Immune Activation In Schizophrenia Research Articles

Toll-Like Receptor mRNA Levels in Schizophrenia: Association With Complement Factors and Cingulate Gyrus Cortical Thinning.

Previous studies revealed innate immune system activation in people with schizophrenia (SZ), potentially mediated by endogenous pathogen recognition receptors, notably Toll-like receptors (TLR). TLRs are activated by pathogenic molecules like bacterial lipopolysaccharides (TLR1 and TLR4), viral RNA (TLR3), or both (TLR8). Furthermore, the complement system, another key component of innate immunity, has previously been linked to SZ. Peripheral mRNA levels of TLR1, TLR3, TLR4, and TLR8 were compared between SZ and healthy controls (HC). We investigated their relationship with immune activation through complement expression and cortical thickness of the cingulate gyrus, a region susceptible to immunological hits. TLR mRNA levels and peripheral complement receptor mRNA were extracted from 86 SZ and 77 HC white blood cells; structural MRI scans were conducted on a subset. We found significantly higher TLR4 and TLR8 mRNA levels and lower TLR3 mRNA levels in SZ compared to HC. TLRs and complemental factors were significantly associated in SZ and HC, with the strongest deviations of TLR mRNA levels in the SZ subgroup having elevated complement expression. Cortical thickness of the cingulate gyrus was inversely associated with TLR8 mRNA levels in SZ, and with TLR4 and TLR8 levels in HC. The study underscores the role of innate immune activation in schizophrenia, indicating a coordinated immune response of TLRs and the complement system. Our results suggest there could be more bacterial influence (based on TLR 4 levels) as opposed to viral influence (based on TLR3 levels) in schizophrenia. Specific TLRs were associated with brain cortical thickness reductions of limbic brain structures.

Association of structural changes of the brain with systemic immune activation in schizophrenia

The goal of this work was to investigate the associations between IL-17A levels and structural MRI findings to clarify immune factors of pathogenesis and search for biomarkers of unfavorable disease course. 45 patients with schizophrenia and 30 healthy volunteers were enrolled into the study. The levels of cytokines (IL-1β, IL-4, IL-6, IL-8, IL-17A) and inflammatory markers were determined by ELISA. MRI scans were performed on a Siemens Magnetom Verio 3T MRI scanner. It was found that elevated levels of cytokine IL-17A are associated with morphometric changes in the frontal cortex, signs of systemic inflammation and Th2 activation of the adaptive immune system in the patients. These findings make an important contribution to understanding the role of immune disorders in the pathogenesis of schizophrenia, including brain structure disorders, and indicate that IL-17A may be a biomarker of these disorders. Confirmation of correlations between structural neuroimaging and markers of inflammation may provide the basis for new interdisciplinary approaches to the diagnosis and prognosis of schizophrenia.

A loss of mature microglial markers without immune activation in schizophrenia.

Microglia, the immune cells of the brain, are important for neurodevelopment and have been hypothesized to play a role in the pathogenesis of schizophrenia (SCZ). Although previous postmortem studies pointed toward presence of microglial activation, this view has been challenged by more recent hypothesis‐driven and hypothesis‐free analyses. The aim of the present study is to further understand the observed microglial changes in SCZ. We first performed a detailed meta‐analysis on studies that analyzed microglial cell density, microglial morphology, and expression of microglial‐specific markers. We then further explored findings from the temporal cortex by performing immunostainings and qPCRs on an additional dataset. A random effect meta‐analysis showed that the density of microglial cells was unaltered in SCZ (ES: 0.144 95% CI: 0.102 to 0.390, p = .250), and clear changes in microglial morphology were also absent. The expression of several microglial specific genes, such as CX3CR1, CSF1R, IRF8, OLR1, and TMEM119 was decreased in SCZ (ES: −0.417 95% CI: −0.417 to −0.546, p < .0001), consistent with genome‐wide transcriptome meta‐analysis results. These results indicate a change in microglial phenotype rather than density, which was validated with the use of TMEM119/Iba1 immunostainings on temporal cortex of a separate cohort. Changes in microglial gene expression were overlapping between SCZ and other psychiatric disorders, but largely opposite from changes reported in Alzheimer's disease. This distinct microglial phenotype provides a crucial molecular hallmark for future research into the role of microglia in SCZ and other psychiatric disorders.

