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Exploring autoimmunity relating to glycolysis (metabolism of glucose) & the enzyme enolase

Discussion in 'General ME/CFS Discussion' started by Bob, Jun 11, 2015.

  1. Bob

    Bob

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    I wasn't sure if this should be a personal blog or a general discussion. I'm brain-storming and exploring an idea, or a potential hypothesis.


    I've been thinking about the two recent papers that show an increase in glucose in blood/tissue in metabolic studies of ME/CFS. One by Prof Julia Newton et al., and the other by CW Armstrong et al. (BTW, @JaimeS has written a blog re the Armstrong paper, and my thoughts follow along similar lines.)

    Both studies found relatively increased levels of glucose: Newton in cultures of tissue biopsies, and Armstrong in blood of ME/CFS patients. This seems to suggest that glucose is being under-utilised or under-metabolised in the energy metabolic pathways. The most obvious metabolic pathway to look at is glycolysis, which is the central glucose energy metabolic pathway that converts glucose to pyruvate and produces ATP in the process.

    There's a helpful wiki page on glycolysis, that outlines all of the steps in the process: http://en.m.wikipedia.org/wiki/Glycolysis

    If any stage in the glycolysis pathway is inhibited or blocked, for whatever reason, then it would probably mean that glucose would not be fully utilised, as there would be a blockage in the pathway.

    Each step of the glycolysis pathway uses a specific enzyme. Last night I couldn't sleep, so i had a look through all the stages of glycolysis and the enzymes used for each stage. (See the glycolysis wiki page, for the list of the enzyme reactions, starting here: http://en.m.wikipedia.org/wiki/Glycolysis#Sequence_of_reactions)

    I had a look to see if there were any known disorders involving deficiencies in the enzymes, to see if there were any similarities or overlaps with ME/CFS. There are recorded disorders in relation to deficiencies in most or all of the enzymes, but none of the disorders seem to quite fit the symptoms of ME/CFS. e.g. Most of them involve anaemia, and at least one of them involves brown urine. The nature of the disease for each of them does not look like ME/CFS.

    Until I got to the penultimate step in glycolysis, which uses the enzyme enolase. There are a couple of disorders involving enolase that i came across. One is a genetic-related deficiency of enolase and the other is an autoimmune illness called Hashimoto's encephalopathy.

    For enolase deficiency, the genetic disorder, the symptoms are listed in wiki as: "Symptoms of enolase deficiency include exercise-induced myalgia and generalized muscle weakness and fatigability, both with onset in adulthood. Symptoms also include muscle pain without cramps, and decreased ability to sustain long term exercise." Similar to ME/CFS? (This is the citation used: http://www.ncbi.nlm.nih.gov/pubmed/11506403)

    For the autoimmune illness related to enolase, Hashimoto's encephaolopathy, the clinical features and laboratory/radiological findings are listed in wikipedia. The clinical features are not identical to ME/CFS but there is much overlap including: concentration and memory problems, headaches, sleep abnormalities. And also the following features, which i often see reported by some ME/CFS patients including a good proportion of severely affected ME/CFS patients: transient speech problems, disorientation, lack of coordination, tremors, jerks in muscles, seizures, partial paralysis on the right-side (Vanessa Li had partial paralysis on one side of her body, if my memory serves me well). Familiar? I've seen all of these symptoms discussed on this forum. (But there are other symptoms listed that we do not regularly see in ME/CFS.)

    I'm not familiar with laboratory findings in ME/CFS, and other people might like to look to see if there are any familiar patterns there. But what caught my eye, and which seems quite significant to my personal circumstances, and perhaps many of us (and perhaps it's something that @Jonathan Edwards might be interested in?) is an association between this autoimmune disorder and a variety of autoimmune thyroid disorders. Thyroid hormone abnormalities are present in more than 80% of cases. The disorder is associated with raised thyroid stimulating hormone (TSH) levels (which i currently have without other abnormalities) in 55% of cases. There is subclinical hypothyroidism in 35% of cases. Overt hypothyroidism in 20% of cases (which i had transiently for about a year, a few years into having ME) (Is a 20% rate of clinical hypothyroidism a similar rate to ME/CFS patients?) And hyperthyroidism in 5% of cases. (I currently have some severe hyperthyroid symptoms, but no abnormal test results other than raised TSH.) So there is a variety of thyroid autoimmune issues related to this autoimmune disorder. However, perhaps unlike many ME/CFS patients, it says that "Thyroid antibodies - both anti-thyroid peroxidase antibodies (anti-TPO, anti-thyroid microsomal antibodies, anti-M) and antithyroglobulin antibodies (anti-Tg) - in the disease are elevated but their levels do not correlate with the severity." (Or perhaps many of us do have elevated thyroid antibodies? I can't remember the results of the forum survey that Jonathan Edwards carried out.) But it doesn't state what proportion of patients have thyroid antibodies, and it doesn't give a reference for the assertion, so perhaps that doesn't apply to all patients with the disorder.

