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The IDO2 tryptophan trap hypothesis

Discussion in 'ME/CFS research news' started by alex3619, Jun 14, 2021.

  1. alex3619

    alex3619 Senior Member (Voting Rights)

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    There are some issues and concerns around the IDO2 tryptophan trap hypothesis about ME. These are my current thought directions, and should not be considered scientific fact. Please comment, add links, agree or disagree, or move this post to somewhere better if you are a moderator.


    Concerns over biases and the Unknown

    There are two big ones here. However let me start with a caveat. If the data is confirmed that over 98% of people with ME have an IDO2 mutation then this is a major leap forward. Its not small. Its the most significant advance in ME research ever. If confirmed, and it leads to tests or treatments, this might win a Nobel prize. Its that big. Of course if its wrong or misleading its a very different thing, which depends on why its wrong or misleading.


    Possible Sample Bias


    The biggest risk is bias, isn't it always? According to a video presentation by Ron Davis perhaps 69/70 patients tested have a mutation in IDO2 that may render this enzyme ineffective. How many of the patients in this sample are severe patients, given the ongoing severe patient study? Its possible that IDO2 may not be causal for ME at all, but rather causal for severity of ME? That is still an advance however.


    Probable Co-Causality

    The more likely concern is that an IDO2 mutation or variant is not causal but co-causal. Indeed this seems overwhelmingly likely. With a prevalence of ME of maybe 0.2% and CFS at maybe 0.4%, and gene variants at maybe 40%, active affect of these variants in this population is very low. Other factors play a huge role, and we are only really discussing the immune activation issue right now. There are possibly other necessary causal factors, and maybe many others.

    It is still possible that its just about immune cells that reach a particular molecular state without needing other factors, but I doubt it. There is however still a chance that this is all that is needed, and perhaps numbers of cells affected are critical in determining outcomes.


    Other Possible Issues of this Hypothesis

    The discussion, at least on forums and maybe not places like OMF, seems to have a focus on blood resident and migrating immune cells, and possibly places like lymph nodes. Probably not all of us, but I would like to expand the focus and explain why this might be very important. Some of this has been touched on in discussions on this forum if I recall correctly.


    Cell Types

    First we don't know its limited to immune cells. Other cells in which the IDO genes are expressed might be impacted. This has many ramifications, but I will discuss some of them in the next concern, even though they also apply here.


    Resident Immune Cells

    Second, the majority of immune cells are not in the blood. They are tissue resident immune cells, especially in the gut. Maybe all tissues have resident immune cells except possibly immune priveliged tissue, though the brain has its own specialized immune system.
    Most pathogens, and some toxins, have tissue specific affinities or impact. With viruses this is in part due to the availability of cell receptors they can bind to.

    So if we have something like Coxsackie virus in a person, it affects tissues including gut, muscle and heart (a specialized muscle). The immune cells in all these places, if they have IDO pathways, may also be affected if the person has an ineffective IDO2 variant. So while the blood immune cells might cause problems all over the body, the affected resident immune cells might cause issues in any tissue that was infected, or by activation from blood or migrating immune cells.

    This means that specific symptoms might arise following the specific pattern of infection of a specific pathogen. No wonder there is so much variation, even ignoring diet, genetics, co-mordities and so on. This raises the question as to whether or not many infections give rise to the core disease, though specific location and severity variations with specific pathogen effects alter symptomology.

    The pattern of tryptophan overloaded cells is also likely to show variation. Their number and distribution are likely to be critical.


    Two IDO2 historical research issues

    It seems to me that the reasons already discussed elsewhere as to why this was missed pretty well cover it. Early genetic studies in ME looked at rare and uncommon mutations. Assumptions meant that researchers were not thinking about common genetic problems.

    Another issue is that IDO2 is a backup gene. With a highly effective primary gene in IDO1, this IDO2 gene was ignored. It did not matter. It took looking into the kinetics (rates of tryptophan conversion over time) to show there was a problem.


    My thoughts on Researchers

    All of our biomedical researchers, and a few dealing with the social and political side, deserve support. I have great regard for Ron Davis and many of his colleagues, but we should not put them on a pedestal. We should listen, critically review, and provide financial and other support when we can. We are participants, even if in a very minor way as engaged patients, or a bigger way as volunteers in studies or regular financial donors.


    Personal Comment

    Am I well enough to blog again? We will see. I have more clarity tonight, right after yet another nap.

    I have had major cognitive issues these last few years, verging on dementia at times, but seem to have been continuously improving over one and a half years of intermittent fasting. My sleep is better, I have fewer symptoms, fewer food intolerances, and better bloodwork. Fasting might not be the reason I seem to be improving though, but I can be hopeful it will continue.

    More blogs to come? This blog only took a couple of hours from first thoughts to the finish, though I will pause for some hours before reviewing it prior to posting. A few hours of moderate clarity matter.

    Let me be clear that there is no sign that fasting is reversing my ME, just improving specific symptoms.
     
    Last edited: Jun 15, 2021
  2. Andy

    Andy Committee Member

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    I assume from this you mean certain selection criteria give prevalences of 0.2% and 0.4%?
     
  3. alex3619

    alex3619 Senior Member (Voting Rights)

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    Yes. The epidemiology is dodgy though, but we do get a sense of the range.
     
  4. Ariel

    Ariel Senior Member (Voting Rights)

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    I look forward to finding out whether there is anything in the IDO2 stuff; it seems that we are likely to get answers about this, at least. You can't say that about much in this area!
     
  5. alex3619

    alex3619 Senior Member (Voting Rights)

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    Whether the theory is right or wrong its great to see hard answers.


    If I am up to it then I will do so. My few hours of clarity are gone for now though. Others might like to give it a go. There is a ton of science on fasting, much of it tied to specific disease or longevity.
     
    Binkie4, Samuel, oldtimer and 3 others like this.
  6. Ariel

    Ariel Senior Member (Voting Rights)

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    Exactly! Will be a step forward either way.
     
  7. Trish

    Trish Moderator Staff Member

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    Amw66 and Hutan like this.
  8. Trish

    Trish Moderator Staff Member

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