The Role of the Nuclear Factor-κB Transcriptional Complex in Cortical Immune Activation in Schizophrenia

BackgroundTranscript levels for cytokines and the viral restriction factor interferon-induced transmembrane protein are markedly higher in the prefrontal cortex in schizophrenia. These gene products are regulated by the nuclear factor-κB (NF-κB) transcriptional complex. NF-κB activity, which requires the formation of NF-κB family member heterodimers, is regulated by activation receptors, kinases, and inhibitors. Whether any of these factors are altered in schizophrenia is not known. It is also unclear whether NF-κB-related disturbances reflect ongoing cortical immune activation or a long-lasting response to a prenatal immune-related insult. MethodsTranscript levels for NF-κB pathway markers were assessed using quantitative polymerase chain reaction in the prefrontal cortex from 1) 62 matched pairs of schizophrenia and unaffected comparison subjects, 2) antipsychotic-exposed monkeys, and 3) adult mice exposed prenatally to maternal immune activation or in adulthood to the immune stimulant polyinosinic-polycytidylic acid. ResultsIn schizophrenia subjects, but not antipsychotic-exposed monkeys, we found higher messenger RNA levels for 1) most NF-κB family members, 2) all NF-κB activation receptors, 3) several kinases, and 4) one inhibitor (IκBα) whose transcript level is itself regulated by NF-κB activity. A similar pattern of elevated NF-κB-related messenger RNA levels was seen in adult mice that received daily polyinosinic-polycytidylic acid injections, but not in adult mice subjected to maternal immune activation in utero. ConclusionsHigher NF-κB activity, evidenced by elevated transcript levels for NF-κB family members, activation receptors, and kinases, may contribute to increased markers of cortical immune activation in schizophrenia.

Molecular mechanisms and timing of cortical immune activation in schizophrenia.

Immune-related abnormalities are commonly reported in schizophrenia, including higher mRNA levels for the viral restriction factor interferon-induced transmembrane protein (IFITM) in the prefrontal cortex. The authors sought to clarify whether higher IFITM mRNA levels and other immune-related disturbances in the prefrontal cortex are the consequence of an ongoing molecular cascade contributing to immune activation or the reflection of a long-lasting maladaptive response to an in utero immune-related insult. Quantitative polymerase chain reaction was employed to measure mRNA levels for immune-related cytokines and transcriptional regulators, including those reported to regulate IFITM expression, in the prefrontal cortex from 62 schizophrenia and 62 healthy subjects and from adult mice exposed prenatally to maternal immune activation or in adulthood to the immune stimulant poly(I:C). Schizophrenia subjects had markedly higher mRNA levels for interleukin 6 (IL-6) (+379%) and interferon-β (+29%), which induce IFITM expression; lower mRNA levels for Schnurri-2 (-10%), a transcriptional inhibitor that lowers IFITM expression; and higher mRNA levels for nuclear factor-κB (+86%), a critical transcription factor that mediates cytokine regulation of immune-related gene expression. In adult mice that received daily poly(I:C) injections, but not in offspring with prenatal exposure to maternal immune activation, frontal cortex mRNA levels were also markedly elevated for IFITM (+304%), multiple cytokines including IL-6 (+493%), and nuclear factor-κB (+151%). These data suggest that higher prefrontal cortex IFITM mRNA levels in schizophrenia may be attributable to adult, but not prenatal, activation of multiple immune markers and encourage further investigation into the potential role of these and other immune markers as therapeutic targets in schizophrenia.

