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Adaptive Immunity in Schizophrenia: Functional Implications of T Cells in the Etiology, Course and Treatment

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Abstract

Schizophrenia is a severe and highly complex neurodevelopmental disorder with an unknown etiopathology. Recently, immunopathogenesis has emerged as one of the most compelling etiological models of schizophrenia. Over the past few years considerable research has been devoted to the role of innate immune responses in schizophrenia. The findings of such studies have helped to conceptualize schizophrenia as a chronic low-grade inflammatory disorder. Although the contribution of adaptive immune responses has also been emphasized, however, the precise role of T cells in the underlying neurobiological pathways of schizophrenia is yet to be ascertained comprehensively. T cells have the ability to infiltrate brain and mediate neuro-immune cross-talk. Conversely, the central nervous system and the neurotransmitters are capable of regulating the immune system. Neurotransmitter like dopamine, implicated widely in schizophrenia risk and progression can modulate the proliferation, trafficking and functions of T cells. Within brain, T cells activate microglia, induce production of pro-inflammatory cytokines as well as reactive oxygen species and subsequently lead to neuroinflammation. Importantly, such processes contribute to neuronal injury/death and are gradually being implicated as mediators of neuroprogressive changes in schizophrenia. Antipsychotic drugs, commonly used to treat schizophrenia are also known to affect adaptive immune system; interfere with the differentiation and functions of T cells. This understanding suggests a pivotal role of T cells in the etiology, course and treatment of schizophrenia and forms the basis of this review.

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References

  • Aberg KA, Liu Y, Bukszár J et al (2013) A comprehensive family- based replication study of schizophrenia genes. JAMA Psychiatry 70:573–581

    Article  CAS  PubMed  Google Scholar 

  • Achiron A, Noy S, Pras E, Lereya J, Hermesh H, Laor N (1994) T-cell subsets in acute psychotic schizophrenic patients. Biol Psychiatry 35:27–31

    Article  CAS  PubMed  Google Scholar 

  • Anderson G, Berk M, Dodd S, Bechter K, Altamura AC, Dell’Osso B, Kanba S, Monji A, Fatemi SH, Buckley P, Debnath M, Das UN, Meyer U, Muller N, Kanchanatawan B, Maes M (2013) Immuno-inflammatory, oxidative and nitrosative stress, and neuroprogressive pathways in the etiology, course and treatment of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 42:1–4

    Article  CAS  PubMed  Google Scholar 

  • Anderson G, Maes M (2013) Schizophrenia: linking prenatal infection to cytokines, the tryptophan catabolite (TRYCAT) pathway, NMDA receptor hypofunction, neurodevelopment and neuroprogression. Prog Neuropsychopharmacol Biol Psychiatry 42:5–19

    Article  CAS  PubMed  Google Scholar 

  • Andreasen NC, Nopoulos P, Magnotta V, Pierson R, Ziebell S, Ho BC (2011) Progressive brain change in schizophrenia: a prospective longitudinal study of first-episode schizophrenia. Biol Psychiatry 70:672–9

    Article  PubMed Central  PubMed  Google Scholar 

  • Amor S, Puentes F, Baker D, van der Valk P (2010) Inflammation in neurodegenerative diseases. Immunology 129:154–69

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Avramopoulos D, Pearce BD, McGrath J, Wolyniec P, Wang R, Eckart N, Hatzimanolis A, Goes FS, Nestadt G, Mulle J, Coneely K, Hopkins M, Ruczinski I, Yolken R, Pulver AE (2015) Infection and inflammation in schizophrenia and bipolar disorder: a genome wide study for interactions with genetic variation. PLoS One 10:e0116696

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Basu S, Dasgupta PS (2000a) Dopamine, a neurotransmitter, influences the immune system. J Neuroimmunol 102:113–24

    Article  CAS  PubMed  Google Scholar 

  • Basu S, Dasgupta PS (2000b) Role of dopamine in malignant tumor growth. Endocrine 12:237–41

    Article  CAS  PubMed  Google Scholar 

  • Basu B, Sarkar C, Chakroborty D, Ganguly S, Shome S, Dasgupta PS, Basu S (2010) D1 and D2 dopamine receptor-mediated inhibition of activated normal T cell proliferation is lost in jurkat T leukemic cells. J Biol Chem 285:27026–32

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Besser MJ, Ganor Y, Levite M (2005a) Dopamine by itself activates either D2, D3 or D1/ D5 dopaminergic receptors in normal human T-cells and triggers the selective secretion of either IL-10, TNFalpha or both. J Neuroimmunol 169:161–171

    Article  CAS  PubMed  Google Scholar 

  • Bettelli E, Korn T, Oukka M, Kuchroo VK (2008) Induction and effector functions of T(H)17 cells. Nature 453:1051–1057

    Article  CAS  PubMed  Google Scholar 

  • Becattini S, Latorre D, Mele F, Foglierini M, De Gregorio C, Cassotta A, Fernandez B, Kelderman S, Schumacher TN, Corti D, Lanzavecchia A, Sallusto F (2015) T cell immunity. Functional heterogeneity of human CD4+ T cell clones primed by pathogens or vaccines. Science 347:400–6

