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Klimas London presentation, CD26/DPPIV impaired in CFS - retroviral involvement?

Discussion in 'XMRV Research and Replication Studies' started by natasa778, May 25, 2010.

  1. subtr4ct

    subtr4ct Senior Member

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    Mrs. subtr4ct has been using Kirkman's DPP-IV enzymes for a couple of years. No appreciable improvement in dysauutonomia (POTS; malfunctioning enteric nervous function as revealed by elctrogastrogram).
  2. Athene

    Athene Never give up

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    Hi Karin,

    I've had very painful and bad reactions to a lot of enzymes but DPP IV doesn't cause any irritation at all, (even though I have very bad diarrhoea these days, which usually leads to a lot of pain with peptidases). So I don't think you need to be scared to try it on an empty stomach.

    On the other hand, like Mrs. Subtr4ct, I have also noticed no improvement in anything so far since taking the stuff.
  3. Frank

    Frank Senior Member

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    I finally have found the study, it's a study of 1990 by Klimas! HERE
  4. xchocoholic

    xchocoholic Senior Member

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    Thanks for the great info here ...

    I need to read all of this again but I'm bumping it to make sure it doesn't get lost.

    I was particularly interested in how DPPIV is related to adenosine deaminase which is an enzyme our bodies need to break down our food down into adenosine. This website says that the lack of this enzyme can cause severe immune dysfunction ... this sounds like a lot of us here, right ? I don't know if I have XMRV but I'm positive for high viral titers to at least 3 known CFS viruses ...

    http://www.medicalhealthtests.com/pathology-test/adenosine-deaminase-test.html

    FWIW ... I've been taking DPP-IV off and on for 4 years now and while it may have lessened a gluten reaction on occasion for me, I certainly didn't notice anything dramatic ... I take it on the rare occasion that I'm eating out and need protection from cross contamination. Otherwise, I'm gf.

    Did anyone who was going to try taking this on a regular basis notice any improvement ?

    And is there a substitute for adenosine deaminase, or is it DPP-IV ?

    thanks .... x

    PS. I started looking closer at adenosine when I learned that caffeine blocks our adenosine receptors ... And adenosine is the A in ATP ... :eek:
  5. richvank

    richvank Senior Member

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    Hi, all.

    I posted this on another thread, but think it might be of interest to people here:

    Hi, Emootje.

    I'd like to comment on DPPIV, also known as CD26 in the immune system.

    Lack of this enzyme has been found to be associated with food sensitivities to casein and gluten in autism patients. Some of the digestive enzyme products used in autism therefore include it.

    As you may know, I believe that autism and ME/CFS are the same disorder from the biochemical perspective (symptoms and epidemiology differing only because of different ages at onset in relation to brain development and puberty). I think this is consistent with the fact that many PWCs are gluten and casein sensitive, and that Dr. Klimas's group has found low DPPIV in ME/CFS.

    I have a hypothesis for the cause of the low DPPIV in autism and CFS. This hypothesis also applies to other secretory proteins that are found to be low in ME/CFS, including several of the peptide hormones (for examples, ACTH, antidiuretic hormone, and growth hormone) as well as perforin. Here it is:

    These proteins that show deficits all normally contain cysteine. When a protein is synthesized inside a cell, the amino acids are first joined together in an appropriate chain by the ribosomes within the cytosol. Then the chain is passed into the endoplasmic reticulum, where the tertiary structure of the protein is formed by linking cysteine residues together with their proper partners to form disulfide cystine bonds. If it is to be a secretory protein, it is then exported from the cell.

    In order for this process to occur properly, the cysteine molecules must be maintained in their reduced state as cysteine, and not be allowed to bind together to form cystine until the appropriate stage of the process in the endoplasmic reticulum.

    Here's where the problem arises in autism and CFS. Glutathione is depleted in the cytosol of cells. Without sufficient glutathione to control the redox potential in the cystosol, the cysteine molecules form disulfide bonds too early. This causes the quality control mechanism to send the malformed proteins to the proteasomes, which take them apart and recycle the amino acids. The result of this continuing recycling is that not enough of the proteins are formed.

