CFS: article on changed gene expression in immune cells:

Discussion in 'Fibromyalgia Main Forum' started by tansy, Jul 20, 2005.

  1. tansy

    tansy New Member

    I have posted this on several threads. The article below has just been pubished and gives more extensive info on the gene and immune sytem changes being found in CFS.

    "Chronic fatigue is not all in the mind"

    23 July 2005
    New Scientist news service
    Rowan Hooper

    AT LONG last, we are beginning to get to grips with chronic fatigue syndrome.
    Differences in gene expression have been found in the immune cells of people
    with the disease, a discovery that could lead to a blood test for the disorder
    and perhaps even to drugs for treating it.

    The symptoms of chronic fatigue syndrome have been compared to those of a
    really bad hangover: extreme weakness, inability to think straight, disrupted
    sleep and headache. But unlike a hangover, the symptoms linger for years,
    devastating people's lives.

    While nobody doubts CFS exists, just about every aspect of it is controversial.
    Some say it is the same as myalgic encephalomyelitis, or ME; others disagree.
    Many specialists are convinced it does have a biological basis, but pinning
    down physical abnormalities common to all patients has proved tough. People
    with CFS have often received little sympathy from doctors who dismiss it as
    "all in the mind".

    Now Jonathan Kerr's team, which is moving to St George's University of London,
    has compared levels of gene expression in the white blood cells of 25 healthy
    individuals with those in 25 patients diagnosed as having CFS according to
    strict criteria. The researchers found differences in 35 of the 9522 genes they
    analysed using DNA chip technology.

    The few similar studies done in the past have produced conflicting results, so
    the team double-checked their results using a more accurate method called
    real-time PCR. That confirmed that 15 of the genes were up to four times as
    active in people with CFS, while one gene was less active. The results will
    appear in the Journal of Clinical Pathology next month.

    Kerr is repeating the study in 1000 CFS patients and healthy controls, this
    time looking at 47,000 gene products. So far, the larger study backs up the
    earlier results, he told New Scientist.

    If Kerr really has succeeded where many have failed, and identified clear
    physical changes in people with CFS, the lingering opinion that it is "all in
    the mind" could finally be laid to rest. "This exciting new work shows that
    some aspects of this complex illness may be understandable in molecular terms,
    and that CFS is not a 'made up' illness," says Russell Lane, a neurologist at
    Charing Cross Hospital in London.

    It should also be possible to develop a blood test for CFS. The team has
    already discovered differences in blood proteins related to the changes in gene

    Kerr hopes the work might even lead to treatments. "We have shown that a
    significant part of the pathogenesis resides in the white blood cells and in
    their activity," he says. "It will open the door to development of
    pharmacological interventions."

    Several of the genes identified by the team in CFS play important roles in
    mitochondria, the power factories of our cells. "The involvement of such genes
    does seem to fit with the fact that these patients lack energy and suffer from
    fatigue," Kerr says.

    One of these gene products, EIF4G1, is involved in protein production in
    mitochondria. It is hijacked by some viruses, so cells may compensate by
    ramping up gene expression. "I am excited by the paper," says Basant Puri, a
    CFS expert at Hammersmith Hospital in London. "The group's finding of
    upregulation of EIF4G1 is consistent with subclinical persistent viral

    This fits in with the idea that CFS is sometimes triggered by viruses such as
    Epstein-Barr, Q fever, enteroviruses and parvovirus B19. "CFS often begins with
    a flu-like illness which never goes away," Kerr says.

    Of the other genes whose expression varies in CFS patients, some are involved
    in regulating the activity of the immune system. Others play important roles in
    nerve cells, including a gene called NTE, which codes for an enzyme affected by
    organophosphates and nerve gases.

    Journal reference: Journal of Clinical Pathology (vol 58, p 823, 860)

  2. CFIDSNicole

    CFIDSNicole New Member

    There seems to be a lot of progress recently, doesn't there? With all the research with the gene abnormalities and then all the other research about cardiac abnormalities and cardiomyopathy and such, I wonder which is correct. Is it an either/or situation or a both/and situaion? Or, will they discover therea re different types of CFIDS?

