HERV-W upregulation expression in bipolar disorder and schizophrenia: unraveling potential links to systemic immune/inflammation status.

BACKGROUND: Bipolar disorder (BD) and schizophrenia (SZ) are the two main mental disorders with unknown etiology that significantly impact individuals' quality of life. The potential pro-inflammatory role in their pathogenesis is postulated and Human Endogenous Retrovirus W (HERV-W) is an emerging candidate to modulate this pathogenic finding. HERVs, ancient retroviruses in the human genome, may play roles in inflammation and disease pathogenesis. Despite HERVs' involvement in autoimmune diseases, their influence on mental disorders remains underexplored. Therefore, the aim of this study was to assess the level of HERV-W-env expression and the systemic inflammatory profile through the concentration of IL-2, IL-4, IL-6, IL-10, TNF-α and INF-γ cytokines in BD and SZ patients. RESULTS: All participants showed HERV-W-env expression, but its expression was higher in mental disorder patients (p < 0.01) than in control. When separated, SZ individuals exhibited higher HERV-W expression than the control group (p < 0.01). Higher serum levels of TNF-α and IL-10 were found in BD (p = 0.0001 and p = 0.001, respectively) and SZ (p = 0.01) and p = 0.01, respectively) than in the control group, while SZ showed decreased levels IFN-γ and IL-2 as compared to controls (p = 0.05) and BD patients (p = 0.05), respectively. Higher TNF-α/IL-4 and TNF-α/IL-10 ratios, and lower IFN-γ/IL-10 were observed in BD and SZ patients than controls. Significant negative correlation between HERV-W-env expression and IL-10 (r=-0.47 p < 0.05), as well as positive correlations between HERV-W-env expression and TNF-α/IL-10 or IFN-γ/IL-10 ratios (r = 0.48 p < 0.05 and r = 0.46 p < 0.05, respectively) were found in BD patients. CONCLUSION: These findings suggest not only a potential link between HERV-W-env expression both in BD and SZ, but also a possible involvement of systemic inflammatory status in BD patients.

Cognition-immune interactions between executive function and working memory, tumour necrosis factor-alpha (TNF-alpha) and soluble TNF receptors (sTNFR1 and sTNFR2) in bipolar disorder.

OBJECTIVES: This study examined cognition-immune interactions, specifically executive function, working memory, peripheral levels of tumour necrosis factor-alpha (TNF-α), and soluble tumour necrosis factor receptors-1 and -2 (sTNFR1 and 2) levels in bipolar disorder (BD) patients in comparison with controls. METHODS: Thirty-one BD participants and twenty-seven controls participated in the study. The neurocognitive assessment was performed through three of CogState Research BatteryTM tasks for executive function and working memory. Plasma levels of TNF-α, sTNFR1, and sTNFR2 were measured after overnight fasting. Sociodemographic data and symptom severity of depression and mania were assessed. RESULTS: BD presented a significantly worse performance in the working memory task (p = .005) and higher levels of TNF-α (p = .043) in comparison to controls. A trend level of significance was found for sTNFR1 between groups (p = .082). Among BD participants, there were significant correlations between sTNFR2 and neurocognitive tasks (Groton Maze Learning Task: ρ = .54, p = .002; Set-Shifting Task: ρ = .37, p = .042; and the Two-Back Task: ρ = -.49, p = .005), and between sTNFR1 and mania, depression and anxiety symptoms (respectively ρ = .37, p = .038; ρ = -.38, p = .037; and ρ = .42, p = .002). CONCLUSION: TNF-α and its receptors might be an important variable in cognitive impairment in BD. Future studies might focus on the development of anti-inflammatory therapeutic targets for cognitive dysfunction in BD.

HLA-E circulating and genetic determinants in schizophrenia and bipolar disorder.

