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Natural killer cells, perforin, and glutathione depletion

Discussion in 'Latest ME/CFS Research' started by richvank, May 23, 2012.

  1. SOC

    SOC Senior Member

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    I have heard the theory that often in the earlier stages of the illness, the immune system is revved up trying to compensate for immune abnormality or the infection so people show signs of an overactive immune system, but after a number of years, the immune system becomes exhausted and then we start to see more flu-like symptoms.

    It's just a theory, and I doubt it applies to all of us, but it's something to consider when considering patients differences.
     
  2. mellster

    mellster Marco

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    Thanks, deifinitely worth considering. The thing for me is that I experienced flu-like symptoms on a consistent basis (thank god not much anymore), but I never caught anything that was going around even when a sick coworker would literally sneeze in my face ;) Prior to the onset in 2009 I used to get at least one nasty cold per year with very sore throat, cough, bronchial, itchy runny nose and runny eyes, the works, and I used to get one flu infection at least every 3 years with high(er) fever, flu-like symptoms, malaise, nausea but no cold symptoms. Those were the two distinct main things I caught once in a while like a lot of other "normal" people. Maybe there is something to the exhaustion theory, but I am not sure about this. Also, the flu-like symptoms since onset are somewhat different from the flu as they resemble more widespread inflammatory/wired feelings more akin to what is describe to cytokines being out of whack/elevated.
     
  3. SOC

    SOC Senior Member

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    Yah, well, it's just a theory. :)

    Have you had any immune tests of the sort that are showing abnormalities in PWME? It might answer some of the questions. Of course, if you're like a lot of us, it may also raise more questions than it answers. ;)
     
  4. mellster

    mellster Marco

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    Symptom wise I am more FM again if at all (like in the beginning), however a flow cytometry last year showed heightened numbers of cd4/cd8 cells and activity as in battling an infection and NK activity declined from 27 to 7 during acute phase and now back to 15 (range being 8-170 with approx. normal of 50) - I believe their activity will continue to ascend as I am still supplementing, so maybe there was just a long drawn out infection battle going on (EBV was the only one that was significantly high, and at some point CPN mildly elevated, both have come down thus far). Otherwise I fit my moms profile with normal blood work but a very slight anemic tendency (still low normal range of RBC/hemoglobin/hematokrit) and low normal WBC as well. Interestingly she is battling recurring herpes blisters, has also a reactive lymph node (on the other side otherwise exact same spot by throat) and chronic gut and fatigue issues, however not even close to CFS or FM. On paper she is super healthy though :) So either genetic or host (infectious) theory, or a combination of both ;)
     
  5. SOC

    SOC Senior Member

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    I'm inclined to agree. :) It sounds like you are making wonderful progress. It looks like you've figured out what works for you. Congratulations!
     
    mellster likes this.
  6. richvank

    richvank Senior Member

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    Hi, LB.

    Yes, unfortunately. I think that the immune system is also having to put energy into cleaning up the damage from oxidative stress, including cells that are dying early (elevated apoptosis rates).

    Best regards,

    Rich
     
  7. richvank

    richvank Senior Member

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    Hi, heaps, mellster and the group.

    Thank you for your comments and questions.

    To try to respond to your questions, I think I should first summarize how the immune system normally responds to viral infections, then discuss what I think the dysfunction in ME/CFS involves, and then comment on your questions:

    So first, how does the immune system normally respond to viral infections? There are basically four types of responses, listed here in roughly the chronological order in which they normally occur:

    1. Type I interferon (interferons alpha and beta) responses
    2. Natural killer cell response
    3. Virus-specific cytotoxic T lymphocyte (CD-8 "killer" T cell) response.
    4. Antibody response

    Type I interferons are secreted by infected cells, to alert nearby cells, and hopefully prevent them from becoming infected. The Interferon responses include the PKR, the 2,5-OAS RNase-L, and the Mx responses, among others. The PKR response inhibits the synthesis of viral proteins inside host cells. The 2,5-OAS RNase-L response degrades viral RNA inside host cells. The Mx response inhibits viral gene expression and assembly of the virions inside host cells.

    The natural killer cells recognize virally infected cells in which the viruses are attempting to hide from the immune system by shutting off the Class I HLA mechanism that the CD-8 cells use to recognize virally infected cells. If the Class I HLA molecules are not displayed on the cell surface, the NK cell kills the cell.

    The CD-8 killer T cells kill cells that are displaying viral antigens by means of the Class I HLA molecules.

    Antibodies against viral antigens are made by B lymphocytes and plasma cells, and they bind to viruses that are outside the host cells, as when an infection is beginning or when viruses are spreading from one host cell to another.
    This neutralizes the viruses, so that they cannot enter new host cells, and it can also "mark" them for attack by other cells of the immune system, such as macrophages.


    O.K., now what happens to these responses in ME/CFS?