    My worry is that they will come up woth a blood test someday and I'll take it and flunk that one, too. Then what's wrong with me?

    Crazy things I think about,
  3. tansy

    tansy New Member

    one of UK top researchers who has earned international recognition for his work has expressed similar concerns which are quoted in this article from the BBC news website. For years we have been told someone thinks they have found a diagnostic test, so I will wait and observe how all this progresses.

    love, Tansy

    *****""Chronic fatigue gene signs found""
    Scientists believe they have pinpointed biological markers of chronic fatigue syndrome which could help develop a test and treatment for the condition.
    CFS, or ME, makes people feel extremely tired, and can cause weakness, headaches, and disrupted sleep.

    Scientists, now based at St George's Hospital, London, found differences in the way genes are expressed in white blood cells of people with CFS/ME.

    But others say the New Scientist findings may not explain all cases.

    It is also due to be published in the Journal of Clinical Pathology.

    The scientists say their findings fit with the understanding that a virus, such as Epstein-Barr, may trigger CFS/ME, because that illness might alter how genes are expressed.

    CFS/ME often first appears as a flu-like illness, but does not then go away.


    The researchers compared levels of gene expression in the white blood cells of 25 healthy people and 25 who had CFS using DNA chip technology.

    They found differences in the behaviour of 35 of the 9,522 genes they analysed.

    Further genetic testing showed 15 of the genes were up to four times more active in people with CFS, while one gene was less active.

    Several genes the team pinpointed play important roles in mitochondria, the "powerhouse" of cells.

    One of the products of these genes is EIF4G1, which is involved in the protein production in mitochondria.

    EIF4G1 is hijacked by some viruses, so cells may compensate by increasing gene expression.

    The genetic differences lead to changes in how blood proteins behave which could allow the development of a blood test for CFS, the team say.

    Other genes are involved in regulating the immune system or playing important roles in nerve cells.

    The team will now carry out further research on 1,000 CFS patients and healthy people.

    Not 'made-up'

    Dr Jonathan Kerr who led the research team, which is currently in the process of moving to St George's, said: "The involvement of such genes does seem to fit with the fact that these patients lack energy and suffer from fatigue."

    He added the work could also potentially lead to a treatment for the condition.

    "We have shown that a significant part of the pathogenesis resides in the white blood cells and in their activity

    "It will open the door to development of pharmacological interventions."

    Dr Russell Lane, a neurologist at Charing Cross Hospital, in London, said: "This exciting new work shows that some aspects of this complex illness may be understandable in molecular terms, and that CFS is not a 'made-up' illness."

    Chris Clark, chief executive of Action on ME, told the BBC News website: "The prospect of having a diagnostic test is very encouraging because many people with ME can currently take well over a year to find out what is wrong with them."

    Dr Neil Abbot of Merge, a charity which funds research into CFS/ME, said: "CFS/ME can have very different effects on patients.

    "We're not looking at just one condition with a definitive patient group.

    "So it might be hard to get a gene signature which works for everyone with CFS/ME."

    But he added: "This research probably won't be the answer for everyone, but it is still very interesting."*****

    Story from BBC NEWS:
    [This Message was Edited on 07/21/2005]
  4. dojomo

    dojomo New Member

    Would love to see studies like this published in the BMJ....what do you think the odds are? (wink)..DJ
  5. tansy

    tansy New Member

    on the BMJ, Wessely et al seem to have more luck publishing their untenable hypotheses than serious researchers in UK medical journal.

    Many UK doctors and researchers complain it very difficult to get papers accepted for publishing on ME/CFS unless they are members of the Royal College of Psychiatrists. The term CFS has to be used as well, not ME which as we all know is the correct term and excludes functional somatic disorders.