    The problem seems to be worst with proteins that contain a lot of cysteine residues. Perforin contains 20. DPPIV contains 12. It also seems to be worse for proteins that are made by cells that do not have a completely functioning transsulfuration pathway, and thus are not able to make cysteine from methionine, so that a scarcity of cysteine shows up first in them. Beside being an important constituent of these proteins, cysteine is also the rate-limiting amino acid for the synthesis of glutathione.

    A counterexample is insulin. It is usually not low in ME/CFS, but does contain cysteine. I suggest that the reason it is O.K. is that it is made in the pancreas, and pancreatic cells do have a complete transsulfuration pathway.

    DPPIV also has an important role (as CD26) on the lymphocytes. Lymphocytes do not have a complete transsulfuration pathway, as far as I know. So low CD26 in ME/CFS would again be consistent with this hypothesis.

    Best regards,

    Rich
  6. Athene

    Athene Never give up

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    That's so interesting, thank you Rich!

    What do you think would be the best strategy to deal with this problem?

    - Take digestive enzymes (eg. Kirkman "DPPIV Forte") - problem is how much, and how long before eating?
    - Take glutathione - but can it be absorbed when taken orally?
    - Take cysteine as well?
    - Just avoid dairy and gluten altogether?

    My son has CFS and Lyme with mild/periodic autism symptoms. The autism used to be full blown and fairly severe - he was unable to understand speech at age 3 and just played with spinning things all the time etc. I achieved a drastic improvement in him by removing gluten and dairy from his diet and many other foods too, but now he eats all except these two foods.
    His gastroenterologist has suggested trying him on dairy and gluten again, partly for nutritional purposes. The Lyme doctor has said a good proportion of children with Lyme don't have gluten adn dairy problems, or intestinal type symptoms anyway, so as far as he is concerned it wold be alright to test it. However I am wary. My son has been on antibiotic treatment for his Lyme disease for 6 months and there have been spectacular improvements in all his formerly catastrophic intestinal and allergy symptoms, but I am not convinced that means he can handle gluten or dairy yet.

    I would really appreciate your advice on how you would approach this and whether you think it is worth experimenting.
    He is 5 years old BTW, so he can explain symptoms to me such as pain, but if he got problems like brain fog for example he wouldn't know how to explain that.
  7. determined

    determined Senior Member

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    I'm curious Athene....do you give your son methylation supplements?
  8. Athene

    Athene Never give up

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    Hi Determined,
    I give him Kirkman multivits specifically for autistic children, which have a balance of all the things we PWCs take for methylation. I also supplement with additional B complex and magnesium and choline (for detox and nervous system).
    I think he detoxes surprisingly well, especially considering all the antibiotics he is taking. I just wish he would drink more water, but... oh well. He's a stubborn little fellow.
  9. richvank

    richvank Senior Member

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    Hi, Athene.

    Well, as you know, I'm a researcher and not a licensed physician, so I cannot give individual treatment advice unless a physician is on board to evaluate my suggestions in the light of the particular case. However, I can talk about where the hypothesis would point. If it is correct, then raising the level of glutathione in the cells should help. For about 5 years, from 1999 through 2004, I encouraged PWCs to boost their glutathione levels in various direct ways. This seemed to help most of them, on a temporary basis, but if they stopped, their symptoms worsened again, so it wasn't a permanent fix. On the other hand, there were others who could not tolerate the glutathione boosting, and we kicked around several possible explanations for that, including mobilization of toxins and killing of pathogens as a result of better function of the immune system and the detoxication system, also including an increase in cysteine levels to the point that auto-oxidation of cysteine was increasing the oxidative stress, also including an increase in sulfite because of overloading of the sulfite oxidase enzyme, and most recently, a deficiency of vitamins B2 and/or B3, which are needed to recycle glutathione when it becomes oxidized.

    I still don't know for sure which if any of these is the explanation for the glutathione intolerance in some PWCs. Testing shows that they are low in it, but giving it directly just doesn't work for some.