    For treatment of the autoimmune disorder it lists the following:


    Anyway, that's as far as I've got in my exploration. It might not be relevant to ME/CFS but perhaps it's food for thought? There do seem to be very similar and specific overlaps between ME/CFS and both of these enolase disorders. I'm not saying that ME/CFS is the same as these specific disorders, but perhaps they are related in some way, directly or indirectly? And I wouldn't be surprised if a minority of us have one of these anolase disorders, but are misdiagnosed.






    Note to self - extra wiki reference - there's more about cellular respiration, here:
    http://en.m.wikipedia.org/wiki/Cell_energy
     
    Last edited: Jun 11, 2015
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  2. Bob

    Bob

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    For anyone familiar/interested in the genetic aspect of ME/CFS, perhaps you'd like to have a look at this interactive diagram (i came across it last night) and see if it has any resonance for you? I think it labels and describes the genes associated with each step of the glycolysis pathway: http://www.wikipathways.org/index.php/Pathway:WP534

    In terms of my discussions, above, in relation to the enolase enzyme, we'd be looking at EN01, EN02 & EN03 on the diagram (situated between 2P-Glycerate and P-enolpyruvate).

    I don't know if this is something that @Valentijn might be interested in?
     
    Last edited: Jun 11, 2015
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  3. Snow Leopard

    Snow Leopard Hibernating

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    It is an interesting hypothesis, but keep in mind that enolase is an intracellular enzyme, which means that for it to be disrupted by an autoantibody, those autoantibodies must first enter the cell. In the case of Hashimoto's encephaolopathy therefore, it may well simply be a marker of the illness (eg cell damage, that led to the immune system being sensitised to a ubiquitous enzyme), rather than a cause.

    On the other hand, the following paper claims that it can enter the cell (I wonder how?):
    http://www.sciencedirect.com/science/article/pii/S0896841104000721
     
    Last edited: Jun 11, 2015
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  4. Jonathan Edwards

    Jonathan Edwards Senior Member

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    I think Hashimoto's encephalopathy was flagged up before but we did not go into it in detail. It definitely appears to be linked in some way to H's thyroid disease. Alpha enolase crops up in a number of autoimmune disorders and so is an antigen that I would be slightly cautious about. It may be a protein that rather easily picks up antibodies for non-specific reasons. On the other hand it may be a 'hanger-on' autoantigen like heat shock protein 60, which seems to be targeted alongside more specific autoantigens in several diseases. So alpha enolase is probably very interesting in autoimmunity, but it may not be a classical autoantigen and it may not be the one that is functionally important.

    As mentioned previously, autoantibodies getting into cells is no longer a mystery because they are transported in by TRIM21.

    It is all very tantalising, but whether it is the answer to a real ME subset or who knows!!
     
  5. JaimeS

    JaimeS Senior Member

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    Thanks, Bob! I really wanted to do that next, but I'm kind of wiped from the blog post - I appreciate that you took this on! (But I am sorry you couldn't sleep...) :hug:

    I think a lot of the illnesses with autoimmune aspects are going to have similar symptoms, so I am tentative about directly linking them, anymore. However, I think it's fascinating that, if corticoids fail, the physicians turn to antimicrobials like chloroquine. Chloroquine is an anti-malarial, and there are certainly malaria-like features in ME as I experience it, including (at the start) a relapsing-remitting course you could set a clock to. (I know it's used in autoimmunity, too; I just think it's interesting.)

    I applaud your research acumen! Is there anything we could do/try that might help provide evidence linking this particular step of glycolysis to our condition? Quinine-related compounds and corticoids help so many conditions... is there any specific way of testing for this?

    -J
     
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  6. Bob

    Bob

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    Thank you Jamie. Your blog gave me a gentle kick-start into looking at this, so thank you for that. :)

    Some of the treatments mentioned, for the enolase-related autoimmune disorder, are being looked into for ME/CFS by Drs Fluge & Mella (i.e. cyclophosphamide, methotrexate). If my memory serves me well, I think methotrexate was not found to be very helpful, but they've found cyclophosphamide to be fast-acting and helpful so far and have recently moved into a phase II trial. (But my memory isn't always accurate.)

    Some ME patients find steroids very helpful, but I think others have found them counter-productive.

    I think intravenous immune globulin has been tested without much success.

    I'm not very familiar with azathioprine and chloroquine, except what you've said about chloroquine. And azathioprine has been discussed on the forum in various places. e.g. here.

