Chronic Fatigue Syndrome (post-infectious):
Clues In The Blood
Date: July 8, 2007
Science Daily — Researchers at UNSW believe that blood may hold vital insights into what is happening in the brain of patients with chronic fatigue syndrome (CFS).
In a study unparalleled in its scope, a team led by UNSW Professor Andrew Lloyd of the Centre for Infection and Inflammation Research, has studied the differences in gene expression patterns in the blood of people who either recover promptly after acute glandular fever or develop the prolonged illness called post-infective syndrome.
The researchers examined six million pieces of gene expression information for analysis in the project, known as the Dubbo Infection Outcomes Study. The study is named after the NSW town in which the work was conducted. The team studied the expression of 30,000 genes in the blood, testing each of the 15 individuals between four and five times over a 12-month period.
The team was able to narrow its findings to the expression of just 35 genes whose pattern of expression correlated closely with the key symptoms of the illness when examined from onset through to recovery. Gene expression is significant because it is the process by which a gene’s DNA sequence is converted into the proteins which ultimately determine the manifestations of disease.
Since 1999, the team has been tracking the long-term health of individuals infected with Ross River virus (RRV), Q fever infection and Epstein-Barr virus, which causes glandular fever.
“These  genes might point to the nature of the disease process that underlies CFS, which is currently unknown,” said Professor Lloyd, who is based in the School of Medical Sciences at UNSW. “None of them are ones that I would have predicted, except for those relating to neurotransmitters,” he concedes. “Some of them relate to transport of zinc and other metal ions within the cell, which may suggest a fundamental disturbance in cellular function.”
The researchers now hope to narrow the focus of research onto the expression of these 35 genes in the blood of a much larger group of subjects from the Dubbo Infection Outcomes Study, with varied patterns of illness and recovery.
“There are very few complex diseases which have been comprehensively analysed, with large scale and longitudinal studies, like this,” said Professor Lloyd. “It sets a standard for highly sophisticated, comprehensive gene expression studies in the blood of all sorts of human diseases from rheumatoid arthritis and multiple sclerosis through to schizophrenia.”The research paper has been published in the Journal of Infectious Diseases.
Note: This story has been adapted from a news release issued by University of New South Wales.
Gene Expression Correlates of Postinfective Fatigue Syndrome after Infectious MononucleosisBarbara Cameron, Sally Galbraith, Yun Zhang, Tracey Davenport, Ute Vollmer-Conna, Denis Wakefield, Ian Hickie, William Dunsmuir, Toni Whistler, Suzanne Vernon, William C. Reeves, Andrew R. Lloyd, and Dubbo Infection Outcomes Study
Background: Infectious mononucleosis (IM) commonly triggers a protracted postinfective fatigue syndrome (PIFS) of unknown pathogenesis.
Methods: Seven subjects with PIFS with 6 or more months of disabling symptoms and 8 matched control subjects who had recovered promptly from documented IM were studied. The expression of 30,000 genes was examined in the peripheral blood by microarray analysis in 65 longitudinally collected samples. Gene expression patterns associated with PIFS were sought by correlation with symptom factor scores.
Results: Differential expression of 733 genes was identified when samples collected early during the illness and at the late (recovered) time point were compared. Of these genes, 234 were found to be significantly correlated with the reported severity of the fatigue symptom factor, and 180 were found to be correlated with the musculoskeletal pain symptom factor. Validation by analysis of the longitudinal expression pattern revealed 35 genes for which changes in expression were consistent with the illness course. These genes included several that are involved in signal transduction pathways, metal ion binding, and ion channel activity.
Conclusions: Gene expression correlates of the cardinal symptoms of PIFS after IM have been identified. Further studies of these gene products may help to elucidate the pathogenesis of PIFS.Source: The Journal of Infectious Diseases
Vol. 196, #1, p 56-66
Date: July 1, 2007
Abnormal gene profile found in chronic fatigue patients
August 12, 2005
London, UK - Patients with chronic fatigue syndrome (CFS) have abnormalities in gene expression, and these changes carry intriguing hints about factors that might trigger or contribute to this syndrome, according to Dr Jonathan R Kerr (now at St George's University of London, UK). Kerr and colleagues at Imperial College, London, report in two papers in the August 2005 issue of the Journal of Clinical Pathology that they have identified a reproducible gene-expression profile in peripheral blood monocytes from CFS patients  and that CFS may be associated with the HLA-DQA1*01 allele .
The fact that we have found reproducible changes in gene function in CFS supports the view that this disease has a biological or organic basis, and is not just in the mind.
"Historically, CFS has been relatively unexplained in terms of biological function. This pilot study was designed to test the hypothesis that abnormalities of gene regulation occur in CFS, and we have shown that to be the case," Kerr tells rheumawire. "We have now taken this a step further and identified the very pathways involved, and that will be described in our next paper. The fact that we have found reproducible changes in gene function in CFS supports the view that this disease has a biological or organic basis and is not just in the mind."
Genes suggest T-cell, neuron, and mitochondrial changes
In the first paper, the researchers describe a characteristic gene-expression profile in CFS patients, which includes upregulation of 15 genes and downregulation of one gene compared with normal controls. They also note that the specific genes involved suggest T-cell activation, neuronal abnormalities, and mitochondrial-function abnormalities.
This study was done using 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. The analysis used a single color microarray representing 9522 human genes, and genes showing differential expression were further analyzed using TaqMan real-time polymerase chain reaction in fresh samples.
Among the genes upregulated were those for neuropathy target esterase (NTE) and eukaryotic translation initiation factor 4G1 (EIF4G1). "These genes are the targets for organophosphates and viruses, respectively," Kerr says. "Therefore, we hypothesize that upregulation of each may reflect a host response to an insult, which attempts to overcompensate in each case."
The upregulated genes could be grouped according to immune, neuronal, mitochondrial, and other functions relevant to CFS. The gene-expression profile suggested T-cell activation, upregulation of protein kinase C family members implicated in various psychiatric and affective disorders, abnormalities of microtubule proteins in neurons, and changes in several aspects of mitochondrial function.
This group is about to begin clinical trials using experimental drugs chosen on the basis of the CSF gene-expression findings.
Kerr predicts that these findings will eventually improve the care of CFS patients by identifying those metabolic pathways that are abnormal in CFS, leading to development of drugs to bring these processes back to normal. He tells rheumawire that his group is about to begin clinical trials using experimental drugs chosen on the basis of the CSF gene-expression findings.
The second paper identifies an association with HLA-DQA1*01 in many CFS patients, but Kerr says that this is not a not a promising drug target and that this line of work will not be taken further unless the HLA region is highlighted in future gene-expression studies. He adds, "We were surprised that we did not find an association with the HLA-DRB1 locus, as this was suggested by previous work in CFS."Sources
1. Kaushik N, Fear D, Richards SCM, et al. Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome. J Clin Pathol 2005; 58:826-832.
2. Smith J, Fritz EL, Kerr JR, et al. Association of chronic fatigue syndrome with human leukocyte antigen class II alleles. J Clin Pathol 2005; 58:860-863.http://www.medscape.com/viewarticle/538308
Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndromeN Kaushik, D Fear, S C M Richards, C R McDermott, E F Nuwaysir, P Kellam, T J Harrison, R J Wilkinson, D A J Tyrrell, S T Holgate, J R Kerr
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.
Conclusions: These results suggest that patients with CFS have reproducible alterations in gene regulation.Accepted for publication 10 February 2005
J Clin Pathol 2005;58:826–832. doi: 10.1136/jcp.2005.025718