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Trouble understanding the Acetylcholine Antibodies thing

Discussion in 'Problems Standing: Orthostatic Intolerance; POTS' started by Malea, Mar 10, 2018.

  1. Malea

    Malea

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    Hello everyone,


    I‘ve been a silent reader for a while and really appreciate all the shared knowledge and experiences in this place.


    I‘ve recently stumbled over Diana Driscoll and her (and others) theory that POTS may be a result of antibodies against the acetylcholine receptors.


    I have a really hard time understanding what is happening in a case like that, so I wanted to ask if someone could help me make understand.


    If there are antibodies against acetylcholine receptor does that mean the receptor for acetylcholine is blocked?


    And in the consequence is there too much or too low acetylcholine in the body?


    And what do anticholinerg medications do? Do they block the receptors, too? I only find explanations that they are working against acetylcholine... but not what that means, practically.


    Thanks a lot, this is all very hard to understand.
     
  2. Hip

    Hip Senior Member

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    In the brain and nerves, messages are transmitted from one neuron to the next by means of chemicals called neurotransmitters. Acetylcholine is one these neurotransmitter chemicals, but there are also others like serotonin, dopamine, noradrenaline, glutamate, etc.

    What happens is that one neuron will secrete a small amount of a neurotransmitter like acetylcholine, which will then float off, and special receptors on adjacent neurons will detect this acetylcholine that has been secreted. This is because when a neurotransmitter arrives at a receptor, it activates the receptor (like turning on a light switch), and so the receiving neuron detects that a neurotransmitter has been secreted. That is how messages are sent from neuron to neuron, by means of these neurotransmitters and receptors.

    Each type of neurotransmitter will have its own receptor, a receptor that only responds to that particular neurotransmitter: acetylcholine has acetylcholine receptors, noradrenaline has adrenergic receptors, and so forth.

    In POTS, recent evidence indicates that there are autoantibodies which target the acetylcholine receptors, and autoantibodies which target the adrenergic receptors.

    Antibodies are made by the immune system, normally for targeting pathogenic infections like viruses or bacteria. Each antibody has its own target, usually a particular pathogen. However, sometimes the immune system goes wrong, and makes antibodies which target a part of the human body, rather than a pathogen. When that happens, we call it an autoimmune attack ("auto" meaning "self"), and the antibodies that target a part of the body are called autoantibodies.

    So the evidence suggests POTS may be an autoimmune condition in which autoantibodies target and attach to acetylcholine receptors and adrenergic receptors.

    When an autoantibody has attached itself to a receptor, it generally does one of two things (both undesirable): it can block the receptor, so that neurotransmitters can no longer activate the receptor and convey a message; or the autoantibody can actually activate the receptor itself, so that the receptor is constantly switched on, and thus receiving a false message. Either situation causes problems, because it means that the normal messages that are sent from neuron to neuron no longer get through.




    Yes, anticholinergic drugs will also block the acetylcholine receptors. This might be useful in cases where there are autoantibodies attaching to and activating the acetylcholine receptors. The anticholinergic drug will attach to the acetylcholine receptor, and block this receptor from being activated.
     
    Last edited: Mar 10, 2018
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  3. Malea

    Malea

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    Oh my god Hip! This is amazing! Thank you so so much for your answer and for making this stuff so much more understandable.


    It was totally new to me that the existence of these antibodies can result in two different problems.


    Is there any way to find out what thing the antibodies are doing ... if they‘re blocking the receptors or activating them?


    (For example: I‘ve read that a lack of acetylcholine can lead to constipation in the long run. I‘ve always had problems with often being constipated. When I take an anticholinergic drug (H-Blocker, Benzodiazepine) this is worsening so much. Could that be a hint that I‘m someone were the receptors are blocked and not activated?)


    And medications like Mestinon or a supplement like Huperzine A.. they‘re also blocking the acetylcholine, right?
    Could this be the reason they‘re working for some people great (the ones with the activated receptors) and for some really bad (the ones with the already blocked receptors)?
     
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  4. Hip

    Hip Senior Member

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    This is harder to determine, but some studies do try to work this out.

    In the case of this POTS study on adrenergic receptor autoantibodies, they found:

    Autoantibodies blocking the alpha-1 adrenergic receptor
    Autoantibodies activating the beta-1 adrenergic receptor
    Autoantibodies activating the beta-2 adrenergic receptor

    You can see what functions these alpha and beta subtypes of the adrenergic receptor are responsible for in this article.



