Advertisement

Is There a Flame in the Brain in Psychosis?

      For many decades, it was believed that the brain was immunologically privileged, hence it was surprising when Shatz and colleagues (
      • Huh G.S.
      • Boulanger L.M.
      • Du H.
      • Riquelme P.A.
      • Brotz T.M.
      • Shatz C.J.
      Functional requirement for class I MHC in CNS development and plasticity.
      ) 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 (
      • McAllister A.K.
      Major histocompatibility complex I in brain development and schizophrenia.
      ,
      • Meyer U.
      Prenatal poly(I:C) exposure and other developmental immune activation models in rodent systems.
      ).
      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

        • Huh G.S.
        • Boulanger L.M.
        • Du H.
        • Riquelme P.A.
        • Brotz T.M.
        • Shatz C.J.
        Functional requirement for class I MHC in CNS development and plasticity.
        Science. 2000; 290: 2155-2159
        • McAllister A.K.
        Major histocompatibility complex I in brain development and schizophrenia.
        Biol Psychiatry. 2014; 75: 262-268
        • Meyer U.
        Prenatal poly(I:C) exposure and other developmental immune activation models in rodent systems.
        Biol Psychiatry. 2014; 75: 307-315
        • Girgis R.R.
        • Kumar S.S.
        • Brown A.S.
        The cytokine model of schizophrenia: emerging therapeutic strategies.
        Biol Psychiatry. 2014; 75: 292-299
        • Corvin A.
        • Morris D.W.
        Genome-wide association studies: Findings at the major histocompatibility complex locus in psychosis.
        Biol Psychiatry. 2014; 75: 276-283
        • McGuffin P.
        • Power R.A.
        Schizophrenia as a human leukocyte antigen-associated disease revisited.
        Am J Psychiatry. 2013; 170: 821-823
        • Bergink V.
        • Gibney S.M.
        • Drexhage H.A.
        Autoimmunity, inflammation, and psychosis: A search for peripheral markers.
        Biol Psychiatry. 2014; 75: 324-331
        • Brown A.S.
        • Begg M.D.
        • Gravenstein S.
        • Schaefer C.A.
        • Wyatt R.J.
        • Bresnahan M.
        • et al.
        Serologic evidence of prenatal influenza in the etiology of schizophrenia.
        Arch Gen Psychiatry. 2004; 61: 774-780
        • Benros M.E.
        • Eaton W.W.
        • Mortensen P.B.
        The epidemiologic evidence linking autoimmune diseases and psychosis.
        Biol Psychiatry. 2014; 75: 300-306
        • Deakin J.
        • Lennox B.R.
        • Zandi M.S.
        Antibodies to the N-methyl-D-aspartate receptor and other synaptic proteins in psychosis.
        Biol Psychiatry. 2014; 75: 284-291
        • Coutinho E.
        • Harrison P.
        • Vincent A.
        Do neuronal autoantibodies cause psychosis? A neuroimmunological perspective.
        Biol Psychiatry. 2014; 75: 269-275
        • Horváth S.
        • Mirnics K.
        Immune system disturbances in schizophrenia.
        Biol Psychiatry. 2014; 75: 316-323
        • Patterson P.H.
        Maternal effects on schizophrenia risk.
        Science. 2007; 26: 576-577
        • Bauman M.D.
        • Iosif A.-M.
        • Smith S.E.P.
        • Bregere C.
        • Amaral D.G.
        • Patterson P.H.
        Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring.
        Biol Psychiatry. 2014; 75: 332-341
        • McGorry P.D.
        Issues for DSM-V: Clinical staging: A heuristic pathway to valid nosology and safer, more effective treatment in psychiatry.
        Am J Psychiatry. 2007; 164: 859-860