    Article  CAS  PubMed  Google Scholar 

  • Beck GC, Brinkkoetter P, Hanusch C, Schulte J, van Ackern K, van der Woude FJ, Yard BA (2004) Clinical review: immunomodulatory effects of dopamine in general inflammation. Crit Care 8:485–91

    Article  PubMed  Google Scholar 

  • Besser MJ, Ganor Y, Levite M (2005b) Dopamine by itself activates either D2, D3 or D1/D5 dopaminergic receptors in normal human T-cells and triggers the selective secretion of either IL-10, TNFalpha or both. J Neuroimmunol 169:161–171

    Article  CAS  PubMed  Google Scholar 

  • Beumer W, Gibney SM, Drexhage RC, Pont-Lezica L, Doorduin J, Klein HC, Steiner J, Connor TJ, Harkin A, Versnel MA, Drexhage HA (2012) The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. J Leukoc Biol 92:959–75

    Article  CAS  PubMed  Google Scholar 

  • Bhadra R, Gigley JP, Khan IA (2011) The CD8 T-cell road to immunotherapy of toxoplasmosis. Immunotherapy 3:789–801

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bhadra R, Cobb DA, Weiss LM, Khan IA (2013) Psychiatric disorders in toxoplasma seropositive patients--the CD8 connection. Schizophr Bull 39:485–9

    Article  PubMed Central  PubMed  Google Scholar 

  • Block ML, Hong JS (2005) Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol 76:77–98

    Article  CAS  PubMed  Google Scholar 

  • Boneberg EM, von Seydlitz E, Pröpster K, Watzl H, Rockstroh B, Illges H (2006) D3 dopamine receptor mRNA is elevated in T cells of schizophrenic patients whereas D4 dopamine receptor mRNA is reduced in CD4 + − T cells. J Neuroimmunol 173:180–187

    Article  CAS  PubMed  Google Scholar 

  • Brito-Melo GE, Nicolato R, de Oliveira AC et al (2012) Increase in dopaminergic, but not serotoninergic, receptors in T-cells as a marker for schizophrenia severity. J Psychiatr Res 46:738–742

    Article  PubMed  Google Scholar 

  • Brochard V, Combadière B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V et al (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119:182–92

    PubMed Central  CAS  PubMed  Google Scholar 

  • Brynskikh A, Warren T, Zhu J, Kipnis J (2008) Adaptive immunity affects learning behavior in mice. Brain Behav Immun 22:861–869

    Article  CAS  PubMed  Google Scholar 

  • Busse S, Busse M, Schiltz K, Bielau H, Gos T, Brisch R, Mawrin C, Schmitt A, Jordan W, Müller UJ, Bernstein HG, Bogerts B, Steiner J (2012) 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 26:1273–9

    Article  CAS  PubMed  Google Scholar 

  • Cazzullo CL, Saresella M, Roda K, Calvo MG, Bertrando P, Doria S, Clerici M, Salvaggio A, Ferrante P (1998) Increased levels of CD8+ and CD4+ 45RA+ lymphocytes in schizophrenic patients. Schizophr Res 31:49–55

    Article  CAS  PubMed  Google Scholar 

  • Chen ML, Tsai TC, Lin YY, Tsai YM, Wang LK, Lee MC, Tsai FM (2011) Antipsychotic drugs suppress the AKT/NF-κB pathway and regulate the differentiation of T-cell subsets. Immunol Lett 140:81–91

    Article  CAS  PubMed  Google Scholar 

  • Chen ML, Tsai TC, Wang LK, Lin YY, Tsai YM, Lee MC, Tsai FM (2012) Clozapine inhibits Th1 cell differentiation and causes the suppression of IFN-γ production in peripheral blood mononuclear cells. Immunopharmacol Immunotoxicol 34:686–94

    Article  CAS  PubMed  Google Scholar 

  • Chiu IM, Chen A, Zheng Y, Kosaras B, Tsiftsoglou SA, Vartanian TK, Brown RH Jr, Carroll MC (2008) T lymphocytes potentiate endogenous neuroprotective inflammation in mouse model of ALS. Proc Natl Acad Sci U S A 105:17913–8

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Coffey CE, Sullivan JL, Rice JR (1983) T lymphocytes in schizophrenia. Biol Psychiatry 18:113–9

    CAS  PubMed  Google Scholar 

  • Craddock RM, Lockstone HE, Rider DA et al (2007) Altered T-cell function in schizophrenia: a cellular model to investigate molecular disease mechanisms. PLoS One 2:e692

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Davis J, Moylan S, Harvey BH, Maes M, Berk M (2014) Neuroprogression in schizophrenia: Pathways underpinning clinical staging and therapeutic corollaries. Aust N Z J Psychiatry 48:512–529