Inflammation: its role in schizophrenia and the potential anti-inflammatory effects of antipsychotics

Over the last few years, inflammation has made a major comeback as a pathogenic theory of schizophrenia. Its effects on monoamine metabolism, neuroendocrine function, and synaptic plasticity have all been proposed as potential pathways mediating the link between inflammation and schizophrenia (Haroon et al. 2012). Further support for a link between activation of the immune system and schizophrenia is seen in this month's issue of Psychopharmacology, where Song et al. report high levels of interleukin (IL)1β, IL6 and tumour necrosis factor (TNF)α in drug naive-first episode schizophrenia patients when compared with healthy controls matched for age, gender, smoking status, and bodymass index (Song et al. 2013). These findings extend a growing body of literature on inflammation in schizophrenia by giving a better insight on longitudinal changes in cytokine levels in the context of treatment with antipsychotics. Recent reviews and meta-analysis of the literature show that increased blood levels of IL1β, IL6 and TNFα are consistently reported in patients at the onset of this disorder (Di Nicola et al. 2013; Miller et al. 2011; Mondelli et al. 2011). However, how much of these peripheral abnormalities reflect central inflammation and contribute to the development of schizophrenia remains still debated. Indeed, while the evidence of increased peripheral immune activation in schizophrenia has become more consistent over the years, the presence of a neuroinflammatory state in these patients has been the object of more controversy. Post-mortem studies in subjects with schizophrenia have reported mixed findings, possibly in relation also to some methodological issues; most postmortem studies have been conducted on relatively small samples, included mainly elderly subjects in whom incidental lesions are common, and have used different methods for counting astrocytes and microglia (Schnieder and Dwork 2011). Nevertheless, more recent studies quantifying microglia activation in vivo, by using positron emission tomography, have reported increased microglia activation (Doorduin et al. 2009; van Berckel et al. 2008) supporting the role of neuroinflammation in the pathophysiology of schizophrenia. Interestingly, cytokine abnormalities differ between acute and stable phases of schizophrenia, suggesting either that some cytokines could be influenced by antipsychotic treatment or that these differences may reflect different stages of illness (Miller et al. 2011). Studies on the effect of antipsychotic treatment on inflammation, and more specifically on cytokine levels, have so far given mixed findings, showing an increase, a decrease, or unchanged levels of cytokines after antipsychotic treatment (reviewed by Zajkowska and Mondelli 2013). One potential explanation for the mixed findings is that antipsychotic agents might exert different effects on the immune system, having both a direct antiinflammatory activity and an indirect pro-inflammatory activity, mediated by their effect on weight-gain and increased adiposity. Interestingly, this dual antiand pro-inflammatory action of antipsychotics is supported by the longitudinal study from Song et al., who observed a decrease in IL1β and IL6 levels in the first weeks of treatment with risperidone, followed by an increase back to baseline levels by the end of 6 months treatment, which happened alongside a steady weight gain (Song et al. 2013). The findings suggest that when V. Mondelli Institute of Psychiatry, Department of Psychological Medicine, King’s College London, London, UK

