Advertisement

Do Neuronal Autoantibodies Cause Psychosis? A Neuroimmunological Perspective

  • Ester Coutinho
    Affiliations
    Nuffield Department of Clinical Neurosciences and Department of Psychiatry, University of Oxford, Oxford, United Kingdom
    Search for articles by this author
  • Paul Harrison
    Affiliations
    Nuffield Department of Clinical Neurosciences and Department of Psychiatry, University of Oxford, Oxford, United Kingdom
    Search for articles by this author
  • Angela Vincent
    Correspondence
    Address correspondence to Angela Vincent, F.R.S., University of Oxford, Nuffield Department of Clinical Neurosciences, Level 6, West Wing, John Radcliffe Hospital, Oxford OX3 9DU, UK
    Affiliations
    Nuffield Department of Clinical Neurosciences and Department of Psychiatry, University of Oxford, Oxford, United Kingdom
    Search for articles by this author
      In the last decade, autoantibodies targeting proteins on the neuronal surface and that are believed to be directly pathogenic have been described in patients with autoimmune encephalitis. Since then, new antigenic targets have been discovered, and new clinical phenotypes have been recognized. The psychotic disorders are one example of this expanding spectrum. Here, we consider the defining criteria of antibody-mediated central nervous system disease and the extent to which the psychiatric data currently satisfy those criteria. We discuss the implications these findings have for our understanding, nosology, and treatment of psychiatric disorders.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Keesey J.
        • Aarli J.
        Something in the blood? A history of the autoimmune hypothesis regarding myasthenia gravis.
        J Hist Neurosci. 2007; 16: 395-412
        • Nastuk W.L.
        • Strauss A.J.
        • Osserman K.E.
        Search for a neuromuscular blocking agent in the blood of patients with myasthenia gravis.
        Am J Med. 1959; 26: 394-409
        • Patrick J.
        • Lindstrom J.
        Autoimmune response to acetylcholine receptor.
        Science. 1973; 180: 871-872
        • Bender A.N.
        • Ringel S.P.
        • Engel W.K.
        • Daniels M.P.
        • Vogel Z.
        Myasthenia gravis: A serum factor blocking acetylcholine receptors of the human neuromuscular junction.
        Lancet. 1975; 1: 607-609
        • Roberts A.
        • Perera S.
        • Lang B.
        • Vincent A.
        • Newsom-Davis J.
        Paraneoplastic myasthenic syndrome IgG inhibits 45Ca2+ flux in a human small cell carcinoma line.
        Nature. 1985; 317: 737-739
        • Shillito P.
        • Molenaar P.C.
        • Vincent A.
        • Leys K.
        • Zheng W.
        • van den Berg R.J.
        • et al.
        Acquired neuromyotonia: Evidence for autoantibodies directed against K+ channels of peripheral nerves.
        Ann Neurol. 1995; 38: 714-722
        • Muldoon L.L.
        • Alvarez J.I.
        • Begley D.J.
        • Boado R.J.
        • Del Zoppo G.J.
        • Doolittle N.D.
        • et al.
        Immunologic privilege in the central nervous system and the blood-brain barrier.
        J Cereb Blood Flow Metab. 2013; 33: 13-21
        • Graus F.
        • Saiz A.
        • Dalmau J.
        Antibodies and neuronal autoimmune disorders of the CNS.
        J Neurol. 2010; 257: 509-517
        • Rogers S.W.
        • Andrews P.I.
        • Gahring L.C.
        • Whisenand T.
        • Cauley K.
        • Crain B.
        • et al.
        Autoantibodies to glutamate receptor GluR3 in Rasmussen’s encephalitis.
        Science. 1994; 265: 648-651
        • Watson R.
        • Jiang Y.
        • Bermudez I.
        • Houlihan L.
        • Clover L.
        • McKnight K.
        • et al.
        Absence of antibodies to glutamate receptor type 3 (GluR3) in Rasmussen encephalitis.
        Neurology. 2004; 63: 43-50
        • Wiendl H.
        • Bien C.G.
        • Bernasconi P.
        • Fleckenstein B.
        • Elger C.E.
        • Dichgans J.
        • et al.
        GluR3 antibodies: Prevalence in focal epilepsy but no specificity for Rasmussen’s encephalitis.
        Neurology. 2001; 57: 1511-1514
        • Buckley C.
        • Oger J.
        • Clover L.
        • Tuzun E.
        • Carpenter K.
        • Jackson M.
        • et al.
        Potassium channel antibodies in two patients with reversible limbic encephalitis.
        Ann Neurol. 2001; 50: 73-78
        • Vincent A.
        • Bien C.G.
        • Irani S.R.
