germany.
authors: J
authors: J
authors: Steiner
authors: Department of Neurology, Charité, University Medicine, Berlin, Germany.|German Center for Neurodegenerative Disorders (DZNE), Berlin, Germany.
authors: B
authors: B
authors: Jurek
authors: Department of Biochemistry I - Receptor Biochemistry, Ruhr University, Bochum, Germany.
authors: R
authors: R
authors: Trippe
authors: Department of Neurology, Charité, University Medicine, Berlin, Germany.|German Center for Neurodegenerative Disorders (DZNE), Berlin, Germany.
authors: H
authors: H
authors: Prüss
authors: Institute of Pharmacology and Toxicology, University Medical Center, Göttingen, Germany.
authors: W-H
authors: WH
authors: Zimmermann
authors: HiQscreen, Geneva, Switzerland.
authors: D
authors: D
authors: Bertrand
authors: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.|DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors: H
authors: H
authors: Ehrenreich
authors: Department of Biochemistry I - Receptor Biochemistry, Ruhr University, Bochum, Germany.
authors: M
authors: M
authors: Hollmann
mesh_terms: D000368:Aged; D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D004705:Endocytosis / Q000502:physiology; D000939:Epitopes / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000276:immunology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism*; D007074:Immunoglobulin G / Q000378:metabolism*; D007075:Immunoglobulin M / Q000378:metabolism*; D057026:Induced Pluripotent Stem Cells / Q000276:immunology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D001523:Mental Disorders / Q000097:blood / Q000276:immunology; D008875:Middle Aged; D009422:Nervous System Diseases / Q000097:blood / Q000276:immunology; D009474:Neurons / Q000276:immunology; D009865:Oocytes; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology*; D014982:Xenopus laevis
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid