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TH2 Immune System Dominance and Heterogeneity in ME/CFS

Discussion in 'Other Health News and Research' started by Marco, May 27, 2010.

  1. slayadragon

    slayadragon Senior Member

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    twitpic.com/photos/SlayaDragon
    Crohn's Disease

    From Wikipedia:

    Crohn's disease (also known as granulomatous, and colitis) is an inflammatory disease of the intestines that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms. It primarily causes abdominal pain, diarrhea (which may be bloody), vomiting, or weight loss,[1][2][3] but may also cause complications outside of the gastrointestinal tract such as skin rashes, arthritis, inflammation of the eye, tiredness, and lack of concentration.[1]

    Crohn's disease is thought to be an autoimmune disease, in which the body's immune system attacks the gastrointestinal tract, causing inflammation; it is classified as a type of inflammatory bowel disease.


    Toxic mold exerts its effects on health largely through inflammation.

    Below are a couple of articles suggesting that various types of trichothecenes (a particular mold toxin) can have specific effects on intestinal cells.

    It thus seems to me possible that the intestinal problems that appear to be Crohn's disease in CFSers actually are being driven by the presence of the toxin.

    Or maybe Crohn's disease itself is driven by the toxin rather than autoimmune.

    Thoughts?

    Thanks, Lisa

    *

    Yang H, Park SH, Choi HJ, Moon Y. Epithelial cell survival by activating transcription factor 3 (ATF3) in response to chemical ribosome-inactivating stress. Biochem Pharmacol. 2009 Mar 15;77(6):1105-15. PMID: 19101521


    Ribotoxic stress responses lead to the expression of genes important for cellular homeostasis by modulating cell survival, proliferation and differentiation.

    ATF3 expression was up-regulated by chemical agents causing ribotoxic stress such as deoxynivalenol and anisomycin in different types of intestinal epithelial cells.

    Moreover, reduction of ATF3 gene expression promoted ribotoxic stress-triggered programmed cell death, implicating a protective role of ATF3 in epithelial cell survival.

    *

    Van De Walle J, Romier B, Larondelle Y, Schneider YJ. Influence of deoxynivalenol on NF-kappaB activation and IL-8 secretion in human intestinal Caco-2 cells. Toxicol Lett. 2008 Apr 1;177(3):205-14. PMID: 18343055


    We hypothesized a link between DON ingestion and intestinal inflammation, and used Caco-2 cells to assess the effects of DON, at plausible intestinal concentrations (250-10,000 ng/ml), on inflammatory mediators acting downstream the MAPKs cascade i.e. activation of nuclear factor-kappaB (NF-kappaB) and interleukin-8 (IL-8) secretion.

    Dose-dependent increases in NF-kappaB activity and IL-8 secretion were observed,

    Phosphorylation of inhibitor-kappaB (IkappaB) increased (1.6-fold) at DON levels <0.5 microg/ml.

    Exposure of Caco-2 cells to pro-inflammatory agents, i.e. 25 ng/ml interleukin-1beta, 100 ng/ml tumor necrosis factor-alpha or 10 microg/ml lipopolysaccharides, activated NF-kappaB and increased IL-8 secretion.

    Synergistic interactions between these stimuli and DON were observed.

    These data show that DON induces NF-kappaB activation and IL-8 secretion dose-dependently in Caco-2 cells, and this effect was accentuated upon pro-inflammatory stimulation, suggesting DON exposure could cause or exacerbate intestinal inflammation.

    *

    Kouadio JH, Dano SD, Moukha S, Mobio TA, Creppy EE. Effects of combinations of Fusarium mycotoxins on the inhibition of macromolecular synthesis, malondialdehyde levels, DNA methylation and fragmentation, and viability in Caco-2 cells. Toxicon. 2007 Mar 1;49(3):306-17. PMID: 17109910.

    We studied the interactive effects of either binary or tertiary mixtures of Fusarium mycotoxins, deoxynivalenol (DON), zearalenone (ZEA), and fumonisin B1 (FB1) on the human intestinal cell line, Caco-2,

    Because FB1 antagonizes the effects of estrogenic Zearalenone, FB1 was assayed against estradiol.

    In NR assay, mixture of FB1 and estradiol and/or ZEA improves Caco-2 cells viability in contrast to individual effects. Mixtures of ZEA or FB1 and DON, display synergistic effects in lipid peroxidation.

    Altogether, the data indicate that mixtures of Fusarium toxins are able to induce lipid peroxidation, DNA damage, DNA fragmentation, DNA methylation, and cytotoxicity in Caco-2 cells, and suggest a potential promoter effect in human intestinal cells.

    *

    Li M, Cuff CF, Pestka JJ. T-2 toxin impairment of enteric reovirus clearance in the mouse associated with suppressed immunoglobulin and IFN-gamma responses. Toxicol Appl Pharmacol. 2006 Aug 1;214(3):318-25. PMID: 16504231


    Trichothecenes are exquisitely toxic to the gastrointestinal (GI) tract and leukocytes and thus are likely to impair gut immunity.

    The purpose of this research was to test the hypothesis that the Type A trichothecene T-2 toxin interferes with the gut mucosal immune response to enteric reovirus infection.

    As compared to vehicle-treated control, T-2-treated mice had dramatically elevated intestinal plaque-forming viral titers after 5 days and failed to completely clear the virus from intestine by 10 days.

    T-2 suppressed IFN-gamma responses in PP to reovirus at 3 and 7 days as compared to infected controls whereas IL-2 mRNA concentrations were unaffected. PP IL-6 mRNA levels were increased 2-fold 2 h after T-2 treatment, but no differences between infected T-2-exposed and infected vehicle-treated mice were detectable over the next 7 days.