    I'd quite like to read up more about the two enolase disorders, to see if Wikipedia has described their symptoms and features accurately. And to make more detailed comparisons with ME/CFS.
     
    Last edited: Jun 29, 2015
  7. halcyon

    halcyon Senior Member

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    I take their wording to mean that the antibodies are entering the tissue from circulation, not that they are penetrating into cells.
     
  8. Jonathan Edwards

    Jonathan Edwards Senior Member

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    Although it does not seem too explicit, since the antigen is intracellular and they report induction of apoptosis they pretty much have to be implying that the antibody is getting into cells I think.

    A word of caution. I have surfed through the stuff on alpha-enolase a bit more and some warning bels are ringing. Autoantibodies to this antigen have been involved in stories that have melted into thin air. It is one of those antibodies that people report finding in almost any disease they think ought to have antibodies but nobody can find one.
     
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  9. halcyon

    halcyon Senior Member

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    Good point, I didn't catch that part.

    Interesting. Know of any good papers discussing this mechanism? All I can find is about TRIM21 dealing with antibody coated pathogens once they've already entered the cell.
     
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  10. Bob

    Bob

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    Thanks for the word of caution. It's all new to me (learning about the metabolic pathway, the enzyme and the autoimmune aspect) so it's helpful to have your note of caution.
     
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  11. Jonathan Edwards

    Jonathan Edwards Senior Member

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    The stuff on TRIM21 coming in to cells with antibody is work discussed with the group involved that may not yet be published, although I would be surprised if not. TRIM21 binds IgG and exists in an extracellular as well as an intracellular form. It is probably supposed only to internalise antibodies when attached to pathogens, but if autoantibodies are stuck to self antigens then presumably they can be internalised as well. There are a number of complications to the way the mechanism might work but at least we know of one potential entry route.
     
  12. Snow Leopard

    Snow Leopard Hibernating

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    It could still be considered a non-specific marker for a group of autoimmune disorders though right? Similar to ANA for example.

    As Halcyon asked, I'm still curious as to how antibodies enter cells and the role of TRIM21 or other transport proteins. Are some types of antibodies more likely to enter cells than others? Is there any way of taking advantage of this process to isolate those antibodies that are entering the cells and potentially characterise them? I also wonder about the possibility (not neccessarily for ME), of autoimmune processes disrupting the BCR internalisation itself, perhaps increasing the likelihood of B cells presenting non-self fragments (for which the BCR had low affinity towards) by the MHC.

    The literature seems to claim several ways for antibodies to enter cells, from receptor-mediated endocytosis (growth factor and scavenger receptors for example), as well as raft-dependent endocytosis. It seems hard to pin anything specific down that could lead to disease.

    Nevertheless, autoantibodies directed towards particular intracellular enzymes seems like a plausible explanation for "quiet autoimmunity", as Bansal put it.

    I personally am wondering about disruptions of fatty acid metabolism, there are several papers indicating disruptions of carnitine transport for example.
     
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  13. MEMum

    MEMum Senior Member

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    Does anyone know anything re antibodies to the pyruvate kinase receptors in the basal ganglia. These have been detected in my daughter who has ME.
     
  14. Jonathan Edwards

    Jonathan Edwards Senior Member

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    I don't think enolase is quite like ANA. Antinuclear antibodies occur in a wide range of diseases simply because there are hundreds of proteins in the nucleus so there are at least thirty diseases each with a different nuclear antigen that shows up as 'ANA+'. Enolase is a single antigen. Some of the assays purporting to measure enolase antibodies have been called into question or withdrawn. It may prove relevant to some conditions but it looks as if some of the reports will prove unhelpful.

    It looks at present as if there are several ways antibodies can get into cells and some do more than others for reasons that are certainly not clear. It has been a taboo area for many years and although that might change it seems likely that making reliable predictions about which antibodies get in will remain tricky for some time.

    I think probably the best example of cell penetrating antibodies linking to disease type is for the antibodies to ribosomal proteins in the myositis related conditions. In effect it seems likely that these antibodies do what ricin does - poison ribosomes. The result with ricin is muscle death - and in severe myositis it is too. Antibodies to different proteins produce similar but subtly different clinical patterns that make at least some sort of sense. It is by no means accepted in the immunology community that cell penetrating antibodies mediate the problem but to my mind it is hard to escape the conclusion that they do.

    I am not aware of any antibodies to proteins involved in lipid metabolism but it is an interesting possibility.
     
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  15. wastwater

    wastwater Senior Member

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    There are some inborn errors of metabolism
    GMDS deficiency and glycosylation are of recent interest to me
     
    Last edited: May 4, 2017

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