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Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood–brain barrier integrity

Molecular Psychiatry volume 19, pages 1143–1149 (2014)Cite this article

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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.

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Acknowledgements

This work was supported by the Max Planck Society, the Max Planck Förderstiftung, and the DFG (CNMPB). Christian Hammer acknowledges grant support by the Daimler and Benz Foundation as well as by the Brain and Behavior Foundation. Suhaidah Mohd Jofrry, through support by the Faculty of Pharmacy, Universiti Teknologi MARA, Bandar Puncak Alam, Selangor, Malaysia, received a scholarship from the Ministry of Higher Education Malaysia. We are grateful to Sylvia Siefarth, Euroimmun, for excellent technical assistance.

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Authors and Affiliations

  1. Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany

    C Hammer, B Stepniak, S Papiol, M Tantra, M Begemann, S Sperling, S Mohd Jofrry, A Gurvich, N Jensen, K Ostmeier & H Ehrenreich

  2. Department of Psychiatry & Psychotherapy, University Medicine Göttingen, Göttingen, Germany

    A Schneider

  3. DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany

    A Schneider, S Papiol, M Tantra, K-A Nave & H Ehrenreich

  4. German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany

    A Schneider

  5. Department of Neurosurgery, University Clinic of Würzburg, Würzburg, Germany

    A-L Sirén

  6. Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Göttingen, Germany

    L A Pardo

  7. Department of Neuroimmunology, Institute for Multiple Sclerosis Research and Hertie Foundation, University Medicine Göttingen, Göttingen, Germany

    F Lühder

  8. Institute for Experimental Immunology, affiliated to Euroimmun, Lübeck, Germany

    C Probst & W Stöcker

  9. Synaptic Systems GmbH, Göttingen, Germany

    H Martens

  10. Institute of Virology, Hannover Medical School, Hannover, Germany

    M Gillis & T F Schulz

  11. Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany

    G Saher & K-A Nave

  12. Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome, Italy

    F Assogna & G Spalletta

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Correspondence to H Ehrenreich.

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Competing interests

Dr Stöcker is a full-time employee of and holds stocks in Euroimmun AG. Dr Martens is a full-time employee of Synaptic Systems GmbH. All other authors declare no conflict of interest.

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Hammer, C., Stepniak, B., Schneider, A. et al. Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood–brain barrier integrity. Mol Psychiatry 19, 1143–1149 (2014). https://doi.org/10.1038/mp.2013.110

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