Anna Boyajyan

Classical pathway complement activity in schizophrenia

There is considerable evidence to suggest a role for complement in the pathogenesis of schizophrenia, but the data related to the classical pathway complement activity in patients with schizophrenia are conflicting. In the present study, the total hemolytic activity of the complement and the activities of individual complement components, C1, C2, C3 and C4, were determined in the blood serum of schizophrenic patients with positive family history of the disease and healthy subjects. In comparison to the healthy subjects, the mean values of the hemolytic activities of the C1, C3 and C4 complement components in the serum of the schizophrenic patients were significantly higher, and the mean value of the hemolytic activity of the C2 complement component was significantly lower. However, no significant difference was found between the mean values of the total hemolytic activity of complement in schizophrenic patients and healthy subjects. The C3 hemolytic activity was 2.17 times higher in medicated patients than in drug-free patients. Within each group examined no significant difference was found between smokers and non-smokers or between males and females. The results of this study suggest that the pathogenesis of schizophrenia is associated with alterations in activities of complement classical pathway components.

Interleukin-6 promoter polymorphism and plasma levels in patients with schizophrenia

Schizophrenia is a severe psychiatric disease with inflammatory component. Several studies indicated the increased blood levels of proinflammatory interleukin-6 cytokine in schizophrenia. However, only limited studies explored the relationship between excess production and genetic variations of this cytokine in schizophrenia, and the results were controversial. Here, we investigated possible association of the interleukin-6 gene (IL6) rs1800795 (-174G/C) polymorphism with schizophrenia and relationship between this polymorphism and interleukin-6 protein (IL-6) blood levels. This polymorphism was found by other researchers to associate with different transcription rates and different plasma levels of IL-6. A total of 208 unrelated Armenians were genotyped by polymerase chain reaction with sequence-specific primers, and IL-6 levels were assessed by enzyme-linked immunosorbent assay. The IL6 rs1800795 alleles and genotypes in both groups were in Hardy-Weinberg (H-W) equilibrium. We found that rs1800795*C allele [38% vs 24%, P = 0.002, odds ratio (OR) = 1.95, 95% confidence interval (CI): 1.18-2.14] and its carriers (62% vs 42%, P = 0.003, OR = 2.28, 95% CI: 1.13-1.94) were more frequent in patients than in controls. IL-6 in patients was 1.5-fold higher than in controls (mean ± SD: 6.41 ± 2.47 pg/ml vs 4.15 ± 1.42 pg/ml, P = 1.9E-19). In both groups, higher IL-6 in rs1800795 GG compared to rs1800795*C allele carriers was observed (GG vs GC + CC, patients: 7.02 ± 2.83 pg/ml vs 5.39 ± 1.2 pg/ml, P = 0.0006; controls: 5.21 ± 1.17 pg/ml vs 3.38 ± 1.03 pg/ml, P = 1.6E-15). In conclusion, we report an association of IL6 rs1800795 and higher IL-6 with schizophrenia. We also conclude that IL6 rs1800795*C allele is linked to increased IL-6 blood levels and may be a risk factor for schizophrenia development at least in Armenian population.

Inflammatory cytokine network in schizophrenia

Abstract Objectives. The purpose of this review is to analyse, sum up and discuss the available literature on the role of inflammation and inflammatory cytokines in the pathogenesis of schizophrenia. Methods. An electronic literature search of peer-reviewed English language articles using Pubmed was undertaken. These articles together with those published by us provided the background for the present review. Results. An overview of the available literature on this issue clearly demonstrated the alterations in mRNA and protein expression levels of several proinflammatory and chemotactic cytokines in patients with schizophrenia. Importantly, some of these changes are genetically determined. It was noteworthy that, depending on the study population, some variations of the data obtained are detected. Conclusions. Altered inflammatory cytokine production, both genetically and environmentally determined, is implicated in schizophrenia and contributes to disease-associated low-grade systemic inflammation. Proinflammatory and chemotactic cytokines and their receptors may represent additional therapeutic targets for treatment of schizophrenia.