    Overall, the results suggest that T-2 toxin increased both the extent of GI tract reovirus infection and fecal shedding which corresponded to both suppressed immunoglobulin and IFN-gamma responses.

    *

    Sergent T, Parys M, Garsou S, Pussemier L, Schneider YJ, Larondelle Y. Deoxynivalenol transport across human intestinal Caco-2 cells and its effects on cellular metabolism at realistic intestinal concentrations. Toxicol Lett. 2006 Jul 1;164(2):167-76. PMID: 16442754.

    Epidemiological studies suggest a link between DON and gastrointestinal illness.

    We investigated the interaction of DON with Caco-2 cells, a widely used in vitro model of the human intestinal barrier.

    These data imply that a chronic exposure to DON contaminated foods may negatively affect human health by altering the intestinal mucosa integrity and by inducing the MAPKs implicated in inflammation.

    *

    Kouadio JH, Mobio TA, Baudrimont I, Moukha S, Dano SD, Creppy EE. Comparative study of cytotoxicity and oxidative stress induced by deoxynivalenol, zearalenone or fumonisin B1 in human intestinal cell line Caco-2. Toxicology. 2005 Sep 15;213(1-2):56-65. PMID: 16019124

    Fusarium toxins such as, deoxynivalenol (DON), zearalenone (ZEN) and fumonisin B1 (FB1) have been shown to cause diverse toxic effects in animals and also suspected of disease causation in humans. From the literature and mechanistic point of view, DON binds to the ribosomal peptidyl-transferase and inhibits protein synthesis specifically and DNA synthesis consequently. ZEN known to be genotoxic, binds to 17-beta-estradiol receptors, induces lipid peroxidation, cell death and inhibits protein and DNA synthesis. FB1 disrupts sphingolipid metabolism, induces lipid peroxidation altering the cell membrane and causing cell death.

    We intended to compare DON, ZEN and FB1 (1-150 microM) cytotoxic effect and the pathways leading to cell death and related to oxidative stress and macromolecules syntheses in a human intestinal cell line in order to tentatively classify them according to their respective potential toxicity.

    The comparison reveals that all three mycotoxins bear, at variable degree, the capability of inducing lipid peroxidation (MDA production) and could be classified above 10 microM in decreasing potency order FB1>DON>ZEN.

    This effect seems to be related to their common target that is the mitochondria as revealed by MTT test and seemingly not related to sphingoids accumulation concerning FB1.

    DON and ZEN also adversely affect lysosomes in contrast to FB1.

    The three mycotoxins inhibit protein synthesis with respective IC50 of 5, 8.8 and 19 microM for DON, FB1 and ZEN confirming that protein synthesis is a specific target of DON.

    DNA synthesis is inhibited by DON, ZEN and FB1 with respective IC50 of 1.7, 10 and 20 microM. However at higher concentrations DNA synthesis seems to be restored for FB1 and DON suggesting a promoter activity.

    Altogether the potency of the three mycotoxins in macromolecules inhibition is DON>ZEN>FB1 in Caco-2 cells. It appears then that FB1 acts rather through lipid peroxidation while DON affects rather DNA and protein synthesis.
     
  2. richvank

    richvank Senior Member

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    Glutathione Depletion--Methylation Cycle Block Hypothesis for ME/CFS and Th2 shift

    Hi, Marco.

    I agree with quite a bit of what you have written, and that the shift to Th2 is a major aspect of CFS. However, I think there are some upstream processes that occur that cause the shift of the adaptive immune response to Th2 in CFS. These processes also explain many of the other features of CFS that I have not been able to explain by the Th2 shift alone.

    Basically, I've suggested that both the initial long-term rise in cortisol and the depletion of glutathione that occur in response to the whole range of stressors that are reported to precede the onset of CFS in different cases are known to suppress Th1 in favor of Th2. So I suggest that those are the initial processes that are involved, and they can be caused by any of a variety of physical, chemical, biological or psychological/emotional stressors, or a combination of several of them together. Under biological, I would include infections with a variety of pathogens, including viruses.

    Below is a "relatively brief" description of the GD-MCB hypothesis. More detailed descriptions can be found at www.cfsresearch.org by clicking on CFS/M.E. and then on my name.

    In a later email, I'll comment more about how I think the shift to Th2 occurs, based on this hypothesis, and what its consequences are.

    Best regards,

    Rich


    1. To get an isolated case of CFS (I'm not talking here about the epidemics or clusters), you have to have inherited some genetic variations from your parents. These are called polymorphisms or single-nucleotide polymorphisms. We know what some of the important ones are, but we don't know all of them yet. This is a topic that needs more research.

    2. You also have to have some things happen in your life that place demands on your supply of glutathione. Glutathione is like a very small protein, and there is some in every cell of your body, and in your blood. It protects your body from quite a few things that can cause problems, including chemicals that are toxic, and oxidizing free radicals. It also helps the immune system to fight bugs (bacteria, viruses, fungi) so that you are protected from infections by them.

    3. Oxidizing free radicals are molecules that have an odd number of electrons, and are very chemically reactive. They are normally formed as part of the metabolism in the body, but if they rise to high levels and are not eliminated by glutathione and the rest of the antioxidant system, they will react with things they shouldn't, and cause problems. This situation is called oxidative stress, and it is probably the best-proven biochemical aspect of chronic fatigue syndrome.

    4. There are a variety of things in your life that can place demands on your glutathione. These include physical injuries or surgery to your body, exposure to toxic chemicals such as pesticides, solvents, or heavy metals like mercury, arsenic or lead, exposure to infectious agents or vaccinations, or emotional stress that causes secretion of a lot of cortisol and adrenaline, especially if it continues over a long time. Just about anything that "stresses" your body or your mind will place a demand on glutathione. All people experience a variety of stressors all the time, and a healthy person's body is able to keep up with the demands for glutathione by recycling used glutathione molecules and by making new ones as needed. However, if a person's body cannot keep up, either because of extra-high demands or inherited genetic polymorphisms that interfere with recycling or making glutathione, or both, the levels of glutathione in the cells can go too low. When glutathione is properly measured in most people with CFS (such as in the Vitamin Diagnostics methylation pathways panel), it is found to be below normal.

    5. One of the jobs that glutathione normally does is to protect your supply of vitamin B12 from reacting with toxins. If left unprotected, vitamin B12 is very reactive chemically. If it reacts with toxins, it can't be used for its important jobs in your body. A routine blood test for vitamin B12 will not reveal this problem. In fact, many people with CFS appear to have elevated levels of B12 in their blood, while their bodies are not able to use it properly. The best test to reveal this is a urine organic acids test that includes methylmalonic acid. It will be high if the B12 is being sidetracked, and this is commonly seen in people with CFS.

    6. When your glutathione level goes too low, your B12 becomes naked and vulnerable, and is hijacked by toxins. Also, the levels of toxins rise in the body when there isn't enough glutathione to take them out, so there are two unfortunate things that work together to sabotage your B12 when glutathione goes too low.

    7. The most important job that B12 has in the body is to form methylcobalamin, which is one of the two active forms of B12. This form is needed by the enzyme methionine synthase, to do its job. An enzyme is a substance that catalyzes, or encourages, a certain biochemical reaction.

    8. When there isn't enough methylcobalamin, methionine synthase has to slow down its reaction. Its reaction lies at the junction of the methylation cycle and the folate cycle, so when this reaction slows down, it affects both these cycles.

    9. The methylation cycle is found in all the cells of the body (not counting the red blood cells, which are unusual in a lot of ways). The methylation cycle has some important jobs to do. First, it acts as a little factory to supply methyl (CH3) groups to a large number of reactions in the body. Some of these reactions make things like creatine, carnitine, coenzyme Q10, phosphatidylcholine, melatonin, and lots of other important substances for the body. It is not a coincidence that these substances are found to be low in CFS, so that people try taking them as supplements. Not enough of them is being made because of the partial block in the methylation cycle. The methylation cycle also supplies methyl groups to be attached to DNA molecules, and this helps to determine whether the blueprints in the DNA will be used to make certain proteins according to their patterns. The "reading" of DNA is referred to as "gene expression." Methyl groups prevent or "silence" gene expression. Overexpression of genes has been observed in CFS patients, and I suspect this is at least partly due to lack of sufficient methylation to silence gene expression.

    10. Another thing that the methylation cycle does is to regulate the overall use of sulfur in the body. Sulfur comes in from the diet in the form of amino acids in protein (methionine and cysteine) and as taurine and some as sulfate. The methylation cycle regulates the production of the various substances that contain sulfur that are needed by the body. The levels of various sulfur metabolites are often found to be abnormal in people with CFS.

    11. One of the most important sulfur-containing substances in the body is glutathione, so now you can see how this is starting to look like a dog chasing its tail! The thing that causes chronic fatigue syndrome to be chronic, and keeps people ill for years and years, is this interaction between glutathione, vitamin B12, and the methylation cycle. When glutathione goes too low, the effect on vitamin B12 slows down the methylation cycle too much. The sulfur metabolites are then dumped into the transsulfuration pathway (which is connected to the methylation cycle) too much, are oxidized to form cystine, pass through hydrogen sulfide, and are eventually converted to thiosulfate and sulfate and are excreted in the urine. This lowers the production of glutathione, which requires cysteine rather than cystine, and now there is a vicious circle mechanism that preserves this malfunction and keeps you sick.

    12. That's the basic biochemical mechanism of CFS. I believe that everything else flows from this. As you know, there are many symptoms in CFS. I won't discuss all of them in detail here, but here's how I believe the fatigue occurs: The cells have little powerplants in them, called mitochondria. Their job is to use food as fuel to produce ATP (adenosine triphosphate). ATP acts as a source of energy to drive a very large number of reactions in the cells. For examples, it drives the contraction of the muscle fibers, and it provides the energy to send nerve impulses. It also supplies the energy to make stomach acid and digestive enzymes to digest our food, and many, many other things.

    When glutathione goes too low in the muscle cells, the levels of oxidizing free radicals rise, and these react with parts of the "machinery" in the little powerplants, lowering their output of ATP. So the muscle cells then experience an energy crisis, and that's what causes the fatigue. Over time, because of the lack of enough glutathione, more problems accumulate in the mitochondria, including toxins, viral DNA, and mineral imbalances. These have been observed in the ATP Profiles and Translocator Protein test panels offered by Acumen Lab in the UK.

    13. There are explanations that flow from this basic mechanism for other aspects of CFS. I haven't figured out explanations for all of the aspects of CFS, but I do think I understand a large number of them in some detail, and I've been able to explain enough of them that I believe this mechanism will account for the rest as well, if we can figure out the underlying biochemistry. My 2007 IACFS conference poster paper presented outlines of many of these explanations.

    14. The involvement of infections by bacteria, viruses and fungi appears to have two aspects in CFS. First, as mentioned above, infectious agents can act as one of the stressors that initially bring down the level of glutathione and produce the onset of isolated cases of CFS in people who are genetically susceptible. I suspect that the clusters or epidemic occurrences of CFS (such as at Incline Village in the mid-80s) were caused by particularly virulent infectious agents, such as powerful viruses, and the genetic factor is less important in these cases.

    15. Second, when a person's glutathione, methylation cycle, and folate cycle are not operating normally because of the vicious circle described above, the immune system does not function properly. In this case, viruses and bacteria that reside inside our cells and that are always in the body in their dormant, resting states are able to reactivate and produce infections, which the immune system is not able to totally put down. This accounts for the observation that most of the viral and intracellular bacterial infections seen in CFS patients are caused by pathogens that most of the population is carrying around in their dormant states.

    16. Third, when the immune system's defenses are down, a person can catch new infections from others or from the environment, and the immune system is not able to defeat them, so they accumulate over time. Dr. Garth Nicolson has found that the longer a person has been ill, the more infections they have, on the average.

    17. Other things that accumulate over time are various types of toxins, because the detox system depends to a large extent on the sulfur metabolism, and it will not be operating properly as long as the person has CFS. The body stores much of these toxins in fat, but as the levels get higher, they begin cause problems throughout the biochemistry of the cells. Many people with CFS have been tested for toxins (most commonly the heavy metal toxins, which are the most easily tested) and they are commonly found to be elevated.

    18. The longer a person is chronically ill with CFS, the more toxins and infections accumulate in their body, and the more symptoms they experience. This explains why the disorder changes over time, and why some people become extremely debilitated after being ill for many years.

    19. The main key to turning this process around is to help the methionine synthase enzyme to operate more normally, so that the partial block in the methylation cycle and the folate cycle are lifted, and glutathione is brought back up to normal. That is what the simplified treatment approach is designed to do, and so far, the evidence is that it does do these things in most people who have CFS. I recommend that people with CFS have the Vitamin Diagnostics methylation pathways panel run to find out if they do in fact have a partial methylation cycle block and glutathione depletion before deciding, with their doctors, whether to try this treatment. This also provides a baseline so that progress can be judged later on by repeating it every few months during the treatment. Symptoms may not be a good guide to judge progress during treatment, because detoxing and die-off can make the symptoms worse, while in fact they are exactly what is needed to move the person toward recovery.

    20. The main question I'm working on now is what else needs to be done to bring people to recovery ? I don't have complete answers to this question yet. Many people may recover from this treatment alone, but it is proving to be a slow process, and we will need more time to see how this will work out. It does appear that people who suffer from illness due to toxic molds do need to remove themselves from environments where these are present. The small amount of evidence I have so far suggests that people who have Lyme disease will need to have that treated in addition. I'm not sure about certain viral infections. They may also need to be treated. We still have a lot to learn, but I'm convinced that the mechanism I have described above is the core of the abnormal biochemistry in CFS, and correcting it needs to be cornerstone of the treatment.
     
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  3. richvank

    richvank Senior Member

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    Link between stressors and immune dysfunction in CFS, according to GD-MCB hypothesis

    Hi, Marco and the group.

    Here is a discussion from my 2004 poster paper (which can be found in its entirety, with references, at www.cfsresearch.org) of a suggested link between the exposure to stressors (physical, chemical, biological and psychological/emotional), all of which cause the same response by the body's nonspecific stress response system, and dysfunction of the immune system in CFS:

    Rich


    HOW DOES THE NEUROENDOCRINE SYSTEM RESPOND TO STRESS?

    • This system manifests both specifically- and nonspecifically-induced responses to stress [32]. The nonspecifically-induced responses address the combined load of all the various types of stress that are being experienced simultaneously.

    • The nonspecific responses are mediated by three parts of this sytem: (1) the hypothalamus-pituitary-adrenal (HPA) axis, which produces cortisol and other glucocorticoids, (2) the sympathetic-adrenomedullary system, which produces epinephrine (adrenaline), and (3) the sympathoneural system, which produces norepinephrine (noradrenaline) [32].

    • Rapid-onset CFS patients report that they had a normal response to stress prior to their onset of CFS. Therefore, it can be surmised that if they experienced a high load of combined long-term stress lasting a few months to several years prior to their onset, they were subject to high levels of both cortisol and adrenaline during this extended period of time.

    • Note that depleted rather than elevated cortisol levels are frequently observed clinically in CFS patients (Cleare [46]). However, the decrease in cortisol secretion occurs later in the pathogenesis: "…the bulk of the data assembled to date is compatible with the view that the disruption in adrenocortical function is a late finding, and that elucidating the status of the central nervous system components which drive the regulation of the HPA axis would be crucial to a more complete understanding of this final event." (Demitrack [47])

    WHAT ARE THE EFFECTS OF ELEVATED LEVELS OF CORTISOL AND ADRENALINE ON THE IMMUNE SYSTEM AND ON GLUTATHIONE LEVELS?

    • Elevation of cortisol is known to suppress the inflammatory response by several mechanisms, including decreasing the expression of cytokines and cell adhesion molecules, and decreasing the production of prostaglandins and leukotrienes [48]. This effect is beneficially used therapeutically in many cases, but it can also have a down side if an infection is present.

    • Elevation of cortisol is also known to suppress cell-mediated immunity and to cause a shift to the Th2 type of immune response. Several mechanisms are involved, including suppressing the secretion of IL-1 by macrophages, inhibiting the differentiation of monocytes to macrophages, inhibiting the proliferation of T lymphocytes, and increasing the production of endonucleases, which increases the rate of apoptosis of lymphocytes [33,48].

    • Long-term elevation of adrenaline can be expected to deplete GSH, because adrenaline decreases the rate of synthesis of glutathione by the liver (Estrela et al. [18]), increases its rate of export from the liver (Sies and Graf [16]; Haussinger et al. [17]; Estrela et al. [18]), and decreases the rate of reduction (recycling) of oxidized glutathione (Toleikis and Godin [19]).