        • Waters P.
        Autoantibodies associated with diseases of the CNS: New developments and future challenges.
        Lancet Neurol. 2011; 10: 759-772
        • Rose N.R.
        • Bona C.
        Defining criteria for autoimmune diseases (Witebsky’s postulates revisited).
        Immunol Today. 1993; 14: 426-430
        • Lancaster E.
        • Lai M.
        • Peng X.
        • Hughes E.
        • Constantinescu R.
        • Raizer J.
        • et al.
        Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: Case series and characterisation of the antigen.
        Lancet Neurol. 2010; 9: 67-76
        • Lancaster E.
        • Martinez-Hernandez E.
        • Dalmau J.
        Encephalitis and antibodies to synaptic and neuronal cell surface proteins.
        Neurology. 2011; 77: 179-189
        • Irani S.R.
        • Michell A.W.
        • Lang B.
        • Pettingill P.
        • Waters P.
        • Johnson M.R.
        • et al.
        Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.
        Ann Neurol. 2011; 69: 892-900
        • Brenner T.
        • Sills G.J.
        • Hart Y.
        • Howell S.
        • Waters P.
        • Brodie M.J.
        • et al.
        Prevalence of neurologic autoantibodies in cohorts of patients with new and established epilepsy.
        Epilepsia. 2013; 54: 1028-1035
        • Zandi M.S.
        • Irani S.R.
        • Lang B.
        • Waters P.
        • Jones P.B.
        • McKenna P.
        • et al.
        Disease-relevant autoantibodies in first episode schizophrenia.
        J Neurol. 2011; 258: 686-688
        • Steiner J.
        • Walter M.
        • Glanz W.
        • Sarnyai Z.
        • Bernstein H.G.
        • Vielhaber S.
        • et al.
        Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: Specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis.
        JAMA Psychiatry. 2013; 70: 271-278
        • Rubio-Agusti I.
        • Dalmau J.
        • Sevilla T.
        • Burgal M.
        • Beltran E.
        • Bataller L.
        Isolated hemidystonia associated with NMDA receptor antibodies.
        Mov Disord. 2011; 26: 351-352
        • Leite M.I.
        • Coutinho E.
        • Lana-Peixoto M.
        • Apostolos S.
        • Waters P.
        • Sato D.
        • et al.
        Myasthenia gravis and neuromyelitis optica spectrum disorder: A multicenter study of 16 patients.
        Neurology. 2012; 78: 1601-1607
        • Kruer M.C.
        • Koch T.K.
        • Bourdette D.N.
        • Chabas D.
        • Waubant E.
        • Mueller S.
        • et al.
        NMDA receptor encephalitis mimicking seronegative neuromyelitis optica.
        Neurology. 2010; 74: 1473-1475
        • Kurian M.
        • Lalive P.H.
        • Dalmau J.O.
        • Horvath J.
        Opsoclonus-myoclonus syndrome in anti-N-methyl-D-aspartate receptor encephalitis.
        Arch Neurol. 2010; 67: 118-121
        • Mackay G.
        • Ahmad K.
        • Stone J.
        • Sudlow C.
        • Summers D.
        • Knight R.
        • et al.
        NMDA receptor autoantibodies in sporadic Creutzfeldt-Jakob disease.
        J Neurol. 2012; 259: 1979-1981
        • Fujita K.
        • Yuasa T.
        • Takahashi Y.
        • Tanaka K.
        • Sako W.
        • Koizumi H.
        • et al.
        Antibodies to N-methyl-D-aspartate glutamate receptors in Creutzfeldt-Jakob disease patients.
        J Neuroimmunol. 2012; 251: 90-93
        • Vincent A.
        • Buckley C.
        • Schott J.M.
        • Baker I.
        • Dewar B.K.
        • Detert N.
        • et al.
        Potassium channel antibody-associated encephalopathy: A potentially immunotherapy-responsive form of limbic encephalitis.
        Brain. 2004; 127: 701-712
        • Paterson R.W.
        • Zandi M.S.
        • Armstrong R.
        • Vincent A.
        • Schott J.M.
        Clinical relevance of positive voltage-gated potassium channel (VGKC)-complex antibodies: Experience from a tertiary referral centre [published online ahead of print June 11].
        J Neurol Neurosurg Psychiatry. 2013;
        • Vincent A.
        • Clover L.
        • Buckley C.
        • Grimley Evans J.
        • Rothwell P.M.
        • Survey U.K.M.G.
        Evidence of underdiagnosis of myasthenia gravis in older people.
        J Neurol Neurosurg Psychiatry. 2003; 74: 1105-1108
        • Moscato E.H.
        • Jain A.
