Immunology of schizophrenia: evidence, perspectives, and challenges
DOI:
https://doi.org/10.25118/2236-918X-6-2-1Keywords:
Immune system, schizophrenia, therapyAbstract
The etiopathogenesis of schizophrenia is complex and involves the interaction between genetic and environmental factors. Changes in the immune system have been identified as possible participants in the pathophysiology of schizophrenia. In this paper, we present a narrative review on immune changes in the pathophysiology of schizophrenia and the potential of
molecules and/or mechanisms of the immune system to work as biomarkers and/or therapeutic targets. While some studies show greater participation of cytokines such as T helper cells (Th1), interferon gamma (IFN-γ), interleukin 2 (IL-2), and tumor necrosis factor alpha (TNF-α), others have observed increased participation of the Th2-type cytokines IL-4, IL-6, and IL-10. Infection by the protozoan Toxoplasma gondii has been identified as a risk factor for schizophrenia, and a possible explanation could be the shift in the balance of tryptophan metabolism, with consequent increase in kynurenines caused by the inflammatory response against the parasite. Clinical trials have been conducted using anti-inflammatory drugs as adjunct strategies to antipsychotic treatment. Promising results, such as reduced negative symptoms and cognitive improvement, have been observed. The use of anti-inflammatory drugs with consequent clinical improvement reinforces the hypothesis of the participation of immune/inflammatory mechanisms in the pathophysiology of schizophrenia.
Downloads
Metrics
References
Vallada Filho HP, Samaia H. Esquizofrenia: aspectos genéti cos e estudos de fatores de risco estudos de fatores de risco. Rev Bras Psiquiatr. 2000;22:2-4.
Ross CA, Margolis RL, Reading, SA, Pletnikov M, Coyle JT. Neurobiology of schizophrenia. Neuron. 2006;52:139-53.
Brown AS. Prenatal infecti on as a risk factor for schizophrenia. Schizophr Bull. 2006;32:200-2.
Cohen M, Solowij N, Carr V. Cannabis, cannabinoids, and schizophrenia: integrati on of the evidence. Aust N Z J Psychiatry. 2008;42:357-68.
Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia, “just the facts” 4. Clinical features and conceptualizati on. Schizophr Res. 2009;110:1-23.
Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterati ons in schizophrenia: clinical status and anti psychoti c eff ects. Biol Psychiatry. 2011;70:663-71.
Potvin S, Sti p E, Sepehery AA, Gendron A, Bah R, Kouassi E. Infl ammatory cytokine alterati ons in schizophrenia: a systemati c quanti tati ve review. Biol Psychiatry. 2008;63:801-8.
Ribeiro-Santos R, Lucio Teixeira A, Salgado JV. Evidence for an immune role on cogniti on in schizophrenia: a systemati c review. Curr Neuropharmacol. 2014;12:273-80.
Muller N, Schwarz MJ. Immune system and schizophrenia. Curr Immunol Rev. 2010;6:213-20.
Müller N. Immunology of schizophrenia. Neuroimmunomodulati on. 2014;21:109-16.
Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe’er I, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature. 2009;460:753-7.
Na KS1, Jung HY, Kim YK. The role of proinfl ammatory cytokines in the neuroinfl ammati on and neurogenesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2014;48:277-86.
Smyth AM, Lawrie SM. The neuroimmunology of schizophrenia. Clin Psychopharmacol Neurosci. 2013;11:107-17.
Vilcek J. The cytokines: an overview. In: Thompson MT, editor. The cytokines handbook. 4th ed. Amsterdam: Elsevier; 2003. p. 3.
Debnath M, Berk M. Th17 pathway-mediated immunopathogenesis of schizophrenia: mechanisms and implicati ons. Schizophr Bull. 2014;40:1412-21.
Zhu J, Yamane H, Paul WE. Diff erenti ati on of eff ector CD4 T cell populati ons (*). Annu Rev Immunol. 2010;28:445-89.
Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implicati ons. Pharmacol Ther. 2011;130:226-38.
Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functi onal features of central nervous system lymphati c vessels. Nature. 2015;523:337-41.
Serhan CN, Savill J. Resoluti on of infl ammati on: the beginning programs the end. Nat Immunol. 2005;6:1191-7.
Smith RS, Maes M. The macrophage-T-lymphocyte theory of schizophrenia: additi onal evidence. Med Hypotheses. 1995;45:135-41.
Monji A, Kato, T, Kanba S. Cytokines and schizophrenia: microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci. 2009;63:257-65.
Dickerson F, Boronow J, Stallings C, Origoni A, Yolken R. Toxoplasma gondii in individuals with schizophrenia: associati on with clinical and demographic factors and with mortality. Schizophr Bull. 2007;33:737-40.
Torrey EF, Bartko JJ, Yolken RH. Toxoplasma gondii and other risk factors for schizophrenia: an update. Schizophr Bull. 2012;38:642-7.