    HOW DO VIRAL INFECTIONS ARISE AT THE ONSET OF CHRONIC FATIGUE SYNDROME?

    I propose that glutathione depletion is the trigger for reactivation of endogenous latent viruses in CFS (hypothesis).

    Here's the support for this hypothesis:
    • Most of the evidence points to reactivation of latent endogenous viruses at the onset of CFS, rather than new, primary infections (Komaroff and Buchwald [49])
    • Infections by members of the Herpes family of viruses, such as Epstein-Barr virus and HHV-6 are commonly found in CFS patients [49].
    • GSH depletion is associated with the activation of several types of viruses [50-53], including Herpes simplex type 1 (HSV-1) [54]. Raising the GSH concentration inhibits replication of HSV-1 by blocking the formation of disulfide bonds in glycoprotein B, a protein that is necessary for proliferation of the virus [54].
    • Glycoprotein B is also found in all other Herpes family viruses studied, including EBV and CMV [55], and very likely is present also in HHV-6 and performs the same vital function there (hypothesis).

    It thus appears very likely that GSH depletion is the trigger for the reactivation of the latent forms of all the Herpes family viruses. Since glutathione likely becomes depleted prior to the onset of CFS, and since infections by these viruses are commonly found in CFS, it seems likely that glutathione depletion initiates the viral infections at the onset of CFS (hypothesis).

    CAN ELEVATED CORTISOL AND DEPLETED GLUTATHIONE EXPLAIN THE IMMUNE DYSFUNCTIONS?
    YES.
    • The shift to the Th2 immune response, as observed in CFS [56], is a known effect of both elevated cortisol [57] and of depleted GSH [58, 59]. I suggest that elevated cortisol produces the shift initially, and that GSH depletion maintains it later, after the cortisol level drops due to later blunting of the HPA axis.
    • The following dysfunctions seen in CFS [60] are known effects of depleted GSH: lowered natural killer cell and cytotoxic T cell cytotoxicity; inability of T cells to proliferate, as seen in decreased mitogen-induced proliferative response of lymphocytes and decrease in delayed-type hypersensitivity [61].

    In addition, I hypothesize the following:
    • The observed chronic immune activation [60] and the observed continuous activation of the RNase-L pathway in CFS [60] result from the failure of cell-mediated immunity to defeat detected infections, owing to the above effects of GSH depletion.
    • The observed low molecular weight RNase-L [62] results from lack of inhibition of caspases because of thiol (GSH) depletion, and they cleave the RNase-L.
    • The observed elevated numbers of immune complexes [60] result from the shift to the Th2 response, which produces elevated levels of antibodies.
    • The observed elevation in antinuclear antibodies [60] results from the observed higher rate of apoptosis [63-66], which is caused by GSH depletion [67].
     
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  4. Tom

    Tom windows exterminator

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    non anything viewpoint

    Cause and Effect.
    Cause internal=genetic, external= too long a list to mention.
    Effect= what we have in all its multiple ways.
    TH2 is this cause or effect?
    From the above it is effect. An effect that causes .
    I would say that one would need to look in the Master Control Room where the 2 hippo's live. Thalmus and Campus. ( different spellings of hippo's but who cares).
    Herein also lies the Master Program that was implanted when you were concieved that would have everything running sweet as a nut if the hippo's didn't get screwed up by Cause.
    Everything then outputted from the Master Control Room is screwed up 6 ways to Sunday.
    Input comes in OK ,from the Senses, from food etc, it's just that the return response from the MCR (hippo's home )that creates the effects.
    So..
    Fix the Hippo's Home , get all additonal crap out, restore the blood brain barrier and Bob should be your uncle unless he's had a sex change.
    Sounds easy when written like this..........if only.

    Me
    On the Perrin technique 3 years plus .Drains the crud out of the lymphatic system ,got these surrounding the MCR and they can cross over.
    Enhansa to get to the rest of the lymphatic system, liver, spleen and GI tract.
    Vegepa to help the brain work again.
    The above is working for me against M.E.:cool:
     
  5. richvank

    richvank Senior Member

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    Susceptibility to mold toxins and their interaction with other toxins in CFS

    Hi, Slayadragon.

    I would like to comment on the questions you raised.

    First, I want to lay out some background material that I will use below.

    The body has both an immune system and a detoxication system. Most toxins are dealt with primariy by the detox system, but some (notably the biotoxins) are handled by the immune system.

    I want to give an overall description of the immune system.

    The immune system is made up of various types of white blood cells, which you can see listed in a report of a complete blood count, as well as some other components, including the complement system.

    Broadly speaking, the immune system can be divided into the innate immune system and the adaptive immune system. Some cells in the immune system (such as the macrophages) play roles in both.

    The innate immune system is ready immediately to respond to threats, and doesn't need to take time to identify the aggressor and tailor itself to it. However, its ability to defeat the threat is limited. The adaptive immune system identifies the threat and mounts a specific response to the particular aggressor. This response takes some time to develop, but it is more potent at eliminating the threat.
    The complement system (including C3 and C4) are part of the innate immune system.

    The adaptive immune system adapts its response to what it perceived to be the threat. If there is more than one threat, it prioritizes to the one it perceives to be the major threat and goes after that one. If and when it is defeated, the adaptive immune system will shift its response to what it perceives to be the next biggest threat, and so on. T and B lymphocytes are part of the adaptive immune system. The so-called antigen-presenting cells (including dendritic cells and macrophages) also play roles in the adaptive immune system.

    The cells of the immune system coordinate their activities by exchanging cytokines with each other. These are chemical messengers.

    When pathogens such as viruses, bacteria, fungi or parasites enter the body, the innate immune system has ways of detecting their presence, putting up an initial defense as a holding action, and spreading the word to the adaptive immune system, so that a more specific response can be launched to knock them out, if possible.

