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Autoimmunity, Inflammation, and Psychosis: A Search for Peripheral Markers

Published:November 27, 2013DOI:https://doi.org/10.1016/j.biopsych.2013.09.037
      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. This activation of the inflammatory response system may be suggestive for microglia activation, as these cells are the macrophages of the brain. Indeed, there is some evidence of activation of the microglia as detected in positron emission tomography scans and in histopathology, and it is assumed that this activation disturbs the development and function of neuronal circuits in the brain. Further, animal models of psychotic conditions (maternal stress and inflammation paradigms) suggest that such monocyte/microglia activation could be seen as the result of a combination of genetic predisposition and an immune-mediated two-hit model. Infection but also environmental stressors during gestation/early life activate microglia, perturbing neuronal development, thereby setting the stage for vulnerability for later psychotic disorders. A second hit, such as endocrine changes, stress, or infection, could further activate microglia, leading to functional abnormalities of the neuronal circuitry in the brain and psychosis.

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      References

        • Yolken R.H.
        • Torrey E.F.
        Are some cases of psychosis caused by microbial agents? A review of the evidence.
        Mol Psychiatry. 2008; 13: 470-479
        • 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
        • Lawrence D.M.
        • Major E.O.
        HIV-1 and the brain: Connections between HIV-1-associated dementia, neuropathology and neuroimmunology.
        Microbes Infect. 2002; 4: 301-308
        • Block M.L.
        • Hong J.S.
        Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism.
        Prog Neurobiol. 2005; 76: 77-98
        • Dube B.
        • Benton T.
        • Cruess D.G.
        • Evans D.L.
        Neuropsychiatric manifestations of HIV infection and AIDS.
        J Psychiatry Neurosci. 2005; 30: 237-246
        • Petito C.K.
        • Torres-Munoz J.E.
        • Zielger F.
        • McCarthy M.
        Brain CD8+ and cytotoxic T lymphocytes are associated with, and may be specific for, human immunodeficiency virus type 1 encephalitis in patients with acquired immunodeficiency syndrome.
        J Neurovirol. 2006; 12: 272-283
        • Carter C.J.
        Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: Cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii.
        Schizophr Bull. 2009; 35: 1163-1182
        • Bertsias G.K.
        • Ioannidis J.P.
        • Aringer M.
        • Bollen E.
        • Bombardieri S.
        • Bruce I.N.
        • et al.
        EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: Report of a task force of the EULAR standing committee for clinical affairs.
        Ann Rheum Dis. 2010; 69: 2074-2082
        • Gabelic T.
        • Adamec I.
        • Mrden A.
        • Rados M.
        • Brinar V.V.
        • Habek M.
        Psychotic reaction as a manifestation of multiple sclerosis relapse treated with plasma exchange.
        Neurol Sci. 2012; 33: 379-382
        • Chastain E.M.
        • Miller S.D.
        Molecular mimicry as an inducing trigger for CNS autoimmune demyelinating disease.
        Immunol Rev. 2012; 245: 227-238
        • Rose N.R.
        • Bona C.
        Defining criteria for autoimmune diseases (Witebsky’s postulates revisited).
        Immunol Today. 1993; 14: 426-430
        • Yu A.Y.
        • Moore F.G.
        Paraneoplastic encephalitis presenting as postpartum psychosis.
        Psychosomatics. 2011; 52: 568-570
        • Shaaban H.S.
        • Choo H.F.
        • Sensakovic J.W.
        Anti-NMDA-receptor encephalitis presenting as postpartum psychosis in a young woman, treated with rituximab.
        Ann Saudi Med. 2012; 32: 421-423
        • Haussleiter I.S.
        • Emons B.
        • Schaub M.
        • Borowski K.
        • Brune M.
        • Wandinger K.P.
        • Juckel G.
        Investigation of antibodies against synaptic proteins in a cross-sectional cohort of psychotic patients.
        Schizophr Res. 2012; 140: 258-259
        • 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
        • Ganguli A.