Schizophrenia (SZ) and bipolar disorders (BD) are severe mental illnesses that lack reliable biomarkers to guide diagnosis and management. As immune dysregulation is associated with these disorders, we utilized the immunoregulatory functions of the natural killer cell inhibitory HLA-E locus to investigate the relationships between HLA-E genetic and expression diversities with SZ and BD risk and severity. Four hundred and forty-four patients meeting DSM-IV criteria for SZ (N = 161) or BD (N = 283) were compared to 160 heathy controls (HC). Circulating levels of the soluble isoform of HLA-E molecules (sHLA-E) were measured and HLA-E*01:01 and HLA-E*01:03 variants genotyped in the whole sample. sHLA-E circulating levels were significantly higher in both SZ and in BD patients compared to HC (pc < 0.0001 and pc = 0.0007 for SZ and BD, respectively). High sHLA-E levels were also observed in stable SZ patients and in acute BD patients experiencing depressive episodes when comparisons were made between the acute and stable subgroups of each disorder. sHLA-E levels linearly increased along HLA-E genotypes (p = 0.0036). In conclusion, HLA-E variants and level may have utility as diagnostic biomarkers of SZ and BD. The possible roles of HLA diversity in SZ and BD etiology and pathophysiology are discussed.

Tryptophan Catabolites in Bipolar Disorder: A Meta-Analysis.

Objective: Tryptophan catabolites (TRYCATs) are implicated in the pathophysiology of mood disorders by mediating immune-inflammation and neurodegenerative processes. We performed a meta-analysis of TRYCAT levels in bipolar disorder (BD) patients compared to healthy controls. Methods: A systematic literature search in seven electronic databases (PubMed, Embase, Web of Science, Cochrane, Emcare, PsycINFO, Academic Search Premier) was conducted on TRYCAT levels in cerebrospinal fluid or peripheral blood according to the PRISMA statement. A minimum of three studies per TRYCAT was required for inclusion. Standardized mean differences (SMD) were computed using random effect models. Subgroup analyses were performed for BD patients in a different mood state (depressed, manic). The methodological quality of the studies was rated using the modified Newcastle-Ottawa Quality assessment Scale. Results: Twenty-one eligible studies were identified. Peripheral levels of tryptophan (SMD = -0.44; p < 0.001), kynurenine (SMD = - 0.3; p = 0.001) and kynurenic acid (SMD = -.45; p = < 0.001) were lower in BD patients versus healthy controls. In the only three eligible studies investigating TRP in cerebrospinal fluid, tryptophan was not significantly different between BD and healthy controls. The methodological quality of the studies was moderate. Subgroup analyses revealed no significant difference in TRP and KYN values between manic and depressed BD patients, but these results were based on a limited number of studies. Conclusion: The TRYCAT pathway appears to be downregulated in BD patients. There is a need for more and high-quality studies of peripheral and central TRYCAT levels, preferably using longitudinal designs.

Inflammatory signaling mechanisms in bipolar disorder.

Bipolar disorder is a decidedly heterogeneous and multifactorial disease, with a high individual and societal burden. While not all patients display overt markers of elevated inflammation, significant evidence suggests that aberrant immune signaling contributes to all stages of the disease, and likely explains the elevated rates of comorbid inflammatory illnesses seen in this population. While individual systems have been intensely studied and targeted, a relative paucity of attention has been given to the interconnecting role of inflammatory signals therein. This review presents an updated overview of some of the most prominent pathophysiologic mechanisms in bipolar disorder, from mitochondrial, endoplasmic reticular, and calcium homeostasis, to purinergic, kynurenic, and hormonal/neurotransmitter signaling, showing inflammation to act as a powerful nexus between these systems. Several areas with a high degree of mechanistic convergence within this paradigm are highlighted to present promising future targets for therapeutic development and screening.

A pilot study indicating the dysregulation of the complement and coagulation cascades in treated schizophrenia and bipolar disorder patients.

