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

Background: Chronic fatigue syndrome (CFS) is a multisystem disease, the pathogenesis of which remains undetermined. Aims: To test the hypothesis that there are reproducible abnormalities of gene expression in patients with CFS compared with normal healthy persons. Methods: 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 ⩾ 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. Results: 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. Conclusion: These results suggest that patients with CFS have reproducible alterations in gene regulation.

[1]  Luis Carrasco,et al.  Cleavage of eIF4G by HIV‐1 protease: effects on translation , 2003, FEBS letters.

[2]  P. Sarnow,et al.  Enterovirus 71 contains a type I IRES element that functions when eukaryotic initiation factor eIF4G is cleaved. , 2003, Virology.

[3]  R. Moss,et al.  TNF-α and Chronic Fatigue Syndrome , 1999, Journal of Clinical Immunology.

[4]  D. Payan,et al.  Systematic identification of regulatory proteins critical for T-cell activation , 2003, Journal of biology.

[5]  Joseph A Maldjian,et al.  Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome , 1999, Journal of the Neurological Sciences.

[6]  B. Pedersen,et al.  [Chronic fatigue syndrome--a controlled cross-sectional study]. , 1994, Ugeskrift for laeger.

[7]  M. Tsang,et al.  Altered cytokine release in peripheral blood mononuclear cell cultures from patients with the chronic fatigue syndrome. , 1991, Cytokine.

[8]  R. Moss,et al.  TNF-alpha and chronic fatigue syndrome. , 1999, Journal of clinical immunology.

[9]  S. Wessely,et al.  Development of a fatigue scale. , 1993, Journal of psychosomatic research.

[10]  R. Cuesta,et al.  Adenovirus‐specific translation by displacement of kinase Mnk1 from cap‐initiation complex eIF4F , 2000, The EMBO journal.

[11]  Franco Cerrina,et al.  Gene expression analysis using oligonucleotide arrays produced by maskless photolithography. , 2002, Genome research.

[12]  J. Connor,et al.  Vesicular Stomatitis Virus Infection Alters the eIF4F Translation Initiation Complex and Causes Dephosphorylation of the eIF4E Binding Protein 4E-BP1 , 2002, Journal of Virology.

[13]  D. Haynes,et al.  Cytokine dysregulation in the post-Q-fever fatigue syndrome. , 1998, QJM : monthly journal of the Association of Physicians.

[14]  J. Darlix,et al.  Conducting the initiation of protein synthesis: the role of eIF4G , 2003, Biology of the cell.

[15]  T. Skern,et al.  The Processing of eIF4GI by Human Rhinovirus Type 2 2Apro: Relationship to Self-Cleavage and Role of Zinc , 2003, Journal of Virology.

[16]  C. Freund,et al.  Recognition Sequences for the GYF Domain Reveal a Possible Spliceosomal Function of CD2BP2* , 2004, Journal of Biological Chemistry.

[17]  M. Antoni,et al.  Cytokine and Other Immunologic Markers in Chronic Fatigue Syndrome and Their Relation to Neuropsychological Factors , 2001, Applied neuropsychology.

[18]  P. Low,et al.  Autonomic dysfunction in peripheral nerve disease , 2003, Muscle & nerve.

[19]  J. Ortín,et al.  PABP1 and eIF4GI associate with influenza virus NS1 protein in viral mRNA translation initiation complexes. , 2003, The Journal of general virology.

[20]  D. Tyrrell,et al.  Circulating tumour necrosis factor-alpha and interferon-gamma are detectable during acute and convalescent parvovirus B19 infection and are associated with prolonged and chronic fatigue. , 2001, The Journal of general virology.

[21]  Elizabeth R. Unger,et al.  Utility of the Blood for Gene Expression Profiling and Biomarker Discovery in Chronic Fatigue Syndrome , 2003, Disease markers.

[22]  K. Takase,et al.  [T cell activation]. , 1995, Ryumachi. [Rheumatism].

[23]  S. Burley,et al.  Recognition of eIF 4 G by Rotavirus NSP 3 Reveals a Basis for mRNA , 2006 .

[24]  M. Zamora,et al.  Generation of Multiple Isoforms of Eukaryotic Translation Initiation Factor 4GI by Use of Alternate Translation Initiation Codons , 2002, Molecular and Cellular Biology.

[25]  James M Barker,et al.  A case-control study to assess possible triggers and cofactors in chronic fatigue syndrome. , 1996, The American journal of medicine.

[26]  A. Chaudhuri,et al.  In vivo magnetic resonance spectroscopy in chronic fatigue syndrome. , 2004, Prostaglandins, leukotrienes, and essential fatty acids.

[27]  C. Staiger,et al.  The gelsolin family of actin regulatory proteins: modular structures, versatile functions , 2003, FEBS letters.

[28]  R. Lloyd,et al.  Cleavage of Poly(A)-Binding Protein by Poliovirus 3C Protease Inhibits Host Cell Translation: a Novel Mechanism for Host Translation Shutoff , 2004, Molecular and Cellular Biology.

[29]  D L Black,et al.  A new regulatory protein, KSRP, mediates exon inclusion through an intronic splicing enhancer. , 1997, Genes & development.

[30]  J. O'Callaghan.  Neurotoxic esterase: not so toxic? , 2003, Nature Genetics.

[31]  M. Pall,et al.  Elevated levels of protein carbonyls in sera of chronic fatigue syndrome patients , 2003, Molecular and Cellular Biochemistry.

[32]  M. Jouvenot,et al.  Expression of gec1/GABARAPL1 versus GABARAP mRNAs in human: predominance of gec1/GABARAPL1 in the central nervous system. , 2003, Brain research. Molecular brain research.

[33]  J. Mcleod,et al.  Autonomic Dysfunction in Peripheral Nerve Disease , 1993, Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society.

[34]  G Lewith,et al.  Identification of novel expressed sequences, up‐regulated in the leucocytes of chronic fatigue syndrome patients , 2003, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[35]  J. Chia,et al.  Diverse etiologies for chronic fatigue syndrome. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[36]  Rosane Nisenbaum,et al.  Integration of gene expression, clinical, and epidemiologic data to characterize Chronic Fatigue Syndrome , 2003, Journal of Translational Medicine.

[37]  S. Burley,et al.  Recognition of eIF4G by rotavirus NSP3 reveals a basis for mRNA circularization. , 2002, Molecular cell.

[38]  Ian Hickie,et al.  The Chronic Fatigue Syndrome: A Comprehensive Approach to Its Definition and Study , 1994, Annals of Internal Medicine.

[39]  M. S. van der Knaap,et al.  Leukoencephalopathy With Vanishing White Matter: From Magnetic Resonance Imaging Pattern to Five Genes , 2003, Journal of child neurology.

[40]  Rosane Nisenbaum,et al.  Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution , 2003, BMC health services research.

[41]  J. Connor,et al.  Vesicular Stomatitis Virus Infection Alters the eIF 4 F Translation Initiation Complex and Causes Dephosphorylation of the eIF 4 E Binding Protein 4 EBP 1 , 2002 .