        • Fitzgerald R.
        • Walker L.
        • Beadsworth M.
        • Mwandumba H.C.
        Voltage-gated, potassium-channel antibody-associated limbic encephalitis presenting as acute psychosis.
        J Neuropsychiatry Clin Neurosci. 2011; 23: E32-E34
        • Tebartz van Elst L.
        • Kloppel S.
        • Rauer S.
        Voltage-gated potassium channel/LGI1 antibody-associated encephalopathy may cause brief psychotic disorder.
        J Clin Psychiatry. 2011; 72: 722-723
        • Ludvigsson J.F.
        • Osby U.
        • Ekbom A.
        • Montgomery S.M.
        Coeliac disease and risk of schizophrenia and other psychosis: A general population cohort study.
        Scand J Gastroenterol. 2007; 42: 179-185
        • Eaton W.W.
        • Pedersen M.G.
        • Nielsen P.R.
        • Mortensen P.B.
        Autoimmune diseases, bipolar disorder, and non-affective psychosis.
        Bipolar Disord. 2010; 12: 638-646
        • Carney C.P.
        • Jones L.E.
        Medical comorbidity in women and men with bipolar disorders: A population-based controlled study.
        Psychosom Med. 2006; 68: 684-691
        • Cassidy F.
        • Ahearn E.
        • Carroll B.J.
        Elevated frequency of diabetes mellitus in hospitalized manic-depressive patients.
        Am J Psychiatry. 1999; 156: 1417-1420
        • van Winkel R.
        • De Hert M.
        • Van Eyck D.
        • Hanssens L.
        • Wampers M.
        • Scheen A.
        • Peuskens J.
        Prevalence of diabetes and the metabolic syndrome in a sample of patients with bipolar disorder.
        Bipolar Disord. 2008; 10: 342-348
        • Padmos R.C.
        • Bekris L.
        • Knijff E.M.
        • Tiemeier H.
        • Kupka R.W.
        • Cohen D.
        • et al.
        A high prevalence of organ-specific autoimmunity in patients with bipolar disorder.
        Biol Psychiatry. 2004; 56: 476-482
        • Kupka R.W.
        • Nolen W.A.
        • Post R.M.
        • McElroy S.L.
        • Altshuler L.L.
        • Denicoff K.D.
        • et al.
        High rate of autoimmune thyroiditis in bipolar disorder: Lack of association with lithium exposure.
        Biol Psychiatry. 2002; 51: 305-311
        • Sokol D.K.
        • O’Brien R.S.
        • Wagenknecht D.R.
        • Rao T.
        • McIntyre J.A.
        Antiphospholipid antibodies in blood and cerebrospinal fluids of patients with psychosis.
        J Neuroimmunol. 2007; 190: 151-156
        • Dickerson F.
        • Stallings C.
        • Origoni A.
        • Vaughan C.
        • Khushalani S.
        • Leister F.
        • et al.
        Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia.
        Biol Psychiatry. 2010; 68: 100-104
        • Dickerson F.
        • Stallings C.
        • Origoni A.
        • Vaughan C.
        • Khushalani S.
        • Yolken R.
        Markers of gluten sensitivity in acute mania: A longitudinal study.
        Psychiatry Res. 2012; 196: 68-71
        • Hillegers M.H.
        • Reichart C.G.
        • Wals M.
        • Verhulst F.C.
        • Ormel J.
        • Nolen W.A.
        • Drexhage H.A.
        Signs of a higher prevalence of autoimmune thyroiditis in female offspring of bipolar parents.
        Eur Neuropsychopharmacol. 2007; 17: 394-399
        • Vonk R.
        • van der Schot A.C.
        • Kahn R.S.
        • Nolen W.A.
        • Drexhage H.A.
        Is autoimmune thyroiditis part of the genetic vulnerability (or an endophenotype) for bipolar disorder?.
        Biol Psychiatry. 2007; 62: 135-140
        • Mueller D.L.