A better understanding of the proteome profile after bipolar disorder (BD) and schizophrenia (SCZ) treatment, besides monitoring disease progression, may assist on the development of novel therapeutic strategies with the ability to reduce or control possible side effects. In this pilot study, proteomics analysis employing nano liquid chromatography coupled to mass spectrometry (nLC-MS) and bioinformatic tools were applied to identify differentially abundant proteins in serum of treated BD and SCZ patients. In total, 10 BD patients, 10 SCZ patients, and 14 healthy controls (HC) were included in this study. 24 serum proteins were significantly altered (p < 0.05) in BD and SCZ treated patients and, considering log2FC > 0.58, 8 proteins presented lower abundance in the BD group, while 7 proteins presented higher abundance and 2 lower abundance in SCZ group when compared against HC. Bioinformatics analysis based on these 24 proteins indicated two main altered pathways previously described in the literature; furthermore, it revealed that opposite abundances of the complement and coagulation cascades were the most significant biological processes involved in these pathologies. Moreover, we describe disease-related proteins and pathways associations suggesting the necessity of clinical follow-up improvement besides treatment, as a precaution or safety measure, along with the disease progression. Further biological validation and investigations are required to define whether there is a correlation between complement and coagulation cascade expression for BD and SCZ and cardiovascular diseases.

COVID-19 patient transcriptomic and genomic profiling reveals comorbidity interactions with psychiatric disorders.

Psychiatric symptoms are seen in some COVID-19 patients, as direct or indirect sequelae, but it is unclear whether SARS-CoV-2 infection interacts with underlying neuronal or psychiatric susceptibilities. Such interactions might arise from COVID-19 immune responses, from infection of neurons themselves or may reflect social-psychological causes. To clarify this we sought the key gene expression pathways altered in COVID-19 also affected in bipolar disorder, post-traumatic stress disorder (PTSD) and schizophrenia, since this may identify pathways of interaction that could be treatment targets. We performed large scale comparisons of whole transcriptome data and immune factor transcript data in peripheral blood mononuclear cells (PBMC) from COVID-19 patients and patients with psychiatric disorders. We also analysed genome-wide association study (GWAS) data for symptomatic COVID-19 patients, comparing GWAS and whole-genome sequence data from patients with bipolar disorder, PTSD and schizophrenia patients. These studies revealed altered signalling and ontology pathways shared by COVID-19 patients and the three psychiatric disorders. Finally, co-expression and network analyses identified gene clusters common to the conditions. COVID-19 patients had peripheral blood immune system profiles that overlapped with those of patients with psychiatric conditions. From the pathways identified, PTSD profiles were the most highly correlated with COVID-19, perhaps consistent with stress-immune system interactions seen in PTSD. We also revealed common inflammatory pathways that may exacerbate psychiatric disorders, which may support the usage of anti-inflammatory medications in these patients. It also highlights the potential clinical application of multi-level dataset studies in difficult-to-treat psychiatric disorders in this COVID-19 pandemic.

Bipolar disorder: An evolutionary psychoneuroimmunological approach.

Bipolar disorder is a mental health disorder characterized by extreme shifts in mood, high suicide rate, sleep problems, and dysfunction of psychological traits like self-esteem (feeling inferior when depressed and superior when manic). Bipolar disorder is rare among populations that have not adopted contemporary Western lifestyles, which supports the hypothesis that bipolar disorder results from a mismatch between Homo sapiens's evolutionary and current environments. Recent studies have connected bipolar disorder with low-grade inflammation, the malfunctioning of the internal clock, and the resulting sleep disturbances. Stress is often a triggering factor for mania and sleep problems, but stress also causes low-grade inflammation. Since inflammation desynchronizes the internal clock, chronic stress and inflammation are the primary biological mechanisms behind bipolar disorder. Chronic stress and inflammation are driven by contemporary Western lifestyles, including stressful social environments, unhealthy dietary patterns, limited physical activity, and obesity. The treatment of bipolar disorder should focus on reducing stress, stress sensitivity, and inflammation by lifestyle changes rather than just temporarily alleviating symptoms with psychopharmacological interventions.

