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V. Lombardi, et al, new poster: HERV in pDC as biomarkers & TLR defects

Discussion in 'Upcoming ME/CFS Events' started by serg1942, Mar 21, 2014.

  1. serg1942

    serg1942 Senior Member

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    I just read what I could from the picture of the poster, and it seems this may be huge! I hope they can elaborate more on the subject and that the poster is readable soon!:

    (...)"These experiments suggest that the expression of HERVs by pDC may be unique to ME and not the result of gut inflammation or consequence of other gut pathologies"(...) We therefore hypothesized that a TLR defect may explain our observations (...)

    Sergio
     

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  2. SOC

    SOC Moderator and Senior Member

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    Translation into layperson,please.....anyone? ;)
     
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  3. serg1942

    serg1942 Senior Member

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    Their first paper found only in CFS patients and not in controls, environmental proteins expressed by gut-resident cells of the immune system called plamacitoid Dendritic Cells (pDC), a type of macrophages. These proteins were expressed by Human Endoretrovirues (HERV) that account for about a 10% of our DNA. What they found could easily be the XMRV sequence (just a possibility).

    Ok, now they have confirmed this, and have discarded it is due to an inflammatory background, because they have examined people with Chron disease but without CFS, and they don't express these proteins. So they explain that this could actually be unique of CFS.

    On the other hand they try to find a mechanism throughout which this process could be happening, and they have confirmed that a problem with the Toll Like Receptor (TRC), a membrane receptor of the Antigen Presenting Cells (APCs) of the innate immune system, could be involved. They have found it defectous in CFS.

    I would need to be able to read the complete paper in order to be more precise, but it seems very promising nonetheless!

    Best!
    Sergio
     
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  4. justy

    justy Senior Member

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    Is this similar to the work KDM was doing? Afraid its all a bit over my head at the moment, but it rang a bell somewhere
     
  5. serg1942

    serg1942 Senior Member

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    Actually it is a second "Lombardi, KDM et al paper", on the same subject, going further this time! ;)
     
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  6. Countrygirl

    Countrygirl Senior Member

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    Sergio, do you have a link to this paper, please? Where was it published?

    I'm afraid I cannot read the small print of the image you posted and my computer won't enlarge it.

    Thank you,

    C.G.
     
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  7. Dolphin

    Dolphin Senior Member

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    I hope this isn't embargoed and that posting a photo like this doesn't jeopardise future publication and media interest.
     
  8. serg1942

    serg1942 Senior Member

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    Hi @Dolphin, Well...the picture has been taken by the own WPI... So, I guess they must hav ensured it's publication already...Hope so!

    And I am sorry @Countrygirl, but the readable article is not out yet!

    Sergio
     
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  9. Countrygirl

    Countrygirl Senior Member

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    Thank you, Sergio.

    C.G.
     
  10. snowathlete

    snowathlete

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    Cool. So they've gone further than their last findings - here's a reminder - and found this is not present in Gastritis or Crohn's disease which both result in inflammation of the gut. It's still not conclusive, but suggests that it is unique to ME/CFS and not a general result that you get with other inflamatory diseases of the gut. And they have some theories as to why this all might be happening.
     
    Last edited: Mar 21, 2014
  11. snowathlete

    snowathlete

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    Thanks for posting this. Where did you see it? On the WPI website or something?
     
  12. serg1942

    serg1942 Senior Member

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    I saw it in the WPI Face Book page...Exactly @snowathlete , it's not been found in crohn disease patients, nor in patients with gastritis, nor in healthy patients, so it is suggestive, though of course nor conclusive.

    They have some very interesting theories about the mechanisms involved, and, as far as I have been able to read, they have actually also found this alteration of the Tol Like receptor only in ME patients... So again, this looks great... I do hope they are not far from putting these results into practice, as they are doing for instance in MS, where they are already trying antoretrovirals to inhibit HERVs...

    Best!
    Sergio
     
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  13. snowathlete

    snowathlete

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    Yes, I just zoomed in and read what I could from it and they've run a bunch of interesting experiments to test out their theories. Very interesting stuff. If confirmed, this could definately lead to potential treatments, antiretrovirals, yes, but other possibilities too, I think.
     
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  14. anciendaze

    anciendaze Senior Member

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    Slight warning here, those plasmacytoid dendritic cells were cultured with small interfering RNA sequences. These normally inhibit gene expression, though it is possible inhibiting expression of one gene can result in derepression of another, or that siRNA can sometimes promote expression. They are provoking this response from a particular class of immune cells. This will be easy for critics to dismiss as unrelated to infectious disease. The big question concerns why patients plasmocytoid dendritic cells respond differently from controls. I'm not sure the work described will be enough to convince anyone that this difference is real and not an artifact.

    The big warning is that scarcely anyone will pay much attention to WPI after the XMRV fiasco.
     
