International ME/CFS and FM Awareness Day Is On May 12, 2018
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Webinar with Dr. Alan Light on Novel Gene Variants in ME/CFS and Fibromyalgia

Discussion in 'Upcoming ME/CFS Events' started by RL_sparky, Jan 31, 2017.

  1. M Paine

    M Paine Senior Member

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    To clarify, if more randomly recombinated B-Cell receptors are activated by means of innate signalling, then there is a greater chance that auto-immunity may occur, by virtue of more general activation occurring. Those same cells would be unlikely to mature in absense of innate signalling via the two-signal requirements for adaptive immune activation
     
    Last edited: Feb 6, 2017
  2. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    No I don't think it is beside the point. B cells are not activated by general business of innate mechanisms. They are activated by specific signals relating to their antigens. And if the antigens are self they are deleted. In order to explain autoimmunity one has to find a reason why a specific negative feedback signal for a specific antigen is specifically converted into a positive feedback signal just for that one antigen. There is no reason to think that general activation of anything is relevant.The maths of the dynamics is wrong.

    Put another way, if the generation of auto reactive B cells capable of survival is random then it will not increase because of non random activation states. Random is random.

    I have no idea what dirty little secret you are referring to. The way the immune system works is pretty well understood and we have every reason to believe it follows understandable mathematical models.
     
  3. M Paine

    M Paine Senior Member

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    The dirty little secret was in reference Dr Janeway's 1989 talk at the Cold Spring Harbour Symposium. In which he theorised that the innate immune system is responsible for recognising microbial components, and subsequently sending a second signal to lymphocytes for activation (the first signal being an antigen). Without that second-signal, activation is unlikely to occur. The "Dirty little secret" portion refers to immunologists of the day conducting adaptive immune experiments, all of which relied on using alum adjuvant to activate innate immunity. Thus bridging the gap between adaptive and innate immunity. I had mistakenly thought that this piece of immunology history was more famous than perhaps it is, my apologies then if it came off as antagonistic. It's quite an interesting talk he gave

    Perhaps I could ask or describe things a little differently. If we have a billion new BCR's generated a day, would you guess that in a person, if some of those naive cells contain potentially auto-reactive anti-bodies? Would then in that case, greater amounts of innate immune activation translate to a greater incidence of acquiring auto-immunity? IE a greater chance of some of those B-Cells maturing and proliferating?
     
    Last edited: Feb 6, 2017
  4. Barry53

    Barry53 Senior Member

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    The medical knowledge is way beyond me, but presumably the fundamental physics must still apply. For -ve feedback to translate into +ve feedback, the phase shift round the loop has to change (by definition). And to then be unstable the loop gain must be > 1. I imagine the loopback paths can get very complex in biology, and maybe the paths themselves get corrupted in their routing and/or composition, thereby maybe changing the feedback charactersitics?
     
    Last edited: Feb 7, 2017
  5. Forbin

    Forbin Senior Member

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    I don't know how germane it is, since it was a study of mice, but this 2012 paper asserts that autoimmune disease can arise when autoantibody producing B-cells fail to be deleted under certain circumstances.

    This from the 2012 Science Daily article (bolding mine):
    The 2012 paper in Immunity is linked below:
     
    Last edited: Feb 7, 2017
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  6. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I had forgotten that quote. Janeway was an interesting heretic and made a useful contribution in making people focus back on innate signalling systems. However, I take all that as read in what I say.

    I think the answer is still that there is no reason to think that activation through these innate pathways is more likely to allow auto reactive B cells to survive. The key point is that most autoimmune processes, once started, seem to go on more or less indefinitely without any evidence of continued presence of any foreign material that might activate through innate receptors. The autoimmune reaction has to run its own show and if it can do that it can do it without any help from innate signals at the beginning too.

    Innate signals that bind to things like carbohydrate receptors or indeed adjuvants will skew cytokine profiles for a while and shift the kinetics of B cell proliferation and selection. However, it is just as likely that this would make it less likely that auto reactive B cells would survive than more, I think. There was once a popular theory that autoimmunity was more likely in hygienic societies because B cells and T cells would be more likely to misbehave if they got bored from not seeing enough microbes. More TNF and less IL-10 might well reduce B cell misbehaviour for instance. I think it is a toss up and all the epidemiological evidence we have is that autoimmune diseases are independent of microbial triggers. ME/CFS might be an exception but I remain to be convinced. And there remains the question of how innate activation can break tolerance long term. I am doubtful that that has ever been shown to occur in humans with realistic amounts of innate signal. Injecting rats with the equivalent of a kilogram of Freund's adjuvant does not seem to me to be relevant.
     
