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.
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Rituximab for Vaccination-Linked Narcolepsy: A Patient Greatly Improves for 2 Months, then Relapses

Discussion in 'Rituximab: News and Research' started by Hip, Dec 9, 2016.

  1. Hip

    Hip Senior Member

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    A patient who developed narcolepsy and severe psychiatric symptoms after a Pandemrix H1N1 vaccination was given rituximab, and his condition ameliorated dramatically.

    However, the positive effects of rituximab unfortunately only lasted for 2 months, after which the patient relapsed, and subsequent treatments with rituximab did not produce any results. The study is here:

    Transient Impact of Rituximab in H1N1 Vaccination-associated Narcolepsy With Severe Psychiatric Symptoms


    People with narcolepsy have a diminished number of hypocretin-producing cells; hypocretin (aka: orexin) is a neurotransmitter that plays a role in regulating sleep-wake cycles. The evidence points to narcolepsy involving an autoimmune attack on the hypocretin cells, so this is why theoretically rituximab might help.

    @Jonathan Edwards, would you know how we might explain the fact that rituximab was pretty effective initially, but then mysteriously stopped working?
     
  2. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    The way the abstract is written suggests the authors did not really know what they were doing. To be of interest there should be other information that would make it interpretable. They say nothing about when the improvement occurred in relation to the treatment, nothing about efficacy of depletion, timing of further doses etc. They do not even give us an indication of what got better.
     
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  3. Hip

    Hip Senior Member

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    @Jonathan Edwards
    Is it possible that a patient can generate antibodies that target and disable the rituximab protein itself, thereby making subsequent rituximab treatments ineffectual?

    This often occurs in interferon treatment, where after some months of treatment, the body may start making antibodies that target and disable the interferon protein, which then makes further interferon treatment ineffective.
     
    Last edited: Dec 14, 2016
  4. Gingergrrl

    Gingergrrl Senior Member

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    Interesting question @Hip and I am curious about the answer, too!
     
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  5. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    It does occur, but very infrequently. If you think about it rituximab is clever in this regard. Antibodies are made by B cells turning into plasma cells. Rituximab removes B cells, so it will remove the cells that might be about to make antibodies to it.
     
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  6. Hip

    Hip Senior Member

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    @Jonathan Edwards
    Another question if I may:

    We know that you don't believe the molecular mimicry theory of autoimmunity holds much water; but I was thinking that when considering the events that might cause autoimmunity, perhaps one could make a distinction between the mechanisms that merely set the target for the autoimmune attack, from the mechanisms that actually initiate or trigger the autoimmune attack, because these could be completely different mechanisms.

    An analogy would be the difference between aiming your rifle's telescopic sight at a target, versus actually pulling the trigger. You can put many targets in the crosshairs of your telescopic sight, but this has no effect until you actually pull the trigger.


    So looking at the cause of autoimmunity in this way, when an infectious pathogen contain molecular structures that closely mimic specific molecular structures in the body, this could be considered as just setting the target of the autoimmune attack; it puts those molecular structures of the body into the crosshairs.

    But until something actually initiates or triggers the autoimmune attack, which is analogous to pulling the rifle trigger, this setting of the molecular target has not effect.


    And if you look at the causes of autoimmunity in this way, then it may help explain why in say 99.99% of cases, vaccination with the Gardasil HPV vaccine or the Pandemrix H1N1 vaccine does not cause the autoimmune condition of narcolepsy, a disease in which there is a loss of hypocretin-producing neurons.

    Because although within these viruses there may be some proteins that are very similar to proteins in the hypocretin-producing neurons, and so this molecular mimicry points the autoimmune target at these neurons, that alone does not trigger autoimmunity; it merely puts the hypocretin-producing neurons in the crosshairs.

    However, if now another independent event occurs which pulls the trigger of our autoimmune rifle, that's when narcolepsy manifests.


    Does that sound like a feasible idea, or are the some flaws in this reasoning?
     
  7. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    The flaw in the reasoning is that nothing puts anything in the cross hairs in an immune response. The key point is the immune response is a selective mechanism, not an instructive one. The same applies to the way the brain builds memory and natural selection leads to new species. Antigens do not stimulate the formation of new antibodies. It is just that when an antigen arrives any antibody already there that binds to it feeds back a signal for making more of the same. Autoantibodies are normally deleted in bone marrow before they get a chance to see any foreign antigen so an antibody that happened to bind to both self and foreign would never get to be stimulated to make more of the same by the foreign antigen.

    If there are B cells that can make autoantibody and for some reason survive there is no need whatever in the story for another, foreign, antigen, to be involved. The self antigen will drive positive feedback for more production. There is no trigger for making an antibody. All antibody species arise at random, just as mutations DNA in other situations do.
     