        Mechanisms maintaining peripheral tolerance.
        Nat Immunol. 2010; 11: 21-27
        • de Haan L.
        • Klaassen R.
        • van Beveren N.
        • Wunderink L.
        • Rutten B.P.
        • van Os J.
        [Psychotic disorders: The need for staging].
        Tijdschr Psychiatr. 2012; 54: 927-933
        • Kendell R.E.
        • Chalmers J.C.
        • Platz C.
        Epidemiology of puerperal psychoses.
        Br J Psychiatry. 1987; 150: 662-673
        • Buyon J.P.
        The effects of pregnancy on autoimmune diseases.
        J Leukoc Biol. 1998; 63: 281-287
        • Weetman A.P.
        Immunity, thyroid function and pregnancy: Molecular mechanisms.
        Nat Rev Endocrinol. 2010; 6: 311-318
        • Haupl T.
        • Ostensen M.
        • Grutzkau A.
        • Burmester G.R.
        • Villiger P.M.
        Interaction between rheumatoid arthritis and pregnancy: Correlation of molecular data with clinical disease activity measures.
        Rheumatology (Oxford). 2008; 47: iii19-iii22
        • Ruiz-Irastorza G.
        • Lima F.
        • Alves J.
        • Khamashta M.A.
        • Simpson J.
        • Hughes G.R.
        • Buchanan N.M.
        Increased rate of lupus flare during pregnancy and the puerperium: A prospective study of 78 pregnancies.
        Br J Rheumatol. 1996; 35: 133-138
        • Confavreux C.
        • Hutchinson M.
        • Hours M.M.
        • Cortinovis-Tourniaire P.
        • Moreau T.
        Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group.
        N Engl J Med. 1998; 339: 285-291
        • Schramm C.
        • Herkel J.
        • Beuers U.
        • Kanzler S.
        • Galle P.R.
        • Lohse A.W.
        Pregnancy in autoimmune hepatitis: Outcome and risk factors.
        Am J Gastroenterol. 2006; 101: 556-560
        • Sliwa K.
        • Fett J.
        • Elkayam U.
        Peripartum cardiomyopathy.
        Lancet. 2006; 368: 687-693
        • Calcagni E.
        • Elenkov I.
        Stress system activity, innate and T helper cytokines, and susceptibility to immune-related diseases.
        Ann N Y Acad Sci. 2006; 1069: 62-76
        • Gleicher N.
        Postpartum depression, an autoimmune disease?.
        Autoimmun Rev. 2007; 6: 572-576
        • Bergink V.
        • Burgerhout K.M.
        • Weigelt K.
        • Pop V.J.
        • de Wit H.
        • Drexhage R.C.
        • et al.
        Immune system dysregulation in first-onset postpartum psychosis.
        Biol Psychiatry. 2013; 73: 1000-1007
        • Alliot F.
        • Godin I.
        • Pessac B.
        Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain.
        Brain Res Dev Brain Res. 1999; 117: 145-152
        • Chan W.Y.
        • Kohsaka S.
        • Rezaie P.
        The origin and cell lineage of microglia: New concepts.
        Brain Res Rev. 2007; 53: 344-354
        • Ginhoux F.
        • Greter M.
        • Leboeuf M.
        • Nandi S.
        • See P.
        • Gokhan S.
        • et al.
        Fate mapping analysis reveals that adult microglia derive from primitive macrophages.
        Science. 2010; 330: 841-845
        • Ginhoux F.
        • Lim S.
        • Hoeffel G.
        • Low D.
        • Huber T.
        Origin and differentiation of microglia.
        Front Cell Neurosci. 2013; 7: 45
        • Kettenmann H.
        • Hanisch U.K.
        • Noda M.
        • Verkhratsky A.
        Physiology of microglia.
        Physiol Rev. 2011; 91: 461-553
        • Monji A.
        • Kato T.A.
        • Mizoguchi Y.