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  7. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    That is the theory we built for RA. We reckoned that the process had 55 essential steps with many negative control steps but 4 steps that might allow positive feedback. We identified a flip from negative to positive feedback for two of these directly involved in proliferation of rheumatoid factor producing B cells. The interesting thing was that these flips looked like built in bugs in the selection programme that the immune system would probably be constantly evolving to minimise.
     
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  8. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I am afraid this is the same old stuff that has been trotted out since I was a student in the 1970s. Scientists seem to be very poor at moving on from fashionable but ill-founded ideas. Immunologists who work on mice tend to know nothing about the epidemiology of human disease. They should stop and ask themselves whether their ideas would match up with what we know about human disease but they are too cocooned to take the trouble. Sadly, the immunology scene seems to have moved into a dumbed-down 'post-truth' scenario much like politics. Old ideas that were found not to work fifty years ago are trendy again. The idea of antigens escaping tolerance because they hide away in special tissues is at least that old and has systematically failed to predict anything useful. But nowadays nobody bothers to check the old literature.
     
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  9. alex3619

    alex3619 Senior Member

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    That seems to be a widespread human trait, and I think in part due to logistical limits as well as more obvious bias. I see that in medicine (generally) and economics. It probably applies elsewhere. Many popular ideas in economics were debunked decades ago, with mathematical disproofs, but still they are taught to budding economists. One of the key principles, which is people can be considered rational agents in economic models, is thoroughly debunked. I think another that will be abandoned in time is the notion that everything, including resources, can be equated with money.
     
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  10. bertiedog

    bertiedog Senior Member

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    @Jonathan Edwards This might be a little off topic so please excuse me but its something I have wondered about and would love to know your answer.

    Is there anyway that you know of that heavy metal poisoning with something like mercury both from dental amalgams and vaccines could set off an autoimmune reaction? The reason I ask is that I was diagnosed through both blood tests and hair analysis that I had well over the range of mercury and around that time also found out that I had high antibodies to my thyroid. At that time it was anti thyroglobulin ones but now its the peroxidase ones.

    Dr M, the well know ME/CFS doctor said that not only did I have this raised level in my blood but my immune system was activated by it and it was activating the immune system. From memory I think it was my lymphocytes that were used for testing.

    Hope you don't mind my asking but I am trying to understand all that I can about autoimmunity.

    Thank you.

    Pam
     
  11. M Paine

    M Paine Senior Member

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    Thanks for the detailed responses @Jonathan Edwards.

    Yes, coincidentally the first PAMP was discovered a year or two after that symposium, so it was certainly on the money.


    I'm not sure I follow this, in order for an auto-reactive B cell to mature, innate activation is required right? Otherwise that B-cell is unlikely to mature, even when it encounters antigen which it can bind. That potentially auto-reactive B-Cell would simply turn over, die, and never be a problem.


    Yes, all this assumes that tolerance to self has been broken, and that B-Cells are being exported which are potentially auto-immunogenic. I'm not sure if Dr Light has the view that innate activation has a role to play in the break down of tolerance, I can't really imagine how innate activation would break tollerance.

    I guess the point I was trying to make, is that an increase in innate activation may increase the likelyhood of a person who is susceptible to auto-immunity, aquiring auto-immunity. This assumes that the person is producing auto-reactive B-Cells (broken tolerance).

    This could be one possible explanation for the observation that CFS follows infection, or vaccination, as innate activation is a requirement in order for B-Cells to mature and proliferate
     
    Last edited: Feb 8, 2017
  12. M Paine

    M Paine Senior Member

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    For those of us who don't know all the old literature, how do B-Cells negatively select for tissue specific antigens?

    In the thymus, medullary thymic epithelial cells present T-Cells with tissue specific antigen for negative selection, is there an analogue for B-Cells in humans?
     
  13. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    As you know, T is for thymus as a site of education and B is for Bursa of Fabricius (birds) or bone marrow (humans) as a site of education. B cells under negative selection for auto reactivity in the bone marrow before they circulate. It is not clear to me that there is quite the same system as in the thymus where more or less every transcribable self protein is presented to naive T cells for negative selection. However, the stereochemistry of antibody and T cell receptor binding is very different and so the need for comprehensive negative selection of B cells in bone marrow may not be as acute as for T cells. There is also negative selection of B cells peripherally from suppressor or regulatory T cells that recognise peptides from self antigens. There is a further negative selection is a B cell meets a self antigen without attached complement.