    This POTS study on acetylcholine receptor autoantibodies found:

    Autoantibodies targeting the muscarinic-1 acetylcholine receptor
    Autoantibodies targeting the muscarinic-2 acetylcholine receptor

    But unfortunately that study did not determine whether those autoantibodies are blocking or activating these receptors.



    And this POTS study on acetylcholine receptor autoantibodies found:

    Autoantibodies targeting the nicotinic alpha-3 acetylcholine receptor
    Autoantibodies targeting the nicotinic beta-4 acetylcholine receptor

    But they did not determine whether these autoantibodies are blocking or activating these receptors.

    Nicotine will activate all nicotinic acetylcholine receptors, by the way, but not the muscarinic acetylcholine receptors.
     
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  5. Hip

    Hip Senior Member

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    For all these various receptors, you can find drugs that agonize the receptor (the technical term for activating the receptor) and drugs that antagonize the receptor (the term for blocking the receptor).

    The following Wikipedia articles are a good source for listing receptor agonist (activating) drugs and receptor antagonist (blocking) drugs:

    Alpha-1 adrenergic receptor agonists and antagonists
    Beta-1 adrenergic receptor agonists and antagonists
    Beta-2 adrenergic receptor agonists and antagonists

    Muscarinic-1 acetylcholine receptor agonists and antagonists
    Muscarinic-2 acetylcholine receptor agonists and antagonists

    Alpha-3 beta-4 nicotinic acetylcholine receptor agonists and antagonists



    In the case of the adrenergic receptors, the finding of the POTS study I mentioned above suggests that POTS patients might benefit from activating the alpha-1 receptor, and there are many alpha-1 agonists in the Wikipedia article that will to this, including midodrine which is used to treat POTS.

    The study findings also suggests that POTS patients might benefit from blocking the beta-1 and beta-2 receptors, and there are many antagonists that can do this: they are known as beta blocker drugs (such as propranolol), which are also known to sometimes help POTS.


    In the case of the acetylcholine receptors, we don't know whether these are being activated or blocked by autoantibodies in POTS, so it's hard to know how to counter these autoantibodies, other than just by trying a few acetylcholine receptor agonists and antagonists, and seeing what the results are.
     
    Last edited: Mar 16, 2018
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  6. Hip

    Hip Senior Member

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    Pyridostigmine (Mestinon) and huperzine A work by increasing levels of acetylcholine, which will increase the activation of all acetylcholine receptors.

    So if you are a POTS patient and had acetylcholine receptors blocked by autoantibodies, pyridostigmine or huperzine A might help.

    Pyridostigmine is used in the treatment of POTS.
     
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  7. lafarfelue

    lafarfelue Senior Member

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    Wow, @Hip! Thanks so much for explaining this all so well. Very grateful to you.

    And thanks @Malea for asking such good questions. :thumbsup:
     
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  8. Gingergrrl

    Gingergrrl Senior Member

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    @Hip this is amazing info that no matter how hard I try, I cannot fully grasp! I have these autoantibodies and I wish I could understand this as well as you do. I have the anti muscarinic and beta adrenergic Abs (but not the anti nicotinic which link to MG).

    I benefit greatly from Midodrine & Atenolol but nothing fully helped me until the autoantibodies themselves were lowered w/IVIG & Rituximab. I still don't get which ones block vs. activate the receptors and I had a horrible reaction to a very low dose of Mestinon in 2014 (in case that gives any clues)?
     
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  9. CCC

    CCC Senior Member

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    @Hip I have to give a plug for Huperzine A here with acetylcholine.

    From a thread on a Lyme forum , these two formed part of a stack that seemed to make quite a difference within a week, and continuing to at least the two-month and the three-month mark.

    We've done a very low-dose version (25 mg huperzine A every second day + ECGC daily + acetylcholine daily), partly because of your cautions on another thread about uridine (which we didn't include) and still seen a significant difference to brain fog, motivation and energy levels.
     
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  10. Hip

    Hip Senior Member

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    Knocking out the autoantibodies (as you did with rituximab) is treating the problem at its source, and treating at source is the better solution, where feasible. Drugs like midodrine may counter the ill effects of the autoantibodies, but such drugs can only do so much.