        • Horikawa H.
        • Seki Y.
        • Kasai M.
        • et al.
        Neuroinflammation in schizophrenia especially focused on the role of microglia.
        Prog Neuropsychopharmacol Biol Psychiatry. 2013; 42: 115-121
        • Steiner J.
        • Bielau H.
        • Brisch R.
        • Danos P.
        • Ullrich O.
        • Mawrin C.
        • et al.
        Immunological aspects in the neurobiology of suicide: Elevated microglial density in schizophrenia and depression is associated with suicide.
        J Psychiatr Res. 2008; 42: 151-157
        • Steiner J.
        • Mawrin C.
        • Ziegeler A.
        • Bielau H.
        • Ullrich O.
        • Bernstein H.G.
        • Bogerts B.
        Distribution of HLA-DR-positive microglia in schizophrenia reflects impaired cerebral lateralization.
        Acta Neuropathol. 2006; 112: 305-316
        • Arnold S.E.
        • Trojanowski J.Q.
        • Gur R.E.
        • Blackwell P.
        • Han L.Y.
        • Choi C.
        Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia.
        Arch Gen Psychiatry. 1998; 55: 225-232
        • Bayer T.A.
        • Buslei R.
        • Havas L.
        • Falkai P.
        Evidence for activation of microglia in patients with psychiatric illnesses.
        Neurosci Lett. 1999; 271: 126-128
        • Falke E.
        • Han L.Y.
        • Arnold S.E.
        Absence of neurodegeneration in the thalamus and caudate of elderly patients with schizophrenia.
        Psychiatry Res. 2000; 93: 103-110
        • Radewicz K.
        • Garey L.J.
        • Gentleman S.M.
        • Reynolds R.
        Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics.
        J Neuropathol Exp Neurol. 2000; 59: 137-150
        • Togo T.
        • Akiyama H.
        • Kondo H.
        • Ikeda K.
        • Kato M.
        • Iseki E.
        • Kosaka K.
        Expression of CD40 in the brain of Alzheimer’s disease and other neurological diseases.
        Brain Res. 2000; 885: 117-121
        • Wierzba-Bobrowicz T.
        • Lewandowska E.
        • Kosno-Kruszewska E.
        • Lechowicz W.
        • Pasennik E.
        • Schmidt-Sidor B.
        Degeneration of microglial cells in frontal and temporal lobes of chronic schizophrenics.
        Folia Neuropathol. 2004; 42: 157-165
        • Wierzba-Bobrowicz T.
        • Lewandowska E.
        • Lechowicz W.
        • Stepien T.
        • Pasennik E.
        Quantitative analysis of activated microglia, ramified and damage of processes in the frontal and temporal lobes of chronic schizophrenics.
        Folia Neuropathol. 2005; 43: 81-89
        • Busse S.
        • Busse M.
        • Schiltz K.
        • Bielau H.
        • Gos T.
        • Brisch R.
        • et al.
        Different distribution patterns of lymphocytes and microglia in the hippocampus of patients with residual versus paranoid schizophrenia: Further evidence for disease course-related immune alterations?.
        Brain Behav Immun. 2012; 26: 1273-1279
        • Fillman S.G.
        • Cloonan N.
        • Catts V.S.
        • Miller L.C.
        • Wong J.
        • McCrossin T.
        • et al.
        Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia.
        Mol Psychiatry. 2013; 18: 206-214
        • Dean B.
        • Gibbons A.S.
        • Tawadros N.
        • Brooks L.
        • Everall I.P.
        • Scarr E.
        Different changes in cortical tumor necrosis factor-alpha-related pathways in schizophrenia and mood disorders.
        Mol Psychiatry. 2013; 18: 767-773
        • Doorduin J.
        • de Vries E.F.
        • Willemsen A.T.
        • de Groot J.C.
        • Dierckx R.A.
        • Klein H.C.
        Neuroinflammation in schizophrenia-related psychosis: A PET study.
