Adaptive Immunity in Schizophrenia: Functional Implications of T Cells in the Etiology, Course and Treatment Monojit Debnath
Journal of Neuroimmune Pharmacology ISSN 1557-1890 J Neuroimmune Pharmacol DOI 10.1007/s11481-015-9626-9
1 23
Your article is protected by copyright and all rights are held exclusively by Springer Science +Business Media New York. This e-offprint is for personal use only and shall not be selfarchived in electronic repositories. If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com”.
1 23
Author's personal copy J Neuroimmune Pharmacol DOI 10.1007/s11481-015-9626-9
INVITED REVIEW
Adaptive Immunity in Schizophrenia: Functional Implications of T Cells in the Etiology, Course and Treatment Monojit Debnath 1
Received: 1 April 2015 / Accepted: 3 July 2015 # Springer Science+Business Media New York 2015
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
* Monojit Debnath
[email protected] 1
Department of Human Genetics, National Institute of Mental Health & Neurosciences, Hosur Road, Bangalore, Karnataka 560029, India
of T cells in the etiology, course and treatment of schizophrenia and forms the basis of this review. Keywords Schizophrenia . Inflammation . T cells . Neurodegeneration
Introduction Mounting evidence based on epidemiological, immunological and gene expression studies points toward immune system dysfunction in schizophrenia (Gardiner et al. 2013; Horváth and Mirnics 2014; Müller and Schwarz 2010; Patterson 2009). Multiple genome wide association studies (GWAS) have provided strong genetic support for immunopathogenetic basis of schizophrenia (Avramopoulos et al. 2015; Debnath et al. 2013; Ripke et al. 2014). A variety of immune system alterations in blood, cerebrospinal fluid (CSF) and brain of schizophrenia patients have consistently been reported (Beumer et al. 2012; Nikkila et al. 1999, 2001; Miller et al. 2013). Further, immunologic aberrations attributing to neuroinflammation in schizophrenia have also been elucidated by neuroimaging and post-mortem brain studies (Doorduin et al. 2009; Monji et al. 2013; Najjar and Pearlman 2015). What is more important is to note that the immune components not only enhance the risk and progression of schizophrenia by mounting immuno-inflammatory responses but also by influencing neurodevelopmental, neurometabolic, neuroendocrine and other etilogical pathways (Debnath et al. 2015; Guest et al. 2011; Vuillermot et al. 2010). For example, maternal immune activation and/or developmental neuroinflammation due to prenatal adversities was shown to impair crucial phases of neurodevelopment and increase the risk of schizophrenia in the offspring (Harvey and Boksa 2012; Meyer 2013). The components and mediators of the immune system also interact
Author's personal copy potentially with the neurotransmitters and modulate dopaminergic as well as glutamatergic neurotransmission in schizophrenia (Song et al. 1999; Muller and Schwarz 2006; Zalcman et al. 1994). These findings thus reinforce the hypothesis that certain immune parameters might act as the common mediators of schizophrenia risk, conferred by various factors and mechanisms. Although dysfunctions of both the innate and adaptive immune systems are evident in schizophrenia, much attention has been paid to the innate immunity and inflammation (Debnath et al. 2011; Kirkpatrick and Miller 2013; de Baumont et al. 2015). Multiple studies including a metaanalysis have suggested a role of chronic low-grade inflammation in schizophrenia (Kirkpatrick and Miller 2013; Najjar et al. 2013). However, there is a considerable lack of information on the influence of adaptive immune system, especially T cells on the core features and severity of schizophrenia. It is now a well established fact that adaptive immunity in conjunction with innate immunity plays active role in brain development and function (Filiano et al. 2014). The ability of T cells to infiltrate brain, activate microglia and induce neuroinflammation is a documented finding; such processes are known to impair higher order brain functions and also lead to neuroprogressive changes (Amor et al. 2010; Engelhardt 2006; González and Pacheco 2014; Hickey et al.1991). Recently, schizophrenia has increasingly been associated with progressive neurodegeneration, and one of the predominant underlying mechanisms appears to be immuno-inflammatory processes (Durrenberger et al. 2014; Pasternak et al. 2012; Pérez-Neri et al. 2006). Further to this, animal studies have established beneficial roles of T cells in cognition and behaviour; for example, T cell replenishment restored cognitive impairment caused by systemic immune deficiency (Brynskikh et al. 2008; Kipnis et al. 2004; Wolf et al. 2009; Ziv et al. 2006). Herein, the relevance of T cells in schizophrenia, more specifically the implications of T cells in the etiology, course and treatment have been highlighted.