    Boy am I am looking forward to the tide eventually turning and watching how the Wessely School attempt to retain their dominanace over national policies on medical investigations and treatments.

    love, Tansy
    [This Message was Edited on 07/21/2005]
  6. CFIDSNicole

    CFIDSNicole New Member

    At least I am not the only one afraid of flunking another test, and at least the doctors recognize that it may not be everyone's answer.

    I'm afraid that if I have one more normal blood test, the doc will have me suited up and sent to a rubber room or something.

    Tansy, you always have the greatest articles! I wonder if it would be a waste of my time to try to send these articles to my GP or my CFIDS doctor.

  7. tansy

    tansy New Member


    Dr Kerr's research will feature in one of the August editions of the BMJ, so we will be able to observe how the UK medical profession react to it and what the psychologisers have to say about it, I am sure they will make their opinions known as they always have done

    Research in which Wessley and Anthony Cleare are involved will also be featured in the BMJ next month, you can find the reference to it on the link provided.

  8. Rosiebud

    Rosiebud New Member

    can you possibly please clarify something for me

    they are saying that 'CFS is the same as M.E., some disagree' - I thought CFS was the 'new' name for M.E., thats what my doc told me anyway.

    Now I find the lines are being blurred with the awful muscle pain aspect of M.E. being left out.

    Do you know anything about this.


  9. tansy

    tansy New Member

    include neuropathic, joint, and muscle pain. CFS was constructed to cover conditions other than ME, the main issue being chronic fatigue. The Oxford definition of CFS is even vaguer than the CDC definition; it was published and put into use by the Wessely School.

    When I was Dx with ME, before the confusing CFS definitions came into use, muscle pain was one of the symptoms used to make that Dx.

    What I hope is that continued gene research also throws light on the symptoms in other chronic fatigue states, including adrenal fatigue, so that everyone gets access to worthwhile funded treatments.

    love, Tansy

    [This Message was Edited on 07/21/2005]
  10. dojomo

    dojomo New Member

    I'll be watching for them and the rapid responses.....DJ
  11. auntcon

    auntcon New Member

    Those of us that have FMS due to an accident?

    I did have CFS (42 titers)

    But the PAIN started after a car hit the wall behind the chair I was sitting in... Constant pain ever since!

    How can that be genetic?

    I DON'T LIKE TO FLUNK TESTS... (It's all in my head ;-D)

  12. Rosiebud

    Rosiebud New Member

    for the explanation. When I was diagnosed it was with M.E. too and muscle pain was a main part of the diagnosis.

    Hopefully their research will uncover something for this too.

    Thanks again

  13. NyroFan

    NyroFan New Member

    Thank you for posting that very interesting article on the study.
  14. bct

    bct Well-Known Member

    bumping for very interesting post. Thanks again Tansy.

  15. tansy

    tansy New Member

    Recognising ME helps sufferers

    Sir - Having suffered from this appalling and extremely debilitating
    multi-faceted condition for over 35 years, I have always been
    convinced that ME has physical causes rather than mental (News, July
    21). However, a major part of my suffering has been the bewilderment
    engendered by the condescending attitude of the numerous consultants
    and doctors I have attended over many years. How much more helpful
    it would have been if the medical profession had simply admitted
    they did not know the causes of my symptoms but had offered to
    support me.

    I was constantly told that I had "had all the tests" and they
    were "all normal" and that was "reassuring", never mind that I was
    still feeling extremely ill and unable to live any normal sort of a
    life. Thank goodness for a few dedicated researchers intent on
    finding the cause of, and cure for, ME which is blighting so many
    lives. It is vital that research continues and a positive diagnostic
    test is developed. Merely being believed, even if a cure is not
    currently possible, would be a big step in the right direction and
    an enormous help to sufferers like myself.

    Mrs Elizabeth Morris, Shrewsbury, Shrops

    Sir - The real scandal is the fact that there has been no government
    funding into the underlying physical cause of an illness that costs
    the nation around £3.5 billion per year. Even after calls for
    research proposals from the Medical Research Council, submissions
    continue to be turned down. The time has come for government to
    invest some serious money into finding the cause of an illness that
    has been neglected for far too long.