    Article  PubMed  Google Scholar 

  • Debnath M, Doyle KM, Langan C, McDonald C, Leonard B, Cannon DM (2011) Recent advances in psychoneuroimmunology: inflammation in psychiatric disorder. Transl Neurosci 2:121–137

    Article  Google Scholar 

  • Debnath M, Cannon DM, Venkatasubramanian G (2013) Variation in the major histocompatibility complex [MHC] gene family in schizophrenia: associations and functional implications. Prog Neuropsychopharmacol Biol Psychiatry 42:49–62

    Article  CAS  PubMed  Google Scholar 

  • Debnath M, Berk M (2014) Th17 pathway-mediated immunopathogenesis of schizophrenia: mechanisms and implications. Schizophr Bull 40:1412–21

    Article  PubMed Central  PubMed  Google Scholar 

  • Debnath M, Venkatasubramanian G, Berk M (2015) Fetal programming of schizophrenia: select mechanisms. Neurosci Biobehav Rev 49:90–104

    Article  PubMed  Google Scholar 

  • de Baumont A, Maschietto M, Lima L, Carraro DM, Olivieri EH, Fiorini A, Barreta LA, Palha JA, Belmonte-de-Abreu P, Moreira Filho CA, Brentani H (2015) Innate immune response is differentially dysregulated between bipolar disease and schizophrenia. Schizophr Res 161:215–21

    Article  PubMed  Google Scholar 

  • DeLisi LE, Goodman S, Neckers LM, Wyatt RJ (1982) An analysis of lymphocyte subpopulations in schizophrenic patients. Biol Psychiatry 17:1003–9

    CAS  PubMed  Google Scholar 

  • Ding M, Song X, Zhao J, Gao J, Li X, Yang G, Wang X, Harrington A, Fan X, Lv L (2014) Activation of Th17 cells in drug naïve, first episode schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 51:78–82

    Article  CAS  PubMed  Google Scholar 

  • Doorduin J, de Vries EF, Willemsen AT, de Groot JC, Dierckx RA, Klein HC (2009) Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med 50:1801–1807

    Article  PubMed  Google Scholar 

  • Drexhage RC, Hoogenboezem TA, Cohen D, Versnel MA, Nolen WA, van Beveren NJ, Drexhage HA (2011) 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 14:746–55

    Article  CAS  PubMed  Google Scholar 

  • Durrenberger PF, Fernando FS, Kashefi SN, Bonnert TP, Seilhean D, Nait-Oumesmar B, Schmitt A, Gebicke-Haerter PJ, Falkai P, Grünblatt E, Palkovits M, Arzberger T, Kretzschmar H, Dexter DT, Reynolds R (2014) Common mechanisms in neurodegeneration and neuroinflammation: a BrainNet Europe gene expression microarray study. J Neural Transm. (in press)

  • Engelhardt B (2006) Molecular mechanisms involved in T cell migration across the blood–brain barrier. J Neural Transm 113:477–85

    Article  CAS  PubMed  Google Scholar 

  • Farooq SM, Ashour HM (2012) Type II collagen induces peripheral tolerance in BALB/c mice via the generation of CD8+ T regulatory cells. PLoS One 7:e48635

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Farooq SM, Ashour HM (2013) Eye-mediated induction of specific immune tolerance to encephalitogenic antigens. CNS Neurosci Ther 19:503–510

    Article  CAS  PubMed  Google Scholar 

  • Farooq SM, Ashour HM (2014) In vitro-induced cell-mediated immune deviation to encephalitogenic antigens. Brain Behav Immun 35:64–9

    Article  CAS  PubMed  Google Scholar 

  • Farooq SM, Elkhatib WF, Ashour HM (2014) The in vivo and in vitro induction of anterior chamber associated immune deviation to myelin antigens in C57BL/6 mice. Brain Behav Immun 42:118–22

    Article  CAS  PubMed  Google Scholar 

  • Filiano AJ, Gadani SP, Kipnis J (2014) Interactions of innate and adaptive immunity in brain development and function. Brain Res. (in press)

  • Franco R, Pacheco R, Lluis C, Ahern GP, O Connell PJ (2007) The emergence of neurotransmitters as immune modulators. Trends Immunol 28:400–407

    Article  CAS  PubMed  Google Scholar 

  • Frydecka D, Beszłej A, Karabon L, Pawlak-Adamska E, Tomkiewicz A, Partyka A, Jonkisz A, Monika SB, Kiejna A (2013) The role of genetic variations of immune system regulatory molecules CD28 and CTLA-4 in schizophrenia. Psychiatry Res 208:197–8

    Article  CAS  PubMed  Google Scholar 

  • Gardiner EJ, Cairns MJ, Liu B, Beveridge NJ, Carr V, Kelly B, Scott RJ, Tooney PA (2013) Gene expression analysis reveals schizophrenia-associated dysregulation of immune pathways in peripheral blood mononuclear cells. J Psychiatr Res 47:425–37

    Article  PubMed  Google Scholar 

  • Garg SK, Banerjee R, Kipnis J (2008) Neuroprotective immunity: T cell-derived glutamate endows astrocytes with a neuroprotective phenotype. J Immunol 180:3866–73