    The adaptive immune system has two types of responses: cell-mediated immunity, and humoral immunity. Cell-mediated immunity includes both the Th1 response of the CD4 or T-helper lymphocytes, and the cytotoxic response of the CD8 or cytotoxic lymphocytes. Humoral immunity involves production of antibodies (immunoglobulins) by the plasma cells, which form from the B lymphocytes. Cell-mediated immunity is necessary to combat intracellular bacteria and viruses. Humoral immunity is used for extracellular bacteria and other extracellular pathogens and also for viruses during the part of their cycle when they are outside of cells. The Th1 response is used to combat intracellular bacteria. The cytotoxic (CD8) T cells kill cells that are infected with viruses.

    The way the adaptive immune system identifies the specific threats in order to tailor its response is as follows: All cells in the body (except red blood cells) have what is called Class I HLA (for "human leukocyte antigen," also called MHC for "major histocompatibility complex") molecules. These are molecules that pick up fragments of proteins from the cytosol (inside matrix) of the cell, and display them on the outside surface of the cell membrane like flags. Proteins are constantly being chopped up inside the cell, both normal human proteins and those from viruses, so by far most of the flags represent normal human proteins. However, if a cell is infected with a virus, some viral protein fragments (peptides) will also be displayed.

    There are receptors on the surface of CD8 T cells that can detect Class I HLA molecules, and if a particular CD8 T cell that is programmed to look for a particular viral peptide finds one, it sounds the alarm via cytokines, causing more of that particular programmed CD8 cell to be cloned, and they go around looking for cells infected with that virus and thus displaying its peptide as a flag. When it finds one, it makes a hole in the cell wall with perforin, and then injects granzymes, which are poison pills, and they kill the cell.

    The antigen-presenting cells also have HLA molecules of a different type--so-called Class II HLA molecules. These molecules display fragments of proteins that come from inside vesicles in these cells, such as from intracellular bacteria. The Class II HLA molecules are recognized by receptors on the CD4 (helper) T cells. When one of these cells detects a protein fragment from an intracellular bacteria, it also sounds an alarm via cytokines and clones itself, and it mounts a Th1 response, which involves activating macrophages to destroy intracellular bacteria that are inside vesicles.

    In the Th2 type of response, B cells detect antigens and present Class II HLA molecules to helper T cells, which then produce Th2 cells, which help the B cells to mount a Th2 or humoral immune response.

    O.K., with that background, let's consider the mold toxins. According to Dr. Shoemaker, people who have certain genotypes of their Class II HLA molecules are susceptible to mold illness, and treating them with cholestyramine can be effective. He also finds that people with mold illness have diminished visual contrast sensitivity, suggesting that neurotoxins are present. From these and other observations, he has built his Biotoxin Pathway hypothesis for mold illness and other biotoxin-related illnesses. While I don't agree with Dr. Shoemaker on everything, I do believe that at least the above aspects of his hypothesis are valid.

    He suggests that normally when mold toxins enter the body, they are taken up by antigen-presenting cells, and fragments of them are presented to helper T cells by Class II HLA molecules. In most people, they are recognized and disposed of, presumably by being digested by macrophages in a Th1 immune response. However, in about a quarter of the population, this system does not work, because particular genotypes of the Class II HLA molecules have been inherited that are apparently incapable of carrying out this function on mold toxins.

    These toxins are therefore allowed to build up in the body. The innate immune system, including the complement system, responds to them, and either the innate immune response or the toxins themselves then produce the complex of symptoms of mold illness.

    O.K., I think Dr. Shoemaker's hypothesis explains why some people are vulnerable to mold toxins, and most aren't.

    Now, as to why stacking one mold exposure on top of another causes worse problems, perhaps the answer lies in over-activation of the innate immune system. I don't think it would involve the adaptive immune system, because it is apparently unable to recognize the toxins in these people.

    As to what the interaction could be with other types of toxins (non-mold), I note that if heavy metal toxins build up, the immune system does respond to the resulting haptens (metals bound to proteins), as evidenced by the Melisa and similar lymphocyte activation tests. I don't know whether the innate immune system also reacts to other types of toxins, but if is does, that might be a way that these different types of toxic exposures could interact.

    I think it's also possible that the body's main detoxication system might respond to the mold toxins, also, and this would be another possibility for an interaction. That is, if the detox system is already dysfunctional because of overload with other types of toxins, it might not be able to handle the added mold toxins, and thus they would be able to build up further. I don't know if any research has been published about the main detox system responding to mold toxins.

    I could conceive of an interaction in the other direction. That is, the mold toxin builds up because of the HLA genotypes, it depletes glutathione, and that interferes with the main detox system. This may be mediated by a partial methylation cycle block, which I view as the hallmark of CFS.

    I guess that's all I have to contribute. This is a very interesting and important topic, in my opinion, but I'm stretched too thin to do a good job of studying it. Perhaps some of my comments will be helpful to you or others who are able to pursue this further.

    Best regards,

    Rich
     
  6. serg1942

    serg1942 Senior Member

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    Hi Lisa,

    A very interesting this thread. After reading it, just want to give my opinion for what it is worth.

    I think the inflammation on CFS in the gut could have an ”easy” explanation. When whatever stressor depletes GSH (in the case of inherited HLA defects, as explained by Rich, fungi could be the stressor), the methylation and folate cycles are partially blocked. This results in a poor repair/Synthesis of DNA/RNA, and this, in turn, lead to inflammation and autoimmunity—The 70% of the immune system resides in the gut. The lymphocytes T need to replicate very quickly, while the B cells don’t. Thus, an excess of B cells plus the lack of T cells cause the known Th2 shift in CFS. The excess of antibodies (produced by B cells) together with an excess of histamine (methylation deactivates histamine, so it rises when there’s a lack of methyl groups) lead to both autoimmunity and inflammation.