    I wonder how often rituximab does help POTS. I can't seem to find any trials of rituximab for pure POTS patients.
     
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  11. Gingergrrl

    Gingergrrl Senior Member

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    I was typing on my phone before and now at my computer so I can reply much clearer! Thank you again for all of your info on this @Hip. From what I described, does it sound like I have autoantibodies that are blocking the receptors or activating them? I am negative on the anti-nicotinic auto-antibodies (which rules out myasthenia gravis) but positive on the anti-muscarnic and beta-adrenergic as well as the N-type calcium channel autoantibody.

    I agree that getting at the source was the best solution vs. Atenolol and Midodrine are just symptom control which can only do so much. My case is so odd (as we've discussed) b/c I saw several "POTS specialists" (both cardios and neuros) and every single one confirmed that I had significant POTS, with two TTT's, but felt that the POTS alone did not explain the level of muscle and breathing weakness (this was all pre-IVIG and Rituximab).

    They mostly dismissed the anti-muscarinic and beta-adrenergic autoantibodies (b/c the tests are from a German lab vs. a US lab) but this is pure nonsense IMO. All US docs view the anti-nicotinic Abs as very serious and the cause of myasthenia gravis. I believe that some day, the autoantibodies that I have will be taken just as seriously, and we will be able to test for them in a US lab, even though this is not the case at present. Luckily my own doctors, take them very seriously now, but most do not.

    I don't really know how the calcium autoantibody relates except that it is considered paraneoplastic and links with small cell lung cancer and LEMS (both of which I do not have, I just have the autoantibody at this time). But LEMS can cause muscle weakness similar to mine. It made me wonder if there is a pre-clinical level (or some other term for it) where you have some of the symptoms but do not meet full criteria for the illness. My EMG was abnormal yet this, too, was totally dismissed by the Neuro who did it.

    All I know is that IVIG and Rituximab turned it around, even though I cannot explain what percent came from each treatment, and I do not know what happens when I stop the treatments?

    I know it is done (not sure about studies?) b/c I had several e-mails w/Dr. Jill Schofield who works w/patients with Autoimmune POTS and other Autoimmune Dysautonomias. I have never seen her, and her waiting list is 2.5 yrs long and is closed. She is also not in my state and does not do Skype or phone calls. I told her my treatment plan w/my own doctors and she felt that I was 100% on the right track. She inquired if I could even go higher with IVIG but I was doing the highest dose that I could physically tolerate and we are in the process of tapering it down as it will be two yrs in July.

    Dr. Schofield (who I learned of when I watched her presentation on this topic with Dysautonomia International) said that many of her patients transition from IVIG to Rituximab (or overlap the two) so I know it is done. But my guess is that there is not any funding for research and each patient has to battle it out with their insurance companies like I did (and continue to do). It would be such an expensive research study, I can't imagine anyone funding it. But I would LOVE for it to happen. The IVIG (a year prior to Ritux) also put my MCAS into remission and it has never returned.
     
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  12. Hip

    Hip Senior Member

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    To my knowledge, I don't think it's possible to say whether autoantibodies are blocking or activating a receptor, unless you are performing a study on them. Since you have POTS, you might expect your autoantibodies to behave in the way that was found in the above POTS studies.
     
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  13. Hip

    Hip Senior Member

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    Don't know if you have already seen it, but this paper finds an association between N-type calcium channel autoantibodies and an extremely rare condition known as autoimmune autonomic ganglionopathy.
     
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  14. kangaSue

    kangaSue Senior Member

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    There's often some confusion around commercial acetylcholine receptor antibody testing.The normal test to be done is only the one for Myasthenia Gravis and that only tests for alpha1 muscle-type nicotonic acetylcholine receptor Ab's.

    The alpha 3 neuronal nicotonic acetylcholine receptor antibodies (found in about 50% of cases of Autoimmune Autonomic Ganglionopathy-AAG) can cause a large degree of autonomic dysfunction but the test for this only done well by a few centres worldwide.

    When alpha 3 Ab's are found in a lower positive titre, they can be a standalone cause of chronic constipation but more commonly causes wider GI dysfunction (Autoimmune Gastrointestinal Dysmotility, a limited form of AAG which used to be known as Autoimmune Autonomic Neuropathy)
    https://www.mayoclinic.org/medical-...ces/autoimmune-gi-dysmotility-a-new-direction
    https://www.ncbi.nlm.nih.gov/pubmed/17101331
     
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  15. Gingergrrl

    Gingergrrl Senior Member

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    Thanks and I was not sure.