    Article  CAS  PubMed  Google Scholar 

  • Gelderblom M, Arunachalam P, Magnus T (2014) γδ T cells as early sensors of tissue damage and mediators of secondary neurodegeneration. Front Cell Neurosci 8:368

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Gendelman HE, Appel SH (2011) Neuroprotective activities of regulatory T cells. Trends Mol Med 17:687–8

    Article  PubMed  Google Scholar 

  • Ghosh MC, Mondal AC, Basu S, Banerjee S, Majumder J, Bhattacharya D, Dasgupta PS (2003) Dopamine inhibits cytokine release and expression of tyrosine kinases, Lck and Fyn in activated T cells. Int Immunopharmacol 3:1019–26

    Article  CAS  PubMed  Google Scholar 

  • Giorelli M, Livrea P, Trojano M (2005) Dopamine fails to regulate activation of peripheral blood lymphocytes from multiple sclerosis patients: effects of IFN-beta. J Interferon Cytokine Res 25:395–406

    Article  CAS  PubMed  Google Scholar 

  • González H, Pacheco R (2014) T-cell-mediated regulation of neuroinflammation involved in neurodegenerative diseases. J Neuroinflammation 11:201

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Guest PC, Martins-de-Souza D, Vanattou-Saifoudine N, Harris LW, Bahn S (2011) Abnormalities in metabolism and hypothalamic-pituitary-adrenal axis function in schizophrenia. Int Rev Neurobiol 101:145–68

    Article  CAS  PubMed  Google Scholar 

  • Harari A, Vallelian F, Pantaleo G (2004) Phenotypic heterogeneity of antigen-specific CD4 T cells under different conditions of antigen persistence and antigen load. Eur J Immunol 34:3525–33

    Article  CAS  PubMed  Google Scholar 

  • Harari A, Vallelian F, Meylan PR, Pantaleo G (2005) Functional heterogeneity of memory CD4 T cell responses in different conditions of antigen exposure and persistence. J Immunol 174:1037–45

    Article  CAS  PubMed  Google Scholar 

  • Harvey L, Boksa P (2012) Prenatal and postnatal animal models of immune activation: relevance to a range of neurodevelopmental disorders. Dev Neurobiol 72:1335–48

    Article  CAS  PubMed  Google Scholar 

  • Hendrix S, Nitsch R (2007) The role of T helper cells in neuroprotection and regeneration. J Neuroimmunol 184:100–12

    Article  CAS  PubMed  Google Scholar 

  • Henneberg A, Riedl B, Dumke HO, Kornhuber HH (1990) T-lymphocyte subpopulations in schizophrenic patients. Eur Arch Psychiatry Neurol Sci 239(5):283–4

    Article  CAS  PubMed  Google Scholar 

  • Herberth M, Krzyszton DN, Koethe D, Craddock MR, Bulger E, Schwarz E, Guest P, Leweke FM, Bahn S (2010) Differential effects on T-cell function following exposure to serum from schizophrenia smokers. Mol Psychiatry 15:364–71

    Article  CAS  PubMed  Google Scholar 

  • Herberth M, Rahmoune H, Schwarz E, Koethe D, Harris LW, Kranaster L, Witt SH, Spain M, Barnes A, Schmolz M, Leweke MF, Guest PC, Bahn S (2014) Identification of a molecular profile associated with immune status in first-onset schizophrenia patients. Clin Schizophr Relat Psychoses 7:207–15

    Article  PubMed  Google Scholar 

  • Hickey WF, Hsu BL, Kimura H (1991) T-lymphocyte entry into the central nervous system. J Neurosci Res 28:254–60

    Article  CAS  PubMed  Google Scholar 

  • Horváth S, Mirnics K (2014) Immune system disturbances in schizophrenia. Biol Psychiatry 75:316–23

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull 35:549–62

    Article  PubMed Central  PubMed  Google Scholar 

  • Ilani T, Ben-Shachar D, Strous RD et al (2001) A peripheral marker for schizophrenia: increased levels of D3 dopamine receptor mRNA in blood lymphocytes. Proc Natl Acad Sci U S A 98:625

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ilani T, Strous RD, Fuchs S (2004) Dopaminergic regulation of immune cells via D3 dopamine receptor: a pathway mediated by activated T cells. FASEB J 18:1600–2

    CAS  PubMed  Google Scholar 

  • Juckel G, Manitz MP, Brüne M, Friebe A, Heneka MT, Wolf RJ (2011) Microglial activation in a neuroinflammational animal model of schizophrenia—a pilot study. Schizophr Res 131:96–100

    Article  PubMed  Google Scholar 

  • Kawano M, Sawada K, Tsuru E, Nishihara M, Kato K, Honer W, Shimodera S (2011) Dopamine receptor D3R and D4R mRNA levels in peripheral lymphocytes in patients with schizophrenia correlate with severity of illness. Open J Psychiatry 1:33–39