T Cell Theory of Schizophrenia Revisited The T cells act as crucial players of the adaptive immune response. Naive CD4+ T cells upon activation differentiate into a variety of effector Th subsets, each with its unique cytokine profile and functions. The Th subsets were initially classified as Th1 and Th2 cells based on their ability to produce different types of cytokines and perform specific effector functions (Mosmann et al. 1986; Mosmann and Coffman 1989). Recently, two more subsets of Th cells such as Th17 and CD4+CD25+FOXP3 regulatory T (Treg) cells have been identified. The Th17 cells play critical roles in infection, autoimmunity, and inflammation, particularly in mucosal surfaces of the lungs, skin, and gut (Bettelli et al. 2008; Weaver
et al. 2013), while the Treg cells are essential in maintaining peripheral tolerance, suppressing activation of the immune system, preventing autoimmune diseases, and limiting chronic inflammation (Sakaguchi 2005). A role of T cells in schizophrenia though was first indicated more than 35 years ago (Nyland et al. 1980), the macrophage-T lymphocyte theory of schizophrenia was proposed in 1992 and this was further supported in 1995 (Smith 1992; Smith and Maes 1995). Subsequent to this, many studies consistently demonstrated aberrant Tcell mediated immunity in schizophrenia (Table 1). This understanding has been strengthened by a recent study that indicated presence of an activated T-cell networks in schizophrenia patients (Drexhage et al. 2011). Additionally, T cell dependent molecular changes leading to altered immune function has also been reported in first-onset schizophrenia patients (Herberth et al. 2014). Further, studies showing increased frequency of activated lymphocytes in the CSF and higher densities of T lymphocytes in the hippocampus of schizophrenia patients provided indirect evidence of blood–brain barrier (BBB) impairment and T-cell infiltration into the brain (Nikkilä et al. 1995; Busse et al. 2012). The T cells are also being associated with psychopathological symptoms and the outcome of neuroleptic treatment in schizophrenia (Muller et al. 1991; 1993). Cigarette smoking causes high mortality in schizophrenia patients (Kelly et al. 2011). Interestingly, cigarette smoking was found to be associated with increased T-cell proliferation in schizophrenia patients (Herberth et al. 2010). It is noteworthy that T cells also influence infection-mediated risk of schizophrenia. The heightened expression of Le(y) antigens on the surface of T lymphocytes, an indicator of viral infection was reported in schizophrenia patients (Kokai et al. 1993). This implies evidence of viral infection in some patients with schizophrenia. Toxoplasma gondii is a strong environmental risk factor of schizophrenia (Yolken et al. 2009). CD8+T cells are crucial in controlling Toxoplasma infection through the production of IFN-γ (Bhadra et al. 2011). It is proposed that the attenuated CD8+T cell response might account for Toxoplasma seropositivity in schizophrenia (Bhadra et al. 2013). Maternal immune activation due to prenatal infection is a predominant risk mechanism of neurodevelopmental origin of schizophrenia (Debnath et al. 2015). Maternal immune stimulation during pregnancy can shape the immunological phenotype of the offspring (Mandal et al. 2013). Animal studies have shown that prenatal infection induced maternal immune activation contributes to hyperactivated immune response in the adult offspring through preferential development of T cells like CD4+T cells and Th17 cells (Luan et al. 2015; Mandal et al. 2010). Taken together, a crucial role
Author's personal copy Table 1
A summary of findings of T cell alterations in schizophrenia
Sl. No.
Reference
Study subjects
Findings
1 2 3 4
Nyland et al. 1980 DeLisi et al. 1982 Coffey et al. 1983 Villemain et al. 1989
Acute schizophrenia patients (n=27) Chronic schizophrenia patients (n=38) Acute or chronic schizophrenia (n=38) Untreated schizophrenia patients (n=16)
Decreased number of T lymphocytes. Higher percentage of T lymphocytes. Reduced percentage of T lymphocytes. No increase in T cell numbers.