    This remains above my grasp to understand and retain but I keep trying! I know I have the autoantibodies and have been given the diagnosis of Autoimmune POTS but exactly what the Abs are doing is too complex for me.

    When I was first diagnosed w/the Calcium Autoantibody, I researched it for a solid year and I have done the high resolution lung cat scans 3x so far since it correlates with small cell lung cancer. I just read the paper that you linked and am 99% certain that I read it when I did my initial research in 2016.

    A friend of mine who did the same autonomic testing as me at Stanford was diagnosed with autoimmune autonomic ganglionopathy (AAG) based on the autoantibody that she was positive for but I was not given that diagnosis. I was just told to have further testing for LEMS and lung cancer (which I did) based on my autoantibody.

    Based on my symptoms (from that paper and others that I have read), I do not match with seronegative AAG. I do have low blood pressure, and match on that symptom, but do not match on the others. My doctor ultimately felt my system was in "autoimmune chaos" based on me having 11 autoantibodies (and probably more) vs. having a true paraneoplastic syndrome or cancer. But I wish I could give the entire thing a cohesive name.

    @kangaSue and I discussed all of this in great detail back in 2016 (and I wish I had her brain and knowledge)! I was tested for the myasthenia gravis and MuSK panel (through Mayo's lab, I did not go there) and it was all negative. So I guess I was just tested for the alpha1 nicotinic receptor (although I will never retain that LOL).

    I am not sure if I was tested for this one unless it was part of Mayo's panel that I did in 2016?

    This is part of why I never felt that AAG was the right match for me b/c I never had constipation as a symptom (and the GI problems that I had were part of my MCAS). My symptoms were a much better match with the muscle weakness of LEMS yet not quite a match with that either. I wish there were more researchers interested in these autoantibodies and can only think of three total (one in the US, one in the UK, and one in Germany). I think they are just not of interest to doctors/researchers, like anything else that is obscure.
     
    Last edited: Mar 11, 2018
  16. kangaSue

    kangaSue Senior Member

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    The Mayo PAVAL panel does test for alpha 3 neuronal nicotonic acetylcholine receptor antibodies so yes, you have had it done.
     
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  17. Malea

    Malea

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    @Hip : I wanted to say thank you again for your answers!! Really really helpful.
     
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  18. Hip

    Hip Senior Member

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    I am pleased you found it useful.
     
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  19. Gingergrrl

    Gingergrrl Senior Member

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    Thank you @kangaSue and in that case, I am negative for those autoantibodies.
     
  20. Malea

    Malea

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    Hello everyone, I‘m back with a question ;)


    I now got tested for the autoantibodies at celltrend and I also took part in a clinical trial for POTS autoantibodies.


    At celltrend I was positive for the alpha1-autoantibodies and Muscarinic4. I was also „at risk“ for the beta2-autoantibodies.


    In the clinical-trial-thing I was positive for beta2 and Muscarinic2.


    Someone of you mentioned AGG, which I hadn‘t heard of before. As I‘ve had constipation problems for the last 15 years and an extreme worsening of it under anticholinergic drugs, I think its possible that I could also have AGG. I will try to test the considering autoantibodies for that, but I was told that 50% of the people with AGG are seronegative. So, a negative result would not mean much.


    Back to the POTS-autoantibodies, I have a doctor who would be willing to try medication for the autoantibodies which unfortunately doesn‘t include IVIG. Right now standing more than 10-20 seconds is nearly impossible for me and I additionally wonder if the autoantibodies-thing is triggering my severe MCAS.


    I first thought of an agonist for the alpha1-blocker oder an antagonist for the beta2. Like Midodrine or Proponalol. (Which have reasons against them... like my cyanotic fingers which could be a problem with Midodrine. Or the Mcas, for which my diagnosing doctor once told me that betablockers are a bad idea because of triggering anaphylaxis).

    I even thought about trying Mestinon.


    My doctor prefers to try Florinef. I was thinking that something that would work against the blocking/activation process of the autoantibodies would help me more. Which, in my understanding, Florinef primarily wouldn’t do.

    But now I‘ve read that Florinef also has little glucocorticoid effects. Could that be indirectly helpful with the autoantibodies?
     
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