    Article  Google Scholar 

  • Kelly DL, McMahon RP, Wehring HJ, Liu F, Mackowick KM, Boggs DL, Warren KR, Feldman S, Shim JC, Love RC, Dixon L (2011) (2011). Cigarette smoking and mortality risk in people with schizophrenia. Schizophr Bull 37(4):832–8

    Article  PubMed Central  PubMed  Google Scholar 

  • Kipnis J, Cohen H, Cardon M, Ziv Y, Schwartz M (2004) T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc Natl Acad Sci U S A 102:8180–8185

    Article  Google Scholar 

  • Kirkpatrick B, Miller BJ (2013) Inflammation and schizophrenia. Schizophr Bull 39:1174–9

    Article  PubMed Central  PubMed  Google Scholar 

  • Kokai M, Hirata I, Adachi M, Hatotani N, Hakomori S, Tachibana T (1993) Elevated Le(y) antigen expression on T-lymphocytes in schizophrenic patients. Eur Arch Psychiatry Clin Neurosci 243:82–6

    Article  CAS  PubMed  Google Scholar 

  • Kwak YT, Koo MS, Choi CH, Sunwoo I (2001) Change of dopamine receptor mRNA expression in lymphocyte of schizophrenia patients. BMC Med Genet 2:3

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Leon-Ponte M, Ahern GP, O Connell PJ (2007) Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor. Blood 109:3139–3146

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Levite M, Chowers Y, Ganor Y, Besser M, Hershkovits R, Cahalon L (2001) Dopamine interacts directly with its D3 and D2 receptors on normal human T cells, and activates beta1 integrin function. Eur J Immunol 31:3504–3512

    Article  CAS  PubMed  Google Scholar 

  • Levite M (2015) Dopamine and T cells: receptors, direct and potent effects, endogenous production and abnormalities in autoimmune, neurological and psychiatric diseases. Acta Physiol (Oxf) (in press)

  • Liu J, Li J, Li T, Wang T, Li Y, Zeng Z, Li Z, Chen P, Hu Z, Zheng L, Ji J, Lin H, Feng G, Shi Y (2011) CTLA-4 confers a risk of recurrent schizophrenia, major depressive disorder and bipolar disorder in the Chinese Han population. Brain Behav Immun 25:429–33

    Article  CAS  PubMed  Google Scholar 

  • Liu L, Yuan G, Cheng Z, Zhang G, Liu X, Zhang H (2013) Identification of the mRNA expression status of the dopamine D2 receptor and dopamine transporter in peripheral blood lymphocytes of schizophrenia patients. PLoS One 8:e75259

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Liu J, Chen J, Ehrlich S et al (2014) Methylation patterns in whole blood correlate with symptoms in schizophrenia patients. Schizophr Bull 40:769–76

    Article  PubMed Central  PubMed  Google Scholar 

  • Luan R, Cheng H, Li L, Zhao Q, Liu H, Wu Z, Zhao L, Yang J, Hao J, Yin Z (2015) Maternal lipopolysaccharide exposure promotes immunological functional changes in adult offspring CD4+ T cells. Am J Reprod Immunol. (in press)

  • Lull ME, Block ML (2010) Microglial activation & chronic neurodegeneration. Neurotherapeutics 7:354–365

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Maino K, Gruber R, Riedel M, Seitz N, Schwarz M, Müller N (2007) T- and B-lymphocytes in patients with schizophrenia in acute psychotic episode and the course of the treatment. Psychiatry Res 152:173–80

    Article  CAS  PubMed  Google Scholar 

  • Mandal M, Marzouk AC, Donnelly R, Ponzio NM (2010) Preferential development of Th17 cells in offspring of immunostimulated pregnant mice. J Reprod Immunol 87:97–100

    Article  CAS  PubMed  Google Scholar 

  • Mandal M, Donnelly R, Elkabes S, Zhang P, Davini D, David BT, Ponzio NM (2013) Maternal immune stimulation during pregnancy shapes the immunological phenotype of offspring. Brain Behav Immun 33:33–45

    Article  CAS  PubMed  Google Scholar 

  • Masserini C, Vita A, Basile R, Morselli R, Boato P, Peruzzi C, Pugnetti L, Ferrante P, Cazzullo CL (1990) Lymphocyte subsets in schizophrenic disorders. Relationship with clinical, neuromorphological and treatment variables. Schizophr Res 3:269–75

    Article  CAS  PubMed  Google Scholar 

  • Matloubi H, Vodjgani M, Nasehi AA, Niknam MH, Kazemnejad A, Salehi E, Aboufazeli T, Gheflati Z (2007) Decreased T cell response to mitogen and increased anti-cytoplasmic antibody in drug-free schizophrenic patients. Iran J Immunol 4:32–7

    CAS  PubMed  Google Scholar 

  • Maxeiner HG, Rojewski MT, Schmitt A, Tumani H, Bechter K, Schmitt M (2009) Flow cytometric analysis of T cell subsets in paired samples of cerebrospinal fluid and peripheral blood from patients with neurological and psychiatric disorders. Brain Behav Immun 23:134–42