5 6
Henneberg et al. 1990 Masserini et al. 1990
Acute schizophrenia patients (n=30) Schizophrenia and schizophrenia spectrum disorders (n=42)
7
Müller et al. 1991
8
Achiron et al. 1994
9
Nikkilä et al. 1995
10 11
Muller et al.1998 Cazzullo et al. 1998
12
Müller et al. 1999
13
Sperner-Unterweger et al. Chronic schizophrenia patients (n=35) and 1999 drug-naive first episode schizophrenic patients (n=21)
14
Mazzarello et al. 2004
15 16
Matloubi et al. 2007 Maino et al. 2007
17
Craddock et al. 2007
18
Steiner et al. 2010
19
Ding et al. 2014
Significant increases in the number of T cells. Increased number of T suppressor lymphocytes in drug naive, while increased number of T helper lymphocytes in the drug-treated schizophrenia patients. Schizophrenia patients in acute stage of illness Increased number of CD3+ and CD4+ cells before and during (n=55) treatment was observed. Untreated schizophrenia patients (n=16) Decreased number of CD4+ 2H4+ (suppressor-inducer) and CD8+ 2H4+ (suppressor-effector) T-cell subsets. Acutely ill schizophrenia patients (n=31) Abnormally high and abnormally low frequencies of CD4+ and/or CD8+ cells in the CSF. Unmedicated schizophrenia patients (n=45) Significantly increased CD8+γ/δ+ lymphocytes. Schizophrenia patients (n=29) A lower level of CD4+ cells, and significantly higher CD4+ 45RA+ (naive) subset. Significantly lower number of CD4+ 45RA(memory) lymphocytes, while the CD8+ supressor/cytotoxic T-cell percentage was significantly higher. schizophrenia patients before (n=45) and Significantly increased percentages of VLA-4+/CD4+ and VLA-4+/ after (n=22) neuroleptic treatment CD8+ cells were observed during antipsychotic treatment.
In the acute state schizophrenic patients, higher CD3+ and CD4+ cells and a higher CD4/CD8 ratio were observed. In first episode patients, all T-cell alterations normalized during treatment. In the chronic group the ratio remained high. Schizophrenia patients (n=24) Decreased percentage of CD8+ and higher CD4+ / CD8+ ratio were reported. Drug-free schizophrenia patients (n=30) Lower T cell responses to mitogen Unmedicated Schizophrenia patients (n=40) In the acute state of psychosis, a significant reduction of the CD3+lymphocyte subpopulation and increased percentage of CD19(+)lymphocytes were observed. In vitro studies of peripheral blood T cells Significantly lower proliferative responses to T cell stimulation with derived from schizophrenia patients anti-CD3. Acute paranoid schizophrenia patients (n=26) Lower level of T helper cells and reduced CD4/CD8 ratio were found during acute psychosis. However, after 6 weeks of medication total number of T cell, T helper, and T suppressor/ cytotoxic cells increased. First episode and drug naïve schizophrenia Significantly higher proportions of Th17 cells. patients (n=69)
of T cells seems imperative in the immune-mediated neurodevelopmental origin of schizophrenia. Recent genetic studies as well as pathway analyses of GWAS data suggest that certain genes involved in T cell functions including antigen processing and cell adhesion confer susceptibility to schizophrenia (Aberg et al. 2013). For instance, CD28 and cytotoxic T lymphocyte antigen-4 (CTLA-4) genes, which modulate T-cell activity were significantly associated with schizophrenia risk (Frydecka et al. 2013; Liu et al. 2011). Epigenetic studies also indicated that genes regulating activation of T cells were found to be
differentially methylated in schizophrenia (Liu et al. 2014). Importantly, a meta-analysis on lymphocytes suggested CD4/CD8 ratio as a state-related marker of schizophrenia as significantly increased ratio was reported in first episode patient, while the ratio diminished following anti-psychotic treatment (Miller et al. 2013). Functional implications of Th17 and Treg cells are also becoming apparent in schizophrenia (Drexhage et al. 2011; Debnath and Berk 2014). Higher number of Th17 cells in drug naïve, first episode schizophrenia patients has been reported recently (Ding et al. 2014). These findings raise the intriguing possibility
Author's personal copy of a dysregulated T cell network in the pathophysiology of schizophrenia, however, knowledge on the precise underlying mechanism is inadequate.
