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Meshing the positive Rituximab treatment results with the GD-MCB hypothesis

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by richvank, Apr 27, 2012.

  1. richvank

    richvank Senior Member

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    Hi, all.

    I would like to do some "thinking out loud" and would appreciate thoughts from those of you who have a theoretical bent.

    As many of you know, I have proposed and continue to modify the GD-MCB hypothesis for the pathogenesis and pathophysiology of ME/CFS as I compare its predictions to real-world observations.

    As many of you also know, the first step in this hypothesis involves the depletion of glutathione by stressors, and that leads to a vicious circle mechanism including functional B12 deficiency, partial methylation cycle block and depletion of folates.

    As many of you also know, for about five years I encouraged people to boost glutathione, but this did not turn out to be a permanent fix to the pathophysiology. Later, based on work in autism by Jill James, I began encouraging people to treat to lift the methylation cycle block using B12 and folate. This turned out to work better for most PWMEs, and it caused glutathione to come up automatically.

    Now that the Korean work has been published showing that glutathione depletion lowers the affinity of the CblC complementation group, it seems clear that this is why glutathione depletion leads to a B12 functional deficiency.

    There has always been the question (and it still remains) as to why we can't just raise glutathione to overcome the B12 functional deficiency, and bring everything back to normal that way.

    O.K., here's what I'm beginning to think about that: The problem is that in order for the cells to make methyl B12 to help the methionine synthase reaction, not only must the CblC complementation group be able to bind cobalamin, there must also be enough SAMe and a high enough ratio of SAMe to SAH to put methyl groups on the cobalamin to make methyl B12 fast enough. However, when the methylation cycle function is partially blocked, these conditions are not present. Also, because NADPH is low, the cells have difficulty recycling glutathione when it becomes oxidized by the oxidative stress that is present, so that just raising glutathione is not enough to overcome the vicious circle mechanism. On the other hand, when the methylation cycle is repaired using B12 and folate, the available SAMe and the ratio of SAMe to SAH are restored, and the synthesis of glutathione is also increased as the sulfur metabolism comes back toward normal operation, and this combination is able to overcome the vicious circle in most cases.

    Now, what's going on in the cases that were treated with Rituximab and achieved long-term recovery? How would that fit in with the GD-MCB hypothesis?

    Well, first, I want to reiterate that ME/CFS is not fundamentally an autoimmune disorder. The available evidence just doesn't support that. However, it is true that there are some reported autoimmune aspects in ME/CFS. For example, Hashimoto's thyroiditis. Another example is the elevated anticardiolipin antibodies shown by Dr. Hokama's work with the ciguatoxin test that turned out to cross-react with anticardiolipin. In addition, some PWCs have slightly elevated ANA (antinuclear antibodies). Drs. Ortega-Hernandez and Shoenfeld have reviewed the observations of antibodies in ME/CFS, and have reported that a few more have also been found.

    What I suggest is that these autoimmune aspects arise as responses to damage by the oxidative stress that is a hallmark of ME/CFS, associated with the glutathione depletion. Oxidative stress damages lipids, proteins and DNA, and leads to early death of some cells. I suggest that the immune system is responding to these damaged molecules by raising antibodies, and in some cases these antibodies cross-react with normal molecules in the body, producing autoimmune reactions. These are not fundamental in the pathophysiology, but are byproducts of the oxidative stress.

    As we know from observed data, there is a shift to the Th2 immune response in ME/CFS, and this is the response that favors production of antibodies. So now we have the combination of preferential production of antibodies coupled with damaged molecules that appear to be foreign to the immune system. I suggest that this favors autoimmune reactions.

    These autoimmune reactions in turn promote inflammation, which in turn exacerbates the oxidative stress, and places an additional load on the antioxidant system, including glutathione. I suggest that these autoimmune reactions thus become part of problem, sustaining the vicious circle mechanism.

    In addition, I suggest that the immune system is also battling actual infections, and is producing antibodies and inflammation to do that, also. Since the Th1 response is not functioning well in ME/CFS, the immune system is having to use antibodies to combat infections such as viruses, intracellular bacteria and fungi, when really, Th1 and cell-mediated immunity are needed to knock them out. So that becomes an ongoing guerrilla war.

    Alright, now enter Rituximab. Rituximab knocks out the B lymphocytes, and thus lowers the levels of antibodies. Over time, this lowers inflammation. I suggest that it also thereby lowers oxidative stress, which is a component of inflammation. This would remove much of the tendency to oxidize glutathione.

    In the cases in which recovery was achieved with Rituximab treatment, I suggest that the oxidative stress was lowered enough that glutathione was able to rise enough to overcome the B12 functional deficiency, even though SAMe and the SAMe/SAH ratio were still lower than normal. I suggest that this was able to overcome the vicious circle mechanism and restore the function of the Th1, so that it was able to put down the viral, intracellular bacterial and fungal infections. Then, when the B lymphocytes later regenerated, an appropriate balance was established between Th1 and Th2, and the immune system was able to re-establish its normal protective role.

    I would appreciate your thoughts on whether you think this makes sense. It's sort of a trial balloon at this point.

    Best regards,

    Rich
     
  2. adreno

    adreno 3% neanderthal

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    Hi Rich,

    If this is the case, then taking antioxidants and anti-inflammatories should have the same effect, that is lower oxidative stress enough for glutathione to come up. Do I understand this correctly, and do you agree? And do we have any cases where this has happened?
     
  3. jeffrez

    jeffrez Senior Member

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    It's an interesting hypothesis. Amplifying on adreno's comment, antioxidants have been the one thing that have never seemed to do anything for me - apart from co q-10, the benefits of which I think are probably coming from a different action than its anti-oxidant capacity. I keep taking them just in case they're having behind the scenes benefits, but no noticeable improvements no matter what antioxidants I take.

    My first question would be what kind of herbs or alternative means might possibly exist that could duplicate the activity of the Rituximab, albeit probably not as powerfully, but perhaps more safely and gently?

    subscribed
     
  4. adreno

    adreno 3% neanderthal

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    Mr. Kite,

    The strongest non-drug agent with this kind of action, that I am aware of, is curcumin:

    Downregulation of B lymphocyte stimulator expression by curcumin in B lymphocyte via suppressing nuclear translocation of NF-?B.
    http://www.ncbi.nlm.nih.gov/m/pubmed/20950605/
     
  5. nanonug

    nanonug Senior Member

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    Rich, isn't the methyl group on the methylcobalamin stolen from methylfolate while homocysteine gets a methyl group from methylcobalamin to become methionine?

    Also, what is the rationale for the high-enough SAMe to SAH ratio? It is my understanding that SAMe is an allosteric inhibitor of MTHFR. As such, if SAMe is too high, it would slow down methylation via methionine synthase including remethylation of cobalamin, no?
     
  6. anciendaze

    anciendaze Senior Member

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    Hi Rich,

    I would follow your observations on the presence of other infections. Infections by either DNA viruses or retroviruses produce either plasmids called episomes or changes in actual chromosomal DNA inside the nuclear membrane. These would go some distance toward explaining ANA and some other autoimmune antibodies. I am seeing more and more work on the role of ubiquitin ligases in the destruction of defective or misfolded proteins. In many cases the degradation of proteins tagged in this way is carried out by precisely the oxidative reactions in which you are interested. An acquired defect in this due to an infectious agent which is itself trying to avoid cellular defenses would fit very well -- considering the incomplete state of our knowledge. I'm thinking there is actual infection being held latent in those B-cells depleted by Rituximab, and the change merely alters the balance between infected and uninfected cells in such a way that sometimes the immune system can purge itself of infected cells. In other cases, the infection spreads between immune cells and becomes reestablished after a period of remission. This fits in with what we know about relapsing/remitting diseases, with which I would classify this one. Considering the length of the pathology any pathogen must replicate very slowly.

    I believe we have confusion stemming from multiple immune defects. Some are inborn or inherited by neonates. Others are acquired as infectious agents permitted by original defects seek to establish themselves. I believe the multiplication of infected immune cells by clonal expansion in response to other immune challenges is central to the "strategy" this particular agent is using. At this time, I can't provide a mechanism which also encompasses the Korean work you reference, but feel confident nearly all the immune system is connected with the process of preserving some kind of homeostasis despite the persistent infection(s).

    Oxidation and antioxidants cannot simply be classified as "good" or "bad" reactions or molecules, these are moral categories. Life requires creating and breaking down many different molecules. The important question is when and where such reactions take place. There is good reason in this disease to believe such reactions are taking place where they are inappropriate.
     
  7. richvank

    richvank Senior Member

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    Hi, adreno (and Mr. Kite).

    Thanks for the responses.

    Well, adreno, going farther out on the limb, that does sound plausible. As you probably know, there is a history of antioxidant-type treatments that haven't brought recovery. Marty Pall has reviewed them. It may be because there was not a strong enough antioxidant effect with these treatments. Also, as you may know, Prof. Lester Packer has introduced the concept of the antioxidant network, in which five of the antioxidants are related by recycling each other. They are glutathione, vitamins C and E, lipoic acid, and Co Q-10. Glutathione is at the basis of this network, so if the others are supplemented, some of them (particularly vitamins C and E) place demands on glutathione to recycle them when they become oxidized. So that may have been a problem with some of these protocols. There are also once-through antioxidants that do not load glutathione down, such as grapeseed extract, pycogenol, resveratrol, citrus bioflavonoids, green tea, beta carotene, etc.

    Maybe the problem is that these have not been able to totally pick up the ball from glutathione.

    One thing that is in the back of my mind is intriguing in this respect, though, and that is vitamin C up to bowel tolerance dosage. Over the past 16 years, I think I have read reports from two people who said that bowel tolerance Vitamin C brought them to recovery. How would this work? Well, the late Dr. Robert Cathcart wrote a paper arguing that at high enough concentration, the equilibrium between glutathione and vitamin C is shifted so that vitamin C regenerates glutathione, rather than the other way around, which is the normal situation.
    If that's true, perhaps that could explain these two cases, and maybe all of this fits together.

    Dr. Cathcart lived to be in his 70s, and he told me that he had taken vitamin C to bowel tolerance every day since he was a teenager. He had had mono then, and he didn't recover. I guess he was one of the approximately 10%, according to the Dubbo study in Australia, who do not pull out of it. I tried to get him to have his glutathione measured, but I don't think he did it before he died. Anyway, he was able to be healthy so long as he kept taking vitamin C at bowel tolerance. That's not the same as totally recovering, but maybe he had inherited a polymorphism that made it difficult for his glutathione system to recover. In the cases of the two people I recall hearing from some years back, I think they reported that they had recovered and did not have to continue the bowel tolerance vitamin C.

    Well, this is not much to go on, but maybe the pieces are starting to fit together. I don't know that I feel confident enough about this to recommend the bowel tolerance vitamin C regime to people, though.

    Best regards,

    Rich
     
  8. richvank

    richvank Senior Member

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    ***Hi, nano.

    Rich, isn't the methyl group on the methylcobalamin stolen from methylfolate while homocysteine gets a methyl group from methylcobalamin to become methionine?

    ***Well, yes, there is sort of a bucket brigade effect going on. But there has to be a methylcobalamin molecule supplied to the methionine synthase enzyme to start with. Every so often, the methylcobalamin gives up its methyl group to homocysteine and then becomes oxidized to the +2 state. When that happens, it is not able to accept another methyl group from methylfolate. Then it either has to be regenerated to methylcobalamin by the action of the methionine synthase reductase enzyme, with the help of SAMe, B2 and B3, or it has to be replaced by a new methylcobalamin molecule. This oxidation is part of the normal regulatory system, because it causes more flow of homocysteine into the transsulfuration pathway to make more glutathione to counter the oxidative stress, as needed, and then later the flow shifts back to making methionine from homocysteine.

    Also, what is the rationale for the high-enough SAMe to SAH ratio? It is my understanding that SAMe is an allosteric inhibitor of MTHFR. As such, if SAMe is too high, it would slow down methylation via methionine synthase including remethylation of cobalamin, no?

    ***Well, that's right, but like everything in biochemistry, it's like Goldilocks. It has to be not too low and not too high. The proper balance needs to be maintained.

    ***Best regards,

    ***Rich
     
  9. richvank

    richvank Senior Member

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    Hi, anciendaze.

    Thanks for the comments. I think I follow at least some of what you have written. I do know that latent EBV viruses hang out in memory B cells, and I guess that Rituximab knocks them out.

    I agree that oxidation is certainly not "all bad," but in ME/CFS, there seems to be too much of it going on, and we need to get it back into proper balance.

    Best regards,

    Rich
     
  10. jenbooks

    jenbooks Guest

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    Haven't read all the answers, but do disagree Rich. Do think the evidence--especially the delayed response to b cell depletion as antibodies dropped off -- and the recrudescence as plasma cells created new b cells--- indicates an immune disorder.

    You might really enjoy reading everything you can that Jonathan Edwards has published and written. He is a retired rheumatologist who with his team spent ten years working out their hypothesis on bcells. He was essentially laughed at until he proved it several times and eventually 2004 NEJM publication--his work directly inspired Fluge and Mella...and others...

    You might also do some research on how bcells and tcells interact. If you want some papers, I have some to send you. I've written an article so probably should wait until it gets published.

    One might ask what is driving the incorrect response. What is driving bcell antibody or autoantibody response--in itself responsible for many of the symptoms of an essentially neurological autoimmune disease--and then inflaming the tcells, creating a toxic round robin?

    Maybe pathogens and toxins combined as well as vulnerable genetics which theoretically could include glutahtione depletion--heavy metals, vaccines, toxins, and pathogens...

    You must pay attention to the fact that the history of bcell depletion and response is a delayed one. You need to think about why. The antibodies slowly fall away, and then the symptoms regress.

    This is a very powerful clue.

    Have fun researching :). And btw, I get IV glutathione every two weeks for years. Definitely could use even more than I get. However I just tried the cream from Lee Silsby that Dreambirdie likes and it's not doing nuthin' for me.
     
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  11. richvank

    richvank Senior Member

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    Hi, jenbooks.

    Thanks for the advice.

    Best regards,

    Rich
     
  12. fla

    fla Senior Member

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    In my case I had three autoimmune disorders before getting M.E. and I've seen many people on the forums report the same thing. With all the joints cracking for years, I would suspect some of us were genetically predisposed to carrying some level of oxidative stress even before coming down with M.E.. Of course the oxidative stress would have become much worse after crashing with M.E. and having glutathione depletion.
     
  13. richvank

    richvank Senior Member

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    Hi, fla.

    That makes sense to me. In view of the finding in autism that a combination of three polymorphisms in enzymes in the glutathione system raise the odds of getting autism by a factor of four, and in view of the commonality of the biochemical abnormalities between autism and ME/CFS, I strongly suspect that polymorphisms in the enzymes of the glutathione system will be found in ME/CFS as well, and that would be consistent with a lifelong tendency toward oxidative stress, even before onset of frank ME/CFS. I think it's very possible that this could provoke autoimmune reactions in someone with perhaps the appropriate additional polymorphisms that led to cross-reactivity of the antibodies produced in response to the damage produced by oxidative stress. I hope I have made sense with this line of reasoning!

    Best regards,

    Rich
     
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  14. jenbooks

    jenbooks Guest

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    A systems approach

    Surely all these factors will be found to be significant, in differing measure depending on the person, their assaults, their innate resilience, their genetics, their glutathione and vitamin/mineral status, the nature of their infections etc etc.

    It makes it tougher to develop a theory of everything though...

    When I sat down to write about bcells my real motivation was to understand how both Rituximab and mold avoidance or general avoidance of triggers could both lead to rather startling recoveries. Both could also have somewhat of a time lag.

    How could Erik Mold Warrior, destined for Ampligen and truly sick with classic ME/CFS, end up climbing Mt Whitney after learning to treat his trigger, a certain kind of mold, as if it were as dangerous as a bioweapon in war? How come Lisa Petrison recovered, after a period of tent camping, some months detoxxing in Death Valley, and for about 18 months instantly leaving any place that seemed to shift, perhaps because of changing winds, or weather conditions, and get to better air--never letting inflammation rise enough etc.

    How could those folks be getting better, and me improve in many substantial ways tent camping for the last 15 months, with some interspersed short and long hotel stays when we'd find a good room where they let us open the door to the outside...but mostly tent camping...and the Rituximab folks getting better, some over time....

    I figured the same pathways were being affected.

    Erik always talks about staying high on your power curve, and "breaking the response".

    Short version of what I concluded: Rituximab goes at it from the bcell and its toxic rogue antibodies, probably autoantibodies directed at the CNS.

    Avoidance goes at it probably by downregulating the maddened, upregulated toll receptors (which are affected by the ongoing rogue Bcells, to whom the tcells may have unwittingly given approval long ago, since tcells do have to approve bcells ultimate antibody production). Erik has talked about toll receptors being affected by these biotoxins, etc. I think Shoemaker does as well.

    So to me, folks like me who couldn't possibly tolerate Rituximab nor have an inclination to take drugs like that, it's avoidance at a level that seems gobsmacking to some but in practice is not as awful as it sounds, is sometimes really annoying frustrating taxing and ridiculous and other times transporting beautiful and splendid, but all in all, teaches by the body's response how many toxins are in the regular world and how deadly they are...and what it feels like to lift a lot of them at once.

    So I think I'm angling in on my toll receptors through this approach. Then they calm down, the tcells calm down, and the bcells calm down, and stop churning out huge amounts of toxic antibodies.

    But from the opposite end, wiping out the bcells temporarily, and letting the antibodies die off, also calms the tcells...

    Some of us by the way genetically have more hyper reactive toll receptors. I was told this is very good when you're fighting malaria in the jungle...but tends to increase your risk for diseases like lupus in modern society...

    Where glutathione plays a role I'm not totally sure. I know mercury poisoning from amalgams radically dropped my glutathione capacity (since mercury displaces selenium and I probably have poor glutathione genes anyway), and I know it's very needed by me, IV. I haven't found any other form to do bupkiss, including the cream from Lee Silsby, I feel nothing from that at all.

    I know glutathione helps the immune system, too, and surely if you raise glutathione status you lower oxidative stress and thus inflammation. It may interact with these b and t cells too, who knows.

    Food for thought above.
     
  15. richvank

    richvank Senior Member

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    Hi, jenbooks.

    Thanks for your thoughts. I'm glad to hear that tent camping has brought so much improvement to your health status.

    I think that one question I would have is whether those suffering from biotoxin illness are in the same subpopulation as those found to benefit from Rituximab treatment. I don't think that everyone who has ME/CFS also has biotoxin illness, based on the results of testing with the visual contrast sensitivity test, the HLA typing panel, the ERMI test, and the rest of Dr. Shoemaker's panel. I think it's important to make sure we are talking about the same group of people when we compare responses to different treatments.

    Best regards,

    Rich
     
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  16. jenbooks

    jenbooks Guest

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    Looks the same

    Rich, Erik was diagnosed as classic ME/CFS by Peterson who even back then did expensive testing not routine today and advised to try Ampligen.
    Lisa was diagnosed as classic ME/CFS by Guyer.
    Me, I'm not a "biotoxin" illness person strictly. I react to chemicals too and at my worst had to boil organic cotton clothing for hours before I could wear it.
    How to differentiate the 15 in Fluge and Mella's study from Lisa and Erik etc if their own doctors found the same objective abnormalities on a history and on blood tests??

    If the endpoint is the same and the immune abnormalities are the same then a valid serious question is, why do two very different strategies have such unexpected success.

    My hypothesis is that the tcell bcell abnormal loop is being re-set in both instances but by different means. One changes environmental triggers radically to quiet toll receptors and the other wipes out bcells and their rogue autoantibodies thus quieting the system. A different entry into the abnormal loop.

    Glutathione, lipids, oxygen etc all play a profound role if they are depleted or disordered but IMHO they may increase vulnerability based on polymorphisms, and replenishing them can be of great value but they play a contributory not causal role.

    I know I'm right! Tee hee. Where's the grinny sign...
     
  17. slayadragon

    slayadragon Senior Member

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    Hi Rich,

    During the past four years, I've interacted extensively with many dozens of people with classic ME/CFS. All of them have been skeptical about whether environmental biotoxins could be a factor for them. Some were just about convinced that they weren't. The only reason that they've been willing to talk to me is because nothing (including, with all due respect, your protocol) helped them enough to bring them back to anything approaching an acceptable life.

    For those who have been curious or committed enough to pursue it, EVERY SINGLE ONE has concluded that biotoxin reactivity is a factor for them. I'm not talking cause here. We need more information (such as a study looking at whether mold exposure is a risk factor for acquiring the illness) before we conclude that. I'm just suggesting that reactivity to the toxins is universal in the illness -- and thus, that any level of avoidance that people are able to pursue may be relevant to their ability to feel better and to benefit from treatment (such as the one that you favor).

    In terms of the measures you bring up, I agree that the visual contrast sensitivity test is not universally positive in this illness. As Shoemaker concedes, there are many false negatives to it. I myself had my own VCS go to normal within a couple of months after moving out of my moldy house, even though I still was quite sick with classic ME/CFS and still getting substantial biotoxin exposures. My own understanding is that biotoxin that is "loose" in the brain may affect vision and thus cause the person to fail the VCS, but that having toxin that is more tightly sequestered in the tissues (including other parts of the brain) still may have a general effect on immune functioning.

