title: Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity.
abstract: In 2007, a multifaceted syndrome, associated with anti-NMDA receptor autoantibodies (NMDAR-AB) of immunoglobulin-G isotype, has been described, which variably consists of psychosis, epilepsy, cognitive decline and extrapyramidal symptoms. Prevalence and significance of NMDAR-AB in complex neuropsychiatric disease versus health, however, have remained unclear. We tested sera of 2817 subjects (1325 healthy, 1081 schizophrenic, 263 Parkinson and 148 affective-disorder subjects) for presence of NMDAR-AB, conducted a genome-wide genetic association study, comparing AB carriers versus non-carriers, and assessed their influenza AB status. For mechanistic insight and documentation of AB functionality, in vivo experiments involving mice with deficient blood-brain barrier (ApoE(-/-)) and in vitro endocytosis assays in primary cortical neurons were performed. In 10.5% of subjects, NMDAR-AB (NR1 subunit) of any immunoglobulin isotype were detected, with no difference in seroprevalence, titer or in vitro functionality between patients and healthy controls. Administration of extracted human serum to mice influenced basal and MK-801-induced activity in the open field only in ApoE(-/-) mice injected with NMDAR-AB-positive serum but not in respective controls. Seropositive schizophrenic patients with a history of neurotrauma or birth complications, indicating an at least temporarily compromised blood-brain barrier, had more neurological abnormalities than seronegative patients with comparable history. A common genetic variant (rs524991, P=6.15E-08) as well as past influenza A (P=0.024) or B (P=0.006) infection were identified as predisposing factors for NMDAR-AB seropositivity. The >10% overall seroprevalence of NMDAR-AB of both healthy individuals and patients is unexpectedly high. Clinical significance, however, apparently depends on association with past or present perturbations of blood-brain barrier function.
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Hammer
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Stepniak
authors.affiliation: 1] Department of Psychiatry & Psychotherapy, University Medicine Göttingen, Göttingen, Germany [2] DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany [3] German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schneider
authors.affiliation: 1] Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany [2] DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Papiol
authors.affiliation: 1] Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany [2] DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Tantra
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Begemann
authors.affiliation: Department of Neurosurgery, University Clinic of Würzburg, Würzburg, Germany.
authors.forename: A-L
authors.initials: AL
authors.lastname: Sirén
authors.affiliation: Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: L A
authors.initials: LA
authors.lastname: Pardo
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Sperling
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Mohd Jofrry
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Gurvich
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Jensen
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Ostmeier
authors.affiliation: Department of Neuroimmunology, Institute for Multiple Sclerosis Research and Hertie Foundation, University Medicine Göttingen, Göttingen, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Lühder
authors.affiliation: Institute for Experimental Immunology, affiliated to Euroimmun, Lübeck, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Probst
authors.affiliation: Synaptic Systems GmbH, Göttingen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Martens
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Gillis
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Saher
authors.affiliation: Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Assogna
authors.affiliation: Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Spalletta
authors.affiliation: Institute for Experimental Immunology, affiliated to Euroimmun, Lübeck, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Stöcker
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: T F
authors.initials: TF
authors.lastname: Schulz
authors.affiliation: 1] DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany [2] Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: K-A
authors.initials: KA
authors.lastname: Nave
authors.affiliation: 1] Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany [2] DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Ehrenreich
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007251:Influenza, Human / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D019964:Mood Disorders / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000276:immunology*; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D001323:Autoantibodies; D016194:Receptors, N-Methyl-D-Aspartate