Functional variants of the genes involved in neurodevelopment and susceptibility to schizophrenia in an Armenian population

Aberrant neurodevelopment contributes to the etiology of schizophrenia. This study aimed to investigate the potential association of netrin G1 (NTNG1) rs628117 and brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) genetic polymorphisms with susceptibility to schizophrenia. One hundred three Armenian patients with schizophrenia and 105 healthy control subjects were genotyped by polymerase chain reaction with sequence-specific primers. Whereas the NTNG1 rs628117 genotypes were equally distributed in the groups, the carriers of the less common BDNF 66Met allele were overrepresented among patients with schizophrenia when compared with healthy controls (55% vs 35%, odds ratio = 2.28, 95% confidence interval 1.14-1.98, p(corrected) = 0.006). Furthermore, the 66Met/Met genotype correlated with earlier disease onset (p = 0.024). In conclusion, our single-cohort study nominates the BDNF 66Met allele as a risk factor for schizophrenia in an Armenian population. This must be confirmed in other Armenian cohorts.

Alternative Complement Pathway in Schizophrenia

In the present study, we evaluated functional activity of the alternative pathway of complement in schizophrenia by measuring the alternative pathway hemolytic activity (AH50) of complement as well as hemolytic activity of the complement C3 component (C3H50) in the blood of patients with schizophrenia and healthy subjects. To assess the influence of neuroleptic treatment on measured parameters, both drug-free and medicated patients were examined. In addition, correlation analysis between AH50 and C3H50 has been performed. The results of the present study clearly demonstrate upregulation of the alternative complement cascade in schizophrenia and activator effect of neuroleptics on complement alternative pathway. Based upon the results obtained we hypothesize that hyperactivation of the alternative complement pathway in schizophrenia is stimulated by apoptotic cells.

Association of C1QB gene polymorphism with schizophrenia in Armenian population

BackgroundSchizophrenia is a complex, multifactorial psychiatric disorder. Our previous findings indicated that altered functional activity of the complement system, a major mediator of the immune response, is implicated in the pathogenesis of schizophrenia. In order to explore whether these alterations are genetically determined or not, in the present study we evaluated the possible association of complement C1Q component gene variants with susceptibility to schizophrenia in Armenian population, focusing on four frequent single nucleotide polymorphisms (SNPs) of C1QA and C1QB genes.MethodsIn the present study four SNPs of the complement C1Q component genes (C1QA: rs292001, C1QB rs291982, rs631090, rs913243) were investigated in schizophrenia-affected and healthy subjects. Unrelated Caucasian individuals of Armenian nationality, 225 schizophrenic patients and the same number of age- and sex-matched healthy subjects, were genotyped. Genotyping was performed using polymerase chain reaction with sequence-specific primers (PCR-SSP) and quantitative real-time (qRT) PCR methods.ResultsWhile there was no association between C1QA rs292001, C1QB rs913243 and rs631090 genetic variants and schizophrenia, the C1QB rs291982*G minor allele was significantly overrepresented in schizophrenic patients (G allele frequency 58%) when compared to healthy subjects (46%, OR = 1.64, pcorr = 0.0008). Importantly, the susceptibility for schizophrenia was particularly associated with C1QB rs291982 GG genotype (OR = 2.5, pcorrected = 9.6E-5).ConclusionsThe results obtained suggest that C1QB gene may be considered as a relevant candidate gene for susceptibility to schizophrenia, and its rs291982*G minor allele might represent a risk factor for schizophrenia at least in Armenian population. Replication in other centers/populations is necessary to verify this conclusion.

Functional characterization of the complement receptor type 1 and its circulating ligands in patients with schizophrenia

BackgroundWhereas the complement system alterations contribute to schizophrenia, complement receptors and regulators are little studied. We investigated complement receptor type 1 (CR1) expression on blood cells, the levels of circulating immune complexes (CIC) containing ligands of CR1, C1q complement protein and fragments of C3 complement protein (C1q-CIC, C3d-CIC), and CR1 C5507G functional polymorphism in schizophrenia patients and controls.ResultsWe found an increased C1q-CIC level and CR1 expression on blood cells, elevated number of CR1 positive erythrocytes and reduced number of CR1 positive lymphocytes and monocytes in patients compared to controls. No difference in the levels of C3d-CIC between groups was observed. Higher CR1 expression on erythrocytes in CC genotype versus CG+GG for both groups was detected, whereas no difference was observed for other cell populations. Our results indicated that schizophrenia is associated with the increased CR1 expression and C1q-CIC level.ConclusionsOur study for the first time indicated that schizophrenia is associated with the increased CR1 expression and C1q-CIC level. Further studies in other ethnic groups are needed to replicate these findings.