    Article  CAS  PubMed  Google Scholar 

  • Mazzarello V, Cecchini A, Fenu G, Rassu M, Dessy LA, Lorettu L, Montella A (2004) Lymphocytes in schizophrenic patients under therapy: serological, morphological and cell subset findings. Ital J Anat Embryol 109:177–88

    PubMed  Google Scholar 

  • Meyer U (2013) Developmental neuroinflammation and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 42:20–34

    Article  CAS  PubMed  Google Scholar 

  • Miller BJ, Gassama B, Sebastian D, Buckley P, Mellor A (2013) Meta-analysis of lymphocytes in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 73:993–9

    Article  CAS  PubMed  Google Scholar 

  • Monji A, Kato T, Kanba S (2009) Cytokines and schizophrenia: microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci 63:257–265

    Article  CAS  PubMed  Google Scholar 

  • Monji A, Kato TA, Mizoguchi Y, Horikawa H, Seki Y, Kasai M, Yamauchi Y, Yamada S, Kanba S (2013) Neuroinflammation in schizophrenia especially focused on the role of microglia. Prog Neuropsychopharmacol Biol Psychiatry 42:115–21

    Article  CAS  PubMed  Google Scholar 

  • Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL (1986) Two types of murine helper T cell clone.I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136:2348–2357

    CAS  PubMed  Google Scholar 

  • Mosmann TR, Coffman RL (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145–173

    Article  CAS  PubMed  Google Scholar 

  • Müller N, Ackenheil M, Hofschuster E, Mempel W, Eckstein R (1991) Cellular immunity in schizophrenic patients before and during neuroleptic treatment. Psychiatry Res 37:147–60

    Article  PubMed  Google Scholar 

  • Müller N, Hofschuster E, Ackenheil M, Eckstein R (1993) T-cells and psychopathology in schizophrenia: relationship to the outcome of neuroleptic therapy. Acta Psychiatr Scand 87:66–71

    Article  PubMed  Google Scholar 

  • Müller N, Schlesinger BC, Hadjamu M, Riedel M, Schwarz M, Ackenheil M, Wank R, Gruber R (1998) Increased frequency of CD8 positive gamma/delta T-lymphocytes (CD8+ gamma/delta+) in unmedicated schizophrenic patients: relation to impairment of the blood–brain barrier and HLA-DPA*02011. Schizophr Res 32:69–71

    Article  PubMed  Google Scholar 

  • Müller N, Riedel M, Hadjamu M, Schwarz MJ, Ackenheil M, Gruber R (1999) Increase in expression of adhesion molecule receptors on T helper cells during antipsychotic treatment and relationship to blood–brain barrier permeability in schizophrenia. Am J Psychiatry 156:634–6

    PubMed  Google Scholar 

  • Muller N, Schwarz M (2006) Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission. Neurotox Res 10:131–48

    Article  CAS  PubMed  Google Scholar 

  • Müller N, Schwarz MJ (2010) Immune system and schizophrenia. Curr Immunol Rev 6:213–220

    Article  PubMed Central  PubMed  Google Scholar 

  • Najjar S, Pearlman DM, Alper K, Najjar A, Devinsky O (2013) Neuroinflammation and psychiatric illness. J Neuroinflammation 10:43

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Najjar S, Pearlman DM (2015) Neuroinflammation and white matter pathology in schizophrenia: systematic review. Schizophr Res 161:102–12

    Article  PubMed  Google Scholar 

  • Nikkilä H, Müller K, Ahokas A, Miettinen K, Andersson LC, Rimón R (1995) Abnormal distributions of T-lymphocyte subsets in the cerebrospinal fluid of patients with acute schizophrenia. Schizophr Res 14:215–21

    Article  PubMed  Google Scholar 

  • Nikkila HV, Muller K, Ahokas A, Miettinen K, Rimo’n R, Andersson LC (1999) Accumulation of macrophages in the CSF of schizophrenic patients during acute psychotic episodes. Am J Psychiatry 156:1725–1729

    CAS  PubMed  Google Scholar 

  • Nikkila HV, Muller K, Ahokas A, Rimo’n R, Andersson LC (2001) Increased frequency of activated lymphocytes in the cerebrospinal fluid of patients with acute schizophrenia. Schizophr Res 49:99–105

    Article  CAS  PubMed  Google Scholar 

  • Noto C, Ota VK, Gouvea ES, Rizzo LB, Spindola LM, Honda PH, Cordeiro Q, Belangero SI, Bressan RA, Gadelha A, Maes M, Brietzke E (2014) Effects of risperidone on cytokine profile in drug-naïve first-episode psychosis. Int J Neuropsychopharmacol 18(4)

  • Nyland H, Naess A, Lunde H (1980) Lymphocyte subpopulations in peripheral blood from schizophrenic patients. Acta Psychiatr Scand 61:313–8