Construction of a nitro-oxidative stress-driven, mechanistic model of mood disorders: A nomothetic network approach.

Major depression is accompanied by increased IgM-mediated autoimmune responses to oxidative specific epitopes (OSEs) and nitric oxide (NO)-adducts. These responses were not examined in bipolar disorder type 1 (BP1) and BP2. IgM responses to malondialdehyde (MDA), phosphatidinylinositol, oleic acid, azelaic acid, and NO-adducts were determined in 35 healthy controls, and 47 major depressed (MDD), 29 BP1, and 25 BP2 patients. We also measured serum peroxides, IgG to oxidized LDL (oxLDL), and IgM/IgA directed to lipopolysaccharides (LPS). IgM responses to OSEs and NO-adducts (OSENO) were significantly higher in MDD and BP1 as compared with controls, and IgM to OSEs higher in MDD than in BP2. Partial Least Squares (PLS) analysis showed that 57.7% of the variance in the clinical phenome of mood disorders was explained by number of episodes, a latent vector extracted from IgM to OSENO, IgG to oxLDL, and peroxides. There were significant specific indirect effects of IgA/IgM to LPS on the clinical phenome, which were mediated by peroxides, IgM OSENO, and IgG oxLDL. Using PLS we have constructed a data-driven nomothetic network which ensembled causome (increased plasma LPS load), adverse outcome pathways (namely neuro-affective toxicity), and clinical phenome features of mood disorders in a data-driven model. Based on those feature sets, cluster analysis discovered a new diagnostic class characterized by increased plasma LPS load, peroxides, autoimmune responses to OSENO, and increased phenome scores. Using the new nomothetic network approach, we constructed a mechanistically transdiagnostic diagnostic class indicating neuro-affective toxicity in 74.3% of the mood disorder patients.

New Evidence of Gut Microbiota Involvement in the Neuropathogenesis of Bipolar Depression by TRANK1 Modulation: Joint Clinical and Animal Data.

Tetratricopeptide repeat and ankyrin repeat containing 1 (TRANK1) is a robust risk gene of bipolar disorder (BD). However, little is known on the role of TRANK1 in the pathogenesis of BD and whether the gut microbiota is capable of regulating TRANK1 expression. In this study, we first investigated the serum mRNA level of TRANK1 in medication-free patients with a depressive episode of BD, then a mice model was constructed by fecal microbiota transplantation (FMT) to explore the effects of gut microbiota on brain TRANK1 expression and neuroinflammation, which was further verified by in vitro Lipopolysaccharide (LPS) treatment in BV-2 microglial cells and neurons. 22 patients with a depressive episode and 28 healthy individuals were recruited. Serum level of TRANK1 mRNA was higher in depressed patients than that of healthy controls. Mice harboring 'BD microbiota' following FMT presented depression-like phenotype. mRNA levels of inflammatory cytokines and TRANK1 were elevated in mice hippocampus and prefrontal cortex. In vitro, LPS treatment activated the secretion of pro-inflammatory factors in BV-2 cells, which was capable of upregulating the neuronal expression of TRANK1 mRNA. Moreover, primary cortical neurons transfected with plasmid Cytomegalovirus DNA (pcDNA3.1(+)) vector encoding human TRANK1 showed decreased dendritic spine density. Together, these findings add new evidence to the microbiota-gut-brain regulation in BD, indicating that microbiota is possibly involved in the neuropathogenesis of BD by modulating the expression of TRANK1.

High-Sensitive c-Reactive Protein Levels in Euthymic Bipolar Patients: Case-Control Study.