    Dr Charles Shepherd, Medical Adviser ME Association Research
    Department, Buckingham
  16. tansy

    tansy New Member

    The full paper is available at

    Extract -

    * Sixteen genes were differentially expressed in patients
    with chronic fatigue syndrome compared with normal
    controls, as assessed by microarray and quantitative
    polymerase chain reaction

    * The involvement of genes from several disparate
    pathways suggests a complex pathogenesis involving
    T cell activation and abnormalities of neuronal and
    mitochondrial function

    * These results suggest possible molecular bases for the
    recognised contributions of organophosphate exposure
    and virus infection


    In our present study, we studied transcript profiles from
    patients with CFS and from sex and age matched normal
    controls from the same area of South East England.

    The expression of 16 genes was significantly different in patients
    compared with controls in both microarray analysis and real
    time PCR.

    These genes may be important in the pathogenesis
    of CFS and can be grouped according to immune, neuronal,
    mitochondrial, and other functions that have particular
    relevance to our present knowledge of the epidemiology of
    CFS (table 4).

    Our present study has certain parallels with
    two published studies in this area, summarised in table 4.

    T cell activation is suggested by upregulation of CD2BP2
    and downregulation of IL-10RA10–12; in addition, PRKCL1
    plays a role in the immune response.

    Genes that are active in
    the immune response have been found to be differentially
    expressed in all studies of gene expression in CFS (table 4).

    Furthermore, genes that are crucial for T cell activation10 have
    also been found to be upregulated in all three studies,
    namely: CD2BP2 and IL-10RA (present study); moesin and
    cathepsin C4; ITGA and NFATC3.5

    These findings are
    consistent with previous work showing that patients with
    CFS have evidence of immune activation, such as increased
    numbers of activated T cells and cytotoxic T cells, and raised
    circulating cytokine concentrations.3 13–19 A neuronal component is
    suggested by the upregulation of

    Protein kinase C family members are implicated in various
    psychiatric and affective disorders, and have been implicated
    in previous gene studies of CFS.5

    NTE is a target for
    organophosphates and chemical warfare agents, both of
    which may precipitate CFS,20 on the basis of a neuropathy
    resulting from inactivation of serine esterase activity.21 GSN
    regulates cell growth and plays a role in amyloidosis (Finnish
    type), which may result in dysfunction of neurones, skeletal
    muscle, and thyroid gland.22 23

    GABARAPL1 is a microtubule
    associated anchor protein with increased expression in
    neuronal cells.24

    KHSRP facilitates splicing of the N1 exon
    of the SRC protooncogene in neuronal but not other cells.25

    EIF2B4 is a mitochondrial translation initiation factor and
    one of the EIF2B family, within which mutations have been
    shown to be associated with central nervous system
    hypomyelination and encephalopathy.26

    Powell and colleagues
    4 have reported upregulation of an EIF2B3 gene
    homologue (BQ580379).

    These findings are interesting in
    that abnormalities in the white matter of the frontal lobes
    have been found in patients with CFS using magnetic
    resonance imaging and have been suggested to account for
    the cognitive defect in CFS.27

    Neuronal gene involvement in
    CFS has also been reported by Vernon and colleagues.5

    Mitochondrial involvement is suggested by the upregulation
    of EIF2B4, EIF4G1 (see above), and MRPL23.
    Mitochondrial gene upregulation has also been reported by
    Powell et al.4

    The cell cycle is implicated by upregulation of ANAPC11,
    which regulates the onset of anaphase by mediation of
    degradation of mitotic cyclins. Powell and colleagues4
    reported upregulation of MAD1L1, which prevents the onset
    of anaphase until all chromosomes are aligned at the
    metaphase plate.

    ``The upregulation of EIF4G1 identified in our present
    study may represent a common host response to persistent
    infection with several different viruses'

    Transcriptional perturbation is suggested by the upregulation
    of POLR2G and BRMS1.