    With the above in mind, and given the fact that the immune system resides mostly in the gut, inflammation and /or autoimmunity seem to be quite plausible on CFS. So, it doesn’t seem to me a problem caused specifically by fungi, but rather by whatever other stressor capable of depleting GSH and/or of inhibiting the methylation cycle, as some heavy metals do.

    Saluditos,
    Sergio
     
  7. Marco

    Marco Old blackguard

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    Thanks for the replies folks. I've had a few busy days which wiped me out and I need time to think about what has been raised - a few brief comments though :

    Rich.

    I've read some of your work at its obviously a much more considered and detailed analysis. Unfortunately I've tried so many remedies over the years that I neither have the finances nor patience to take on another protocol without solid proof that it will work. Having read about the methylation issues though I did pick up glutathione, alpha lipoic acid, grape seed extract and zinc supplements to see if they had any effect on oxidative stress. I appreciate that there's more to removing methylation blocks than just taking the supplements, but worth a try. Interestingly I notice that all four supplements are considered by some to be immune modulators capable of shifting the balance away from TH2 dominance.

    I'm also intrigued that you mention a predisposition to glutathione depletion. Usually, I'm wary of any mention of predisposing factors. It always sounds too much like 'bad genes'. But it does factor into the discussion of why some people develop immune disturbances and others don't when confronted with the same triggers.

    On that point, from discussions on this forum, its clear that many PWCs had mild symptoms, before becoming ill, that have similarities to the symptoms found in ME:CFS and autism. I wonder if this predisposition to glutathione depletion would predict such symptoms prior to the 'crash' into illness?

    Frequent colds and flus v no colds and flus?

    I'm pretty sure this fits in with the TH2 dominant theory. I suspect that those who experience frequent colds and flus are likely to have a current viral infection, but are not (yet) TH2 dominant, so their weakened immune system causes them to contract every bug doing the rounds and they experience the associated symptoms. Those TH2 dominant also have a weakened TH1 arm and are also susceptible to whatever bugs are current. They also pick up the viruses and have a growing viral load. However, because the TH2 arm is overstimulated, they already experience the inflammatory symptoms on an ongoing basis and therefore the usual tell tale signs of a cold or flu are either lessened or go unnoticed.

    It has also been mentioned many times that many of us feel a little better when we contract colds and flus. Again this is consistent. The TH2 arm is the first line of defence and tries to neutralise the bug before it enters the cell, at which stage the TH1 arm takes over. It is possible that the TH2 inflammatory reaction is temporarily occupied trying to deal with the new pathogen and for a while doesn't over react to innoccuous substances like food and common chemicals. Potentially, we might experience a lessening of the usual inflammatory symptoms when we contract a cold or flu, and personally, I find my GI symptoms almost disappear when I suspect I have a cold.

    Light sensitivity.

    Could be that there is a histamine reaction (another TH2 function) causing light sensitivity. Or, if problems are more severe, a viral infection causing encephalitis?

    Crohn's

    I wasn't aware that PWC's had a higher incidence of Crohn's which is considered a TH1 dominant autoimmune disease? I do wonder if those reporting Crohn's have been diagnosed as such or are suffering Crohn's like symptoms. We can have pretty spectacular GI and malabsorption problems in the absence of Crohn's.

    Mold

    I have to admit that I'm not that familiar with the topic and at first sight it seems a little 'out there' to me (and this from the man who started a post on underwear phobia):ashamed:. I've lived in old mouldy Edwardian terrace houses - while entirely healthy - and have been ill while living in three dry modern houses. I have noticed though that humid days make my problems much worse. I'm now living in a warmer, drier climate but in an old mouldy farmhouse with no change in symptoms. I always feel better outside in the fresh air though - so perhaps there is something in it.

    Tom

    I'm glad the Perrin Technique seems to be working for you and noticed the importance you place on lymphatic drainage/purging toxins. The one remedy that I've noticed an improvement with over the years is Essiac Tea - which is proposed as a 'cure' for cancer. I believe it has a similar detox action. The only reason I stopped using it was the fact thats its a little expensive unless you brew your own, and I found over time that the benefits waned. I might go back to it though and cycle it.


    I'm getting more convinced that immune dysregulation underlies many illness including ME/CFS, Autism as well as supposedly 'mental illnesses'. With perfect timing, this thread recently appeared :

    http://www.forums.aboutmecfs.org/sh...mmune-system-with-mental-health-and-behaviour
     
  8. Countrygirl

    Countrygirl Senior Member

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    I have just found the answer to our problems!! :victory: :D No worries about diet, toxins, molds or TH2 dominance..........the solution (or part of it) is simple :Retro smile:....................live in a pyramid!!:eek:

    I have just read the experiment carried out by Dr Bhat with Indian rodents. In his conclusion to his study, he claims that the evidence is that living in pyramid-shaped rooms reduces one's oxidative and neuroendocrine stress. So had we better start building....................????? My present rooms are rectangular, so I haven't got an earthly...........................

    Does the size of the pyramid matter? Could we construct our own....................Would the neighbours, visiting GPs (oh, sorry, I forgot.........they don't visit) think we were quackers................??? I'm going to hunt out some cardboard...........:D:D Perhaps those Egyptians knew a thing or two, afterall.

    (I think I heard of this a few years ago. It didn't seem to catch on. I can't think why :tear:)
     
  9. Tom

    Tom windows exterminator

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    Hi Marco,
    enhansa , which I started taking 3months ago, is used predominately for autism.
    Now got my brain back..just a bit slow.
    No sensory effects , eg no migraines , no light sensetivity ,no sound sensetivity, no fog ,no etc etc.
    Still lack strength and stamina and if I really overdo it I have to sleep about 18 hours out of a day then back to how I was.