    The ERMI test measures whether people are living in a blatantly moldy house. This is good for people to know, since no one -- and especially people who have CFS -- should be living or working in a moldy building. However, this has nothing to do with whether people have biotoxin illness, in terms of a) whether they are reacting to small amounts of biotoxin in their environments or b) whether they previously were exposed to moldy buildings. Once certain people have been made ill by mold, this illness does not go away just because they move out of the moldy place. Part of this illness is a hyperreactivity to various biotoxins -- ones that can be present in buildings (even ones that don't seem that bad on the ERMI), in the outside air, or on their contaminated possessions. In addition, this is a poisoning, not an allergy. For instance, if biotoxins are sequestered in the brain, this can affect cognition regardless of what current exposure is.

    Shoemaker's panel is extensive and takes skill to read. Just because (for instance) C4a happens to be low on a particular day does not mean that people do not have mold illness or even that they are not being exposed to large amounts of mold. Unfortunately, there is no one single measure that shows whether people have mold illness, which is why Shoemaker requires such a wide panel (costing more than $1k). I would be interested in seeing the panel results of people with severe ME/CFS that you cite as not having mold illness, therefore.

    In terms of HLA DR, every single severely ill ME/CFS patient that I have encountered (and who has gotten the test) has one of the following genotypes as described by Shoemaker: 1) Multi-Susceptible (or Multi-Susceptible + Something Else), 2) Lyme Susceptible + Low MSH, 3) Mold Susceptible + Low MSH. This is the worst 5% of all genotypes, according to Shoemaker. (Of these severely ill sufferers, I would guess that a whopping 25% or so have Multi-Susceptible + Mold-Susceptible, Multi-Susceptible + Low MSH, or double Multi-Susceptible -- equal to about 1/4 of 1% of the population.) Of the moderately ill CFS patients I have encountered, some have the preceding genotypes, and some have specific other genotypes (Mold-Susceptible, Lyme-Susceptible or Low MSH). Again, many of these patients have no belief that mold is a factor for them and had the test performed either a) routinely by their regular CFS/Lyme doctors or b) out of desperation, because they felt like there was no other treatment possibility that might help available to them. I'm thus interested in the HLA DR types and the specific case histories of the "ME/CFS" patients that you have seen that you don't think are biotoxin illness patients.

    Ever since the beginning of this illness, people have been dismissing biotoxins as "just one factor that only applies to some people." Certainly, we don't know for sure that it is relevant to everyone. Stating before we have the proper data that it _doesn't_ apply to everyone is being unscientific though.

    Best, Lisa
     
  18. jenbooks

    jenbooks Guest

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    Thanks for that input, Lisa.

    Also, what I'm saying is, if the abnormalities and tests and history and endpoint are the same, then the illness is what it is. Cancer has many causes. But it's cancer.

    Looking at the pathways and the abnormalities and different modes of success will give us powerful clues to what is happening and why.

    Wiping out bcells does not lead instantly to recovery, that's the important point that nobody should miss in the rituximab study. It requires the antibodies to slowly fall away. That is when recovery happens. It tracks very closely with the antibodies. And since plasma cells in the marrow are long lived, and will replete the b-cell population, retreatment is necessary (even Fluge and Mella are attempting to see how often or shall I say how least often treatment is required).

    My personal feeling about rituximab is if someone is living the life of living dead, and wants to try it, I think that's very reasonable. If somebody can go from bedridden to back to work as two Fluge and Mella patients did, that's profound. But Erik is back to work, too. Lisa is doing her own version of work (working on this subject). But my interest in the study is in the clues it provided, just as Lisa and Erik and others and myself provide clues.

    I think it's the tcell bcell loop. I think avoiders are addressing toll receptors primarily and perhaps Erik is right and some toxins bind to toll receptors. I don't know enough about them but I do know they are being studied in autoimmune disease esp TRL7. In addition, I do know that some people are born with more easily triggered TLR's as I said. Like all polymorphisms, good in one environment, maybe not in another.

    By wiping out the bcells and antibodies, the loop is temporarily stopped *that* way. The tcells, absent the rogue antibody churning bcells, are no longer getting signals to upregulate upregulate upregulate and arm the forces.
     