    In late 2004, S. Jill James et al. published some research in autism that indicated that glutathione is also low in that disorder, and in addition, there is a problem with the methylation cycle, which is upstream of glutathione synthesis in the sulfur metabolism. They found that treating to lift a partial block in the methylation cycle caused glutathione to come up automatically, without direct boosting. I suspected that the same might be true in ME/CFS, and that has proven to be true, based on lab testing and treatment experience. So now I recommend treating the partial methylation cycle block, and that has been more successful. There are several methylation protocols in use now, and I don't know which is the best. One of them is the so-called Simplified Treatment Approach that I have suggested, and which was recently revised in March, 2011. It has been posted on another thread, in the Methylation forum.

    If glutathione is to be given directly, I now favor using the liposomal forms. If tolerated, I think this is about the best direct way to raise glutathione in the tissues, at least temporarily, and it may help with the DPPIV deficiency, but I don't have any clinical data to back this up. If that is not tolerated, treating the more fundamental issue with the methylation cycle should raise glutathione on a more permanent basis.

    Digestive enzymes containing DPPIV should be helpful, on a temporary basis. I note that there is a study published from Stanford University that found that a combination of DPPIV and another enzyme from Aspergillus seemed to be more effective in breaking down gluten, but I don't know if this combination is commercially available. The abstract is pasted below, and the full paper is available free at PubMed, by typing the PBID number in the search box, and then clicking on the symbol at the upper right.

    Taking cysteine as L-cysteine is generally not such a good idea, because it can become toxic at high enough dosages, I think because of its tendency to auto-oxidize, contributing to oxidative stress. N-acetylcysteine is a safer form, but if there is a high body burden of mercury, Dr. David Quig of Doctor's Data Lab has written that the dosage should be limited to 300 mg per day to avoid moving mercury into the brain.

    Of course, avoiding dairy and gluten will work, too, but as you are probably more aware than I am, this is not an easy diet to maintain.

    My hope is that in the long run, fixing the partial methylation cycle block so that glutathione comes up to normal will end up fixing this problem as well as many others in ME/CFS as well as in the autism spectrum. We are finding that it is not the magic bullet for a complete treatment, because of other issues that arose before onset or that accumulated after onset, but it does deal with the vicious circle mechanism that appears to be at the heart of the pathophysiology of these disorders, in my opinion.

    Best regards,

    Rich

    PLoS One. 2009 Jul 21;4(7):e6313.
    A food-grade enzyme preparation with modest gluten detoxification properties.
    Ehren J, Morn B, Martin E, Bethune MT, Gray GM, Khosla C.
    Source

    Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
    Abstract
    BACKGROUND AND AIMS:

    Celiac sprue is a life-long disease characterized by an intestinal inflammatory response to dietary gluten. A gluten-free diet is an effective treatment for most patients, but accidental ingestion of gluten is common, leading to incomplete recovery or relapse. Food-grade proteases capable of detoxifying moderate quantities of dietary gluten could mitigate this problem.
    METHODS:

    We evaluated the gluten detoxification properties of two food-grade enzymes, aspergillopepsin (ASP) from Aspergillus niger and dipeptidyl peptidase IV (DPPIV) from Aspergillus oryzae. The ability of each enzyme to hydrolyze gluten was tested against synthetic gluten peptides, a recombinant gluten protein, and simulated gastric digests of whole gluten and whole-wheat bread. Reaction products were analyzed by mass spectrometry, HPLC, ELISA with a monoclonal antibody that recognizes an immunodominant gluten epitope, and a T cell proliferation assay.
    RESULTS:

    ASP markedly enhanced gluten digestion relative to pepsin, and cleaved recombinant alpha2-gliadin at multiple sites in a non-specific manner. When used alone, neither ASP nor DPPIV efficiently cleaved synthetic immunotoxic gluten peptides. This lack of specificity for gluten was especially evident in the presence of casein, a competing dietary protein. However, supplementation of ASP with DPPIV enabled detoxification of moderate amounts of gluten in the presence of excess casein and in whole-wheat bread. ASP was also effective at enhancing the gluten-detoxifying efficacy of cysteine endoprotease EP-B2 under simulated gastric conditions.
    CONCLUSIONS:

    Clinical studies are warranted to evaluate whether a fixed dose ratio combination of ASP and DPPIV can provide near-term relief for celiac patients suffering from inadvertent gluten exposure. Due to its markedly greater hydrolytic activity against gluten than endogenous pepsin, food-grade ASP may also augment the activity of therapeutically relevant doses of glutenases such as EP-B2 and certain prolyl endopeptidases.

