Schizophrenia and Psychoneuroimmunology: an Integrative View

REVIEW

CURRENT OPINION Schizophrenia and psychoneuroimmunology: an integrative view

Barbara Sperner-Unterwegera and Dietmar Fuchsb

Purpose of review Since decades immunological aberrancies have been reported in schizophrenia patients. As schizophrenia represents a heterogenous disorder with a variety of clinical manifestations, complex interactions between the immune system in the brain might have important etiological implications. Recent findings Recent findings of altered expression of immune-related genes, changes of peripheral and central cytokines, antibodies and immune cells point toward dysbalanced immune response processes in schizophrenia. Summary Based on immunogenetic factors, immune dysfunctions caused by infections, increased autoimmune reactivity and low-grade inflammatory processes in the periphery as well as in central nervous system may affect neurobiological circuits including changed neurotransmitter metabolisms contributing to pathophysiological alterations in schizophrenia. These immunological abnormalities might provide tools for better diagnostic characterization of this heterogenous disease and on the other side, they may also support the development of immune-related therapeutic strategies. Keywords immune response, neurotransmitter pathways, psychoneuroimmunology, schizophrenia

INTRODUCTION schizophrenia [1&&,2&&,3]. Genome-wide association In the past, pathophysiological studies related to studies (GWASs) show the strongest signal for schizophrenia often applied unidimensional con- schizophrenia on chromosome 6p22.1, in a region cepts, like for instance focusing on disturbances related to the major histocompatibility complex of dopaminergic and glutaminergic neurotrans- (MHC) and other immune functions such as the mission, with limited clinical breakthroughs. As human leukocyte antigen (HLA) alleles [4]. A schizophrenia is a complex and heterogeneous dis- recently published analysis on genetic pleiotropy order, systemic research approaches considering between schizophrenia and multiple sclerosis – an interacting biological circuits seem more appropriate inflammatory, demyelinating disease of the central to better understand involved pathophysiological nervous system (CNS) – demonstrated genetic over- processes. In this context, a broad spectrum of lap in the MHC region implicating shared molecular immune system dysfunctions has constantly been pathways [5]. Regarding immune changes in the reported as possible underlying mechanisms, which CNS, microglia, a main cell component of combine genetic susceptibility, environmental influences such as infections, stress, nutrition and aDepartment of Psychiatry and Psychotherapy, Division of Psychoso- neurodevelopmental/neurodegenerative changes b including metabolic alterations of neurotransmitter matic Medicine and Division of Biological Chemistry, Biocenter, Medical University Innsbruck, Austria pathways. Correspondence to Barbara Sperner-Unterweger, MD, Medical Univer- Investigations of immune parameters measured sity Innsbruck, Department of Psychiatry and Psychotherapy, Division of in the periphery indicate abnormalities of the innate Psychosomatic Medicine, Anichstrasse 35, 6020 Innsbruck, Austria. Tel: as well as the adaptive immune response and especi- ++43 (0)512 504 23691; fax: ++43 (0)512 504 24778; e-mail: ally emphasize the role of infections, increased [email protected] autoimmune reactivity and chronic low-grade Curr Opin Psychiatry 2015, 28:201–206 inflammatory processes in the pathophysiology of DOI:10.1097/YCO.0000000000000153