Complement C4B protein in schizophrenia

Partial and/or complete deficiency of the complement protein C4 is associated with autoimmune and infectious diseases. Infectious or autoimmune processes may have a role in schizophrenia. Previous reports suggest abnormalities in the complement C4B isotype in schizophrenia and other mental disorders. We assessed C4A and C4B isotypes and serum C4B protein concentration in Armenian schizophrenic patients. Although there was no difference in frequency of C4BQ0, C4B serum protein level was significantly decreased in the schizophrenic patients compared with healthy controls.

Activated phenotype of circulating neutrophils in familial Mediterranean fever

Familial Mediterranean fever (FMF) is autoinflammatory disorder, characterized by MEFV gene mutations and recurrent episodes of fever and serosal or synovial inflammation. Neutrophils are the predominant effector cells of acute inflammatory attacks in FMF; however pathogenic role and molecular phenotype of these cells remain largely unknown. To gain insight into the processes that contribute to the self-directed autoinflammation we characterized expression of a spectrum of genes involved in regulation of inflammation in unstimulated and LPS-activated neutrophils from FMF patients. Expression of 12 candidate immune genes encoding for inflammation-related molecules was assessed by quantitative RT-PCR in freshly isolated and LPS-stimulated peripheral polymorphonuclear neutrophils from fifteen FMF patients in attack-free period and ten healthy volunteers as controls. The relative expression was calculated using the second derivative method; the target gene expression was normalized to the expression of RPL32 gene. FMF neutrophils were characterized by up-regulated baseline gene expression of c-FOS (9.5-fold, p < 0.05), IL-8 (12-fold, p < 0.05), MMP9 (8-fold, p < 0.01), TLR2 (7-fold, p < 0.05) compared to the neutrophils from control subjects, a trend was also evident towards increased caspase-1 expression (3-fold, p = 0.09). Discriminant analysis clustered the patient and control subjects into two distinct groups (Wilkss lambda = 0.165, p = 0.042). Further, LPS-induced alterations of expression profiles were shared between FMF and healthy neutrophils, the profile consisting namely of up-regulated IL-1β, TLR4, IL-8, and TNFAIP6 transcripts. Present study demonstrates distinct expression patterns of pre-activated neutrophils during attack-free period of FMF when compared to neutrophils from healthy controls. Furthermore, our data emphasize the importance of host-derived ligands in activation of FMF neutrophils.

Brain-derived neurotrophic factor blood levels are decreased in schizophrenia patients and associate with rs6265 genotypes.

OBJECTIVES A growing number of studies implicate brain-derived neurotrophic factor (BDNF), an important promoter of synaptic transmission and neural plasticity, in the pathogenesis of schizophrenia. However, the existing data are controversial, that may reflect population differences between studied groups. DESIGN AND METHODS In the present study we performed a comparative analysis of BDNF plasma levels and its relation with rs6265 (G196A; Val66Met) polymorphism of BDNF gene (BDNF) in schizophrenia-affected and healthy subjects (controls) of the Armenian population. To check the influence of antipsychotics on BDNF plasma levels both medicated and non-medicated patients were involved in this study. Patients with paranoid form of schizophrenia chronically treated with typical antipsychotics (n=103), age- and sex-matched controls (n=105), and 25 antipsychotic-naive first-episode schizophrenia patients were involved. The levels of BDNF in the blood plasma were measured with a solid-phase enzyme-linked immunosorbent assay. RESULTS Decreased plasma levels of BDNF in both medicated and non-medicated schizophrenia patients compared to controls were observed. No significant difference in BDNF levels between medicated and non-medicated patients was detected. It was also detected that, compared to individuals homozygous for the standard allele (G/G) of rs6265, carriers of the rs6265 minor allele (A/G+A/A), which is significantly more frequent in schizophrenia patients than in controls, had decreased BDNF levels. CONCLUSIONS The data obtained suggested that the pathogenesis of schizophrenia is characterized by genetically predetermined decreased blood levels of BDNF. These results indicated that genetically determined alterations of neuroimmune modulators may be among the risk factors of schizophrenia and contribute to disease-specific pathologic changes in functional activity of both the neuronal synaptic plasticity and the immune system.