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Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome.

ABSTRACT: Chronic fatigue syndrome (CFS) is a multisystem disease, the pathogenesis of which remains undetermined.To test the hypothesis that there are reproducible abnormalities of gene expression in patients with CFS compared with normal healthy persons.To gain further insight into the pathogenesis of this disease, gene expression was analysed in peripheral blood mononuclear cells from 25 patients with CFS diagnosed according to the Centers for Disease Control criteria and 25 normal blood donors matched for age, sex, and geographical location, using a single colour microarray representing 9522 human genes. After normalisation, average difference values for each gene were compared between test and control groups using a cutoff fold difference of expression > or = 1.5 and a p value of 0.001. Genes showing differential expression were further analysed using Taqman real time polymerase chain reaction (PCR) in fresh samples.Analysis of microarray data revealed differential expression of 35 genes. Real time PCR confirmed differential expression in the same direction as array results for 16 of these genes, 15 of which were upregulated (ABCD4, PRKCL1, MRPL23, CD2BP2, GSN, NTE, POLR2G, PEX16, EIF2B4, EIF4G1, ANAPC11, PDCD2, KHSRP, BRMS1, and GABARAPL1) and one of which was downregulated (IL-10RA). This profile suggests T cell activation and perturbation of neuronal and mitochondrial function. Upregulation of neuropathy target esterase and eukaryotic translation initiation factor 4G1 may suggest links with organophosphate exposure and virus infection, respectively.These results suggest that patients with CFS have reproducible alterations in gene regulation.

SUBMITTER: Kaushik N

PROVIDER: S-EPMC1770875 | biostudies-literature | 2005 Aug

REPOSITORIES: biostudies-literature

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Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome.

Kaushik N N Fear D D Richards S C M SC McDermott C R CR Nuwaysir E F EF Kellam P P Harrison T J TJ Wilkinson R J RJ Tyrrell D A J DA Holgate S T ST Kerr J R JR

Journal of clinical pathology 20050801 8

<h4>Background</h4>Chronic fatigue syndrome (CFS) is a multisystem disease, the pathogenesis of which remains undetermined.<h4>Aims</h4>To test the hypothesis that there are reproducible abnormalities of gene expression in patients with CFS compared with normal healthy persons.<h4>Methods</h4>To gain further insight into the pathogenesis of this disease, gene expression was analysed in peripheral blood mononuclear cells from 25 patients with CFS diagnosed according to the Centers for Disease Con ...[more]

PMID: 16049284

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Project description:Interferon-alpha (IFN-?) treatment for infectious disease and cancer causes high rates of depression and fatigue, and has been used to investigate the impact of inflammatory cytokines on brain and behavior. However, little is known about the transcriptional impact of chronic IFN-? on immune cells in vivo and its relationship to IFN-?-induced behavioral changes.Genome-wide transcriptional profiling was performed on peripheral blood mononuclear cells (PBMCs) from 21 patients with chronic hepatitis C virus (HCV) either awaiting IFN-? therapy (n=10) or at 12 weeks of IFN-? treatment (n=11).Significance analysis of microarray data identified 252 up-regulated and 116 down-regulated gene transcripts. Of the up-regulated genes, 2'-5'-oligoadenylate synthetase 2 (OAS2), a gene linked to chronic fatigue syndrome (CFS), was the only gene that was differentially expressed in patients with IFN-?-induced depression/fatigue, and correlated with depression and fatigue scores at 12 weeks (r=0.80, p=0.003 and r=0.70, p=0.017 respectively). Promoter-based bioinformatic analyses linked IFN-?-related transcriptional alterations to transcription factors involved in myeloid differentiation, IFN-? signaling, activator protein-1 (AP1) and cAMP responsive element binding protein/activation transcription factor (CREB/ATF) pathways, which were derived primarily from monocytes and plasmacytoid dendritic cells. IFN-?-treated patients with high depression/fatigue scores demonstrated up-regulation of genes bearing promoter motifs for transcription factors involved in myeloid differentiation, IFN-? and AP1 signaling, and reduced prevalence of motifs for CREB/ATF, which has been implicated in major depression.Depression and fatigue during chronic IFN-? administration were associated with alterations in the expression (OAS2) and transcriptional control (CREB/ATF) of genes linked to behavioral disorders including CFS and major depression, further supporting an immune contribution to these diseases.

Project description:BackgroundMyalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious and complex physical illness that affects all body systems with a multiplicity of symptoms, but key hallmarks of the disease are pervasive fatigue and 'post-exertional malaise', exacerbation after physical and/or mental activity of the intrinsic fatigue and other symptoms that can be highly debilitating and last from days to months. Although the disease can vary widely between individuals, common symptoms also include pain, cognitive deficits, sleep dysfunction, as well as immune, neurological and autonomic symptoms. Typically, it is a very isolating illness socially, carrying a stigma because of the lack of understanding of the cause and pathophysiology.MethodsTo gain insight into the pathophysiology of ME/CFS, we examined the proteomes of peripheral blood mononuclear cells (PBMCs) by SWATH-MS analysis in a small well-characterised group of patients and matched controls. A principal component analysis (PCA) was used to stratify groups based on protein abundance patterns, which clearly segregated the majority of the ME/CFS patients (9/11) from the controls. This majority subgroup of ME/CFS patients was then further compared to the control group.ResultsA total of 60 proteins in the ME/CFS patients were differentially expressed (P < 0.01, Log10 (Fold Change) > 0.2 and < -0.2). Comparison of the PCA selected subgroup of ME/CFS patients (9/11) with controls increased the number of proteins differentially expressed to 99. Of particular relevance to the core symptoms of fatigue and post-exertional malaise experienced in ME/CFS, a proportion of the identified proteins in the ME/CFS groups were involved in mitochondrial function, oxidative phosphorylation, electron transport chain complexes, and redox regulation. A significant number were also involved in previously implicated disturbances in ME/CFS, such as the immune inflammatory response, DNA methylation, apoptosis and proteasome activation.ConclusionsThe results from this study support a model of deficient ATP production in ME/CFS, compensated for by upregulation of immediate pathways upstream of Complex V that would suggest an elevation of oxidative stress. This study and others have found evidence of a distinct pathology in ME/CFS that holds promise for developing diagnostic biomarkers.

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Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome.

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Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome.

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