fluid (CSF) and plasma [13,14&,15,16]. Epigenetic KEY POINTS dysregulation of immune-related genes by DNA Environmental-immune-gene interactions point towards methylation in brain and peripheral tissues, for a dysbalanced immune response in schizophrenia. example lymphocytes, has also been found in schizophrenia patients [17,18]. The hypothesis that Abnormalities of the innate and the adaptive immune neurodegenerative/neuroinflammatory diseases, system in the periphery as well as in CNS may although clinically characterized as distinct entities, contribute to pathophysiological processes in schizophrenia. exhibit common neuropathological changes has been investigated by Durrenberger et al. [19] by Changes of neurotransmitter metabolisms – for generating comparative GWASs data for Alzheimer’s example in the kynurenine pathway and in the disease, amyotrophic lateral sclerosis, Huntington’s phenylalanine pathway – may indicate interactions disease, multiple sclerosis, Parkinson’s disease and between the immune system and neurobiological circuits. schizophrenia. Against the assumption, the analysis demonstrated that for the selected diseases, only a few single specific genes could be found in common. Several of them were related to inflammation. On neuroinflammation, has also been reported to be the one hand, these results support the common relevant in schizophrenia [6&]. Furthermore, micro- role of neuroinflammation and on the other the glia activation and increased astrocytes reactivity uniqueness of the microenvironment for the devel- influence neurotransmission, for instance kynure- opment of each disease is underlined [19]. nine and phenylalanine pathways [7,8&]. Although immunogenetic factors may contrib- To address an integrative view of immune- ute to the pathophysiological processes of schizo- mediated pathophysiological mechanisms in schizophrenia, at least in a subgroup of patients, phrenia, this review summarizes recent research environmental influences, which can be also genet- data on peripheral and cerebral immune changes ically influenced like autoimmune disorders and an in relation to genetics and neurotransmitter path- increased susceptibility to infections [20&], must be ways. considered too. Different infections during preg- nancy or in the perinatal period leading to a persist- ent proinflammatory state have been considered to IMMUNE CHANGES IN SCHIZOPHRENIA IN activate an ‘‘immuno-phenotype’’ and thus induce RELATION TO GENETICS aberrant neurodevelopment. There is converging Developing techniques in genetic research offer evidence that interleukin-6, a predominately pro- more accurate methods like messenger RNA (mRNA) inflammatory cytokine related to Th2-type immune sequencing (RNASeq) and GWASs. There is some response, might be involved in the pathogenesis of evidence that expression of inflammation-related schizophrenia. The relationship between functional genes in certain regions of schizophrenia brains, interleukin-6 gene polymorphism and reduced for example the hippocampus, may lead to clinical hippocampal volume, which has been recently symptoms of the disease such as cognitive deficits observed in antipsychotic naive patients with schizo- [9]. Recently, GWASs have indicated a strong phrenia, support this evidence [21]. Most data on relationship between genes regulating immune this environmental-immune-gene interaction are response, like those belonging to the MHC region, derived from animal models of maternal immune and schizophrenia [10&&]. MHC gene polymor- activation (MIA) [22&]. Interestingly, there are some phisms may cause greater susceptibility of individ- hints that maternal stress-induced activation of uals for specific antigens. In post-mortem brains of immune pathways within the placenta may contrib- patients with schizophrenia, a high concordance ute to prenatal stress programming effects on the between the expression of highly susceptible schizo- offspring [23,24]. Another investigation on prenatal phrenia genes and genetic findings regarding the immune-related insults demonstrated age-depend- MHC region has also been reported [11]. Recently ent long-term GABAnergic changes in the prefrontal published GWASs indicate that the MHC molecule- region [25]. In contrast to these MIA-related effects mediated glutamatergic receptor function may be in animals, a case–control study within a popu- related to cognitive impairments in schizophrenia lation register investigation did not find differences [12]. Regarding studies of cytokine and neurotropic in inflammatory markers at the time of birth factors encoding genes, results are contradictory and in individuals who later in life developed schizo- often not significant in genome-wide comparisons, phrenia [26]. The importance of including environ- but some of them show good consistence between mental factors like maternal infection in genetic the changed cytokine levels in cerebrospinal studies has been underlined by a recently reported