T Cells as a Mediator of Neuro-Immune Interactions: Dopaminergic Regulation of T Cells Growing evidence reveals that neurotransmitters which commonly mediate interactions into the nervous system can also regulate immune cells and immunity (Franco et al. 2007). In addition to their expression in the nervous system, the receptors for several neurotransmitters including dopamine, glutamate, serotonin etc. are also expressed on the surface of immune cells (Besser et al. 2005a, b; Leon-Ponte et al. 2007; Pacheco et al. 2004). Dysregulation of the expression and activation of the receptors for neurotransmitters on the immune cells can lead to autoimmunity or malignancies. This understanding has generated considerable interest in delineating the pathobiological underpinnings of various central nervous system (CNS) disorders. Dopamine alteration is the oldest and most enduring hypothesis of schizophrenia (Howes and Kapur 2009). Apart from its role as neurotransmitter, the immunomodulatory effects of dopamine, especially on T cells are being recognized increasingly (Basu and Dasgupta 2000a; Beck et al. 2004; Ilani et al. 2004; Pacheco et al. 2009; Prado et al. 2013; Sarkar et al. 2010). Dopamine interacts directly with the dopaminergic receptors expressed on the surface of T cells and also plays a significant role in migration, homing and proliferation of T cells (Besser et al. 2005a, b; Levite et al. 2001; Watanabe et al. 2006). Dopamine can activate resting T cells by stimulating the release of cytokine and the expression of surface integrins; on the contrary, dopamine is also shown to inhibit proliferation of activated T cells by down-regulating non-receptor tyrosine kinases (Levite et al. 2001; Ghosh et al. 2003). Dopamine receptors are seven-transmembrane G proteincoupled receptors and classified into two distinct subgroups with opposite actions on adenylate cyclase. The D1-like (D1 and D5) receptors, coupled to Gαs increase intracellular cAMP; signaling via D1-like receptors inhibits immune response (Saha et al. 2001). Conversely, D2-like (D2, D3, and D4) receptors, coupled to Gαi decrease intracellular cAMP and these often exert immunostimulatory effects (Sibley et al. 1993; Besser et al. 2005a, b; Saha et al. 2001). In addition, dopamine is known to differentially favour CD4+ T cell differentiation into Th1 or Th17 inflammatory cells based on the activation of specific dopamine receptors on dendritic and T cells. For example, stimulation of dopamine receptor D5 expressed on dendritic cells has been shown to potentiate Th17–mediated immunity (Prado et al. 2012). Dopamine also differentially modulates T cell functions in the pathological conditions like malignancies and autoimmune diseases (Basu and Dasgupta 2000b; Pacheco et al.
2014). In malignancies, increased dopamine level inhibits proliferation and cytotoxicity of CD4+ and CD8+ T cells and this might suppress anti-neoplasmic immune response (Saha et al. 2001; Basu et al. 2010). However, decreased levels of dopamine found in autoimmune conditions could be responsible for an exacerbated response of autoreactive T cells (Giorelli et al. 2005; Levite 2015). In schizophrenia, the expression of dopamine receptors has not only been observed in the brain but also on immune cells. In the peripheral lymphocytes of schizophrenia patients, significantly increased mRNA expression of D2 and D3 receptors (Kwak et al. 2001; Ilani et al. 2001; Zvara et al. 2005) and reduced gene expression of dopamine D3 receptor (Vogel et al. 2004) were reported. A study has shown significantly higher mRNA levels for D3 receptor and lower for D4 receptor in T cells of schizophrenia patients (Boneberg et al. 2006). Furthermore, higher percentages of CD4+D4+, CD8+D4+ and CD8+D2+ cells were observed in schizophrenia patients; and these increases were found to be associated with schizophrenia severity (Brito-Melo et al. 2012). Certain studies on the contrary have reported no differences in mRNA expression of D2, D3 and D4 receptors on lymphocytes of schizophrenia patients, however, such studies importantly have demonstrated the influence of dopamine receptors expression on the psychopathology of schizophrenia. For example, expression of D3 receptor was found to be inversely correlated with the total positive and negative syndrome scale (PANSS) score, while D4 receptor expression was positively correlated with working memory scales (Kawano et al. 2011). Similarly, the mRNA levels of D2 receptor was found to correlate with positive symptoms in acute schizophrenia patients (Liu et al. 2013). Interestingly, in one study though no difference in the expression of D3 receptor mRNA levels was observed between schizophrenia patients and controls, but significant variation was noticed among schizophrenia subtypes (Urhan-Kucuk et al. 2011). Taken together, these studies further highlight important roles of dopamine on the regulation of T-cell mediated immunity in schizophrenia.
