Invest in ME Conference 12: First Class in Every Way
OverTheHills wraps up our series of articles on this year's 12th Invest in ME International Conference (IIMEC12) in London with some reflections on her experience as a patient attending the conference for the first time.
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Humoral Immunity Profiling of Subjects with Myalgic Encephalomyelitis

Discussion in 'Latest ME/CFS Research' started by Theodore, Dec 17, 2016.

  1. Theodore

    Theodore Senior Member

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    France
    Humoral Immunity Profiling of Subjects with Myalgic Encephalomyelitis Using a Random Peptide Microarray
    Differentiates Cases from Controls with High Specificity and Sensitivity


    Sahajpreet Singh, Phillip Stafford, Karen A.Schlauch, Richard R.Tillett , Martin Gollery, Stephen Albert Johnston, Svetlana F. Khaiboullina, Kenny L. De Meirleir, Shanti Rawat, Tatjana Mijatovic, Krishnamurthy Subramanian, András Palotás, Vincent C.Lombardi

    Received: 3 June 2016 /Accepted: 29 November 2016

    Abstract

    Myalgic encephalomyelitis (ME) is a complex, heterogeneous illness of unknown etiology. The search for bio-markers that can delineate cases from controls is one of the most active areas of ME research; however, little progress has been made in achieving this goal. In contrast to identifying biomarkers that are directly involved in the pathological process, an immuno signature identifies antibodies raised to proteins expressed during, and potentially involved in, the pathological process. Although these proteins might be unknown, it is possible to detect antibodies that react to these proteins using random peptide arrays. In the present study, we probe a custom 125,000 random 12-mer peptide microarray with sera from 21 ME cases and 21 controls from the USA and Europe and used these data to develop a diagnostic signature. We further used these peptide sequences to potentially uncover the naturally occurring candidate antigens to which these antibodies may specifically react with in vivo. Our analysis revealed a subset of 25 peptides that distinguished cases and controls with high specificity and sensitivity. Additionally, Basic Local Alignment Search Tool (BLAST) searches suggest that these peptides primarily represent human self antigens and endogenous retroviral sequences and, to a minor extent, viral and bacterial pathogens.
     
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  2. A.B.

    A.B. Senior Member

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    As the authors acknowledge in the paper, these results need to be confirmed. With so many peptides being tested, and the number of patients and controls being relatively small, it is easy to generate false positives.
     
  3. Daisymay

    Daisymay Senior Member

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    MEMum, Luther Blissett and Theodore like this.
  4. trishrhymes

    trishrhymes Senior Member

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    They make it clear it's a proof of concept pilot study. Looks like incredibly complicated lab and computer analysis, but potentially interesting.
     
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  5. Daisymay

    Daisymay Senior Member

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    Attached Files:

  6. RogerBlack

    RogerBlack Senior Member

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    If, and this is a truly massive if, this turns out to be meaningful, the final test may not be particularly expensive. https://www.biocat.com/products/SPC.014.001-PEP - this is a HIV protein coat microarray, which seems to be $400 for a divisible by 9 test, and is broadly comparable as I understand it to the test they did - but of course would involve different peptides.

    I have not clicked 'send me a quote' on http://www.cambridgepeptides.com/peptideArrays.shtml after typing in the required peptides here :)

    I do idly wonder if they would supply non-labs if I did. (I would suspect that a fully custom peptide array - note one run off in numbers as for the HIV test would be considerably more expensive)
     
    Last edited: Dec 17, 2016
  7. Research 1st

    Research 1st Severe ME, POTS & MCAS.

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    Hello Theodore and friends.
    The following thoughts of mine may be of interest to some of you.
    Before my speculation party...

    The specific juicy bit for me from this new December 2016 De Meirleir et al paper, personally, is the following:

    gp120 isn't a Formula 1 motor race, but an envelope protein of HIV human retrovirus.
    Note they say the following regarding Rv's (repeat of above).

    In other-words the ME researchers are practically dismissing HIV involvement but not another HERV, which is logical and sensible at the point in time.