Gastrointestinal inflammation and associated immune activation in schizophrenia

Immune factors are implicated in normal brain development and in brain disorder pathogenesis. Pathogen infection and food antigen penetration across gastrointestinal barriers are means by which environmental factors might affect immune-related neurodevelopment. Here, we test if gastrointestinal inflammation is associated with schizophrenia and therefore, might contribute to bloodstream entry of potentially neurotropic milk and gluten exorphins and/or immune activation by food antigens. IgG antibodies to Saccharomyces cerevisiae (ASCA, a marker of intestinal inflammation), bovine milk casein, wheat-derived gluten, and 6 infectious agents were assayed. Cohort 1 included 193 with non-recent onset schizophrenia, 67 with recent onset schizophrenia and 207 non-psychiatric controls. Cohort 2 included 103 with first episode schizophrenia, 40 of whom were antipsychotic-naïve. ASCA markers were significantly elevated and correlated with food antigen antibodies in recent onset and non-recent onset schizophrenia compared to controls (p≤0.00001–0.004) and in unmedicated individuals with first episode schizophrenia compared to those receiving antipsychotics (p≤0.05–0.01). Elevated ASCA levels were especially evident in non-recent onset females (p≤0.009), recent onset males (p≤0.01) and in antipsychotic-naïve males (p≤0.03). Anti-food antigen antibodies were correlated to antibodies against Toxoplasma gondii, an intestinally-infectious pathogen, particularly in males with recent onset schizophrenia (p≤0.002). In conclusion, gastrointestinal inflammation is a relevant pathology in schizophrenia, appears to occur in the absence of but may be modified by antipsychotics, and may link food antigen sensitivity and microbial infection as sources of immune activation in mental illness.

Serum levels of IL-6, IL-10 and TNF-&amp;#945; in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance

OBJECTIVE: Previous reports suggest that cytokines act as potential mediators of the interaction between the immune and neuroendocrine systems, and that a proinflammatory state may be associated with bipolar disorder and schizophrenia. The aim is to compare cytokine levels in both disorders. METHOD: Twenty euthymic bipolar disorder patients, 53 chronic stabilized schizophrenia patients and 80 healthy controls were recruited. Subjects were all non-smokers and non-obese. Cytokines TNF-α, IL-6, and IL-10 were examined by sandwich ELISA. RESULTS: IL-6 levels were increased in schizophrenia patients when compared to controls (p < 0.0001) and euthymic bipolar disorder patients (p < 0.0001). IL-6 levels were no different in controls compared to euthymic bipolar disorder patients (p = 0.357). IL-10 was lower in controls compared to schizophrenia patients (p = 0.001) or to bipolar disorder patients (p = 0.004). There was no significant difference in TNF-α serum levels among the groups (p = 0.284). Gender-based classification did not significantly alter these findings, and no correlation was found between the antipsychotic dose administered and cytokine levels in patients with schizophrenia. DISCUSSION: These findings evidence a chronic immune activation in schizophrenia. Bipolar disorder seems to present an episode-related inflammatory syndrome. Increased anti-inflammatory factor IL-10 in bipolar disorder and schizophrenia suggests different patterns of inflammatory balance between these two disorders. Results further support the need to investigate cytokines as possible biomarkers of disease activity or treatment response.

Increased annexin-V and decreased TNF-alpha serum levels in chronic-medicated patients with schizophrenia

Schizophrenia (SZ) is a chronic severe mental disorder. Increased inflammatory processes have been shown in acute and chronic SZ. Apoptotic processes may alter the neuronal network and are involved in the pathogenesis of several neurodegenerative diseases, such as SZ. Annexin-V seems to have a role on inhibition of pro-inflammatory activities during apoptosis. Tumor necrosis factor (TNF-alpha) is a cytokine involved in systemic inflammation and is a member of a group of cytokines which stimulate acute phase reactions. A chronic immune activation in SZ has been shown. The aim of this study was to compare annexin-V and TNF-alpha serum levels in chronic medicated patients with SZ and healthy controls. Thirty-eight outpatients from the HCPA Schizophrenia Program and 38 healthy controls were enrolled to this study protocol. Annexin-V and TNF-alpha serum levels were measured with ELISA. Serum annexin-V levels were significantly higher in patients with SZ than in controls (p<0.001) and TNF-alpha significantly lower (p<0.001). The present result of increased annexin-V and decreased serum levels of TNF-alpha compared to controls may be a result of the stabilization phase of psychosis and a reduction in metabolic brain aggression. In this complex picture, increased levels of annexin-V and decreased levels of TNF-alpha in our sample would be explained by illness stability and chronic treatment. Our findings support the hypothesis of a state dependant process of inflammation in SZ. Further prospective studies to clarify the findings described in this paper are needed.

