The 12th Invest in ME Research Conference June, 2017, Part 2
MEMum presents the second article in a series of three about the recent 12th Invest In ME International Conference (IIMEC12) in London.
Discuss the article on the Forums.

Jarred Younger on Neuroinflammation in ME/CFS and Fibromyalgia

Discussion in 'Latest ME/CFS Research' started by zzz, Jul 15, 2015.

  1. zzz

    zzz Senior Member

    Messages:
    570
    Likes:
    2,536
    Oregon
    There's an excellent article on Health Rising discussing Jarred Younger's work on neuroinflammation in ME/CFS and fibromyalgia. It's entitled The Neuroinflammation Man: Jarred Younger on Inflammation, Fibromyalgia and Chronic Fatigue Syndrome. I found it to be a fascinating discussion of the mechanisms of neuroinflammation, including some of the latest research findings, as well as possible directions for future treatments. I think that Younger makes an excellent case for how central neuroinflammation may be in ME/CFS and related disorders, and how important it is to treat it.
     
    Last edited: Jul 15, 2015
    merylg, rosie26, Wayne and 12 others like this.
  2. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

    Messages:
    1,214
    Likes:
    4,528
    I think its an interesting hypophesis, but I dont like that they completely ignore the results from Haukeland on Rituximab in the article. That would be the first thing I would ask about..
     
  3. Sasha

    Sasha Fine, thank you

    Messages:
    12,782
    Likes:
    34,193
    UK
    This is particularly interesting:

     
  4. Sasha

    Sasha Fine, thank you

    Messages:
    12,782
    Likes:
    34,193
    UK
    And:

     
    Bob likes this.
  5. Sasha

    Sasha Fine, thank you

    Messages:
    12,782
    Likes:
    34,193
    UK
    Bob likes this.
  6. JPV

    JPV ɹǝqɯǝɯ ɹoıuǝs

    Messages:
    858
    Likes:
    1,079
    Sounds like two different approaches to me. Younger seems to be focused on directly inhibiting microglial activity. Rituximab, if I understand it correctly, kills off unhealthy B cells which are replaced with healthy ones. The goal being to control overactive immune system activity.
     
    Last edited: Jul 16, 2015
    Tammy, girlinthesnow and zzz like this.
  7. Sasha

    Sasha Fine, thank you

    Messages:
    12,782
    Likes:
    34,193
    UK
    What do you reckon to this line of research, @Jonathan Edwards? Do they tie in at any point?
     
    Marky90 likes this.
  8. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

    Messages:
    1,214
    Likes:
    4,528
    It seems so JPV, but I dont find it it reasonable to stick ones head in the sand with two thirds responding to rtx.

    Jonathan had a very interesting comment in another thread:

    "There is a mechanism that we have been discussing amongst scientists in the UK interested in the potential role of B cells. Rituximab must be working by removing B cells, I think, since it really does nothing to anything else. If we think the Norwegian data indicate a real effect I think we have to take into account that this effect takes about 6 months to be fully apparent. That points strongly in the direction of the effect being through antibody production rather than some immediate effect of B cells through something like antigen presentation.

    So how would blocking new antibody production over a six month period help if these were not autoantibodies? I think there is a genuine alternative possibility. The antibody that declines with six months of B cell depletion is antibody produced by short lived (mostly splenic?) plasma cells. This sort of antibody probably includes a relative high proportion of low affinity/broad specificity antibody - sort of rough and ready dirty antibody. If we postulate that ME in the chronic phase is due to a hypersensitivity of brain stem/autonomic circuits to very low level immune danger signals it might be that what generates symptoms are the normally trivial levels of cytokine or other signal that occur as part of normal daily clearance of toxic material and low grade microbes. A good part of those signals may be triggered by interactions with 'rough and ready' antibody. So if the immune system is 'flushed out' of such antibody without the ability to top it up then symptoms may improve.

    We considered this idea because we needed to to think about how one might see improvement with rituximab and yet find no apparent 'abnormality' in B cells or antibody levels or specificities.
    "

    Now that hypophesis would be so interesting to pursue.. Or at least hear Youngers` thoughts on
     
    merylg, leokitten, waiting and 5 others like this.
  9. Vojta

    Vojta Senior Member

    Messages:
    156
    Likes:
    278
    Czech Republic
    This excellent article also makes sense in context of neuroborreliosis. As some ME/CFS specialists suggest these days that many patients could have seronegative lyme.

    http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1000659
    "We report findings that implicate microglia, a macrophage cell type in the CNS, as the key responders to infection with B. burgdorferi. We also present evidence indicating that this organism is not directly toxic to neurons; rather, a bystander effect is generated whereby the inflammatory surroundings created by microglia in response to B. burgdorferi may themselves be toxic to neuronal cells."

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847353/
    "...apoptotic death of neurons and oligodendrocytes following spirochete treatment, suggesting that in addition to direct damage by the bacteria, the glial response to B. burgdorferi likely also contributes to cell death."
    "..evidences suggest that inappropriate immune activation may be playing a role during chronic disease. Therefore, the dampening of microglial pro-inflammatory cascades to favor anti-inflammatory pathways following pathogen eradication may benefit patient outcome from Lyme neuroborreliosis, although this conjecture remains speculative at the present time."
     
    Bob, Marky90 and Valentijn like this.
  10. SilverbladeTE

    SilverbladeTE Senior Member

    Messages:
    2,909
    Likes:
    3,562
    Somewhere near Glasgow, Scotland
    Also shows that M.E. *IS* a reasonable term for this illness and should never have been changed for political concerns.
    Nomenclature of disease is often little to do with the mechanics of the illness anyway, based on old terms etc.
     