T-Cell Network and Neuroprogression in Schizophrenia The significance of neuroprogressive changes in the risk and progression of schizophrenia are being appreciated widely in recent times (Andreasen et al. 2011; Davis et al. 2014; Stein and Broome 2015). Several underlying mechanisms including neurotransmitter abnormality, immuno-inflammatory, oxidative and nitrosative stress (IO&NS) pathway, mitochondrial dysfunction, tryptophan catabolite (TRYCAT) pathway etc. contribute to neuroprogressive changes in schizophrenia (Anderson and Maes 2013; Venkatasubramanian and Debnath 2013; Debnath and Berk 2014; Rajasekaran et al.
Author's personal copy 2015). Amongst these, the IO&NS pathway has emerged as one of the predominant mechanisms of neuroprogression in schizophrenia (Anderson et al. 2013). T cell-mediated immunity has dual effects in brain; it either exacerbates neurotoxic response or provides neuroprotection. Several studies have provided substantial evidence toward neuroprotective potential of T cells (Hendrix and Nitsch 2007; Chiu et al. 2008; Xin et al. 2011). Despite these advances, the precise mechanism(s) of T-cell induced neuroprotection is incompletely understood. In an in vitro study, when T cells were co-cultured with astrocytes, T cell derived glutamate was found to induce the release of neuroprotective thiols (cysteine, glutathione and cysteinylglycine) and lactate from astrocytes and thus endowed astrocytes with a neuroprotective phenotype (Garg et al. 2008). T cell-dependent neuroprotective response seems to be provided also by Treg cells (Gendelman and Appel 2011), possibly by up-regulating the expression of neurotrophic factors and down-regulating the synthesis of pro-inflammatory cytokines and reactive oxygen species (ROS). An increasing body of evidence suggests pivotal roles of activated T cells in inflammatory and degenerative CNS disorders, and they are believed to actively contribute to neuronal damage (Brochard et al. 2009; Gelderblom et al. 2014; González and Pacheco 2014; Maxeiner et al. 2009; Zhang et al. 2013). Encephalitogenic inflammatory CD4+T cells such as Th1, Th17, GM-CSF producer CD4+ T cells and γδT-cells strongly induce chronic neuroinflammation. Altered distributions of T-cell subsets in CSF and higher densities of T lymphocytes in the hippocampus indicate T cell infiltration in the brain of schizophrenia patients (Nikkilä et al. 1995; Busse et al. 2012). Cytokines derived from T cells can potentially activate the production of pro-inflammatory cytokines, which in turn can induce microglia activation. Activated microglia as a chronic source of neurotoxic factors such as inflammatory cytokines and ROS can cause progressive neuron damage and/or neurodegeneration (Block and Hong 2005; Lull and Block 2010). In schizophrenia, emerging research is increasingly pointing toward a compelling link between microglia activation and brain injury due to neuroinflammation (Juckel et al. 2011; Monji et al. 2009; van Berckel et al. 2008). Although these findings suggest a role of T cell mediated immunity in neuroprogressive changes of schizophrenia, it has been contested by other studies. Decreased T cell numbers or dampened T cell immunity in schizophrenia patients has been reported by many studies. Skin reactivity to antigens, an in vivo measure of cell-mediated immunity has also suggested decreased T cell immune response in schizophrenia patients (Riedel et al. 2007). Interestingly, higher percentages of anti-inflammatory Treg cells were reported in schizophrenia (Drexhage et al. 2011). Taken together, these data indicate neuroprotective and/or anti-inflammatory functions of T cells, and based on this it can be assumed that the impaired T cell function in a subset of patients might
contribute to the development of schizophrenia. Notably, T cell responses are known to be functionally and phenotypically heterogeneous (Harari et al. 2004; Harari et al. 2005; Becattini et al. 2015). The role of T cells in different pathological conditions might not be uniform. Further, T cell mediated responses might be genetically determined. Therefore, implications of T-cell immunity on the underlying pathogenetic pathways of schizophrenia should be interpreted with caution.