    It's a long slow road to recovery , keep putting one foot a little in front of the other.

    Tom
     
  10. slayadragon

    slayadragon Senior Member

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    Thanks to everybody for the interesting replies. I will respond to them soon.

    Marco, I put a response to your comment about mold on this thread (currently post #161):

    http://www.forums.aboutmecfs.org/sh...oach-to-Address-CFS-Viruses&p=86988#post86988

    Best, Lisa
     
  11. Marco

    Marco Old blackguard

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    Thank you Slayadragon

    I've read your post and started on the abstracts you posted on another thread.

    I can see now how the mold issue is far from easily discounted. I find the whole thing very unsettling and I'm not sure how one would cope with that as the problem as avoidance seems nigh on impossible.

    Tom - I've had a little dig around on enhansa and some of the improvements look pretty spectacular. I know we speculate a lot about the possible links between childhood autism onset and adult ME onset. But I'm curious why you decided to try enhansa?
     
  12. richvank

    richvank Senior Member

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    Mold toxin, oxidative stress, glutathione depletion and CFS

    Hi, Slayadragon.

    Several of the abstracts you posted describe evidence that mold toxins produce oxidative stress and glutathione depletion in their hosts.

    As you know, the GD--MCB hypothesis proposes that CFS begins (in a person who has inherited an appropriate set of polymorphisms) when glutathione is pushed down far enough to remove protection from vitamin B12 and thereby bring on a partial block in the methylation cycle, which then forms a chronic vicious circle with the glutathione depletion, thus producing CFS.

    Based on the above, it seems that a link (or "the" link) between mold toxins and CFS in genetically susceptible people is the promotion of oxidative stress by the toxins, bringing down the glutathione levels.

    Combining this with Dr. Shoemaker's work on the HLA genotypes, it appears that a person who has inherited both a set of susceptible HLA genotypes and the genetic predisposition toward developing a partial methylation cycle block when glutathione goes low enough is a person who is susceptible to developing both mold illness and CFS if exposed to an appropriate level of mold toxin.

    This link is similar to the one I suggested to exist between Lyme disease and CFS in a 2009 poster paper (which can be found at www.cfsresearch.org). In Lyme disease, it has been found that the Borrelia burgdorferi bacteria also cause a depletion of glutathione in their hosts.

    According to the GD-MCB hypothesis, anything that can take glutathione down low enough in a person who is genetically susceptible to developing the partial methylation cycle block is a potential cause for CFS in that person. This includes a wide variety of stressors, some of them toxins or pathogens, but also physical stressors such as trauma or extreme overexercise, or psychological/emotional stressors. In studying the histories of many PWCs over the past several years, I have found that in many cases the person was subject to a combination of stressors that were present simultaneously, some of them long-term.

    Best regards,

    Rich
     
  13. natasa778

    natasa778 Senior Member

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    that is great to hear!!! :victory:

    how much do you take per day?
     
  14. slayadragon

    slayadragon Senior Member

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  15. Tom

    Tom windows exterminator

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  16. Tom

    Tom windows exterminator

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    Hi again Natasa,
    I should say that it's been a three way combination , Perrin a great big help, vegepa helps alz heimers so why not M.E, and the Enhansa has sharpened things up considerably.
    Been off anti-depressants for 3 days now,after 10 years , Gives an idea of how well I feel.
    Still pace , still avoid things that kick things off , still a very long way from recovered ,but I feel good.

    Tom
     
  17. natasa778

    natasa778 Senior Member

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    Hi Diesel, thanks for that - I actually started another thread on this, asking if anyone noticed improvements in mental function while running a high fever.

    I was asking because there is a large subgroup of kids with Autism who 'wake up' and become 'less autistic' during fever. Main improvements in speech, communication and sociability etc

    My two pet theories for this: one is changes in neuronal membrane excitability due to change in body temperature (as in effects of temperature on membrane conductance/depolarisation).

    The other theory of mine is that temperature could simply be keeping (XMRV?) viral levels down. Hyperthermic therapy has been used in HIV positive patients by several docs, noticable lowering of viral load during the therapy... the only trouble is that the high temperature that are needed for this cannot be induced for long periods of time without harm... so the therapy has not caught on.

    Of course those two theories are not mutually exclusive... (and there would be room for another one :)
     
  18. natasa778

    natasa778 Senior Member

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    Thanks Tom!
     
  19. Rosemary

    Rosemary Senior Member

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    yes Natasa I remember that study by Dr Zimmerman

    Fever can temporarily unlock autism's grip

    http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20071203/autism_fever_071203/20071203?hub=Health

    Dr. Andrew Zimmerman, a pediatric neurologist at Baltimore's Kennedy Krieger Institute, who was one of the study authors, says the findings give researchers important clues about autism.


    "The results of this study are important because they show us that the autistic brain is plastic, or capable of altering current connections and forming new ones in response to different experiences or conditions," he said.


    He said the effect of fever on behaviour was likely to be observed only in children, whose brains are more "plastic" than those of adults.


    Zimmerman hopes the research could point the way to better treatments that would "reconnect" the autistic brain.
     
  20. HopingSince88

    HopingSince88 Senior Member

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    This certainly sounds about right for me. Language is controlled in the left brain, and I have great difficulties here. I think logic is also centered there, and mine is completely missing, along with a lack of ability to prioritize or sequence. :eek: However, the 'big picture'-spatial-creative-feeling side of me seems to be completely in charge and mostly doing well. :D
     

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