Peripheral immuno-inflammatory abnormalities in ultra-high risk of developing psychosis

Zeni-Graiff, Maiara; Rizzo, Lucas B.; Mansur, Rodrigo B.; Maurya, Pawan Kumar; Sethi, Sumit; Cunha, Graccielle R.; Asevedo, Elson; Pan, Pedro Mário; Zugman, André; Yamagata, Ana S.; Higuchi, Cinthia Hiroko; Bressan, Rodrigo A.; Gadelha, Ary; Brietzke, Elisa

doi:10.1016/j.schres.2016.06.031

Cited by 51 publications

(34 citation statements)

References 35 publications

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“…This observation supports the previously expressed idea that Th17 cells have a role beyond combating infection and the development of autoimmunity, namely, in contributing to the development of SSD (Debnath and Berk, 2014). In line with our results, increased Th17 proportions have been reported in drug naïve first episode schizophrenia patients and in recent onset schizophrenia patients (12; Zeni-Graiff et al, 2016). Opposite results have also been published, yet not on the cellular level, but on the circulating levels of IL-17, the primary cytokine produced by activated Th17 cells: Zeni-Graiff et al (Noto et al, 2015) found decreased levels of IL-17, in children at ultra-high risk for psychosis.…”

Section: Discussionsupporting

confidence: 93%

A pilot study on immuno-psychiatry in the 22q11.2 deletion syndrome: A role for Th17 cells in psychosis?

Vergaelen

Schiweck

Steeland

et al. 2018

Brain, Behavior, and Immunity

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Background: A growing body of evidence supports a role for immune alterations in Schizophrenia Spectrum Disorders (SSD). A high prevalence (25–40%) of SSD has been found in patients with 22q11.2 deletion syndrome (22q11.2DS), which is known for T-cell deficits due to thymus hypoplasia. This study is the first to explore the association between the T-cell subsets and psychotic symptoms in adults with 22q11.2DS. Methods: 34 individuals (aged 19–38 yrs.) with 22q11.2DS and 34 healthy age- and gender matched control individuals were included. FACS analysis of the blood samples was performed to define T-cell subsets. Ultra-high risk for psychosis or diagnosis of SSD was determined based on CAARMS interviews and DSM-5 criteria for SSD. Positive psychotic symptom severity was measured based on the PANSS positive symptoms subscale. Results: A partial T-cell immune deficiency in 22q11.2DS patients was confirmed by significantly reduced percentages of circulating T and T-helper cells. Significantly higher percentages of inflammatory Th1, Th17, and memory T-helper cells were found in adults with 22q11.2DS. Most importantly an increased Th17 percentage was found in adults with psychotic symptoms as compared to non-psychotic adults with 22q11.2DS, and Th17 percentage were related to the presence of positive psychotic symptoms. Conclusions: Given the literature on the role of T cells and in particular of Th17 cells and IL-17 in hippocampus development, cognition and behavior, these results support the hypothesis for a role of Th17 cells in the development and/or regulation of psychotic symptoms in 22q11.2DS. This pilot study underlines the importance to further study the role of T-cell defects and of Th17 cells in the development of psychiatric symptoms. It also supports the possibility to use 22q11.2DS as a model to study T-cell involvement in the development of SSD.

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Section: Discussionsupporting

confidence: 93%

A pilot study on immuno-psychiatry in the 22q11.2 deletion syndrome: A role for Th17 cells in psychosis?

Vergaelen

Schiweck

Steeland

et al. 2018

Brain, Behavior, and Immunity

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“…Its primary role is the regulation of immune cells with biological functions of apoptotic cell death, and inhibition of tumorigenesis and viral replication. Dysregulation of TNF-α production may causes negative symptoms of psychosis and schizophrenia [66, 67]. Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors.…”

Section: Resultsmentioning

confidence: 99%

Epigenetic profiling of human brain differential DNA methylation networks in schizophrenia

Lee

Huang

2016

BMC Med Genomics

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BackgroundEpigenetics of schizophrenia provides important information on how the environmental factors affect the genetic architecture of the disease. DNA methylation plays a pivotal role in etiology for schizophrenia. Previous studies have focused mostly on the discovery of schizophrenia-associated SNPs or genetic variants. As postmortem brain samples became available, more and more recent studies surveyed transcriptomics of the diseases. In this study, we constructed protein-protein interaction (PPI) network using the disease associated SNP (or genetic variants), differentially expressed disease genes and differentially methylated disease genes (or promoters). By combining the different datasets and topological analyses of the PPI network, we established a more comprehensive understanding of the development and genetics of this devastating mental illness.ResultsWe analyzed the previously published DNA methylation profiles of prefrontal cortex from 335 healthy controls and 191 schizophrenic patients. These datasets revealed 2014 CpGs identified as GWAS risk loci with the differential methylation profile in schizophrenia, and 1689 schizophrenic differential methylated genes (SDMGs) identified with predominant hypomethylation. These SDMGs, combined with the PPIs of these genes, were constructed into the schizophrenic differential methylation network (SDMN). On the SDMN, there are 10 hypermethylated SDMGs, including GNA13, CAPNS1, GABPB2, GIT2, LEFTY1, NDUFA10, MIOS, MPHOSPH6, PRDM14 and RFWD2. The hypermethylation to differential expression network (HyDEN) were constructed to determine how the hypermethylated promoters regulate gene expression. The enrichment analyses of biochemical pathways in HyDEN, including TNF alpha, PDGFR-beta signaling, TGF beta Receptor, VEGFR1 and VEGFR2 signaling, regulation of telomerase, hepatocyte growth factor receptor signaling, ErbB1 downstream signaling and mTOR signaling pathway, suggested that the malfunctioning of these pathways contribute to the symptoms of schizophrenia.ConclusionsThe epigenetic profiles of DNA differential methylation from schizophrenic brain samples were investigated to understand the regulatory roles of SDMGs. The SDMGs interplays with SCZCGs in a coordinated fashion in the disease mechanism of schizophrenia. The protein complexes and pathways involved in SDMN may be responsible for the etiology and potential treatment targets. The SDMG promoters are predominantly hypomethylated. Increasing methylation on these promoters is proposed as a novel therapeutic approach for schizophrenia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-016-0229-y) contains supplementary material, which is available to authorized users.

