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Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

Discussion in 'General ME/CFS News' started by Sasha, Jul 30, 2013.

  1. user9876

    user9876 Senior Member

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    I was wondering if the autonomic system is misfunctioning by having messages blocked with an antibody then what type of effect would this lead to.

    Generally control systems tend to be complex dynamic systems with all sorts of feedback loops that determine how the system responds to both internal and external stimuli. Hence exercise or light might lead to messages that are mis-processes leading to a bad response but this in turn may lead to additional signals (from internal measures) making things worse. Hence the stimuli might cause a small immediate effect that gradually leads to cascade of bad control messages hence a crash. I was thinking it could be a bit like the economy going into recession where the initial build up of bad debt little immediate effect with consequential shock comming sometime later.

    The problem is dynamic systems with multiple feedback loops can be hard to predict, hence the need for modelling.
     
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  2. Sasha

    Sasha Fine, thank you

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    In the CAA newsletter just out, there's a news item that a Michael Cooperstock has partnered with Columbia University and the University of Oklahoma to look for CNS autoantibodies in the blood of samples from the SolveCFS Biobank (I think that's the CAA-funded biobank).

    There's no more info than that but here's a link to the newsletter (that item is on p. 2):

    http://www.cfids.org/solvecfs/summer2013.pdf

    Here's some more info from the CAA's Research 1st site:

    • Autoantibody Study – Michael Cooperstock, M.D., University of Missouri is working with immunology experts from University of Oklahoma and Columbia University to look for antibodies in ME/CFS patients that may be attacking the central nervous system. Each investigator is using their specialized technique to examine specimens from the SolveCFS BioBank.
     
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  3. Marco

    Marco Old blackguard

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    I'd be interested in Prof Edwards views on this also. Autonomic dysfunction and peripheral neuropathy seem to be very common in autoimmune diseases.

    I'd suggested heat shock proteins as a mechanism that fits neatly timewise with the 48hr PEM/PENE described in the International Consensus Criteria. But there's a potentially more direct model. I've been working on a neuroinflammatory model of ME/CFS that involves an imbalance between excitatory glutamate and inhibitory GABA. Lenny Jason proposes a similar model involving neurological kindling where, over time, the threshold at which brain regions develop seizure like activity is reduced until even trivial sensory input can induce seizure like activity that propagates to other brain regions. Kindling may be induced by acute high level stimulus (a severe acute viral infection or concussion - its worth checking out the symptoms of 'post concussion syndrome') or by an ongoing low level infection for example.

    A hyperexcitable nervous system could explain the various hypersensitivities and a 'seizure' state might equate to a 'crash'. Ronnbeck and Hansson propose a similar model of mental fatigue in which the brain becomes 'locked' after overstimulation.

    This model might also result in reduced pre-frontal cortex inhibition of sympathetic nervous system activity leading to a 'sympathetic dominant' ANS state. As appears to be the case in numerous recent studies.

    Antibodies to excitatory or inhibitory neurotransmitters or their intermediaries (antibodies to GAD, GABA, glutamate transporters) or cytokines which promote neuroinflammation (TNF-a in primary biliary cirrhosis) or antimitochondrial antibodies (PBC, MELAS, inflammatory myopathies) could be driving hypersensitivity and a neuroinflammatory vicious cycle.

    Quite why the symptoms of PEM are so long lasting in comparison to the acute attacks seen in stiff person syndrome or narcolepsy for example is harder to explain. Perhaps this is where the underproduction of heat shock proteins comes in?

    Anyway that's my layman's take on it.
     
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  4. Snow Leopard

    Snow Leopard Senior Member

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    I'm curious as to how you worked this out. :)
     
  5. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    It's a long time since I studied the immune system and I can't remember for how long antibodies typically remained bound, but I seem to recall that it's quite brief, and that the binding sets off further reactions. But the
    sounds plausible to me. No individual antibodies would have to remain bound for long - there might just be a continuing stream of strong-binding and perhaps poorly-specific antibodies.

    Hopefully Jonathan Edwards can tell me/us whether either of us is talking rubbish! :)
     
  6. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    What rang alarm bells for me in Sasha's message was the word 'gym' which in me brings out the equivalent of Dracula's reaction to garlic, as does the word 'marathon'.

    I would have thought that either of these activities would risk causing a crash in anyone who has had ME before. How they do it is another question, of course but, as many of you know, my own pet theory relates to acidosis, and loops based thereon, perhaps involving leaky gut in some, and perhaps excessive permeability of other barriers in others (e.g. BBB).

    If correct, this would support the hypothesis that there is a continuing predisposition to (re-)developing ME/other autoimmune diseases, which also seems to be supported by the fact that many people treated with rituximab have to be re-treated.