    Referencing HERV's then has potential to correlate with theories or anecdotal preliminary evidence (unpublished) that ME is indeed associated to retroviruses (HERV's - of unknown cause why they become pathogenic) and these same infections are found in other autoimmune illnesses affecting neurology, such as Multiple Sclerosis:

    MS patient walks after taking HIV drugs
    Source: http://www.bbc.co.uk/news/uk-england-sussex-34659771

    Could HIV drugs help treat MS?
    http://www.nhs.uk/news/2014/08August/Pages/HIV-drugs-could-treat-multiple-sclerosis.aspx

    HIV and lower risk of MS revealed
    Source: http://jnnp.bmj.com/content/early/2014/07/16/jnnp-2014-307932.long




    Now we also know there is some evidence for not just MS, but also HIV and HERV's being linked, because:

    HIV is associated to HERV production:

    And by another group 3 years later....



    Moving away from RV's for a moment to the stomach bacteria ideas we've all been hearing of in vague snippets of research. Well if people (who haven't tested their own 'gut flora') were skeptical I wouldn't be, as bacteria in the stomach is now being associated to 'hardcore' degenerative neurological diseases like PD never mind ME.

    Parkinson's disease appears to be connected to Bacterial translocation in the gut:
    Source: http://www.bbc.co.uk/news/health-38173287

    Back to RV's and getting very hypothetical, but please hear me out just in case there is some vague link to my thoughts:

    I spotted Sphigomyelin was mentioned by Dr Navieux regarding the recent Mitchocondrial blood test that is being researched in CFS in America and this was one of the analytes I believed measured in a 'test' that appears to be available for a sizeable cost (cost helps to fund research) privately on an experimental basis at least.

    Well people with long memories, may recall that the twin girls with 'XMRV' (not XMRV but maybe another RV) have ultra rare childhood Alzheimer's - Niemann-Pick disease Turns out Neiman Pick is associated to Sphigomyelin deficiency.
    Source: http://nnpdf.org/the-disease/overview/

    And? Well shouldn't RV's be associated to Sphigomyelin then if the twin girls who had the dud XMRV assay maybe had another RV?

    Well look what I discovered. Sphingolipid defects are associated to an RV: HIV-1 to be exact.
    (NB: Neiman Pick if I remember correctly causes hyper cholesterol) and of note XMRV is directed by cholesterol.

    Also note, 3 years before that published paper, the twin girls parents were discussing this on their own charity website:

    Hence it was logical for Mikovits to test the girls for XMRV (wrong name) and it was positive - because it wasn't XMRV it was something else....not contamination as it's the sick people who test positive at far higher rates - if the lab was contaminated all people would test positive, or there wouldn't be a 20 fold slide to people with a neuro disease testing positive - that's the smoking gun at the end of the day - simtaneously after claiming to the public retroviruses don't exist in CFS via the botched Lipin/Alter CFS study the US blood safety groups behind closed doors used this company to clean US blood donors blood of potential retroviruses (2011 onwards). A most curious decision if no retroviruses were found - why waste millions of dollars on money on pointless technology said only to be needed by a 'fradulent researcher'? So that's all we needed to know. She found something in CFS, not XMRV Silverman, something else...
    http://interceptbloodsystem.com/blood-center/intercept

    So now it might get really interesting RE: GP120 of the new December 2016 De Meirleir finding, Dr Davis/Navieux, Fluge & Mella and ME regarding the following in retroviral disease:


    So now we are linking a neurogenerative disease and HIV dementia, and in addition abnormal prion protein production and HIV GP120
    The text reads:

    Why mention the prions and ME if the above is about vCJD/HIV?
    Well from my links above we have learn't that HIV can interfere with HERV's and also HERV's are associated to autoimmune diseases such as MS and ME is increasingly linked to Autoimmunity, and perhaps even HERV's now also - or will be. If you read the research on the above, then prions are associated to all three, regarding gp120 which cropped up in this De Meirleir et al, recent study.

    So why is this relevant to ME?
    Because KDM also found, in severely affected especially, PrPC in blood (using an experimental assay) is abnormally low - practically zero left - and in saliva, misfolded prions are detected in ME sufferers. No published work to my knowledge, but some basic information here.