        • Peng X.
        • Hughes E.G.
        • Dalmau J.
        • Balice-Gordon R.J.
        Mechanisms underlying autoimmune synaptic encephalitis leading to disorders of memory, behavior and cognition: Insights from molecular, cellular and synaptic studies.
        Eur J Neurosci. 2010; 32: 298-309
        • Hughes E.G.
        • Peng X.
        • Gleichman A.J.
        • Lai M.
        • Zhou L.
        • Tsou R.
        • et al.
        Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis.
        J Neurosci. 2010; 30: 5866-5875
        • Lai M.
        • Hughes E.G.
        • Peng X.
        • Zhou L.
        • Gleichman A.J.
        • Shu H.
        • et al.
        AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location.
        Ann Neurol. 2009; 65: 424-434
        • Bien C.G.
        • Vincent A.
        • Barnett M.H.
        • Becker A.J.
        • Blumcke I.
        • Graus F.
        • et al.
        Immunopathology of autoantibody-associated encephalitides: Clues for pathogenesis.
        Brain. 2012; 135: 1622-1638
        • Irani S.R.
        • Alexander S.
        • Waters P.
        • Kleopa K.A.
        • Pettingill P.
        • Zuliani L.
        • et al.
        Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia.
        Brain. 2010; 133: 2734-2748
        • Hutchinson M.
        • Waters P.
        • McHugh J.
        • Gorman G.
        • O’Riordan S.
        • Connolly S.
        • et al.
        Progressive encephalomyelitis, rigidity, and myoclonus: A novel glycine receptor antibody.
        Neurology. 2008; 71: 1291-1292
        • McKeon A.
        • Martinez-Hernandez E.
        • Lancaster E.
        • Matsumoto J.Y.
        • Harvey R.J.
        • McEvoy K.M.
        • et al.
        Glycine receptor autoimmune spectrum with stiff-man syndrome phenotype.
        JAMA Neurol. 2013; 70: 44-50
        • Adell A.
        • Jimenez-Sanchez L.
        • Lopez-Gil X.
        • Romon T.
        Is the acute NMDA receptor hypofunction a valid model of schizophrenia?.
        Schizophr Bull. 2012; 38: 9-14
        • Inta D.
        • Monyer H.
        • Sprengel R.
        • Meyer-Lindenberg A.
        • Gass P.
        Mice with genetically altered glutamate receptors as models of schizophrenia: A comprehensive review.
        Neurosci Biobehav Rev. 2010; 34: 285-294
        • Nobile C.
        • Michelucci R.
        • Andreazza S.
        • Pasini E.
        • Tosatto S.C.
        • Striano P.
        LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy.
        Hum Mutat. 2009; 30: 530-536
        • Strauss K.A.
        • Puffenberger E.G.
        • Huentelman M.J.
        • Gottlieb S.
        • Dobrin S.E.
        • Parod J.M.
        • et al.
        Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2.
        N Engl J Med. 2006; 354: 1370-1377
        • Stogmann E.
        • Reinthaler E.
        • Eltawil S.
        • El Etribi M.A.
        • Hemeda M.
        • El Nahhas N.
        • et al.
        Autosomal recessive cortical myoclonic tremor and epilepsy: Association with a mutation in the potassium channel associated gene CNTN2.
        Brain. 2013; 136: 1155-1160
        • Penagarikano O.
        • Geschwind D.H.
        What does CNTNAP2 reveal about autism spectrum disorder?.
        Trends Mol Med. 2012; 18: 156-163
        • Friedman J.I.
        • Vrijenhoek T.
        • Markx S.
        • Janssen I.M.
        • van der Vliet W.A.
        • Faas B.H.
        • et al.
        CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy.
        Mol Psychiatry. 2008; 13: 261-266
        • Manto M.
        • Dalmau J.
        • Didelot A.
        • Rogemond V.
        • Honnorat J.
        In vivo effects of antibodies from patients with anti-NMDA receptor encephalitis: Further evidence of synaptic glutamatergic dysfunction.
        Orphanet J Rare Dis. 2010; 5: 31
        • Manto M.
        • Dalmau J.
        • Didelot A.
        • Rogemond V.
        • Honnorat J.
        Afferent facilitation of corticomotor responses is increased by IgGs of patients with NMDA-receptor antibodies.
        J Neurol. 2011; 258: 27-33
        • Coesmans M.
        • Smitt P.A.
        • Linden D.J.
        • Shigemoto R.
        • Hirano T.
        • Yamakawa Y.
        • et al.
        Mechanisms underlying cerebellar motor deficits due to mGluR1-autoantibodies.
        Ann Neurol. 2003; 53: 325-336
        • McCarthy A.
