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The spread of EBV to ectopic lymphoid aggregates may be the final common pathway in the pathogenesis

Discussion in 'Latest ME/CFS Research' started by Kati, May 11, 2017.

  1. Kati

    Kati Patient in training

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    The spread of EBV to ectopic lymphoid aggregates may be the final common pathway in the pathogenesis of ME/CFS

    http://www.medical-hypotheses.com/article/S0306-9877(16)30867-2/fulltext (behind a pay wall, but possibly accessible through Sci-hub.io)

    Author: Willy Eriksen
    Affiliation: Domain for Mental and Physical Health, Norwegian Institute of Public Health, Box 4404 Nydalen, 0403 Oslo, Norway

    Abstract:

    According to the hypothesis presented here, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) develops over 3 steps:

    Step 1 is characterized by the aggregation of lymphoid cells in dorsal root ganglia or other nervous structures.

    The cause of this formation of ectopic lymphoid aggregates may be an acute infection, asymptomatic reactivations of a common neurotropic virus, exposure to a neurotoxin, or physical injury to peripheral nerves.

    In step 2, Epstein-Barr virus (EBV)-infected lymphocytes or monocytes bring EBV from the circulation to one or several of these lymphoid aggregates, whereupon cell-to-cell transmission of EBV and proliferation of latently EBV-infected lymphocytes lead to the presence of many EBV-infected cells in the lymphoid aggregates.

    The EBV-infected cells in the aggregates ignite an inflammation in the surrounding nervous tissue.

    This local inflammation elicits, in turn, a wave of glial cell activation that spreads from the EBV-infected area to parts of the nervous system that are not EBV-infected, disturbing the neuron-glial interaction in both the peripheral – and central nervous system.

    In step 3, immune cell exhaustion contributes to a consolidation of the pathological processes. There might be a cure: Infusions of autologous EBV-specific T-lymphocytes can perhaps remove the EBV-infected cells from the nervous system


    Bolding, underline mine. Text split in paragraph to ease reading.
     
  2. alex3619

    alex3619 Senior Member

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    I wonder how easy it would be to test this hypothesis. It might require specialized testing at autopsy.
     
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  3. RogerBlack

    RogerBlack Senior Member

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    Wouldn't this imply that at least for step 3, Rituximab is useless?
     
  4. Daffodil

    Daffodil Senior Member

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    havent rich people like Cher been doing this sort of treatment in Germany for yrs?
     
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  5. sdmcvicar

    sdmcvicar

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    WARNING: Wild supposition ahead while I'm short on sleep.

    It might also be possible to make a murine model of this. I have no idea how (or even if) EBV has any effect on mice, but one might inject herpes virus-infected lymphocytes to the relevant area and see if/how symptoms are replicated. Also, if this hypothesis specifies a particular cytokine causing the glial activation, methods for inducing the cytokine response in an animal model (hypoxia/LPS/transgenic mutations to increase cytokine expression) may have already been worked out in studies of other neurodegenerative disorders. This could allow labs already studying these models to write grants with a specific emphasis on trying to learn about CFS/ME.

    Told you it was wild.
     
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  6. CFS_for_19_years

    CFS_for_19_years Hoarder of biscuits

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  7. ash0787

    ash0787 Senior Member

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    Would such an EBV infection disappear in symptoms entirely within 5 days and not show up at all on a blood test a month later which was specifically looking for it ?
     
  8. sdmcvicar

    sdmcvicar

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    Herpesviruses are well known to go dormant in cells for periods of time - the same way cold sores disappear to come back in the same place years later. When the virus is active, blood tests can detect viral proteins in the blood from cells that have lysed, and antibodies being used to combat viral infection. If the virus is not actively replicating, it's not necessarily going to show up in blood tests for it, though you should have some residual level of antibodies to it. That's the reason a doctor can tell you if you've previously had mononucleosis.

    That being said, this would be something of an odd niche for EBV to reside in, more akin to viral meningitis. The thing is, if the virus was latent in lymphoid aggregates, you'd need to biopsy them and subject the tissue to PCR sequencing for viral DNA and the few mRNAs that the virus expresses during latent infection. That's the kind of this that @alex3619 was referring to in his post.

    So the short answer is: It's possible.
     
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  9. perovyscus

    perovyscus

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    RTX is talked about in the paper. I am not sure what you mean, here. I think you understand more about CFS than I do, but RTX would reduce viral load in the periphery, and as a result the CNS would have less of a reservoir for T-cell activation, since that interchange exists. The depletion of Th2 could lead (and that's a huge leap) to endogenous production of HSCells which would be differentiated into the needed cells the author describes. I do not know much about how RTX works outside of its targeted action; I am sure researchers have done some work in this regard, but I am not aware of it.

    The conceptual framework the author provides has been the understanding of viral-onset CFS for the past 20 years, and is very similar to the model of multiple sclerosis.

    Ex vivo autologous transplantation has been around for the same period of time, and was successful in a low-quality trial of CFS patients. This treatment is the same for genetic chronic epstein barr virus, which has a much larger and higher-quality evidence base.

    You could biopsy the DRG under anesthesia, but I am not sure what purpose that would serve. Because CFS likely has a blood brain barrier defect, it is unlikely full remission would occur in the stem cell treatment.