    Nielk and JPV like this.
  11. Scarecrow

    Scarecrow Revolting Peasant

    Messages:
    1,899
    Likes:
    5,373
    Scotland
    Just thinking aloud here. Bear with me, it may be nonsense.

    Rituximab as a potential therapy for ME came about by chance observation. As far as I know it was because a couple of patients reported an improvement in their ME symptoms while receiving treatment for lymphoma. Fluge & Mella were intrigued and trialled it on a small number of ME patients. Who knows what they were thinking in terms of mechanism of action at this point. Perhaps it was little more than simple curiosity. Could it possibly work or were the patient reports of improvement simply coincident with the lymphoma treatment? Obviously, they now have theories about what could be going on. Significantly, they're not limiting potential therapies to rituximab.

    If the theory of over-sensitised microglia in ME is correct how would you go about joining up the dots between microglia and rituximab? Cytokines, perhaps? Surprisingly (to me at any rate) rituximab has been used in HIV patients with MCD, which is a lymphoproliferative disorder "with marked systemic symptoms attributed to cytokine disarray".
     
    merylg and leokitten like this.
  12. Scarecrow

    Scarecrow Revolting Peasant

    Messages:
    1,899
    Likes:
    5,373
    Scotland
    oops! posted too soon. Sorry.
     
  13. Scarecrow

    Scarecrow Revolting Peasant

    Messages:
    1,899
    Likes:
    5,373
    Scotland
    I don't think that there is a suggestion that MCD is an autoimmune disease. Rituximab therapy decreased the levels of certain cytokines.
    The rituximab was given in four doses at weekly intervals. The cytokine reduction happens relatively quickly but it's long lasting. Here's the link to the original MCD rituximab study.
    http://www.ncbi.nlm.nih.gov/pubmed/19224759

    We already know that the average response time to rituximab in ME responders is very nearly six months. Does this mean that it can't be anything to do with lowered cytokine production?

    Here's where I start speculating wildly. In the absence of a stimulating factor (rather than an agent that actively switches the microglia into an alternative state), how long would it take for the sensitised microglia to resume their resting state? Could we be talking about months?

    Edited to add that I don't think it's necessary for Younger to be thinking too deeply about rituximab.

    If the sensitised microglia theory is correct (for some) and rituximab is effective (for some), it will either be because they are connected in some way or because of subsets.
     
    Last edited: Jul 16, 2015
    leokitten likes this.
  14. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

    Messages:
    1,214
    Likes:
    4,528
    I dont have the answers Scarecrow, But I have a huge gut feeling it*s either antiautobodies attacking.. Something. Or its something to do with how the microglia (or alike?)responds to antibodies. Thats my conclusion from reading the literature on this almost everyday (and of course not my own hypophesises), for a prolonged period of time. Hopefully none of those two alternatives are dead wrong :)
     
  15. Scarecrow

    Scarecrow Revolting Peasant

    Messages:
    1,899
    Likes:
    5,373
    Scotland
    Yeah we're in the same boat there. For certain.

    I can't help thinking about the rapid shifts in symptoms that so many of us can relate to. A rapid worsening doesn't perplex me too much but if autoantibodies were responsible, why would some people experience rapid improvements, which can sometimes manifest in around 15 minutes? Just beyond weird.
     
    Marky90 likes this.
  16. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

    Messages:
    1,214
    Likes:
    4,528
    I think such rapid improvements are rare? Personally I get huge improvement from alcohol, which points towards issues with vasodilation (but then again it could be something else). I guess we are all differently affected by this disease. Which kinda makes sense when you take into consideration that we got different immune systems..
     
    leokitten and Scarecrow like this.
  17. Jonathan Edwards

    Jonathan Edwards "Gibberish"

    Messages:
    5,228
    Likes:
    31,909
    Like the Chinese, US researchers hate anything not invented in their country. Science is a bit like a baseball match for them it sometimes seems. One gets used to it.
     
  18. Jonathan Edwards

    Jonathan Edwards "Gibberish"

    Messages:
    5,228
    Likes:
    31,909
    Microglial activation is one of the areas I think is most worthy of study. I am all for it.

    I hate the term neuroinflammation though. It is a trendy buzzword that confuses everyone. This is not really inflammation in any helpful sense. It is a new type of problem that deserves its proper name - which is:

    microglial activation.
     
    merylg, Sidereal, leokitten and 6 others like this.
  19. Jonathan Edwards

    Jonathan Edwards "Gibberish"

    Messages:
    5,228
    Likes:
    31,909
    To be fair to Younger, I suspect he was not asked to talk about wider options. And a B cell/antibody mechamism would tie in to microglial activation very easily. Presumably autoantibodies or maybe not-so-auto-but-bad-antibodies would activate either microglia directly or via interactions with antibody Fc receptors on cells in the peripheral immune system, with nerve signals sent on to annoy the microglia. There are any number of ways of doing that. One idea I was intrigued by was that it was through the Fc receptor Fc R1, which is on microglia and which might not trigger typical inflammation but might lead to gamma interferon production for instance.

    Thinking about the other current thread on rituximab it might well be useful to give inhibitors of microglial activation for a quick response and then follow up with rituximab or a newer better B cell drug to deal with longer term remission.
     
  20. Scarecrow

    Scarecrow Revolting Peasant

    Messages:
    1,899
    Likes:
    5,373
    Scotland
    If microglia are implicated and effective inhibitors can be found or developed, why not keep taking them?
     
    zzz and Sasha like this.

See more popular forum discussions.

Share This Page