202 www.co-psychiatry.com Volume 28 Number 3 May 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Schizophrenia and psychoneuroimmunology Sperner-Unterweger and Fuchs interaction between maternal cytomegalovirus infec- IMMUNE CHANGES IN SCHIZOPHRENIA IN tion and a gene that has not been implicated in the RELATION TO NEUROTRANSMITTER pathogenesis of schizophrenia up to now [27]. How- PATHWAYS ever, this also demonstrates the heterogeneous and By focusing on possible autoimmune mechanisms complex area of research. in schizophrenia, the question for disease specific Observations that schizophrenia patients autoantibodies with a direct pathogenetic effect suffer more often from infections, during child- arises. Recently, among different small studies and hood and also in later life, point at changed genetic case reports, there has been an interesting publi- susceptibility to different agents, including viral cation about anti-N-methyl-D-aspartate (NMDA) [28] and food antigens [29,30] (for example, an receptor antibodies and surface dopamine-2 recep- increased seroprevalence of Toxoplasma gondii tor antibodies in children with the first episode of IgM was reported in patients with acute psychosis acute psychosis [35&]. Although similar results have and this suggests that infections may be relevant been reported in adults with schizophrenia [36] to the etiopathophysiology of relapse in some pointing at an impaired glutaminergic/dopamin- patients with schizophrenia [31&]). An association ergic neurotransmission, there are also negative was also found between T. gondii antibody titers studies, which found comparable seroprevalence and history of suicide attempts in patients with rates for all screened autoantibodies including schizophrenia [32]. Furthermore, the increased food-derived antigens in healthy and ill individuals rate of infections may also contribute to the well [37,30]. This heterogeneous picture of autoantibody established positive association between auto- results has been shown in serum as well as in CSF. immune diseases and schizophrenia according to Besides these changes in the adaptive immune Benros et al. [33] who showed in their nationwide system, signs of inflammatory processes – primarily Danish register study an increased risk for auto- reflecting chronic low-grade inflammation and immune diseases [incidence rate ratio of 1.53 (95% changed regulative immune mechanisms – have confidence interval, CI ¼ 1.46–1.62)] in persons been presented in numerous publications over dec- with schizophrenia. In individuals with hospital ades. In this context, a huge body of literature about contacts because of infections as well as psychosis, changed blood levels of pro/anti-inflammatory before receiving an autoimmune diagnosis, the cytokines, chemokines, neurotrophic factors and combined risk of autoimmune diseases was 2.70 acute-phase proteins is available [38&&,39,40]. There (95% CI ¼ 2.51–2.89). As already known from are also hints that some of these peripheral immune previous investigations, a family history of schizo- activation markers can be influenced by antipsy- phrenia slightly increased the overall risk of devel- chotic medication [41–43]. A meta-analysis of cyto- oping autoimmune diseases (incidence rate kine changes in first-onset drug-naı¨ve schizophrenia ratio ¼ 1.06, 95% CI ¼ 1.02–1.09). The co-occur- patients compared with matched healthy controls rence of schizophrenia and autoimmune diseases found that the levels of interleukin-1RA, interleu- might be based on shared risk genes and genetic kin-10 and interleukin-15 were significantly higher variants related to the MHC region. Vice versa, in patients across the cohorts [44&]. These data may psychological stress and effects of medical treat- also indicate a special role of the Th2-type immune ment, for example antipsychotic medication, response in the pathogenesis of schizophrenia. After could also contribute to autoimmune disease treatment with atypical antipsychotics, levels of activity. To better understand the genetic overlap, interleukin-1RA and interleukin-10 were decreased. a comparison between schizophrenia and three Interestingly, changes in interleukin-10 levels sig- immune disorders (type 1 diabetes, rheumatoid nificantly correlated with improvements of psycho- arthritis and Crohn’s disease) and a comparison pathology. These results suggest alterations of pro- between schizophrenia and two primarily not and anti-inflammatory response mechanisms. immune-related diseases (bipolar disorder and Decreased interleukin-10 levels possibly implicated type 2 diabetes) was done by performing a poly- in the negative syndrome and cognitive impairment genic risk score analysis [34]. The genetic liability at the acute stage of schizophrenia have also been for schizophrenia significantly predicted disease described by another group [45]. status of all three immune disorders. This implied A study that is however based on a rather that immune disorder patients showed an small sample size tried to perform a comprehensive increased genetic risk of schizophrenia compared correlation between inflammatory markers and psy- with population-based controls. The genetic over- chopathology and demonstrated decreased levels of lap of schizophrenia with immune disorders was interferon-g and interleukin-2 levels and significant 1%, and of schizophrenia with bipolar disorder associations between psychopathological scores and 6%. various cytokines such as G-CSF, interleukin-1b,