    Taken in combination this may all link as PrPC is neuroprotective, specifically against oxidative stress, and oxidative stress is associated to CFS biological research, including some neuroimaging studies that seem to show accelerated ageing of the brain, with changes in 'matter' volume and in the Nakatomi paper, neuroinflammation damage.

    It thus wouldn't be a surprise to find some form of HERV retrovirus/autoimmunity/infections driving ME all along - perhaps rather like MS and perhaps like element of HIV dementia (remember decades ago, Dr Paul Cheney's comment that a doctor in his Hospital mistook CFS brain scans for AIDS patients?).

    I think somewhere in all this I've posted there is something of some interest towards CFS, ME, HIV and Dementia, with the whole point of my post suggesting HERV's may well be involved and it's not just KDM's group thinking along this line.[/quote]
     
    Last edited: Dec 17, 2016
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  8. halcyon

    halcyon Senior Member

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    I'd be curious to hear Naviaux expand further on this which is mentioned in his CDR paper:
    Some recent research has shown that activation of HERVs during an immune response might be a critical step in immune activation of B cells. So finding evidence of increased HERV activity in ME might be an expected thing if ME is indeed a state of chronic immune activation.
     
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  9. roller

    roller wiggle jiggle

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    from TABLE 4


    Virus
    Numbers
    found
     6 gp120 protein, human immunodeficiency virus 1 CAD87195 Q70QU7
     3 Polyprotein GB virus Ccpz ADL29714 E0ADF8
     4 Envelope glycoprotein I human herpesvirus 2 AMB66322 P06764
     4 Phosphoprotein canine distemper virus AJO72800 P06940
     3 RNA-dependent RNA polymerase rodent Paramyxovirus BAO04373 U6C7N8
     3 Outer capsid protein Porcine rotavirus C AJL35076 A0A0C5B2I7

    Bacteria
    found
     4 Hypothetical protein [Serratia marcescens] WP_033638106
     5 diaminopimelate aminotransferase [Paenibacillus senegalensis] WP_010273745
     3 Peptidase M16 [Anaerofustis stercorihominis] WP_007050391 B1C8L1
     3 Type IV secretion protein Rhs [Hafnia alvei] WP_004091469 G9Y4S5
     3 SusC/RagA family TonB-linked outer membrane protein [Bacteroides nordii] WP_007483701 I9H2D3
     
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  10. RogerBlack

    RogerBlack Senior Member

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    It's important to note that all of the above papers do not refer to complete viruses.
    Viral genomes comprise a large fraction (>8%) of the human genome, but these are not complete viruses. These are viruses that have once got in, and become encoded in often tiny fragments in the genome - they are not in humans infective, as they are all broken. These are Human Endogenous Reteroviruses. - HERV.

    They vary from whole genes - syncytin is a gene stolen from viruses early in mammals evolution that helps form a key part of the placenta - to tiny fragments that are used in regulating other human genes.

    There are no complete virus sequences in the human, and without doing genetic engineering to put together the halves, nobodies ever gotten actual virus.

    Note the paper cited refers to mice - there are actual infectious reteroviruses intact in the mouse.

    A lot of papers in the post a couple of the above do not make it clear that they are not talking about - when talking about HERV transcription - talking about whole viruses. They're talking about the manufacture of single proteins from parts of the HERV genomes that are unbroken.

    A virus will have several-many genes - they all need to work to transmit the virus. Those genes can still make proteins (but not whole virus) if they are activated.

    The above referred to 'antiretrovirals make you better' - does not mean any involvement of HERVs - it may be affecting other viruses in the body, latent or not.

    http://www.microbe.tv/twiv/twiv-382/ may be interesting this is partially on the topic, covering the role in the placenta, and other topics.
     
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  11. anciendaze

    anciendaze Senior Member

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    I will just add a small note here limited to one observation. Viral envelopes are especially subject to change which is called pseudotyping because of the ease with which they change envelopes. Many papers using the word will be about deliberate pseudotyping in the laboratory, but there is no question natural pseudotyping does take place in hosts with viral coinfections.