    My view is that if the underlying abnormality can be found, and lifestyle changes made to adjust to it, recurrence might be prevented. We already have collective experience that certain lifestyle changes help many, notably pacing and dietary changes, so even without having to know exactly why, we can use these. The more severely-affected, and those who don't find any benefit from lifestyle changes alone, may find that a course of rituximab followed by rigorous adherence to pacing and diet does the trick.

    Ever the optimist! :)
     
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  7. alex3619

    alex3619 Senior Member

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    In addition to the remission-recurrence issue, another problem the autoantibody theory faces is why there is a major crash following excess activity or an immunological trigger. I don't think this one is as hard to explain though. If our mitochondria are dysfunctional from immunological attack, then the problems Myhill pointed out with substrate depletion in the mitochondria during exercise might explain the crash. I am not sure about this though. Immunological triggers might also cause clonal expansion of the B cells creating the autoantibodies too. The question is: under what conditions would such clonal expansion occur? Would this tell us something about what is happening?

    On the other hand, the short duration of some crashes might indicate non-antibody causation, perhaps something to do with cytokines.

    In my view every model out there has problems at this point. Its the science that will help sort them out.
     
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  8. Legendrew

    Legendrew Content team

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    After suffering with yet another migraine yesterday I got to wondering how this could tie in with autoimmunity/autoantibodies (for a few months now headaches/migraines have been my most troublesome symptom). I know from reading into this that migraines are a much more common problem for ME sufferes than the general population, with many suffering with them prior to Me, and wondered whether this is true in any other autoimmune disease. As I understand it migraines themselves are not fully understood but it is thought to be problems in bloodflow within the brain. For me at least, during a migraine now I also suffer from an increased internal tremor which I normally only experience after a lot of overexertion.
     
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  9. Marco

    Marco Old blackguard

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    It may not tie directly in with autoimmunity but it does tie in with neuroinflammation where neurotransmitters may be impacted by autoimmunity :

     
  10. froufox

    froufox Senior Member

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    Curiously, Ive also had a lot of these type of symptoms both prior to, and since becoming ill with ME, although in my case they've definitely been a lot more severe since becoming more ill. I was always prone to episodes of sleep paralysis throughout my life since i was a child, but Ive not had that for many yrs now, since my ME became more severe. However, since I became more severe, I started to get narcolepsy a LOT (not sure if it was "true" narcolepsy but it was an excessive desire to sleep and feels like you cannot control it ... it always seemed related to my gut/what i had eaten ... I thought it was due to "brain allergies"). Ive not had that for many yrs either now, but in the last 10 yrs or so, Ive the hypnagogic hallucinations quite regularly, and recently Ive had them almost every night. Again, in my case, taking antibiotics did lessen the frequency. But anyway its interesting how the symptoms of narcolepsy have changed over the course of my illness, if it is true narcolepsy, as ive never been diagnosed officially.

    sorry, this was a reply to Marco's post no. 359 on page 18, but i messed up on the quote thing!
     
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  11. user9876

    user9876 Senior Member

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    I did a little monte carlo simulation selecting people from a large set with the appropriate mix of profiles then looked at the distributions.
     
  12. Jonathan Edwards

    Jonathan Edwards Board Member

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    The remarkable thing about antibodies is that they are proteins which are all more or less identical except for their antigen binding sites, which are carried on the ends of two arms a bit like crab claws. The binding sites can be more or less any shape and so can mimic any other receptor or enzyme or adhesion protein you like, at least in theory. Some autoimmune diseases are easy to explain. In people with antibodies to the basal layer of skin they makes the skin come off in blisters - not too puzzling. In RA things are more subtle because the antibodies are not in fact against joints. They seem to cause the problems they do by forming small complexes that happen to bind a particular receptor. That receptor turns out to be present in joints, pericardium, pleura, lung, eye sclera, subcutaneous tissue, but only at pressure points, bone marrow, lymph node and spleen. And the disease affects those 9 places and nowhere else much. It was finding something that was present at all 9 sites that led us to the B cell story and rituximab.

    So the autonomic system could be affected by antibodies to neurotransmitters or receptors or it could be that autonomic nerves can get caught up in some more general antibody interaction. The question would be how all the different features can be tied together with one explanation. The problem might be that this might be oversimplifying if there are several diseases going on. Cytokines or neurotransmitters and receptor might be in the story. And even with one story different symptoms might come from different steps in a chain. The problem for me is less thinking of an explanation and more of trying to narrow things down.
     