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  15. snowathlete

    snowathlete

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    [my bolding] Yes, there is still no answer for why this is happening in the first place. But someone else could attempt to replicate their initial finding of HERV expression occuring in ME/CFS but not controls. If they managed to replicate that then that would be a major breakthrough in itself, and following that we'd need to figure out if the WPI's theories of what exactly is happening with the pDCs is correct or some other process is occuring. Treatments could follow that, even without us discovering what kicks all this off in the first place, though of course that question would be a lot easier to answer once the context is nailed down.

    I agree that coming from the WPI, there may be more reluctance to spend cash to try and replicate their findings. But given the potential here, hopefully someone will.
     
  16. WNM

    WNM

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    Thanks for posting Sergio!

    Gut immune activation/inflammation/gastritis does occur in ME/CFS (see and see). Although the lack of HERVs in Crohn's and gastritis does seem to suggest inflammation is not the cause of increased HERV expression. Reading the print I gather that this new research was prompted by another study which showed that suppression of TL3/7/9 signaling could increase HERV expression. So they then looked at what else popped up when TLR7/9 signaling was suppressed and they found increased expression of several proteins, but most strongly the PI3K binding protein PLCL3 (phospholipase C-like 3). They then found this protein was also increased in ME pDCs, suggesting increased PLCL3 and HERV expression may be caused by a TLR7/9 deficit.

    This aberrant DC function could seriously skew immune responses. DCs are the main antigen presenting cells in the gut and responsible for educating lymphocytes in the GALT (i.e. the largest collection of lymphoid tissue in the body). Altered dendritic cell function is also implicated in IBD also btw.

    Speculation... is some infection evading the immune system by suppressing the TLR7/9-PI3K pathway on DCs? A similar scenario occurs with Yersinia enterocolitica infection. Evidence of enterovirus (82%) and Parvovirus B19 (40%) have been identified in the gut of many with ME. Of note despite the gastritis, H. pylori infection is apparently not present in ME/CFS (see and see).

    Edited.
     
    Last edited: Mar 21, 2014
  17. anciendaze

    anciendaze Senior Member

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    Just a comment on h. pylori. Just having the bacteria is not enough to cause gastritis, about half the human race has h. pylori in the stomach, and sometimes it turns up in more surprising places.

    I've long suspected that antibiotic treatment of h. pylori for peptic ulcers only interrupts one stage in a more complex pathology. Plasmacytoid dendritic cells would be a good place to look deeper for specific immune dysfunction which allows h. pylori overgrowth. Narrow immune dysfunction could be behind any number of conditions currently listed as either idiopathic or unknown etiology. This need not be confined to the gut. Here's a paper on viral infections in idiopathic myocardial dysfunction. I ran into this because I was searching for left-ventricular dysfunction, which shows up in a surprising number of severe ME/CFS patients.
     
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  18. snowathlete

    snowathlete

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    I think this is the other study that they are referring to.
    http://www.ncbi.nlm.nih.gov/pubmed/23142781

    As someone with an IBD this is especially interesting. Such a pDC dysfunction as is described here could well lead to it. Thanks for posting that, I hadn't seen that one before.

    I noticed from a few recent posts that KDM seems to have started testing patients for Yersinia, so you could well be hitting the nail on the head there.
     
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  19. WNM

    WNM

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    Some specifics on TLR signaling. The TLRs 3, 7 and 9 are intracellular. TLR7 and 9 are expressed in pDCs (endoplasmic reticulum and endosomes). TLR7 recognises viral RNA, and TLR9 viral and bacterial DNA. TLR7/9 signal transduction requires the Myd88 adaptor and leads to activation NF-kB and IRF7 which induce inflammatory cytokine and type I IFN respectively. pDCs are a particularly notorious source of IFN.

    Hence suppression of these signaling pathways is likely to hamper immunity. pDCs are important for simulating the growth and differentiation of lymphocyte subsets. In the poster paper they are suggesting impaired pDC function may lower IFN stimulation of NK cell activity. They also suggest it may alter something to the effect of B cells and immune responses to commensal bacteria which may account for bacterial overgrowth and dysbiosis.

    This reminds me a bit of Crohn's disease. In Crohn's there is evidence of immune suppression which is thought to impair acute immune responses (to bacteria and foreign antigen), lead to inadequate microbial clearance and consequent chronic inflammation. Obviously Crohn's is very different to ME; there is severe small intestinal inflammation! ME immunology should be quite distinct; perhaps being more on the viral angle (?). All speculation of course.
     
    Last edited: Mar 21, 2014
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  20. Firestormm

    Firestormm Guest

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    https://www.facebook.com/1548011796...79671/10152307504509672/?type=1&stream_ref=10

    They say it is an abstract and will be published in six months. Suggests the paper has been submitted I suppose. Hand-out of the abstract is being given at the IACFS/ME conference presumably in the genomics presentation.

    mecfsforums have the results from the abstract above, in full: http://www.mecfsforums.com/index.php/topic,19705.0/topicseen.html

    Personally, I think you need a decoding device to work it out. But then I am simply stupid :whistle:
     
    Last edited: Mar 21, 2014

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