        J Nucl Med. 2009; 50: 1801-1807
        • van Berckel B.N.
        • Bossong M.G.
        • Boellaard R.
        • Kloet R.
        • Schuitemaker A.
        • Caspers E.
        • et al.
        Microglia activation in recent-onset schizophrenia: A quantitative (R)-[11C]PK11195 positron emission tomography study.
        Biol Psychiatry. 2008; 64: 820-822
        • Banati R.B.
        Visualising microglial activation in vivo.
        Glia. 2002; 40: 206-217
        • Rothermundt M.
        • Arolt V.
        • Weitzsch C.
        • Eckhoff D.
        • Kirchner H.
        Immunological dysfunction in schizophrenia: A systematic approach.
        Neuropsychobiology. 1998; 37: 186-193
        • Drexhage R.C.
        • Hoogenboezem T.A.
        • Cohen D.
        • Versnel M.A.
        • Nolen W.A.
        • van Beveren N.J.
        • Drexhage H.A.
        An activated set point of T-cell and monocyte inflammatory networks in recent-onset schizophrenia patients involves both pro- and anti-inflammatory forces.
        Int J Neuropsychopharmacol. 2011; 14: 746-755
        • Zorrilla E.P.
        • Cannon T.D.
        • Gur R.E.
        • Kessler J.
        Leukocytes and organ-nonspecific autoantibodies in schizophrenics and their siblings: Markers of vulnerability or disease?.
        Biol Psychiatry. 1996; 40: 825-833
        • Nikkila H.V.
        • Muller K.
        • Ahokas A.
        • Miettinen K.
        • Rimon R.
        • Andersson L.C.
        Accumulation of macrophages in the CSF of schizophrenic patients during acute psychotic episodes.
        Am J Psychiatry. 1999; 156: 1725-1729
        • Padmos R.C.
        • Hillegers M.H.
        • Knijff E.M.
        • Vonk R.
        • Bouvy A.
        • Staal F.J.
        • et al.
        A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes.
        Arch Gen Psychiatry. 2008; 65: 395-407
        • Drexhage R.C.
        • van der Heul-Nieuwenhuijsen L.
        • Padmos R.C.
        • van Beveren N.
        • Cohen D.
        • Versnel M.A.
        • et al.
        Inflammatory gene expression in monocytes of patients with schizophrenia: Overlap and difference with bipolar disorder. A study in naturalistically treated patients.
        Int J Neuropsychopharmacol. 2010; 13: 1369-1381
        • Di Nicola M.
        • Cattaneo A.
        • Hepgul N.
        • Di Forti M.
        • Aitchison K.J.
        • Janiri L.
        • et al.
        Serum and gene expression profile of cytokines in first-episode psychosis.
        Brain Behav Immun. 2013; 31: 90-95
        • Theodoropoulou S.
        • Spanakos G.
        • Baxevanis C.N.
        • Economou M.
        • Gritzapis A.D.
        • Papamichail M.P.
        • Stefanis C.N.
        Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients.
        Schizophr Res. 2001; 47: 13-25
        • Muller N.
        • Wagner J.K.
        • Krause D.
        • Weidinger E.
        • Wildenauer A.
        • Obermeier M.
        • et al.
        Impaired monocyte activation in schizophrenia.
        Psychiatry Res. 2012; 198: 341-346
        • Biswas S.K.
        • Lopez-Collazo E.
        Endotoxin tolerance: New mechanisms, molecules and clinical significance.
        Trends Immunol. 2009; 30: 475-487
        • Achiron A.
        • Noy S.
        • Pras E.
        • Lereya J.
        • Hermesh H.
        • Laor N.
        T-cell subsets in acute psychotic schizophrenic patients.
        Biol Psychiatry. 1994; 35: 27-31
        • Villemain F.
        • Chatenoud L.
        • Galinowski A.
        • Homo-Delarche F.
        • Ginestet D.
        • Loo H.
        • et al.
