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Episode-specific differential gene expression of peripheral blood mononuclear cells in rapid cycling supports novel treatment approaches.

ABSTRACT: Molecular mechanisms underlying bipolar affective disorders are unknown. Difficulties arise from genetic and phenotypic heterogeneity of patients and the lack of animal models. Thus, we focused on only one patient (n = 1) with an extreme form of rapid cycling. Ribonucleic acid (RNA) from peripheral blood mononuclear cells (PBMC) was analyzed in a three-tiered approach under widely standardized conditions. Firstly, RNA was extracted from PBMC of eight blood samples, obtained on two consecutive days within one particular episode, including two different consecutive depressive and two different consecutive manic episodes, and submitted to (1) screening by microarray hybridizations, followed by (2) detailed bioinformatic analysis, and (3) confirmation of episode-specific regulation of genes by quantitative real-time polymerase chain reaction (qRT-PCR).Secondly, results were validated in additional blood samples obtained one to two years later. Among gene transcripts elevated in depressed episodes were prostaglandin D synthetase (PTGDS) and prostaglandin D2 11-ketoreductase (AKR1C3), both involved in hibernation. We hypothesized them to account for some of the rapid cycling symptoms. A subsequent treatment approach over 5 months applying the cyclooxygenase inhibitor celecoxib (2 x 200 mg daily) resulted in reduced severity rating of both depressed and manic episodes. This case suggests that rapid cycling is a systemic disease, resembling hibernation, with prostaglandins playing a mediator role.

SUBMITTER: Begemann M

PROVIDER: S-EPMC2424319 | biostudies-literature | 2008 Sep-Oct

REPOSITORIES: biostudies-literature

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Episode-specific differential gene expression of peripheral blood mononuclear cells in rapid cycling supports novel treatment approaches.

Begemann Martin M Sargin Derya D Rossner Moritz J MJ Bartels Claudia C Theis Fabian F Wichert Sven P SP Stender Nike N Fischer Benjamin B Sperling Swetlana S Stawicki Sabina S Wiedl Anne A Falkai Peter P Nave Klaus-Armin KA Ehrenreich Hannelore H

Molecular medicine (Cambridge, Mass.) 20080901 9-10

Molecular mechanisms underlying bipolar affective disorders are unknown. Difficulties arise from genetic and phenotypic heterogeneity of patients and the lack of animal models. Thus, we focused on only one patient (n = 1) with an extreme form of rapid cycling. Ribonucleic acid (RNA) from peripheral blood mononuclear cells (PBMC) was analyzed in a three-tiered approach under widely standardized conditions. Firstly, RNA was extracted from PBMC of eight blood samples, obtained on two consecutive da ...[more]

PMID: 18552976

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Project description:BackgroundAltered expression of transcription factor specificity protein 4 (SP4) has been found in the postmortem brain of patients with psychiatric disorders including schizophrenia and bipolar disorder. Reduced levels of SP4 protein have recently been reported in peripheral blood mononuclear cells in first-episode psychosis. Also, SP4 levels are modulated by lithium treatment in cultured neurons. Phosphorylation of SP4 at S770 is increased in the cerebellum of bipolar disorder subjects and upon inhibition of NMDA receptor signaling in cultured neurons. The aim of this study was to investigate whether SP4 S770 phosphorylation is increased in lymphocytes of first-episode psychosis patients and the effect of lithium treatment on this phosphorylation.MethodsA cross-sectional study of S770 phosphorylation relative to total SP4 immunoreactivity using specific antibodies in peripheral blood mononuclear cells in first-episode psychosis patients (n = 14, treated with lithium or not) and matched healthy controls (n = 14) by immunoblot was designed. We also determined the effects of the prescribed drugs lithium, olanzapine or valproic acid on SP4 phosphorylation in rat primary cultured cerebellar granule neurons.ResultsWe found that SP4 S770 phosphorylation was significantly increased in lymphocytes in first-episode psychosis compared to controls and decreased in patients treated with lithium compared to patients who did not receive lithium. Moreover, incubation with lithium but not olanzapine or valproic acid reduced SP4 phosphorylation in rat cultured cerebellar granule neurons.ConclusionsThe findings presented here indicate that SP4 S770 phosphorylation is increased in lymphocytes in first-episode psychosis which may be reduced by lithium treatment in patients. Moreover, our study shows lithium treatment prevents this phosphorylation in vitro in neurons. This pilot study suggests that S770 SP4 phosphorylation could be a peripheral biomarker of psychosis, and may be regulated by lithium treatment in first-episode psychosis.

Project description:IntroductionIn sarcoidosis, peripheral lymphopenia and anergy have been associated with increased inflammation and maladaptive immune activity, likely promoting development of chronic and progressive disease. However, the molecular mechanisms that lead to reduced lymphocyte proportions, particularly CD4+ T-cells, have not been fully elucidated. We posit that paradoxical peripheral lymphopenia is characterized by a dysregulated transcriptomic network associated with cell function and fate that results from altered transcription factor targeting activity.MethodsMessenger RNA-sequencing (mRNA-seq) was performed on peripheral blood mononuclear cells (PBMCs) from ACCESS study subjects with sarcoidosis and matched controls and findings validated on a sarcoidosis case-control cohort and a sarcoidosis case series. Preserved PBMC transcriptomic networks between case-control cohorts were assessed to establish cellular associations with gene modules and define regulatory targeting involved in sarcoidosis immune dysregulation utilizing weighted gene co-expression network analysis and differential transcription factor involvement analysis. Network centrality measures identified master transcriptional regulators of subnetworks related to cell proliferation and death. Predictive models of differential PBMC proportions constructed from ACCESS target gene expression corroborated the relationship between aberrant transcription factor regulatory activity and imputed and clinical PBMC populations in the validation cohorts.ResultsWe identified two unique and preserved gene modules significantly associated with sarcoidosis immune dysregulation. Strikingly, increased expression of a monocyte-driven, and not a lymphocyte-driven, gene module related to innate immunity and cell death was the best predictor of peripheral CD4+ T-cell proportions. Within the gene network of this monocyte-driven module, TLE3 and CBX8 were determined to be master regulators of the cell death subnetwork. A core gene signature of differentially over-expressed target genes of TLE3 and CBX8 involved in cellular communication and immune response regulation accurately predicted imputed and clinical monocyte expansion and CD4+ T-cell depletion.ConclusionsAltered transcriptional regulation associated with aberrant gene expression of a monocyte-driven transcriptional network likely influences lymphocyte function and survival. Although further investigation is warranted, this indicates that crosstalk between hyperactive monocytes and lymphocytes may instigate peripheral lymphopenia and underlie sarcoidosis immune dysregulation and pathogenesis. Future therapies selectively targeting master regulators, or their targets, may mitigate dysregulated immune processes in sarcoidosis and disease progression.

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Episode-specific differential gene expression of peripheral blood mononuclear cells in rapid cycling supports novel treatment approaches.

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Episode-specific differential gene expression of peripheral blood mononuclear cells in rapid cycling supports novel treatment approaches.

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