    Article  CAS  PubMed  Google Scholar 

  • Pacheco R, Ciruela F, Casado V, Mallol J, Gallart T, Lluis C, Franco R (2004) Group I metabotropic glutamate receptors mediate a dual role of glutamate in T cell activation. J Biol Chem 279:33352–33358

    Article  CAS  PubMed  Google Scholar 

  • Pacheco R, Prado CE, Barrientos MJ, Bernales S (2009) Role of dopamine in the physiology of T-cells and dendritic cells. J Neuroimmunol 216:8–19

    Article  CAS  PubMed  Google Scholar 

  • Pacheco R, Contreras F, Zouali M (2014) The dopaminergic system in autoimmune diseases. Front Immunol 5:117

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Pae CU, Yoon CH, Kim TS, Kim JJ, Park SH, Lee CU, Lee SJ, Lee C, Paik IH (2006) Antipsychotic treatment may alter T-helper (TH) 2 arm cytokines. Int Immunopharmacol 6:666–71

    Article  CAS  PubMed  Google Scholar 

  • Pasternak O, Westin CF, Bouix S, Seidman LJ, Goldstein JM, Woo TU, Petryshen TL, Mesholam-Gately RI, McCarley RW, Kikinis R, Shenton ME, Kubicki M (2012) Excessive extracellular volume reveals a neurodegenerative pattern in schizophrenia onset. J Neurosci 32:17365–72

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Patterson PH (2009) Immune involvement in schizophrenia and autism: etiology, pathology and animal models. Behav Brain Res 204:313–21

    Article  CAS  PubMed  Google Scholar 

  • Pérez-Neri I, Ramírez-Bermúdez J, Montes S, Ríos C (2006) Possible mechanisms of neurodegeneration in schizophrenia. Neurochem Res 31:1279–94

    Article  PubMed  CAS  Google Scholar 

  • Prado C, Contreras F, González H, Díaz P, Elgueta D, Barrientos M, Herrada AA, Lladser Á, Bernales S, Pacheco R (2012) Stimulation of dopamine receptor D5 expressed on dendritic cells potentiates Th17-mediated immunity. J Immunol 188:3062–70

    Article  CAS  PubMed  Google Scholar 

  • Prado C, Bernales S, Pacheco R (2013) Modulation of T-cell mediated immunity by dopamine receptor d5. Endocr Metab Immune Disord Drug Targets 13:184–94

    Article  CAS  PubMed  Google Scholar 

  • Rajasekaran A, Venkatasubramanian G, Berk M, Debnath M (2015) Mitochondrial dysfunction in schizophrenia: pathways, mechanisms and implications. Neurosci Biobehav Rev 48C:10–21

    Article  CAS  Google Scholar 

  • Riedel M, Spellmann I, Schwarz MJ, Strassnig M, Sikorski C, Möller HJ, Müller N (2007) Decreased T cellular immune response in schizophrenic patients. J Psychiatr Res 41:3–7

    Article  PubMed  Google Scholar 

  • Ripke S, Neale BM, Corvin A et al (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–427

    Article  PubMed Central  CAS  Google Scholar 

  • Saha B, Mondal AC, Basu S, Dasgupta PS (2001) Circulating dopamine level, in lung carcinoma patients, inhibits proliferation and cytotoxicity of CD4+ and CD8+ T cells by D1 dopamine receptors: an in vitro analysis. Int Immunopharmacol 1:1363–74

    Article  CAS  PubMed  Google Scholar 

  • Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25 + CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352

    Article  CAS  PubMed  Google Scholar 

  • Sarkar C, Basu B, Chakroborty D, Dasgupta PS, Basu S (2010) The immunoregulatory role of dopamine: an update. Brain Behav Immun 24:525–8

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sibley DR, Monsma FJ Jr, Shen Y (1993) Molecular neurobiology of dopaminergic receptors. Int Rev Neurobiol 35:391–415

    Article  CAS  PubMed  Google Scholar 

  • Smith RS (1992) A comprehensive macrophage-T-lymphocyte theory of schizophrenia. Med Hypotheses 39:248–257

    Article  CAS  PubMed  Google Scholar 

  • Smith RS, Maes M (1995) The macrophage-T-lymphocyte theory of schizophrenia: additional evidence. Med Hypotheses 45:135–41

    Article  CAS  PubMed  Google Scholar 

  • Song C, Merali Z, Anisman H (1999) Variations of nucleus accumbens dopamine and serotonin following systemic interleukin-1, interleukin-2 or interleukin-6 treatment. Neuroscience 88:823–836

    Article  CAS  PubMed  Google Scholar 

  • Sperner-Unterweger B, Whitworth A, Kemmler G, Hilbe W, Thaler J, Weiss G, Fleischhacker WW (1999) T-cell subsets in schizophrenia: a comparison between drug-naive first episode patients and chronic schizophrenic patients. Schizophr Res 38:61–70

    Article  CAS  PubMed  Google Scholar 

  • Steiner J, Jacobs R, Panteli B, Brauner M, Schiltz K, Bahn S, Herberth M, Westphal S, Gos T, Walter M, Bernstein HG, Myint AM, Bogerts B (2010) Acute schizophrenia is accompanied by reduced T cell and increased B cell immunity. Eur Arch Psychiatry Clin Neurosci 260:509–18