      Linked Article

      • Autoimmunity, Inflammation, and Psychosis: A Search for Peripheral Markers
        Biological PsychiatryVol. 75Issue 4
        • Preview
          Accumulating evidence supports the view that deregulation of the immune system represents an important vulnerability factor for psychosis. In a subgroup of psychotic patients, the high comorbidity with autoimmune and chronic inflammatory conditions suggests a common underlying immune abnormality leading to both conditions. The reviewed data of affective and nonaffective psychosis show that if immune biomarkers exist for such immune abnormality, they may be found in raised macrophage/monocyte inflammatory activation patterns (monocytosis, high-inflammatory gene expression, raised glucocorticoid receptor β/glucocorticoid receptor α ratio, and high levels of proinflammatory and anti-inflammatory monocyte/macrophage derived cytokines in serum/plasma), reduced T cell numbers/proliferation, and TH1 skewing.
        • Full-Text
        • PDF
      • The Epidemiologic Evidence Linking Autoimmune Diseases and Psychosis
        Biological PsychiatryVol. 75Issue 4
        • Preview
          This review summarizes the epidemiologic evidence linking autoimmune diseases and psychosis. The associations between autoimmune diseases and psychosis have been studied for more than a half century, but research has intensified within the last decades, since psychosis has been associated with genetic markers of the immune system and with excess autoreactivity and other immune alterations. A range of psychiatric disorders, including psychosis, have been observed to occur more frequently in some autoimmune diseases, such as systemic lupus erythematosus and multiple sclerosis.
        • Full-Text
        • PDF
      • Immune System Disturbances in Schizophrenia
        Biological PsychiatryVol. 75Issue 4
        • Preview
          Epidemiological, genetic, transcriptome, postmortem, peripheral biomarker, and therapeutic studies of schizophrenia all point to a dysregulation of both innate and adaptive immune systems in the disease, and it is likely that these immune changes actively contribute to disease symptoms. Gene expression disturbances in the brain of subjects with schizophrenia show complex, region-specific changes with consistently replicated and potentially interdependent induction of serpin peptidase inhibitor, clade A member 3 (SERPINA3) and interferon inducible transmembrane protein (IFITM) family transcripts in the prefrontal cortex.
        • Full-Text
        • PDF
      • Major Histocompatibility Complex I in Brain Development and Schizophrenia
        Biological PsychiatryVol. 75Issue 4
        • Preview
          Although the etiology of schizophrenia (SZ) remains unknown, it is increasingly clear that immune dysregulation plays a central role. Genome-wide association studies reproducibly indicate an association of SZ with immune genes within the major histocompatibility complex (MHC). Moreover, environmental factors that increase risk for SZ, such as maternal infection, alter peripheral immune responses as well as the expression of immune molecules in the brain. MHC class I (MHCI) molecules might mediate both genetic and environmental contributions to SZ through direct effects on brain development in addition to mediating immunity.
        • Full-Text
        • PDF
      • The Cytokine Model of Schizophrenia: Emerging Therapeutic Strategies
        Biological PsychiatryVol. 75Issue 4
        • Preview
          We discuss the rationale for a trial of a novel biological immunotherapy in schizophrenia (SCZ). Available antipsychotic treatments for SCZ are often limited by partial effectiveness and significant side effects. The search for novel medications is of high priority. All current antipsychotics function primarily by blocking D2-type dopamine receptors. An emerging theory of SCZ postulates disturbances of cytokines and inflammatory mediators (i.e., the cytokine model), possibly originating in part from infectious exposures.
        • Full-Text
        • PDF
      • Prenatal Poly(I:C) Exposure and Other Developmental Immune Activation Models in Rodent Systems
        Biological PsychiatryVol. 75Issue 4
        • Preview
          It is increasingly appreciated that altered neuroimmune mechanisms might play a role in the development of schizophrenia and related psychotic illnesses. On the basis of human epidemiological findings, a number of translational rodent models have been established to explore the consequences of prenatal immune activation on brain and behavioral development. The currently existing models are based on maternal gestational exposure to human influenza virus, the viral mimic polyriboinosinic-polyribocytidilic acid [Poly(I:C)], the bacterial endotoxin lipopolysaccharide, the locally acting inflammatory agent turpentine, or selected inflammatory cytokines.
        • Full-Text
        • PDF
      • Antibodies to the N-Methyl-D-Aspartate Receptor and Other Synaptic Proteins in Psychosis
        Biological PsychiatryVol. 75Issue 4
        • Preview
          This review concentrates on the evidence for autoantibodies to cell surface synaptic proteins in psychosis and schizophrenia. We and others have recently found antibodies to the N-methyl-D-aspartate receptor in first-episode psychosis. We describe the evidence for pathogenicity and disease-relevance of these antibodies, which builds on the novel field in neuroimmunology of cell surface antibody–associated central nervous system disorders. Relevant autoantibodies in psychosis and schizophrenia are likely to be those directed to cell surface proteins, in which the likelihood of pathogenicity is greater.
        • Full-Text
        • PDF
      • Do Neuronal Autoantibodies Cause Psychosis? A Neuroimmunological Perspective
        Biological PsychiatryVol. 75Issue 4
        • Preview
          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.
        • Full-Text
        • PDF
      • Activation of the Maternal Immune System During Pregnancy Alters Behavioral Development of Rhesus Monkey Offspring
        Biological PsychiatryVol. 75Issue 4
        • Preview
          Maternal infection during pregnancy is associated with an increased risk of schizophrenia and autism in the offspring. Supporting this correlation, experimentally activating the maternal immune system during pregnancy in rodents produces offspring with abnormal brain and behavioral development. We have developed a nonhuman primate model to bridge the gap between clinical populations and rodent models of maternal immune activation (MIA).
        • Full-Text
        • PDF
      • Genome-wide Association Studies: Findings at the Major Histocompatibility Complex Locus in Psychosis
        Biological PsychiatryVol. 75Issue 4
        • Preview
          The major histocompatibility complex (MHC) is one of the most intensively investigated, genetically diverse regions of the genome. In its extended form, it encodes more than 400 genes critical to immunity but is also involved in many other functions. In 2009, three simultaneously published genome-wide association studies (GWAS) reported the first compelling evidence for involvement of the MHC in schizophrenia susceptibility. In this review, we describe the structure and function of the MHC, discuss some of the challenges for genetic analysis of the region, and provide an update on findings from GWAS studies before describing potential approaches to interpreting the role of the locus in schizophrenia etiology.
        • Full-Text
        • PDF