    Powell and colleagues4 reported
    the upregulation of genes homologous with POLR1B
    (BQ580386) and RCOR3 (BQ580388), which are each
    involved in transcriptional regulation.

    Upregulated peroxisomal function is suggested by the
    upregulation of ABCD4 and PEX16, which may suggest
    enhanced defence to oxidative stress in CFS.

    Oxidative stress
    has already been suggested as a disease mechanism in
    CFS.28 29

    Persistent virus infection is a recognised feature of CFS,
    which is interesting in the light of our finding of upregulation
    of EIF4G1 transcript variant 5, a mitochondrial translation
    initiation factor.

    Whistler and colleagues6 have also reported
    this finding in patients with CFS who have rapid (?triggered
    by virus infection) as compared with insidious onset.

    is a component of the protein complex, EIF4F, which is
    crucial in translation through its involvement in the
    recognition of the mRNA cap, ATP dependent unwinding of
    59 terminal secondary structure, and recruitment of mRNA to
    the ribosome.30

    Various viruses have developed strategies to
    divert EIF4G1 from its utilisation by the cellular machinery to
    facilitate production of viral proteins.30

    The best characterised
    example is that of poliovirus,31 32 but this has also been
    demonstrated to occur with coxsackie virus,33 rhinoviruses,34
    rotavirus,35 influenza virus,36 adenovirus,37 vesicular stomatitis
    virus,38 and human immunodeficiency virus 1.39

    the upregulation of EIF4G1 identified in our present study
    may represent a common host response to persistent
    infection with several different viruses.

    The vulnerability of
    EIF4G1 to virus modification may have particular importance
    for the development of CFS after an acute virus infection.40

    In conclusion, we report the differential expression of 16
    human genes in patients with CFS compared with normal

    The involvement of genes from several disparate
    pathways suggests a complex pathogenesis involving T cell
    activation and abnormalities of neuronal and mitochondrial
    function, and suggests possible molecular bases for the
    recognised contributions of organophosphate exposure and
    virus infection, respectively.

    [This Message was Edited on 07/28/2005]
  17. tansy

    tansy New Member

    Gene Research: A Scientific 'Signature' for ME/CFS?

    DNA HelixThe work by Dr John Gow and colleagues (University Department of Neurology, University of Glasgow), to whom MERGE has contributed interim funding for the verification of potentially important genes, is one of a number of ongoing research projects seeking a 'biomarker' for the illness ME/CFS using novel microarray technology. In this experimental technique, a sample of blood or tissue is taken, applied to a glass slide (microarray) containing more than 20,000 gene identifiers, and examined to determine which genes in the sample are being expressed.

    As has been reported in a series of articles — in the Scotsman, the Evening Times, and on the BBC — the pilot data obtained by Dr Gow's team have suggested alterations to genes controlling the metabolism of prostaglandin and those regulation-specific immune cells. This is interesting work which deserves to be supported into its mature phase when a specific "gene signature" for particular proteins may be revealed.

    Contemporaneously, microarray investigations using samples from ME/CFS patients are being undertaken by other research groups: a team led by Dr Jonathan Kerr at St Mary’s Campus Imperial College London, supported by the CFSRF, is honing in on 15 genes; and Suzanne Vernon, team leader of the Centers for Disease Control and Prevention's molecular epidemiology program in Atlanta is investigating gene expression profiles in the large Wichita clinical data set (see From Scepticism to Science). The preliminary findings of these groups suggest dysregulation of genes involved in immune pathways, supporting the many reports in the literature of immune dysregulation in the pathogenesis of ME/CFS.

    These developments are welcome: few areas of biomedical research into ME/CFS can boast more than two separate research groups simultaneously engaged on a common quest. It is likely to be a long search, however. Experience from the use of genome-wide scanning technologies for cancer screening has shown that discovery and validation of biomarkers requires multiple phases of research. In a lucid commentary, Sullivan Pepe et al. (2001) identified issues to be addressed for the design of biomarker studies, and outlined a five-phase structure for investigation — from phase 1 pre-clinical exploratory studies to identify leads for potentially useful biomarkers and prioritise identified leads, through phase 2 involving the development of a clinical biomarker assay and assessment of its ability to distinguish patients and controls, to subsequent phases of increasingly stringent validation involving longitudinal, prospective, and large, expensive control studies.