Antipsychotic Treatment and T Cell Responses in Schizophrenia Antipsychotic drugs (APDs) that are commonly used to treat schizophrenia patients can modulate immune system. One of the underlying mechanisms is by regulating differentiation of T cell subsets. Atypical APDs like clozapine and risperidone were shown not only to effectively reduce production of IFN-γ for CD4(+) T cells in PBMC but also Th1 cell differentiation and T-bet expression (Chen et al. 2011; Chen et al. 2012). In contrast, typical APD like haloperidol increased the production of IFN-γ for CD4(+) T cells in PBMC, while decreased the differentiation of Th2 by inhibiting expression of GATA-3 (Chen et al. 2011). Antipsychotic treatment also altered Th2 arm of cytokines (Pae et al. 2006). The impact of APDs on T cell profile in schizophrenia has also been examined, however, the findings are quite inconsistent. Both the beneficial, i.e., improving peripheral immune functions and immuno-dampening effects of APDs are being reported. In drug naïve schizophrenia patients increased number of T suppressor lymphocytes were noticed, however, in drug-treated patients the number of T helper lymphocytes were found to increase (Masserini et al. 1990). In addition, higher CD3+ and CD4+ cells and a higher CD4/CD8 ratio observed in acute state became normalized during neuroleptic treatment (Sperner-Unterweger et al. 1999). Amongst the significantly increased absolute measures of total lymphocytes, CD3 and CD4 cells as well as CD4/CD8 ratio observed in drug-naïve first-episode psychosis in a meta-analysis, the ratio of CD4/CD8 was found to decrease following antipsychotic treatment for acute psychosis (Miller et al. 2013). On the contrary, a lower count of T helper cells and a reduced CD4/CD8 ratio noticed during acute psychosis was found to normalize after 6 weeks of medication (Steiner et al. 2010). Interestingly, on examining the expression pattern of adhesion molecule receptors (VLA-4 and LFA-1) on CD4+ and CD8+ T lymphocytes in schizophrenia patients before and during antipsychotic treatment, significant increases in the percentage of VLA-4+/CD4+ and VLA-4+/CD8+ cells during antipsychotic treatment was demonstrated. The increases of these cells were found to correlate with the disturbance of blood– brain barrier (Müller et al. 1999). Further to this, 12 week
Author's personal copy treatment of Ginko biloba extract plus a stable dose of haloperidol increased CD3+, CD4+, IL-2 secreting cells and CD4/CD8 ratio which were significantly lower at baseline in schizophrenia patients (Zhang et al. 2006). The suppressive effects of risperidone on monocytic, Th2 and T-regulatory functions were also evident in first episode psychosis patients (Noto et al. 2014). Contradictorily, in an interesting study Müller et al. (1991) argued that immune alterations in schizophrenia may not be due to antipsychotic treatment as increased numbers of CD3+ and CD4+ cells were observed both before and during treatment. The role of adaptive immunity, especially T cells is also becoming apparent in Anterior Chamber Associated Immune Deviation (ACAID), a systemic form of immune tolerance which is induced by the injection of antigens into the anterior chamber (AC) of the eye (Farooq and Ashour 2012). Recent studies suggest ACAID as an emerging therapeutic tool in the treatment of neuroinflammatory disorders (Farooq and Ashour 2014a). A variety of antigens are known to potentially induce ACAID-mediated immune tolerance following their injection into the AC. Recent studies have demonstrated that encephalitogenic antigens like Myelin oligodendrocyte glycoprotein (MOG) and Myelin basic protein (MBP) which have been implicated in neuroinflammatory disorders including schizophrenia can induce ACAID– mediated tolerance (Farooq and Ashour 2013; Farooq et al. 2014b). In mice, the MOG/MBP-driven tolerance was shown to be mediated via splenic CD8+ T cells (Farooq and Ashour 2013). Given the significance of such studies, it seems reasonable to further investigate the role of ACAID in schizophrenia. Such understanding will have significant implications in therapeutic management of schizophrenia.
Conclusion Immune dysregulation contributing to risk and progression of schizophrenia is a documented finding. The consequences of T cell alterations in schizophrenia i.e., its abilities to induce neuroinflammation and subsequently neurodegeneration has generated renewed interest in delineating the immunopathogenesis of schizophrenia. It is now known that T cell mediated autoimmunity is essential in physiological defense, maintenance and repair of the adult brain. However, if such responses are unchecked, it might trigger autoimmune reaction. Although the presence of activated immune system has been highlighted in schizophrenia, there is a considerable lack of information on the availability of autoimmune clones that are specifically reactive to CNS antigens including major myelin proteins. Future studies should pay more attention on this aspect. In addition to its dual role; both neuroprotective and neurodegenerative, T cells are also being shown to be
the targets of neurotransmitters like dopamine. The precise knowledge of deregulation of dopamine receptors expression on T cells and understanding of the impact of the activation of each dopamine receptor on T cell physiology will have translational implications for the management of schizophrenia. Conflict of Interest The author declares that he has no conflicts of interest to disclose.