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“…Khoury and Nasrallah (2018) reviewed 15 studies and found a possible role of plasma levels of IL-1β, IL-7, CXCL-8, matrix metalloproteinase (MMP)-8 and albumin as predictors of psychotic transition [83]. Other studies found higher IL-6 and lower IL-17 levels compared to healthy controls [84] and higher IL-6 levels when comparing who convert to psychosis with those who did not convert [85]. Kappelmann et al (2018) in a large population study with 638,213 men in Sweden found associations between erythrocyte sedimentation rate (ESR), a marker of low-grade inflammation, IQ, and subsequent psychosis, suggesting that inflammatory abnormalities may influence schizophrenia risk by affecting neurodevelopment [86].…”

Section: Irs and Cirs In Patients At High Risk For Psychosis And Firsmentioning

confidence: 99%

The Role of Aberrations in the Immune-inflammatory Reflex System (IRS) and the Compensatory Immune-regulatory Reflex System (CIRS) in Different Phenotypes of Schizophrenia: The IRS-CIRS Theory of Schizophrenia

Roomruangwong¹,

Noto²,

Kanchanatawan³

et al. 2018

Preprint

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In this paper we propose a novel theoretical framework, which was previously developed for major depression and bipolar disorder, namely the compensatory immune-regulatory reflex system (CIRS), as applied to the neuro-immune pathophysiology of schizophrenia and its phenotypes, including first episode psychosis (FEP), acute relapses, chronic and treatment resistant schizophrenia (TRS), comorbid depression, and deficit schizophrenia. These schizophrenia phenotypes and manifestations are accompanied by increased production of positive acute phase proteins, including haptoglobin and α2-macroglobulin, complement factors, and macrophagic M1 (IL-1β, IL-6 and TNF-α), T helper (Th)-1 (interferon-γ and IL-2R), Th-2 (IL-4, IL-5), Th-17 (IL-17) and T regulatory (Treg; IL-10 and transforming growth factor (TGF)-β1) cytokines, cytokine-induced activation of the tryptophan catabolite (TRYCAT) pathway as well as chemokines, including CCL-11 (eotaxin), CCL-2, CCL-3 and CXCL-8. While the immune profiles in the different schizophrenia phenotypes indicate activation of the immune-inflammatory response system (IRS), there are simultaneous signs of CIRS activation, including increased levels of the IL-1 receptor antagonist (sIL-1RA), sIL-2R and tumor necrosis factor-a receptors, Th-2 and Treg phenotypes with increased IL-4 and IL-10 production, and increased levels of TRYCATs and haptoglobin, α2-macroglobulin and other acute phase reactants, which have immune-regulatory and anti-inflammatory effects. Signs of activated IRS and CIRS pathways are also detected in TRS, chronic and deficit schizophrenia indicating that these conditions are accompanied by a new homeostatic setpoint between upregulated IRS and CIRS components. In FEP, increased baseline CIRS activity is a protective factor which may predict favorable clinical outcomes. Moreover, impairments in the CIRS are associated with deficit schizophrenia and greater impairments in semantic and episodic memory. It is concluded that CIRS plays a key role in the pathophysiology of schizophrenia by negatively regulating the primary IRS and contributing to recovery from the acute phase of illness. Components of the CIRS may offer promising therapeutic targets for schizophrenia.

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Peripheral immuno-inflammatory abnormalities in ultra-high risk of developing psychosis

Cited by 51 publications

References 35 publications

A pilot study on immuno-psychiatry in the 22q11.2 deletion syndrome: A role for Th17 cells in psychosis?

A pilot study on immuno-psychiatry in the 22q11.2 deletion syndrome: A role for Th17 cells in psychosis?

Epigenetic profiling of human brain differential DNA methylation networks in schizophrenia

The Role of Aberrations in the Immune-inflammatory Reflex System (IRS) and the Compensatory Immune-regulatory Reflex System (CIRS) in Different Phenotypes of Schizophrenia: The IRS-CIRS Theory of Schizophrenia

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