    Despite all these mechanisms there is a potential possibility of a B cell clone being expanded following stimulation by foreign antigen and having a B cell receptor that binds tightly to a elf epitope. However, this is probably not enough to be a problem, except in unusual situations such as where the antibodies that result act as endocrine receptor agonists or antagonists. Antibody binding to self antigens happens all the time and only causes trouble if complement is engaged by cross linked immunoglobulins or some other secondary mechanism.

    The key piece of evidence, though, I think is the fact that we meet millions of foreign antigens with close similarity to self every day and for at least 99.99999999% of these encounters no autoreactivity arises. When auto reactivity does arise there is no evidence that there is any cross reactivity to anything in particular. The whole cross reactivity story arose from what was thought to occur in rheumatic fever in the 1960s but in the end nobody ever found any evidence for such in rheumatic fever. As we came to understand effector mechanisms better it became clear that rheumatic fever lesions are almost certainly caused by immune complexes containing the foreign antigen. There is no plausible mechanism invoking self-reaction that I know of.
     
  14. Barry53

    Barry53 Senior Member

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    Are the control loops well enough understood to be able to model mathematically in terms of control theory? e.g. Is it, for instance, possible to identify if the control structure entails cascade control loops (nested, where an inner loop's controlled output provides the setpoint/target input for the next-outer loop), and their behaviours; etc,etc. If so, is it then possible to create software simulations of these control 'strategies' for sub-system under investigation? If this is possible you can then of course run accelerated what-if experiments, much faster than in real time. Even if the modelling only partially reflects the real world, but is in the right ball park, it might still be possible to experiment with it and see what maybe gets it closer to real world behaviour (and misbehaviour), and maybe learn something that way? Sometimes half-stumbling on a possible answer can narrow the research focus and complexities, albeit of course sometimes in completely the wrong direction!

    I suspect I may not understand the answer, but I would nonetheless like to ask: Did you get to understand what it was that caused the two control steps you mention to flip from -ve to +ve feedback, when investigating RA?
     
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  15. M Paine

    M Paine Senior Member

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    Thanks @Jonathan Edwards.

    It's hard to work out what would be causing auto-reactive B-Cells to mature in absense of cross-reactivity... I'm hearing that your view is that likely occurs in absense of foreign antigen?

    Switching direction a bit here, but do you know if anyone has tried monoclonal antibodies against regulatory T-Cells (If such a thing exists) in conjunction with BCDT in any other autoimmune diseases?

    * Edit: Last question has been patially answered elsewhere in this thread: http://forums.phoenixrising.me/inde...-use-of-very-low-dose-cyclophosphamide.38523/
     
    Last edited: Feb 9, 2017
  16. Forbin

    Forbin Senior Member

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    I guess my question is...

    If ME does turn out to be an autoimmune disease, what is the significance of the number of patients who report a sudden onset in the aftermath of some kind of "flu-like" infection (influenza, strep throat, enterovirus, etc...). In his talk in Norwich, Dr. Fluge said that, "It's a sudden start in many patients. 70% [of ME patients] get this after infections."*

    If the disease is autoimmune, what, if any, relationship is there between infection and the development of autoimmune disease?


    *[In addition to "infections," Fluge's slide also mentions "other immunological triggers."]
     
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  17. Barry53

    Barry53 Senior Member

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    Also, what % of ME sufferers who's ME were apparently triggered by an infection, also have some kind of immune issue such as hayfever, eczema, etc, and maybe food allergies.
     
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  18. Tyto alba

    Tyto alba

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    I wonder if it is possible that when ME develops and sets in permenantly it is the result of the entry into a hysteresis state, through one or probably more likely several loops.
     
  19. trishrhymes

    trishrhymes Senior Member

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    Oxford dictionary:
    Hysteresis:
    The phenomenon in which the value of a physical property lags behind changes in the effect causing it, as for instance when magnetic induction lags behind the magnetizing force.

    I gather it's a term used in physics. There is a danger in popping it into a discussion about a medical condition, especially one which has been wrongly described by the very similar word 'hysteria'. Especially when it's being read by people with a bit of brain fog.....

    :aghhh:
     
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  20. Tyto alba

    Tyto alba

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    Most definitely nothing to do with hysteria!


    Edit to add:
    I was wondering if such looping behaviour could be the driver behind the cycle of ME symptoms.
     
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