References Aberg KA, Liu Y, Bukszár J et al (2013) A comprehensive family- based replication study of schizophrenia genes. JAMA Psychiatry 70:573– 581 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 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) Immunoinflammatory, oxidative and nitrosative stress, and neuroprogressive pathways in the etiology, course and treatment of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 42:1–4 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 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 Amor S, Puentes F, Baker D, van der Valk P (2010) Inflammation in neurodegenerative diseases. Immunology 129:154–69 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 Basu S, Dasgupta PS (2000a) Dopamine, a neurotransmitter, influences the immune system. J Neuroimmunol 102:113–24 Basu S, Dasgupta PS (2000b) Role of dopamine in malignant tumor growth. Endocrine 12:237–41 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 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 Bettelli E, Korn T, Oukka M, Kuchroo VK (2008) Induction and effector functions of T(H)17 cells. Nature 453:1051–1057 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 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
Author's personal copy 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 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 Bhadra R, Gigley JP, Khan IA (2011) The CD8 T-cell road to immunotherapy of toxoplasmosis. Immunotherapy 3:789–801 Bhadra R, Cobb DA, Weiss LM, Khan IA (2013) Psychiatric disorders in toxoplasma seropositive patients–the CD8 connection. Schizophr Bull 39:485–9 Block ML, Hong JS (2005) Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol 76:77–98 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 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 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 Brynskikh A, Warren T, Zhu J, Kipnis J (2008) Adaptive immunity affects learning behavior in mice. Brain Behav Immun 22:861–869 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 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 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 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 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 Coffey CE, Sullivan JL, Rice JR (1983) T lymphocytes in schizophrenia. Biol Psychiatry 18:113–9 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 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 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 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 Debnath M, Berk M (2014) Th17 pathway-mediated immunopathogenesis of schizophrenia: mechanisms and implications. Schizophr Bull 40:1412–21 Debnath M, Venkatasubramanian G, Berk M (2015) Fetal programming of schizophrenia: select mechanisms. Neurosci Biobehav Rev 49: 90–104 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 DeLisi LE, Goodman S, Neckers LM, Wyatt RJ (1982) An analysis of lymphocyte subpopulations in schizophrenic patients. Biol Psychiatry 17:1003–9 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 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 Drexhage RC, Hoogenboezem TA, Cohen D, Versnel MA, Nolen WA, van Beveren NJ, Drexhage HA (2011) An activated set point of Tcell and monocyte inflammatory networks in recent-onset schizophrenia patients involves both pro- and anti-inflammatory forces. Int J Neuropsychopharmacol 14:746–55 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 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 Farooq SM, Ashour HM (2013) Eye-mediated induction of specific immune tolerance to encephalitogenic antigens. CNS Neurosci Ther 19:503–510 Farooq SM, Ashour HM (2014) In vitro-induced cell-mediated immune deviation to encephalitogenic antigens. Brain Behav Immun 35:64–9 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 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 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 Gardiner EJ, Cairns MJ, Liu B, Beveridge NJ, Carr V, Kelly B, Scott RJ, Tooney PA (2013) Gene expression analysis reveals schizophreniaassociated dysregulation of immune pathways in peripheral blood mononuclear cells. J Psychiatr Res 47:425–37 Garg SK, Banerjee R, Kipnis J (2008) Neuroprotective immunity: T cellderived glutamate endows astrocytes with a neuroprotective phenotype. J Immunol 180:3866–73 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
Author's personal copy Gendelman HE, Appel SH (2011) Neuroprotective activities of regulatory T cells. Trends Mol Med 17:687–8 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 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 González H, Pacheco R (2014) T-cell-mediated regulation of neuroinflammation involved in neurodegenerative diseases. J Neuroinflammation 11:201 Guest PC, Martins-de-Souza D, Vanattou-Saifoudine N, Harris LW, Bahn S (2011) Abnormalities in metabolism and hypothalamic-pituitaryadrenal axis function in schizophrenia. Int Rev Neurobiol 101:145– 68 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 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 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 Hendrix S, Nitsch R (2007) The role of T helper cells in neuroprotection and regeneration. J Neuroimmunol 184:100–12 Henneberg A, Riedl B, Dumke HO, Kornhuber HH (1990) T-lymphocyte subpopulations in schizophrenic patients. Eur Arch Psychiatry Neurol Sci 239(5):283–4 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 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 Hickey WF, Hsu BL, Kimura H (1991) T-lymphocyte entry into the central nervous system. J Neurosci Res 28:254–60 Horváth S, Mirnics K (2014) Immune system disturbances in schizophrenia. Biol Psychiatry 75:316–23 Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull 35:549–62 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 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 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 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 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 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