    @RogerBlack has given the standard expert response to the question of activating HERVs, in the sense of creating transmissible infectious agents from HERVs. One problem with this is that HERV-Fc1 is scarcely more crippled than some murine viruses which are both endogenous and exogenous, it has a misplaced stop codon and a frameshift. These could be corrected by a tiny recombination event, or the change could take place by RNA splicing after transcription from DNA. Such are not rare events. (Consider recent work showing the prevalence of spliced epitopes. This is quite enough to provoke immune response.)

    A second problem turns up when you consider that all experts are sure that any gamma retrovirus found in human cell cultures is the result of contamination.

    Throughout much of the furor over XMRV I kept asking where the envelope sequence with the immunosuppressive domain originated, as opposed to the whole virus. The only answer I got was that it must have come from a mouse; end of discussion.

    Had we gone looking for viruses with immunosuppressive domains in envelopes, especially viruses in the herpes family, we could have avoided a great deal of vicious argument of zero medical value to patients.

    Added: before we go around another familiar loop in this argument, based on the fact that pseudotyped envelopes are not transmissible, I want to mention the known susceptibility of herpes-type viruses to actual gene insertions.
     
    Last edited: Dec 18, 2016
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  12. roller

    roller wiggle jiggle

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    diagnosed by meirleir.
    he is the most experienced one worldwide.
    has probably the most customers worldwide.
    he gets those that didnt get help elsewhere.

    if he says they have ME then they have ME.
    they dont have CFS.
     
  13. roller

    roller wiggle jiggle

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    could someone please explain what they say about Burkholderia bacteria?

     
  14. lansbergen

    lansbergen Senior Member

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    When something must be kept under the carpet ypu will not get answers.

    It is a pity because activation could be part of the immune response and researching it deeper could reveal clues.
     
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  15. lansbergen

    lansbergen Senior Member

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    https://www.researchgate.net/public...oviruses_in_the_plasma_of_major_burn_patients

    The prevalence of human endogenous retroviruses in the plasma of major burn patients

    Article in Burns: journal of the International Society for Burn Injuries 39(6) · January 2013 with 6 Reads DOI: 10.1016/j.burns.2012.12.013 · Source: PubMed

    abstract
    Background: Approximately 8% of the human genome is composed of retroviral sequences, which are known as human endogenous retroviruses (HERVs) and, have been implicated in both health status and disease. Recently, indirect evidence for a possible role of retroviral elements in the systemic response to stress signals has been provided by several studies. In the present study, we sought to evaluate the relationship between HERVs and major burn in humans. Method: We investigated the prevalence of HERV families by reverse transcriptase PCR (RT-PCR) in cell-free plasma samples from patients with burns and from normal individuals. Results: Different prevalences of HERV families were observed in the plasma samples from the burn patient group and normal group. Compared with the prevalences of HERV-W and HERV-K in the normal group, in the burn patient group, the prevalence of HERV-W was significantly lower (P<0.001), but the prevalence of HERV-K was higher (P=0.059). Conclusions: Our study of the prevalences of HERVs revealed that the activation of certain HERV families may be influenced not only by burns but also by the initial treatments that were used to address these injuries.
     
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  16. lansbergen

    lansbergen Senior Member

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  17. lansbergen

    lansbergen Senior Member

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  18. lansbergen

    lansbergen Senior Member

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  19. RogerBlack

    RogerBlack Senior Member

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    This is detecting genetic material from reteroviral sequences transcribed in the human - not whole endogenous reteroviruses, and the next paper you link is again not involving whole viruses.

    That does not of course mean that transcripts of HERV genes doesn't happen, and may be important in certain disease states, or that some of these transcripts may go on to be expressed.

    The immume system and the body as a whole uses lots of these fragments for many purposes, including normal regulation.
    Simple findings of expressed proteins or RNA of viral origin does not mean that in many ways the response is not 'self' - if it's been long enough ago, it may be an integral part of the reaction to disease or other states.
     
  20. lansbergen

    lansbergen Senior Member

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    it is a long time ago but was XMRV not about reteroviral sequences?
     

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