    Article  PubMed  Google Scholar 

  • Stein K, Broome MR (2015) Neuroprogression in schizophrenia: pathways and underpinning clinical staging and therapeutic corollaries. Aust N Z J Psychiatry 49:183–4

    Article  PubMed  Google Scholar 

  • Urhan-Kucuk M, Erdal ME, Ozen ME, Kul S, Herken H (2011) Is the dopamine D3 receptor mRNA on blood lymphocytes help to for identification and subtyping of schizophrenia? Mol Biol Rep 38:2569–72

    Article  CAS  PubMed  Google Scholar 

  • van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, Caspers E, Luurtsema G, Windhorst AD, Cahn W, Lammertsma AA, Kahn RS (2008) Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol Psychiatry 64:820–2

    Article  PubMed  Google Scholar 

  • Venkatasubramanian G, Debnath M (2013) The TRIPS (Toll-like Receptors in Immune-inflammatory PathogenesiS) Hypothesis: A Novel Postulate to Understand Schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 44C:301–311

    Article  CAS  Google Scholar 

  • Villemain F, Chatenoud L, Galinowski A, Homo-Delarche F, Ginestet D, Loo H, Zarifian E, Bach JF (1989) Aberrant T cell-mediated immunity in untreated schizophrenic patients: deficient interleukin-2 production. Am J Psychiatry 146(5):609–16

    Article  CAS  PubMed  Google Scholar 

  • Vogel M, Pfeifer S, Schaub RT, Grabe HJ, Barnow S, Freyberger HJ, Cascorbi I (2004) Decreased levels of dopamine D3 receptor mRNA in schizophrenia and bipolar patients. Neuropsychobiology 50:305–10

    Article  CAS  PubMed  Google Scholar 

  • Vuillermot S, Weber L, Feldon J, Meyer U (2010) A longitudinal examination of the neurodevelopmental impact of prenatal immune activation in mice reveals primary defects in dopaminergic development relevant to schizophrenia. J Neurosci 30:1270–87

    Article  CAS  PubMed  Google Scholar 

  • Watanabe Y, Nakayama T, Nagakubo D, Hieshima K, Jin Z, Katou F, Hashimoto K, Yoshie O (2006) Dopamine selectively induces migration and homing of naïve CD8+ T cells via dopamine receptor D3. J Immunol 176:848–856

    Article  CAS  PubMed  Google Scholar 

  • Weaver CT, Elson CO, Fouser LA, Kolls JK (2013) The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annu Rev Pathol 8:477–512

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wolf SA, Steiner B, Akpinarli A, Kammertoens T, Nassenstein C, Braun A, Blankenstein T, Kempermann G (2009) CD4-positive T lymphocytes provide a neuroimmunological link in the control of adult hippocampal neurogenesis. J Immunol 182:3979–3984

    Article  CAS  PubMed  Google Scholar 

  • Xin J, Wainwright DA, Mesnard NA, Serpe CJ, Sanders VM, Jones KJ (2011) IL-10 within the CNS is necessary for CD4+ T cells to mediate neuroprotection. Brain Behav Immun 25:820–9

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yolken RH, Dickerson FB, Fuller Torrey E (2009) Toxoplasma and schizophrenia. Parasite Immunol 31:706–15

    Article  CAS  PubMed  Google Scholar 

  • Zalcman S, Green-Johnson JM, Murray L et al (1994) Cytokine-specific central monoamine alterations induced by interleukin-1, −2 and −6. Brain Res 643:40–49

    Article  CAS  PubMed  Google Scholar 

  • Zhang XY, Zhou DF, Cao LY, Wu GY (2006) The effects of ginkgo biloba extract added to haloperidol on peripheral T cell subsets in drug-free schizophrenia: a double-blind, placebo-controlled trial. Psychopharmacol (Berl) 188:12–7

    Article  CAS  Google Scholar 

  • Zhang J, Ke KF, Liu Z, Qiu YH, Peng YP (2013) Th17 cell-mediated neuroinflammation is involved in neurodegeneration of aβ1-42-induced Alzheimer’s disease model rats. PLoS One 8:e75786

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, Cohen H, Kipnis J, Schwartz M (2006) Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 9:268–275

    Article  CAS  PubMed  Google Scholar 

  • Zvara A, Szekeres G, Janka Z, Kelemen JZ, Cimmer C, Sántha M, Puskás LG (2005) Over-expression of dopamine D2 receptor and inwardly rectifying potassium channel genes in drug-naiveschizophrenic peripheral blood lymphocytes as potential diagnostic markers. Dis Markers 21:61–9

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Debnath, M. Adaptive Immunity in Schizophrenia: Functional Implications of T Cells in the Etiology, Course and Treatment. J Neuroimmune Pharmacol 10, 610–619 (2015). https://doi.org/10.1007/s11481-015-9626-9

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