Serum levels of IL-6, IL-10 and TNF-α in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance

Previous reports suggest that cytokines act as potential mediators of the interaction between the immune and neuroendocrine systems, and that a proinflammatory state may be associated with bipolar disorder and schizophrenia. The aim is to compare cytokine levels in both disorders. Twenty euthymic bipolar disorder patients, 53 chronic stabilized schizophrenia patients and 80 healthy controls were recruited. Subjects were all non-smokers and non-obese. Cytokines TNF-α, IL-6, and IL-10 were examined by sandwich ELISA. IL-6 levels were increased in schizophrenia patients when compared to controls (p < 0.0001) and euthymic bipolar disorder patients (p < 0.0001). IL-6 levels were no different in controls compared to euthymic bipolar disorder patients (p = 0.357). IL-10 was lower in controls compared to schizophrenia patients (p = 0.001) or to bipolar disorder patients (p = 0.004). There was no significant difference in TNF-α serum levels among the groups (p = 0.284). Gender-based classification did not significantly alter these findings, and no correlation was found between the antipsychotic dose administered and cytokine levels in patients with schizophrenia. These findings evidence a chronic immune activation in schizophrenia. Bipolar disorder seems to present an episode-related inflammatory syndrome. Increased anti-inflammatory factor IL-10 in bipolar disorder and schizophrenia suggests different patterns of inflammatory balance between these two disorders. Results further support the need to investigate cytokines as possible biomarkers of disease activity or treatment response.

Analysis of peripheral immune activation in schizophrenia using quantitative reverse-transcription polymerase chain reaction (RT-PCR)

Immune system abnormalities in schizophrenia include a shift from a Type 1 (cellular) to a Type 2 (humoral) immune response. To characterize the activation status of the immune system in schizophrenia, we examined the pattern of gene expression in peripheral blood cells for three Th1 cytokines (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2)), and one Th2 cytokine (interleukin-10 (IL-10)). In a cross-sectional study, we used quantitative reverse-transcription polymerase chain reaction (RT-PCR) to compare the mRNA levels of IFN-γ, TNF-α, IL-2, and IL-10 in peripheral blood mononuclear cells (PBMCs) between 15 schizophrenia patients and 15 matched healthy controls. Expression of IFN-γ and TNF-α was significantly reduced in patients with schizophrenia compared with normal controls. No differences in IL-2 and IL-10 gene expression were observed. These results are consistent with impaired Type 1 cellular immunity in schizophrenia. While the data illustrate the potential utility of mRNA-based approaches for the identification and analysis of immune biomarkers for neuropsychiatric disorders, correlation of gene expression with direct measures of cytokine concentrations is required.

Indicators of chronic immune activation in schizophrenia

An abstract is not available for this content so a preview has been provided. As you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

A comprehensive macrophage-T-lymphocyte theory of schizophrenia

Chronic macrophage activation with subsequent failure of activated macrophages to properly control T-lymphocyte secretion of interleukin-2 and interleukin-2 receptors is proposed as the basic biological mechanism of schizophrenia. Fundamental to this theory are the clinical observations on interluekin-2 provoking the active phase symptoms of schizophrenia in psychiatrically normal human volunteers and macrophage cytokines producing the prodromal and residual phase symptoms. This theory provides a completely new and unified mechanism for the antipsychotic action of typical and atypical neuroleptics, bromocriptine, naloxone and DMSO. Furthermore, this hypothesis reveals why the dopamine theory of schizophrenia was a false lead. The effects of prolactin, estrogens and androgens are consistent with the model. Age of onset, male/female incidence, course of the disease from prodromal to active to residual phase, the protection afforded by rheumatoid arthritis and the close relationship between depression and schizophrenia can be explained by this theory. The gastrointestinal tract is suggested as the preferred site to investigate for the cause of the immune activation in schizophrenia.