    The publicly available preliminary information on the status of genome-wide scanning technologies in ME/CFS suggests that most work is presently in or around the phase 1 stage, and that much progress in bioassay development and validation studies will be required before a valid 'gene signature' can be unveiled.

    Of course, the same problems that confront all researchers in ME/CFS also apply to research groups using microarray technology. One is that 'diagnosis' of the illness is most often based on a ragbag of common non-specific symptoms, resulting in a diverse group of patients. As Jason et al. (2005) have pointed out in an excellent recent review, "Subgrouping is the key to understanding how CFS begins, how it is maintained… and in the best case, how it can be prevented, treated and cured." It is unlikely, therefore, that a single biomarker or cluster will be found able to detect all cases as currently defined, although microarray technology does have the potential to make diagnosis more precise in the long term.

    Another problem is that obtaining and maintaining funding haunts the efforts of all biomedical researchers in ME/CFS, and it is particularly acute in these gene biomarker studies which will require million of dollars to come to a definitive conclusion. At MERGE, we echo the comment of Alex Fergusson MSP in the Parliamentary members' business debate (Thursday 9 June 2005; motion S2M-2852) on the subject of a cure for myalgic encephalomyelitis, that it is entirely unacceptable that major funding bodies seem prepared to see novel gene research grind to a halt — particularly when large traunches of money have been allocated to research on non-curative psychosocial strategies designed to 'manage' symptoms.

    Illnesses are most easily accepted when they have a specific clinical or scientific 'signature'— a biochemical test, a cluster of specific symptoms or signs, etc. — that confers legitimacy in the eyes of healthcare professionals. Until then, patients are in a no-man's land between the living and the well, subject to a variety of quasi-therapeutic interventions and the ministrations of charlatans.

    ME/CFS has been called the "disease of a thousand names", but it has also been the disease of a thousand false dawns and a thousand broken promises. Yet, the discovery of a clinical or scientific 'signature' for ME/CFS, indicative of the physical terrain, would transform this situation at a single sharp stroke. In the longer term, work using genome-wide scanning technologies has the potential to reveal such a 'signature': to quote Steinau et al. (2004), "Biomarkers characteristic of CFS could contribute to precision in case ascertainment, identify heterogeneity in the CFS population to clarify contributing pathways to disease, suggest novel therapeutic targets, and provide indicators of disease progression and prognosis."

    Many people have made contact about supporting Dr Gow's work through MERGE, and we are delighted to accept contributions specifically targeted at this study. Potential contributors should make clear in their letters and e-mails that their donation is to be spent on the 'University of Glasgow Gene Expression' project.


    Jason LA, et al. Chronic Fatigue Syndrome: The Need for Subtypes. Neuropsychology Review 2005; 15(1):29-58.

    Sullivan Pepe M, et al. Phases of biomarker development for early detection of cancer. J Natl Cancer Inst 2001; 93:1054-61.

    Steinau M, et al. Differential-display PCR of peripheral blood for biomarker discovery in chronic fatigue syndrome. J Mol Med 2004; 82(11):750-5.

  18. dojomo

    dojomo New Member

    Bumping for those interested in the breakdown of affected Genes.

    Tansy, I noticed no rapid respones yet on this article, is it because it's not in the main journal. Is this info being circulated by the UK activists?

    Thanks for posting......DJ
  19. tansy

    tansy New Member

    I am sure it will bring about some interesting responses especially from the Wessely School.

    Yes this article has been circulated to all the relevant UK groups.

    love, Tansy
  20. neen85

    neen85 New Member

    I am sure I will have to go back and read parts of this over again! I,too would love to see the tide turn over your way! Daneen

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