0951-7367 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. www.co-psychiatry.com 203 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Schizophrenia and related disorders interleukin-1RA, interleukin-3, interleukin-6, inter- and the results supported the concept of immuno- leukin-9, interleukin-10, sCD40L and tumor logical crosstalk between periphery and intrathecal necrosis factor-b. Statistical analyses of immune immunity [51]. Cerebral inflammatory processes pathways further revealed that these cytokines are are not only shown on the transcriptome level in involved in the interleukin-17/Th17 pathway, post-mortem studies [52,53], as already mentioned which is known to be part of the immune defense above, but increased proinflammatory cytokines against extracellular bacteria and some fungi and have also been reported in CSF of schizophrenia play a major role in the pathogenesis of several patients [54]. Regarding cell components, microglia autoimmune and inflammatory disorders [46]. In representing the equivalent of monocytes in the a group of drug-naive first-episode patients an acti- brain has found to be involved in immune activation of Th17 cells, which seemed to be associated vation in CNS. Interestingly, microglia can express with therapeutic response after risperidone has also the endogenous NMDA glutamate receptor agonist been observed recently [47]. Regarding peripheral quinolinic acid (QUIN). Very recently in a study of immune cells, summarized data point at raised schizophrenia patients, CSF interleukin-6 and monocyte inflammatory activation pattern together kynurenine and kynurenic acid (KYNA) – both with reduced numbers and reduced proliferation downstream metabolites of tryptophan – were ana- activity of circulating lymphocytes, in particular T lyzed. Results revealed a correlation between inter- cells. Previously published studies have reported leukin-6 and the tryptophan/KYNA ratio, indicating T-cell aberrancies in relation to disease status and that interleukin-6 interferes with the KYN pathway in relation to treatment effects, for example a higher [55]. These findings are in line with earlier studies ratio between T-helper cells and T-cytotoxic cells indicating that a shift in the kynurenine pathway (CD4/CD8) in acutely relapsed schizophrenia towards enhanced KYNA formation might be patients with a decrease after antipsychotic treat- involved in the pathophysiology of schizophrenia. ment and absolute numbers of natural killer cells Furthermore, the CSF QUIN/KYNA ratio was found (CD56) appeared to be a trait marker, as levels to be lower in patients than in controls, supporting significantly increased following antipsychotic the production of KYNA over QUIN [56&]. A semi- therapy [48]. Interleukin-2, which is mainly pro- quantitative assessment of QUIN-immunoreactive duced by T cells after interaction of MHC/antigen/ microglial cells in the hippocampus demonstrated T-cell receptor, induces effector T- and B-cells devel- reduced cells in schizophrenia postmortem tissues opment and leads to activation and proliferation compared with controls [57]. Taking together the of natural killer cells. Comparing schizophrenia inflammatory influences on the tryptophan/kynur- patients and healthy controls, lower levels of enine pathway, an impaired glutaminergic neuro- Th1-type cytokine interleukin-2 were found and transmission might be considered relevant in the were associated with negative symptoms and cog- pathophysiological processes of schizophrenia. nitive deficits [49]. This finding could relate again From the data, it seems that a shift away from QUIN to a suppressed Th1-type immunity because of toward KYNA may represent a consequence of a shift ongoing activation of Th2-type immune response. toward Th2-type immunity away from Th1. Besides Despite the numerous immunological findings influences on the kynurenine pathway, inflamma- in patients with schizophrenia, it is important to tory mechanisms might have also implications on emphasize that pathophysiologically relevant the dopaminergic neurotransmission. It has been immune alterations might only be present in a shown that inflammatory cytokines can change subgroup. With a multiplex immunoassay analysis, enzymatic activity of the phenylalanine hydroxyl- acutely ill antipsychotic-naive patients have been ase, which catalyzes the conversion of phenyl- divided in two distinct subgroups by using either alanine to tyrosine, both precursor amino acids immune molecules or growth factors and hor- required for the synthesis of dopamine. In a com- mones. Such subgroup identification by means of parison between 950 schizophrenia patients and molecular abnormalities might be interesting for 1000 healthy controls, plasma levels of phenyl- clinical treatment as well as for a better character- alanine and phenylalanine/tyrosine ratio have been ization of this heterogeneous disorder [50]. found elevated, whereas tyrosine did not differ The pathophysiological relevance of peripheral between both groups [8&]. Oxidative stress was dis- immune alterations reflecting the situation in CNS cussed earlier to slow down phenylalanine has been discussed contradictory in the past, but a hydroxylase (PAH) activity when it contributes to recent study used multiplex ELISA to compare an accelerated breakdown of BH4. As a consequence, inflammatory cytokines in serum and CSF of the biosynthesis of downstream metabolites DOPA, patients with different neuropsychiatric disorders adrenaline and noradrenaline and thus supply of related to inflammation including schizophrenia, the neurotransmitters are disturbed.

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Elevated levels of plasma & phenylalanine in schizophrenia: a guanosine triphosphate cyclohydrolase-1 changed neurotransmitter metabolisms, which metabolic pathway abnormality? PLoS One 2014; 9:e85945. This study explains a possible role of phenylalanine and tyrosine in relation to result in neurodevelopmental/neurodegenerative inflammation and pathophysiologic mechansisms in schizophrenia. alterations yielding to the heterogenous clinical 9. Hwang Y, Kim J, Shin JY, et al. Gene expression profiling by mRNA sequencing reveals increased expression of immune/inflammation-related genes in symptoms of schizophrenia. Immune alterations the hippocampus of individuals with schizophrenia. Transl Psychiatry 2013; in schizophrenia may reflect underlying pathophy- 3:e321. doi:10.1038/tp.2013.94. siological mechanisms at least for a subgroup of 10. Corvin A, Morris DW. Genome-wide association studies: findings at the major && histocompatibility complex locus in psychosis. 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