  19. slayadragon

    slayadragon Senior Member

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    >Also, what I'm saying is, if the abnormalities and tests and history and endpoint are the same, then the illness is what it is. Cancer has many causes. But it's cancer. Looking at the pathways and the abnormalities and different modes of success will give us powerful clues to what is happening and why.

    Definitely I agree with this part.

    Hopefully eventually I can learn enough about Rituximab to have a stronger opinion about how it is working.

    Today, a Cheney patient wrote to me the following:

    >If you kill off the B cells and get a bacterial or fungal infection your chances aren't good. Talked to PRC (Paul R. Cheney) Thursday about it. He won't take the risk.

    I thought this was interesting because a lot of people living in moldy buildings apparently have various low-grade fungal infections (such as aspergillus), acquired as a result of a double whammy of having low immune systems and constant exposures to environmental molds that can colonize humans.

    I never had a test for anything like that though, even when I started getting pneumonia-like lung issues. I've not heard of many other CFS patients being tested for fungal infections either.

    My lung issues resolved shortly after I got out of my very bad house (I was temporarily living in what turned out to be a moderately bad place and hadn't even gotten rid of the possessions at that point). Maybe it was c. pneumoniae (I had a high IgG), but something like aspergillus doesn't sound inconceivable.

    Staying in the bad house and nuking the B cells does sound like it could have tipped me over into death, considering how close I was to it anyway.

    So my feeling here is that if people want to consider Rituximab, maybe they should make sure they're not in a horrific environment first, before purposely depleting an additional component of their immune system. Then again, maybe if they get out of the bad environment, they will feel better enough just from that that they won't be so desperate that they feel compelled to try something like Rituximab.

    Again, I really don't like the assumption (with no proof at all) that Rituximab won't work on people who benefit from mold avoidance. That's suggesting that the mold reactivity is not an integral part of the illness, and that should not be just assumed without any evidence that that's the case.

    Best, Lisa
     
  20. richvank

    richvank Senior Member

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    ***Hi, jenbooks.

    Rich, Erik was diagnosed as classic ME/CFS by Peterson who even back then did expensive testing not routine today and advised to try Ampligen.
    Lisa was diagnosed as classic ME/CFS by Guyer.
    Me, I'm not a "biotoxin" illness person strictly. I react to chemicals too and at my worst had to boil organic cotton clothing for hours before I could wear it.

    ***I would not argue that Erik, Lisa or you do not have ME/CFS. I think I have good reasons to believe that all of you do.

    How to differentiate the 15 in Fluge and Mella's study from Lisa and Erik etc if their own doctors found the same objective abnormalities on a history and on blood tests??

    ***What I have tried to do is to distinguish between etiologies and pathophysiology. I've suggested that all of you (and they) have a common pathophysiology, which characterizes the same disorder, ME/CFS, but the routes by which you all got there (the etiologies) may vary from one case to another.

    If the endpoint is the same and the immune abnormalities are the same then a valid serious question is, why do two very different strategies have such unexpected success.

    ***I'm suggesting that the endpoint (the pathophysiology of ME/CFS) is indeed the same. I'm not sure what you mean about the immune abnormalities being the same. If you mean the immune dysfunctions that I'm suggesting result from the glutathione depletion, methylation cycle partial block, and folates depletion, then I would say that those are part of the common pathophysiology. However, this does not shed any light on the etiologies that led to that pathophysiology, or in particular, whether they were the same for the people in the Rituximab study and for those who have biotoxin illness.

    My hypothesis is that the tcell bcell abnormal loop is being re-set in both instances but by different means. One changes environmental triggers radically to quiet toll receptors and the other wipes out bcells and their rogue autoantibodies thus quieting the system. A different entry into the abnormal loop.

    ***I guess that with your model I would be concerned that if the people who had biotoxin illness were re-exposed to biotoxins after their "recovery" from the Rituximab treatment, they would relapse.

    Glutathione, lipids, oxygen etc all play a profound role if they are depleted or disordered but IMHO they may increase vulnerability based on polymorphisms, and replenishing them can be of great value but they play a contributory not causal role.

    ***O.K. We are all certainly free to have our opinions! :D

    I know I'm right! Tee hee. Where's the grinny sign...

    ***See above.

    ***Best regards,

    ***Rich
     

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