Bipolar disorder is a chronic, disabling disease that is characterized by the recurrence of thymic episodes. The role of the immune-inflammatory system in the etiopathogenesis of this affection arouses the interest of research. The aim of this work was to determine the plasma levels of the high sensitivity C reactive protein (hs-CRP) in patients with bipolar disorder in remission phase by comparing them to a control group.A case-control cross-sectional study was conducted from 56 subjects with bipolar disorder in clinical remission, and 56 volunteers and healthy control subjects.Mean plasma hs-CRP was significantly higher in patients with bipolar disorder than control subjects. In bipolar patients, a hs-CRP elevation was significantly associated with the disease severity item mean score.Through this study, bipolar disorder appears to be associated with a state of chronic inflammation. This should lead to randomized controlled trials evaluating the value of anti-inflammatory drugs in the management of bipolar disorder.

Impairments in Peripheral Blood T Effector and T Regulatory Lymphocytes in Bipolar Disorder Are Associated with Staging of Illness and Anti-cytomegalovirus IgG Levels.

There is now evidence that, based on cytokine profiles, bipolar disorder (BD) is accompanied by simultaneous activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS), and that both components may be associated with the staging of illness. Nevertheless, no BD studies have evaluated the IRS/CIRS ratio using CD (cluster of differentiation) molecules expressed by peripheral blood activated T effector (Teff) and T regulatory (Treg) subpopulations. This study examined Teff/Treg subsets both before and after ex vivo anti-CD3/CD28 stimulation using flow cytometric immunophenotyping in 25 symptomatic remitted BD patients and 21 healthy controls and assessed human cytomegalovirus (HCMV)-specific IgG antibodies. BD is associated with a significantly lowered frequency of unstimulated CD3 + CD8 + CD71+ and CD4 + CD25 + FOXP3 and increased CD4 + CD25 + FOXP3 + CD152+ frequencies and with lowered stimulated frequencies of CD3 + CD8 + CD71+, CD4 + CD25 + FOXP3 + CD152+, and CD4 + CD25 + FOXP3 + GARP cells and, consequently, by an increased stimulated Teff/Treg ratio. Moreover, the number of manic, but not hypomanic or depressive episodes, is significantly and negatively associated with the stimulated proportions of CD3 + CD4 + CD154+, and CD69+ and CD71+ expression on CD4+ and CD8+ cells, while duration of illness (≥ 10 years) is accompanied by a depleted frequency of stimulated CD152+ Treg, and CD154+ and CD71+ CD4+ T cells. BD and anti-human cytomegalovirus (HCMV) IgG levels significantly interact to decrease the expression of CD4 + CD25 + FOXP+GARP T phenotypes. In conclusion, in BD patients, immune injuries, staging, and HCMV seropositivity interact and cause CIRS dysfunctions and exaggerated IRS responses, which play a key role in parainflammation and neuroaffective toxicity. HCMV seropositivity contributes to an immune-risk phenotype in BD.

Lateralization of increased density of Iba1-immunopositive microglial cells in the anterior midcingulate cortex of schizophrenia and bipolar disorder.

There is increasing evidence from genetic, biochemical, pharmacological, neuroimaging and post-mortem studies that immunological dysregulation plays a crucial role in the pathogenesis of psychoses. The involvement of microglia in schizophrenia and bipolar disorder (BD) has remained controversial, however, since results from various post-mortem studies are still inconclusive. Here, we analyzed the estimated density of microglia of age-matched individuals with schizophrenia (n = 17), BD (n = 13), and non-psychiatric control subjects (n = 17) in the anterior midcingulate cortex (aMCC), a brain area putatively involved in the pathogenesis of psychoses, using ionized calcium binding adaptor molecule 1 (Iba1)-immunohistochemistry. The microglial cells displayed a homogenously distributed Iba1-staining pattern in the aMCC with slightly varying activation states in all three groups. The estimated microglial densities did not differ significantly between individuals with schizophrenia, BD and control subjects. Remarkably, when both hemispheres were investigated separately within the three groups, the density was significantly lateralized towards the right aMCC in schizophrenia (p = 0.01) and-even more evident-in BD subjects (p = 0.008). This left-right lateralization was not observed in the control group (p = 0.52). Of note, microglial density was significantly lower in BD individuals who did not commit suicide compared with BD individuals who died from suicide (p = 0.002). This difference was not observed between individuals with BD who committed suicide and controls. The results, tentatively interpreted, suggest a hitherto unknown increased lateralization of microglial density to the right hemisphere in both psychiatric groups. If confirmed in independent samples, lateralization should be considered in all post-mortem studies on microglia. Density differences between suicide and non-suicide individuals needs further elucidation.