    A large scale trial similar to CEBV in CFS would and still is blindingly obvious to me. The upfront cost is so expensive you need a private partner (who holds the platform rights) or a research budget higher than the total allotment for CFS. The platform holder now pursues diseases with higher penetration and for extremely rare diseases is subsidized by the orphan allotment.

    Often times when the conclusion is "More research needs to be done to further our understanding...", that is the conclusion.
     
  10. TenuousGrip

    TenuousGrip Senior Member

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    Interesting.

    Since I scored really high on Stanford's EBV panel, I've looked here and there, online.

    It seems EBV has the propensity/capacity to screw with nearly everything it touches, to explain most of our common signs/symptoms, and to evade detection and opsonization by the immune system with great skill.

    I know EBV has come in and out of favor as a possible underlying cause, but .....
     
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  11. Murph

    Murph :)

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    This is an interesting hypothesis. And I note that it is only a hypothesis - he has none of his own data at this stage, so far as I can tell. But it's interesting that like Davis, he is an outside researcher who has a family member with me/cfs.

    Overall, you'd have to say the chance that he's figured it all out - etiology and cure - just by sitting and thinking is roughly zero percent, but that doesn't mean we can't get some benefit from looking at his ideas.

    1. I like that he proposes a theory that explains the chronic nature of the disease and the acute nature of PEM. I'm not sure too many researchers have a model that does so.

    2. Another aspect I like is he suggests the use of some muscles might cause PEM more readily than others, depending on which nerves are infected. That fits somewhat with my experience. When I use my arms that is normally the end for me, but I can walk a bit. The theory may also explain something I spotted just yesterday when I was looking at an old post by Whitney Dafoe:

    "The pain is a broad ache type, only in the back of the legs, in the back of the thighs and the back of my calves, but not the top of my thighs at all. It's brought on by walking. Specifically walking, crawling doesn't even seem to trigger it much. It's bad enough now that walking to the kitchen and back can trigger it so I've tried to stay in the wheelchair or in bed almost all the time but that's only going to make it worse in the long term."


    3. I like that his theory is potentially consistent with Naviaux, Fluge and Mella, etc. It is clear he is very familar with their work.

    "These findings of Ron Davis and others are fully consistent with my hypothesis. These findings indicate that there are substances in the serum of ME/CFS patients that influence the metabolism of healthy cells that are brought in contact with the serum. These substances may be the cytokines secreted from the activated glial cells (see above)."
     
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  12. CFS_for_19_years

    CFS_for_19_years Hoarder of biscuits

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    Full text:
    http://sci-hub.cc/10.1016/j.mehy.2017.02.011

    https://tracyduvall.com/2017/06/10/eriksens-mecfs-hypothesis-interview/

     
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  13. jpcv

    jpcv Senior Member

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    Not all cass of ME/CFS are triggered / caused by EBV
     
  14. Gemini

    Gemini Senior Member

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    Thanks for posting links to Duvall's Q&A with Dr. Eriksen, @CFS_for_19_years.

    Is the specific, easy "testing" Dr. Eriksen refers to described in his paper, by any chance?

    "The hypothesis that I have presented can explain all symptoms and is consistent with all important research findings. It can be tested in a relatively easy way. And if the test is positive, one has both discovered a major cause of ME/CFS and found a cure. This constellation of aspects is quite unique, I think."
     
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  15. Barry53

    Barry53 Senior Member

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    Is it necessarily confined to EBV? Or is EBV the only one that has been investigated in this context before?
     
  16. Barry53

    Barry53 Senior Member

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    Would be really good for other researchers to cast their eyes over this, and if it looked promising maybe something further.
     
    Sushi likes this.
  17. AdamS

    AdamS Senior Member

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    This isn't something I ever considered before, but it's very interesting. My 2-3 acute episodes/relapses (ones that left me in bed, crawling to the bathroom for a few weeks) all happened after I trained chest at the gym, usually dumbell press with heavy weights! Whether this means that my upper body muscles are more sensitive to PEM i'm not sure...don't fancy finding out either haha!

    For me the lactic ache described by Whitney is predominantly in my quadraceps though, so at the front rather than the back.
     
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  18. Alvin2

    Alvin2 The good news is patients don't die the bad news..

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    Theories are a dime a dozen, we need data
     
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  19. AdamS

    AdamS Senior Member

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    It's hard to argue with that really. I agree that assumptions need testing and validating rapidly in order to know if they are worth perservering with. In my opinion this whole write a hypothesis and wait 3 months just to get published seems ridiculous. Theories are quite good for generating test ideas/experiments though.

    I love what Davis is doing, quickly testing assumptions based on threads of info...e.g TCA cycle deficiencies and then tweaking the tests based on the findings to uncover more about the illness. He's not wasting time and even sends out video updates...now that is the future!
     
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  20. Alvin2

    Alvin2 The good news is patients don't die the bad news..

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    Indeed i agree


    @Janet Dafoe (Rose49)
    I do wonder if all these ideas are getting to Dr Davis to test, though that could easily overload him, he would probably need an assistant who works with his research that we can send theories to who can parse and filter then present to Dr Davis to consider and if reasonable experiment on.
     
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