    PMID:
    19621078
  10. Glynis Steele

    Glynis Steele Senior Member

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    Hi Athene,

    I would proceed with extreme caution, if you are thinking of re-introducing gluten and casein to your son's diet, as I have heard on other discussion groups that other kids have regressed when trying this. This being said, if you son's gut function has improved, then it might be worth a try, but do it very slowly, tiny amounts at a time with a break inbetween, and only introduce one thing, so you can monitor how your son seems, before moving onto something else.

    Here is a good site about enzymes and austim. Hope it goes well.

    http://enzymestuff.com/dietsgfcf.htm#11

    Glynis
  11. determined

    determined Senior Member

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    low perforin....but gene expression down-regulated

    I've read Rich's hypothesis regarding methylation cycle problems possibly leading to a low level of perforin and other cysteine-rich secretory proteins. But I'm not sure I understand how to interpret the fact that, in Dr. Klima's study, gene expression is down-regulated for perforin. Shouldn't the gene expression be UP-regulated to compensate for the low functional levels of perforin?
  12. Athene

    Athene Never give up

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    Just wanted to thank Rich for that really helpful explanation.
    And I think I will heed Glynis' warning and play safe for now. We have got used to managing a gluten + dairy free diet so why take chances?
    I'll focus on supplementation and hope he can continue to heal...
  13. maryb

    maryb iherb code TAK122

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    Athene how do you go one with dairy/casein free in particular, my grandson is 15 and growing by the day, he is talking about removing dairy but how on earth do you find enough calcium in particular in a diet typical of teenagers, or in your case an active growing 5 year old?
  14. Athene

    Athene Never give up

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    Hi MaryB,

    We eat a lot of fish but it is still not enough in my opinion, so we both supplement calcium, with vitamin D to make sure we absorb it. I think it is really important at all ages. As a middle aged woman I am quite aware that I am about to enter osteoporosis territory...

    When you take out dairy you need to be sure to eat lots of vegetables too, as milk provides such a broad range of vits and minerals, and soya or rice milk doesn't come close to replacing it. I give my son a multivitamin and mineral supplement. We also eat a lot of eggs. Eggs get a bad press because of fats, but neither of us have a cholesterol problem and eggs are so rich in nutrients - another almost complete nutrition food.

    Quite a lot of soya products have added calcium - soya milk and yoghurt for example. But always calculate the amount, because as you say, growing kids need the right dosage. There are calcium age charts on the internet.
  15. richvank

    richvank Senior Member

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    Hi, determined.

    Thanks for pointing this out. I'll look into it and ponder my hypothesis some more.

    Rich
  16. richvank

    richvank Senior Member

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    Hi, determined.

    Were you referring to the published study by Klimas et al. in Gulf War Illness? I just checked that paper, and neither the results for the perforin levels or the perforin gene expression showed statistically significant differences between the patients and the normals. Is there a newer study on ME/CFS that hasn't been published yet?

    Rich
  17. Sushi

    Sushi Moderator and Senior Member Albuquerque

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    Hi Rich,

    I have a question about perforin levels of perforin gene expression. I just got a test back that gives my Perforin mRNA expression as very elevated over the reference range. Is this the value that is being discussed here, or something different? (It was noted that my innate immune system was activated)

    Thanks!
    Sushi
  18. Emootje

    Emootje Senior Member

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    Same here
    Perforin mRNA expression 2720 [250-750]
  19. determined

    determined Senior Member

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    I only have a print-out of what appears to be a discussion section of a published paper. I can't find the name of the article right now, but here are the statements I was wondering about:

    "RNA expression profiles of one subject with CFS and an age- and sex-matched control showed differential expression of 10 genes. Of these, five were down-regulated and one was perforin."

    The responses of Sushi and emmootje make sense to me. If perforin levels are low, transcription rates of the gene should be high, mRNA levels should be high. Now that I look back at it, there were only two people being studied.

    I'll try to find the article, Rich.
  20. determined

    determined Senior Member

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