        • Dineen J.
        • McKenna P.
        • Keogan M.
        • Sheehan J.
        • Lynch T.
        • et al.
        Anti-NMDA receptor encephalitis with associated catatonia during pregnancy.
        J Neurol. 2012; 259: 2632-2635
        • Kumar M.A.
        • Jain A.
        • Dechant V.E.
        • Saito T.
        • Rafael T.
        • Aizawa H.
        • et al.
        Anti-N-methyl-D-aspartate receptor encephalitis during pregnancy.
        Arch Neurol. 2010; 67: 884-887
        • Magley J.
        • Towner D.
        • Tache V.
        • Apperson M.L.
        Pregnancy outcome in anti-N-methyl-D-aspartate receptor encephalitis.
        Obstet Gynecol. 2012; 120: 480-483
        • Titulaer M.J.
        • McCracken L.
        • Gabilondo I.
        • Armangue T.
        • Glaser C.
        • Iizuka T.
        • et al.
        Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: An observational cohort study.
        Lancet Neurology. 2013; 12: 157-165
        • Thieben M.J.
        • Lennon V.A.
        • Boeve B.F.
        • Aksamit A.J.
        • Keegan M.
        • Vernino S.
        Potentially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody.
        Neurology. 2004; 62: 1177-1182
        • Irani S.R.
        • Bera K.
        • Waters P.
        • Zuliani L.
        • Maxwell S.
        • Zandi M.S.
        • et al.
        N-methyl-D-aspartate antibody encephalitis: Temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes.
        Brain. 2010; 133: 1655-1667
        • Strous R.D.
        • Shoenfeld Y.
        Schizophrenia, autoimmunity and immune system dysregulation: A comprehensive model updated and revisited.
        J Autoimmun. 2006; 27: 71-80
        • Jones A.L.
        • Mowry B.J.
        • Pender M.P.
        • Greer J.M.
        Immune dysregulation and self-reactivity in schizophrenia: Do some cases of schizophrenia have an autoimmune basis?.
        Immunol Cell Biol. 2005; 83: 9-17
        • Rothermundt M.
        • Arolt V.
        • Bayer T.A.
        Review of immunological and immunopathological findings in schizophrenia.
        Brain Behav Immun. 2001; 15: 319-339
        • Eaton W.W.
        • Byrne M.
        • Ewald H.
        • Mors O.
        • Chen C.Y.
        • Agerbo E.
        • et al.
        Association of schizophrenia and autoimmune diseases: Linkage of Danish national registers.
        Am J Psychiatry. 2006; 163: 521-528
        • Benros M.E.
        • Nielsen P.R.
        • Nordentoft M.
        • Eaton W.W.
        • Dalton S.O.
        • Mortensen P.B.
        Autoimmune diseases and severe infections as risk factors for schizophrenia: A 30-year population-based register study.
        Am J Psychiatry. 2011; 168: 1303-1310
        • Messias E.L.
        • Chen C.Y.
        • Eaton W.W.
        Epidemiology of schizophrenia: Review of findings and myths.
        Psychiatr Clin North Am. 2007; 30: 323-338
        • Fritzsche M.
        Geographical and seasonal correlation of multiple sclerosis to sporadic schizophrenia.
        Int J Health Geogr. 2002; 1: 5
        • Stefansson H.
        • Ophoff R.A.
        • Steinberg S.
        • Andreassen O.A.
        • Cichon S.
        • Rujescu D.
        • et al.
        Common variants conferring risk of schizophrenia.
        Nature. 2009; 460: 744-747
        • Jia P.
        • Wang L.
        • Meltzer H.Y.
        • Zhao Z.
        Common variants conferring risk of schizophrenia: A pathway analysis of GWAS data.
        Schizophr Res. 2010; 122: 38-42
        • Tsutsui K.
        • Kanbayashi T.
        • Tanaka K.
        • Boku S.
        • Ito W.
        • Tokunaga J.
        • et al.
        Anti-NMDA-receptor antibody detected in encephalitis, schizophrenia, and narcolepsy with psychotic features.
        BMC Psychiatry. 2012; 12: 37

      Linked Article

      • Is There a Flame in the Brain in Psychosis?
        Biological PsychiatryVol. 75Issue 4
        • Preview
          For many decades, it was believed that the brain was immunologically privileged, hence it was surprising when Shatz and colleagues (1) reported in 2000 that a number of immune proteins (cytokines and major histocompatibility complex [MHC] proteins) were not just present in the brain but were localized at functional synapses. Subsequent work has shown that these molecules play a major role in brain development as well as in mature synaptic function and plasticity (2,3).
        • Full-Text
        • PDF