Kirkpatrick B, Miller BJ (2013) Inflammation and schizophrenia. Schizophr Bull 39:1174–9 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 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 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 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 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 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 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 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 Maino K, Gruber R, Riedel M, Seitz N, Schwarz M, Müller N (2007) Tand B-lymphocytes in patients with schizophrenia in acute psychotic episode and the course of the treatment. Psychiatry Res 152:173–80 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 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 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 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 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 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 Meyer U (2013) Developmental neuroinflammation and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 42:20–34
Author's personal copy Miller BJ, Gassama B, Sebastian D, Buckley P, Mellor A (2013) Metaanalysis of lymphocytes in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 73:993–9 Monji A, Kato T, Kanba S (2009) Cytokines and schizophrenia: microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci 63:257– 265 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 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 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 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 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 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 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 Muller N, Schwarz M (2006) Schizophrenia as an inflammationmediated dysbalance of glutamatergic neurotransmission. Neurotox Res 10:131–48 Müller N, Schwarz MJ (2010) Immune system and schizophrenia. Curr Immunol Rev 6:213–220 Najjar S, Pearlman DM, Alper K, Najjar A, Devinsky O (2013) Neuroinflammation and psychiatric illness. J Neuroinflammation 10:43 Najjar S, Pearlman DM (2015) Neuroinflammation and white matter pathology in schizophrenia: systematic review. Schizophr Res 161: 102–12 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 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 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 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
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 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 Pacheco R, Contreras F, Zouali M (2014) The dopaminergic system in autoimmune diseases. Front Immunol 5:117 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 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 Patterson PH (2009) Immune involvement in schizophrenia and autism: etiology, pathology and animal models. Behav Brain Res 204:313– 21 Pérez-Neri I, Ramírez-Bermúdez J, Montes S, Ríos C (2006) Possible mechanisms of neurodegeneration in schizophrenia. Neurochem Res 31:1279–94 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 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 Rajasekaran A, Venkatasubramanian G, Berk M, Debnath M (2015) Mitochondrial dysfunction in schizophrenia: pathways, mechanisms and implications. Neurosci Biobehav Rev 48C:10–21 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 Ripke S, Neale BM, Corvin A et al (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–427 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 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 Sarkar C, Basu B, Chakroborty D, Dasgupta PS, Basu S (2010) The immunoregulatory role of dopamine: an update. Brain Behav Immun 24:525–8 Sibley DR, Monsma FJ Jr, Shen Y (1993) Molecular neurobiology of dopaminergic receptors. Int Rev Neurobiol 35:391–415 Smith RS (1992) A comprehensive macrophage-T-lymphocyte theory of schizophrenia. Med Hypotheses 39:248–257 Smith RS, Maes M (1995) The macrophage-T-lymphocyte theory of schizophrenia: additional evidence. Med Hypotheses 45:135–41 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 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 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
Author's personal copy Stein K, Broome MR (2015) Neuroprogression in schizophrenia: pathways and underpinning clinical staging and therapeutic corollaries. Aust N Z J Psychiatry 49:183–4 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 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 Venkatasubramanian G, Debnath M (2013) The TRIPS (Toll-like Receptors in Immune-inflammatory PathogenesiS) Hypothesis: A N o v e l P o s t u l a t e t o U n d e r s t an d S c h i z o p h r e n i a . P r o g Neuropsychopharmacol Biol Psychiatry 44C:301–311 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 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 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 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
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 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 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 Yolken RH, Dickerson FB, Fuller Torrey E (2009) Toxoplasma and schizophrenia. Parasite Immunol 31:706–15 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 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 Zhang J, Ke KF, Liu Z, Qiu YH, Peng YP (2013) Th17 cell-mediated neuroinflammation is involved in neurodegeneration of aβ1-42induced Alzheimer’s disease model rats. PLoS One 8:e75786 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 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