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  13. Jonathan Edwards

    Jonathan Edwards Board Member

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    I think that's fair. Once bound antibodies tend to get processed either inside or outside a cell within minutes. On the other hand an antibody that itself triggers no reaction, like maybe in myasthenia gravis, might sit around on a receptor for hours or even days. In lymph node and perhaps bone marrow there is a special environment that can hold antibodies in place on the surface of dendritic cells possibly for months or years but that is not likely to be relevant here. One odd thing about rituximab (itself an antibody) is that it disappears quite quickly from the bloodstream but goes on affecting bone marrow for at least 6 months.
     
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  14. Marco

    Marco Old blackguard

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    Hi Froufox - Not to derail the conversation any further, when I was having the sleep paralysis/ hypnogogics (now 25 years plus ago) - these were the full blown incubus/succubus stuff of legend - you feel that there's a person/thing on top of you holding you tight down and squeezing the breath out of you -plus in my case the auditory hallucinations (in case anyone thinks I'm slightly unhinged - these are fairly common and these are common symptoms). Anyway, I eventually convinced myself that I wasn't being stalked by something supernatural ;) and that the attacks would eventually fade even if it took a few hours. The moment I accepted them and was no longer afraid of them they started to fade away and never returned.

    Like you I do recall similar but not as frequent symptoms in childhood (well prior to ME/CFS). I occasionally used to wake up from a repeating nightmare that I was smothering in the bedclothes.

    Definitely some predisposition there I think.
     
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  15. froufox

    froufox Senior Member

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    eek that sounds very unpleasant so i'm glad u don't get them anymore! Interesting how accepting them made them go away in your case, thats never happened with me even tho they don't really bother me hugely. Yes agree about the predisposition. My hypnagogic hallucinations arent very nice but i can cope with them...they usually involve spiders of one sort or another. Either a huge one suspended over my body, or others on my bed or crawling up the wall, not nice as im quite scared of spiders, but id rather have that than the sleep paralysis..always hated that! :eek:

    yes sorry to derail the thread!
     
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  16. Marco

    Marco Old blackguard

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    Is there any possibility that this might offer an alternative mechanism to the blood brain barrier problem and why 'stress' has such negative consequences in a number of autoimmune diseases (another mouse model) ?

    Mood Is Influenced by Immune Cells Called to the Brain in Response to Stress

    http://www.sciencedaily.com/releases/2013/08/130821151602.htm

    Thanks to kaffiend for posting this on another thread.
     
  17. Jonathan Edwards

    Jonathan Edwards Board Member

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    To be honest I find that study difficult to interpret. Monocytes migrate into all tissues pretty much and I think it may be a mistake to call this 'immunity'. I am not clear why they thought the monocytes were causing anxiety if they were already causing the anxiety socially. I fin this sort of mouse study a bit far away from the problem in hand!
     
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  18. Legendrew

    Legendrew Content team

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    @Jonathan Edwards Can I just ask you your opinions on the pathogen side of things- I think this has already been touched upon a few times but I just wanted to clarify things in my own mind. I know from experience a large number of people believe that chronic viral, bacterial and fungi infections could be the causative factor in this disease and I know numerous studies have been carried out in the past and are currently underway looking to find these things. From a personal viewpoint I find it hard to believe considering that most of those suggested are seemingly just as prevalent in the general population. Would the symptoms people associate with these chronic infections come down to the autoimmune process itself or would they come through the proposed sensory gating issues leading to overreaction within the body to inert, chronic infections? I understand that people get very heated sometimes when it comes to people disagreeing with the pathogen ideas, but personally I don't think the evidence is there to support it and if I was I think the studies looking at this would have come up with more startling results.

    Certainly some people see benefit from antiviral drugs such as Valcyte however in this recent study http://onlinelibrary.wiley.com/doi/10.1002/jmv.23713/abstract the results have been very disappointing leading me to believe that either the sub-set of patients whose primary issue is chronic viral infections are very small, or perhaps those who improve on Valcyte in the longer term are perhaps benefiting from its immunomodulatory effects and not necessarily its antiviral properties. To me this would make more sense considering people who also improve on Ampligen which has similar proposed immunomodulatory effects.
     
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  19. Jonathan Edwards

    Jonathan Edwards Board Member

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    Yes, I agree. I doubt the persistent presence of pathogens is important. I think the symptoms are more likely to be caused by the mediators that normally respond to pathogens but in ME they just keep going without, or with no more than the trivial endemic microbes that we all have.
     
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  20. Firestormm

    Firestormm Guest

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    Can you expand on that a bit more, Professor? Especially in respect of the 'mediators' and how they might result in the kind of symptoms we collectively experience perhaps. Thanks.
     
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