        Aberrant T cell-mediated immunity in untreated schizophrenic patients: Deficient interleukin-2 production.
        Am J Psychiatry. 1989; 146: 609-616
        • Maino K.
        • Gruber R.
        • Riedel M.
        • Seitz N.
        • Schwarz M.
        • Muller N.
        T- and B-lymphocytes in patients with schizophrenia in acute psychotic episode and the course of the treatment.
        Psychiatry Res. 2007; 152: 173-180
        • Steiner J.
        • Jacobs R.
        • Panteli B.
        • Brauner M.
        • Schiltz K.
        • Bahn S.
        • et al.
        Acute schizophrenia is accompanied by reduced T cell and increased B cell immunity.
        Eur Arch Psychiatry Clin Neurosci. 2010; 260: 509-518
        • Bessler H.
        • Levental Z.
        • Karp L.
        • Modai I.
        • Djaldetti M.
        • Weizman A.
        Cytokine production in drug-free and neuroleptic-treated schizophrenic patients.
        Biol Psychiatry. 1995; 38: 297-302
        • Ganguli R.
        • Brar J.S.
        • Chengappa K.R.
        • DeLeo M.
        • Yang Z.W.
        • Shurin G.
        • Rabin B.S.
        Mitogen-stimulated interleukin-2 production in never-medicated, first-episode schizophrenic patients. The influence of age at onset and negative symptoms.
        Arch Gen Psychiatry. 1995; 52: 668-672
        • Hornberg M.
        • Arolt V.
        • Wilke I.
        • Kruse A.
        • Kirchner H.
        Production of interferons and lymphokines in leukocyte cultures of patients with schizophrenia.
        Schizophr Res. 1995; 15: 237-242
        • Arolt V.
        • Rothermundt M.
        • Wandinger K.P.
        • Kirchner H.
        Decreased in vitro production of interferon-gamma and interleukin-2 in whole blood of patients with schizophrenia during treatment.
        Mol Psychiatry. 2000; 5: 150-158
        • Riedel M.
        • Spellmann I.
        • Schwarz M.J.
        • Strassnig M.
        • Sikorski C.
        • Moller H.J.
        • Müller N.
        Decreased T cellular immune response in schizophrenic patients.
        J Psychiatr Res. 2007; 41: 3-7
        • Craddock R.M.
        • Lockstone H.E.
        • Rider D.A.
        • Wayland M.T.
        • Harris L.J.
        • McKenna P.J.
        • Bahn S.
        Altered T-cell function in schizophrenia: A cellular model to investigate molecular disease mechanisms.
        PLoS One. 2007; 2: e692
        • Miller B.J.
        • Buckley P.
        • Seabolt W.
        • Mellor A.
        • Kirkpatrick B.
        Meta-analysis of cytokine alterations in schizophrenia: Clinical status and antipsychotic effects.
        Biol Psychiatry. 2011; 70: 663-671
        • Modabbernia A.
        • Taslimi S.
        • Brietzke E.
        • Ashrafi M.
        Cytokine alterations in bipolar disorder: A meta-analysis of 30 studies.
        Biol Psychiatry. 2013; 74: 15-25
        • Potvin S.
        • Stip E.
        • Sepehry A.A.
        • Gendron A.
        • Bah R.
        • Kouassi E.
        Inflammatory cytokine alterations in schizophrenia: A systematic quantitative review.
        Biol Psychiatry. 2008; 63: 801-808
        • Goldstein B.I.
        • Kemp D.E.
        • Soczynska J.K.
        • McIntyre R.S.
        Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: A systematic review of the literature.
        J Clin Psychiatry. 2009; 70: 1078-1090
        • Hope S.
        • Dieset I.
        • Agartz I.
        • Steen N.E.
        • Ueland T.
        • Melle I.
        • et al.
        Affective symptoms are associated with markers of inflammation and immune activation in bipolar disorders but not in schizophrenia.
        J Psychiatr Res. 2011; 45: 1608-1616
        • Langan C.