A comparison study of metabolic profiles, immunity, and brain gray matter volumes between patients with bipolar disorder and depressive disorder.

BACKGROUND: Previous individual studies have shown the differences in inflammatory cytokines and gray matter volumes between bipolar disorder (BD) and unipolar depression (UD). However, few studies have investigated the association between pro-inflammatory cytokines and differences in brain gray matter volumes between BD and UD. METHODS: In this study, 72 BD patients and 64 UD patients were enrolled, with comparable gender and age distributions (33.8% males and an average age of 39.3 ± 13.7 years). Each participant underwent metabolic profiling (including body mass index (BMI), glucose, triglyceride, high-density lipoprotein (HDL), leptin, insulin, adiponectin), pro-inflammatory cytokine (including soluble interleukin-6 receptor (sIL-6R), soluble interleukin-2 receptor (sIL-2R), C-reactive protein (CRP), soluble tumor necrosis factor receptor type 1 (sTNF-R1) examinations, and structural magnetic resonance imaging exams. Voxel-based morphometry was performed to investigate the gray matter volume differences between BD and UD patients. Correlations between pro-inflammatory cytokines and the gray matter volume difference were analyzed. RESULTS: Compared to UD patients, the BD group had significantly higher BMI, and higher levels of sIL-6R and sTNF-R1 than the UD patients. The BMI significantly correlated with the level of pro-inflammatory cytokines. Adjusted for age, sex, BMI, duration of illness and total intracranial volume, the BD individuals had significantly more reduced gray matter volumes over 12 areas: R. cerebellar lobule VIII, R. putamen, L. putamen, R. superior frontal gyrus, L. lingual gyrus, L. precentral gyrus, R. fusiform gyrus, L. calcarine, R. precuneus, L. inferior temporal gyrus, L. hippocampus, and L. superior frontal gyrus. These 12 gray matter volume differences between BP and UD patients negatively correlated with sIL-6R and sTNF-R1 levels. CONCLUSIONS: Our results suggested that BD patients had higher BMI and pro-inflammatory cytokine levels in comparison to UD patients, especially IL-6 and sTNF-R1, which may contribute to greater gray matter reductions in BD patients in comparison to UD patients. The results support the neuro-inflammation pathophysiology mechanism in mood disorder. It is clinically important to monitor BMI, which, in this investigation, positively correlated with levels of inflammatory cytokines.

A mood state-specific interaction between kynurenine metabolism and inflammation is present in bipolar disorder.