Anderson G, Maes M. Schizophrenia: linking prenatal infecti on to cytokines, the tryptophan catabolite (TRYCAT) pathway, NMDA receptor hypofuncti on, neurodevelopment and neuroprogression. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:5-19.
Notarangelo FM, Wilson EH, Horning KJ, Thomas MA, Harris TH, Fang Q, et al. Evaluati on of kynurenine pathway metabolism in Toxoplasma gondii-infected mice: Implicati ons for schizophrenia. Schizophr Res. 2014;152:261-7.
Schwarcz R, Hunter CA. Toxoplasma gondii and schizophrenia: linkage through astrocyte-derived kynurenic acid? Schizophr Bull. 2007;33:652-3.
Tomasik J, Schultz TL, Kluge W, Yolken RH, Bahn S, Carruthers VB. Shared immune and repair markers during experimental toxoplasma chronic brain infection and schizophrenia. Schizophr Bull. 2016;42:386-95.
Maes M, Bocchio Chiavetto L, Bignotti S, Battisa Tura GJ, Pioli R, Boin F, et al. Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor. Schizophr Res. 2002;54:281-91.
Schwarz MJ, Muller N, Riedel M, Ackenheil M. The Th2-hypothesis of schizophrenia: a strategy to identify a subgroup of schizophrenia caused by immune mechanisms. Med Hypotheses. 2001;56:483-6.
Sirota P, Hadi E, Djaldetti M, Bessler H. Difference in inflammatory cytokine production by mononuclear cells from obese and non-obese schizophrenic patients. Acta Psychiatr Scand. 2015;132:301-5.
Matsumoto A, Ohta N, Goto Y, Kashiwa Y, Yamamoto S, Fujino Y. Haloperidol suppresses murine dendritic cell maturation and priming of the T helper 1-type immune response. Anesth Analg. 2015;120:895-902.
Tourjman V, Kouassi E, Koué ME, Rocchetti M, Fortin-Fournier S, Fusar-Poli P, et al. Antipsychotics’ effects on blood levels of cytokines in schizophrenia: a meta-analysis. Schizophr Res. 013;151:43-7.
Kato TA, Monji A, Mizoguchi Y, Hashioka S, Horikawa H, Seki Y, et al. Anti-Inflammatory properties of antipsychotics via microglia modulations: are antipsychotics a ‘fire extinguisher’ in the brain of schizophrenia? Mini Rev Med Chem. 2011;11:565-74.
Meyer U, Schwarz MJ, Müller N. Inflammatory processes in schizophrenia: a promising neuroimmunological target for the treatment of negative/cognitive symptoms and beyond. Pharmacol Ther. 2011;132:96-110.
Dickerson F, Stallings C, Origoni A, Boronow J, Yolken R. C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia. Schizophr Res. 2007;93:261-5.
Martinez-Cengotitabengoa M, Mac-Dowell KS, Leza JC, Mico JA, Fernandez M, Echevarria E, et al. Cognitive impairment is related to oxidative stress and chemokine levels in first psychotic episodes. Schizophr Res. 2012;137:66-72.
Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling J, Richardson P, et al. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacol. 2012;26:85-93.
Levkovitz Y, Mendlovich S, Riwkes S, Braw Y, Levkovitch-Verbin H, Gal G, et al. A doubleblind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry. 2010;71:138-49.
Schwieler L, Erhardt S, Erhardt C, Engberg G. Prostaglandin-mediated control of rat brain kynurenic acid synthesis--opposite actions by COX-1 and COX-2 isoforms. J Neural Transm (Vienna). 2005;112:863-72.
Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H. Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebocontrolled trial. J Clin Psychiatry. 2010;71:520-7.
Zhang Y, Chen DC, Tan YL, Zhou DF. A doubleblind, placebo-controlled trial of celecoxib added to risperidone in first-episode and drug-naive patients with schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2006;256:50.
Rapaport MH, Delrahim KK, Bresee CJ, Maddux RE, Ahmadpour O, Dolnak D. Celecoxib augmentation of continuously ill patients with schizophrenia. Biol Psychiatry. 2005;57:1594-6.
Downloads
Published
How to Cite
Conference Proceedings Volume
Section
License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Debates em Psiquiatria allows the author (s) to keep their copyrights unrestricted. Allows the author (s) to retain their publication rights without restriction. Authors should ensure that the article is an original work without fabrication, fraud or plagiarism; does not infringe any copyright or right of ownership of any third party. Authors should also ensure that each one complies with the authorship requirements as recommended by the ICMJE and understand that if the article or part of it is flawed or fraudulent, each author shares responsibility.
Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) - Debates em Psiquiatria is governed by the licencse CC-By-NC
You are free to:
- Share — copy and redistribute the material in any medium or format
- Adapt — remix, transform, and build upon the material
The licensor cannot revoke these freedoms as long as you follow the license terms. Under the following terms:
- Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
- NonCommercial — You may not use the material for commercial purposes.
No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.