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  8. Hip

    Hip Senior Member

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    If they are random, how can we explain certain regularities, such as the cases of narcolepsy that followed Pandemrix H1N1 vaccination?

    It says here that researchers found a viral protein in the Pandemrix vaccine that mimicked the structure of the hypocretin receptor, and they also found autoantibodies to this receptor in people who had narcolepsy appear following Pandemrix vaccination.

    Whereas in the Focetria H1N1 vaccine, which has not been linked to narcolepsy, the researchers found much lower levels of this viral protein which mimics the hypocretin receptor.
     
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  9. Snow Leopard

    Snow Leopard Hibernating

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    I think Hip might be referring to the fact that many molecular mimicry models rely on somatic hypermutation of the BCR, initially stimulated by the (mimicry) antigen, until a BCR is formed that binds to the autoantigen by mistake. But this is of course a minor hurdle, the B Cell still needs to be activated by the T-Cell before it can mature into a plasma cell.

    It begs the question how infections or vaccinations (in rare cases) are seemingly involved in triggering illness.

    The specific antibody in autoimmune narcolepsy is proposed to specific for Tribbles homolog 2 (Trib2)... I wonder how this would fit into the type of models you have proposed for other autoimmune illnesses.

    But I'd also like to ask about Guillain-Barré syndrome, cases of which are often initially triggered by influenza antigens. The specific autoantibodies target gangliosides, which interestingly enough are implicated in cell entry by influenza. Other cases have been linked with bacterial infection, often with those specific bacterial toxins being shown to bind to gangliosides too.
    (though not absolutely essential for infection).
     
    Last edited: Dec 16, 2016
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  10. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I keep re-scanning the narcolepsy literature. Despite the fact that it has been suggested that the immune responses are now understood the more I look the less consistent things seem. There does appear to be an increased incidence after a specific vaccine but the immunological story looks much less firm.

    You can always find a protein in a virus that mimics something in the human. Tested in vitro antibody populations show a degree of cross-reactivity to all sorts of things. A PhD student put on to a project assuming they have to find some 'mimicry' will find some. The unreliability of such findings is shown by the fact that over time people find 'mimicry' with all sorts of different antigens.

    The difficulty in science today is that the majority of young scientists are under the impression that the point of science is to prove the theory you already believe in is right. I had lunch with my old research team from 1990 a fortnight ago. We were discussing this and one of the team was relating how this was exactly what he thought he was supposed to do until he joined our group and suddenly realised that that was not the point at all.

    As I have discussed before, it is perfectly possible that there are exceptions to the general principle I have suggested about mimicry not making sense. However, starting with the general theory that autoimmunity follows mimicry is the wrong end to start. The vast majority of autoimmune diseases show no reason to suggest mimicry. If there are exceptions then they must be making use of exceptional mechanisms. If those can be identified that would be very interesting but for both narcolepsy and Guillain Barre the stories do not appear to have settled out in the way that they have for things like myasthenia gravis or Wegener's granulomatosis. In those conditions there was only ever one story of one antigen and once published everyone else confirmed the findings.

    If hypermutation throws up antibodies with high self affinity and that is all that is needed to produce autoimmunity then we should all be getting autoimmunity every day. Small changes in CDR can induce sudden changes in affinity spectrum so B cells mutating while bound to a microbial antigen should be spinning off antibodies that happen to bind to dozens of self antigens. If this was a relevant mechanism one would end up with a much messier story for autoimmunity.
     
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  11. rosamary

    rosamary Senior Member

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    Surely this is what some of the OLD 'scientists' in the U.K. do with ME research. (Made me laugh when I read that bit).

    You'll have to try to get this concept across to them. They probably haven't heard of it.
     
  12. Gingergrrl

    Gingergrrl Senior Member

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    @Jonathan Edwards Are the autoantibodies which are caused by molecular mimicry the ones that are most likely to be responsive to RTX and if so, is there any type of list?

    I hope this question makes sense written as it does in my mind LOL. I know most uses of RTX are "off label" but am trying to predict effectiveness for certain Auto Abs based on Hip's questions (if such a thing can be determined)?
     
  13. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    In my view autoantibodies are nothing to do with molecular mimicry. It is a old theory that gets trundled out for ever but the evidence for it is pretty much zero.
     
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  14. Gingergrrl

    Gingergrrl Senior Member

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    Thank you and I wish I understood all of this better! I've put a lot of time into learning about IVIG and plan to learn more about RTX next. I appreciate you answering all of our endless questions!

    The center where I am getting IVIG also does RTX (for chemo) and other reasons but I would not be doing it until minimum of six months of high dose IVIG (June 2017) so I have time to learn more.
     
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