        • McDonald C.
        Neurobiological trait abnormalities in bipolar disorder.
        Mol Psychiatry. 2009; 14: 833-846
        • Beumer W.
        • Drexhage R.C.
        • De Wit H.
        • Versnel M.A.
        • Drexhage H.A.
        • Cohen D.
        Increased level of serum cytokines, chemokines and adipokines in patients with schizophrenia is associated with disease and metabolic syndrome.
        Psychoneuroendocrinology. 2012; 37: 1901-1911
        • Giovanoli S.
        • Engler H.
        • Engler A.
        • Richetto J.
        • Voget M.
        • Willi R.
        • et al.
        Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice.
        Science. 2013; 339: 1095-1099
        • Meyer U.
        • Feldon J.
        • Yee B.K.
        A review of the fetal brain cytokine imbalance hypothesis of schizophrenia.
        Schizophr Bull. 2009; 35: 959-972
        • Boksa P.
        Effects of prenatal infection on brain development and behavior: A review of findings from animal models.
        Brain Behav Immun. 2010; 24: 881-897
        • Boksa P.
        Maternal infection during pregnancy and schizophrenia.
        J Psychiatry Neurosci. 2008; 33: 183-185
        • Brown A.S.
        Exposure to prenatal infection and risk of schizophrenia.
        Front Psychiatry. 2011; 2: 63
        • Suvisaari J.
        • Haukka J.
        • Tanskanen A.
        • Hovi T.
        • Lonnqvist J.
        Association between prenatal exposure to poliovirus infection and adult schizophrenia.
        Am J Psychiatry. 1999; 156: 1100-1102
        • Buka S.L.
        • Cannon T.D.
        • Torrey E.F.
        • Yolken R.H.
        Maternal exposure to herpes simplex virus and risk of psychosis among adult offspring.
        Biol Psychiatry. 2008; 63: 809-815
        • Mortensen P.B.
        • Pedersen C.B.
        • Hougaard D.M.
        • Norgaard-Petersen B.
        • Mors O.
        • Borglum A.D.
        • Yolken R.H.
        A Danish National Birth Cohort study of maternal HSV-2 antibodies as a risk factor for schizophrenia in their offspring.
        Schizophr Res. 2010; 122: 257-263
        • van Os J.
        • Selten J.P.
        Prenatal exposure to maternal stress and subsequent schizophrenia. The May 1940 invasion of The Netherlands.
        Br J Psychiatry. 1998; 172: 324-326
        • Malaspina D.
        • Corcoran C.
        • Kleinhaus K.R.
        • Perrin M.C.
        • Fennig S.
        • Nahon D.
        • et al.
        Acute maternal stress in pregnancy and schizophrenia in offspring: A cohort prospective study.
        BMC Psychiatry. 2008; 8: 71
        • Bayer T.A.
        • Falkai P.
        • Maier W.
        Genetic and non-genetic vulnerability factors in schizophrenia: The basis of the “two hit hypothesis”.
        J Psychiatr Res. 1999; 33: 543-548
        • Maynard T.M.
        • Sikich L.
        • Lieberman J.A.
        • LaMantia A.S.
        Neural development, cell-cell signaling, and the “two-hit” hypothesis of schizophrenia.
        Schizophr Bull. 2001; 27: 457-476
        • Dantzer R.
        Cytokine, sickness behavior, and depression.
        Neurol Clin. 2006; 24: 441-460
        • Sathyasaikumar K.V.
        • Stachowski E.K.
        • Wonodi I.
        • Roberts R.C.
        • Rassoulpour A.
        • McMahon R.P.
        • Schwarcz R.
        Impaired kynurenine pathway metabolism in the prefrontal cortex of individuals with schizophrenia.
        Schizophr Bull. 2011; 37: 1147-1156

      Linked Article

      • Is There a Flame in the Brain in Psychosis?
        Biological PsychiatryVol. 75Issue 4
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          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).
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