OBJECTIVES: Cytokines are thought to contribute to the pathogenesis of psychiatric symptoms by kynurenine pathway activation. Kynurenine metabolites affect neurotransmission and can cause neurotoxicity. We measured inflammatory markers in patients with bipolar disorder (BD) and studied their relation to kynurenine metabolites and mood. METHODS: Patients with BD suffering from an acute mood episode were assigned to the depressive (n = 35) or (hypo)manic (n = 32) subgroup. Plasma levels of inflammatory markers [cytokines, C-reactive protein] and kynurenine metabolites [tryptophan (TRP), kynurenine (KYN), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KYNA)] were measured on 6 time points during 8 months follow-up. Biological marker levels in patients were compared to controls (n = 35) and correlated to scores on mood scales. Spearman correlations and linear mixed models were used for statistical analysis. RESULTS: Twenty patients of the manic subgroup, 29 of the depressive subgroup, and 30 controls completed the study. The manic subgroup had a rapid remission of mood symptoms, but in the depressive subgroup subsyndromal symptoms persisted. No differences in inflammation were found between groups. A strong correlation between tumor necrosis factor-α and KYN, KYN/TRP, 3-HK and QA (ρ > 0.60) was specific for the manic group, but only at baseline (during mania). The depressive subgroup had a lower neuroprotective ratio (KYNA/3-HK, P = .0004) and a strong association between interferon-y and kynurenine pathway activation (P < .0001). KYNA was low in both patient groups versus controls throughout the whole follow-up (P = .0008). CONCLUSIONS: Mania and chronic depressive symptoms in BD are accompanied by a strong interaction between inflammation and a potentially neurotoxic kynurenine metabolism.

Postmortem evidence of brain inflammatory markers in bipolar disorder: a systematic review.

Bipolar disorder (BD) is a chronic affective disorder with extreme mood swings that include mania or hypomania and depression. Though the exact mechanism of BD is unknown, neuroinflammation is one of the numerous investigated etiopathophysiological causes of BD. This article presents a systematic review of the data regarding brain inflammation evaluating microglia, astrocytes, cytokines, chemokines, adhesion molecules, and other inflammatory markers in postmortem BD brain samples. This systematic review was performed according to PRISMA recommendations, and relevant studies were identified by searching the PubMed/MEDLINE, PsycINFO, EMBASE, LILACS, IBECS, and Web of Science databases for peer-reviewed journal articles published by March 2019. Quality of included studies appraised using the QUADAS-2 tool. Among the 1814 articles included in the primary screening, 51 articles measured inflammatory markers in postmortem BD brain samples. A number of studies have shown evidence of inflammation in BD postmortem brain samples. However, an absolute statement cannot be concluded whether neuroinflammation is present in BD due to the large number of studies did not evaluate the presence of infiltrating peripheral immune cells in the central nervous system (CNS) parenchyma, cytokines levels, and microglia activation in the same postmortem brain sample. For example, out of 15 studies that evaluated microglia cells markers, 8 studies found no effect of BD on these cells. Similarly, 17 out of 51 studies evaluating astrocytes markers, 9 studies did not find any effect of BD on astrocyte cells, whereas 8 studies found a decrease and 2 studies presented both increase and decrease in different brain regions. In addition, multiple factors account for the variability across the studies, including postmortem interval, brain area studied, age at diagnosis, undergoing treatment, and others. Future analyses should rectify these potential sources of heterogeneity and reach a consensus regarding the inflammatory markers in postmortem BD brain samples.

Host-parasite interaction associated with major mental illness.

Clinical studies frequently report that patients with major mental illness such as schizophrenia and bipolar disorder have co-morbid physical conditions, suggesting that systemic alterations affecting both brain and peripheral tissues might underlie the disorders. Numerous studies have reported elevated levels of anti-Toxoplasma gondii (T. gondii) antibodies in patients with major mental illnesses, but the underlying mechanism was unclear. Using multidisciplinary epidemiological, cell biological, and gene expression profiling approaches, we report here multiple lines of evidence suggesting that a major mental illness-related susceptibility factor, Disrupted in schizophrenia (DISC1), is involved in host immune responses against T. gondii infection. Specifically, our cell biology and gene expression studies have revealed that DISC1 Leu607Phe variation, which changes DISC1 interaction with activating transcription factor 4 (ATF4), modifies gene expression patterns upon T. gondii infection. Our epidemiological data have also shown that DISC1 607 Phe/Phe genotype was associated with higher T. gondii antibody levels in sera. Although further studies are required, our study provides mechanistic insight into one of the few well-replicated serological observations in major mental illness.