    Well, the Type I interferon responses continue to work, and even though they are intended to be short term responses to hold back the viral infection until the "cavalry" in the form of the CD-8 killer cells arrives, and the CD-8 cells, together with the NK cells, knock out the viral infection, in ME/CFS the interferon responses continue to work overtime (and even become dysregulated in the case of the RNase-L) because the CD-8 killer cells are not able to take over. Sadly, the "cavalry" never arrives, leaving the "civilians" to battle the "Indians" in an ongoing guerrilla war.
    What causes the formation of the dysregulated low-molecular-weight RNase-L molecules? I propose that glutathione depletion is responsible. It activates calpain, and calpain cleaves the normal RNase-L molecules. The cleaved parts join together, forming the unregulated LMW RNase-L.

    Both the NK cells and the CD-8 killer T cells are rendered impotent by their inability to make perforin and granzymes in normal amounts. Furthermore, the CD-8 killer T cells are not able to multiply to outnumber the "bad guys" as they should. Why does this happen? I propose that it is a result of glutathione depletion and depletion of folates, respectively, which are part of the GD-MCB vicious circle mechanism that I believe is at the basis of the pathogenesis of ME/CFS.

    Antibody production continues, and in fact may be increased, because of the shift toward the Th2 immune response in ME/CFS, which favors humoral immunity, i.e. the production of antibodies by B lymphocytes and plasma cells. What causes this shift? Again, I have proposed that glutathione depletion is responsible, in this case in the "naive" T cells.

    So what we have are heightened interferon and antibody responses, but failure of the main "kill" mechanisms. The result is that latent viruses in the body (such as EBV, CMV and HHV6) are able to reactivate, and the immune system continues to fight with the weapons it has left, confining the viruses and keeping the host alive, but not winning the war against the viruses by completely knocking them out or putting them back into latency.

    Now, what about your questions?

    Would interferon treatment work? Well, to some degree, but without the other dysfunctional immune responses to help them, they cannot completely knock out the viruses.

    Why don't PWMEs get colds and flus? I think it's because of the constantly elevated interferon responses. This produces what has been called the "antiviral state." With this going on, it's difficult for a newly introduced virus to get a foothold.

    Does this have anything to do with the elevated cytokines in ME/CFS? Yes. The immune system is well aware that there are enemies inside the perimeter, and it is sounding the alarm, trying to organize the defense. The cells of the immune system are sending chemical messages back and forth to each other in the form of cytokines. However, because the NK cells and the CD-8 cells are impotent, even though the trumpet sounds, they don't respond, because they are not able to, so the messages just keep flying back and forth, unheeded.

    So what's the solution to this problem? How do we win the war? Well, I'm still working on that, but I think that a big part of it will be to restore glutathione, folates and methylation, and that will probably require a methylation protocol.
    Beyond that, because viruses that are well-entrenched have various ways of foiling the immune system, even though the immune system is restored, other measures will likely also be needed. One interesting one is GcMAF, which overcomes one of the strategies used by viruses to foil the immune system, i.e. nagalase. Antivirals are another possibility, especially in view of some success using them, as in Dr. Lerner's experience.

    I hope this is helpful.

    Best regards,

    Rich
     
  8. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    Have you got any other info to relate this to the nk bright cell abnormalites found in the bond study?

    Of interest one of my tests i was on an interferon inducer which greatly increased my nk function (this test has been very low on all other tests) but my bright cell function remained low. Symptom wise i did improve some.

    Antivirals over time have improved my lymphocyte numbers and sub sets from high to almost normal. Besides the 1 above test, my nk test and nk bright cell test have been very low, probably worsened. AVs have improved me from a 3 to a 6 sometimes a 7(lerners fatigue scale). these nk cells i think are possibly whats holding me back from more improvement.

    nk cell activity 51(13.8-34.8) , DIM 73(60-88), bright 1.95(5-10) , on an interferon inducer at the time and antivirals.

    next my last test not on an interferon inducer but still on antivirals as above, a recent lymph sub set test was almost normal. cd8 numbers within normal range.
    nk activity 2(13.8-34.8), DIM NK 90.27(60-88), bright nk 1.43(5-10)

    I was on antivirals this whole study, my nk activity ranged from 1-51, bright nk ranged from .93-4.32(all but one test was under 2)

    I just post the above for interest and to show that av's have helped me but i dont think im over the line yet, the one thing not improving is the nk bright cells.

    cheers!!!
     
    Xandoff likes this.
  9. richvank

    richvank Senior Member

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    Hi, heaps.

    I don't think that much is known yet about the CD56+ bright CD16- NK cells. Apparently they are normally involved in controlling inflammation, and are preferentially attracted to areas where there is inflammation. They are not as sensitive to damage by oxidative stress as are the CD56-dim CD16+ NK cells.

    My guess is that development of these cells is controlled by certain cytokines. Because of the vicious circle mechanism I have described, the immune system is dysfunctional. Part of that dysfunction may involve abnormal levels of the cytokines involved in stimulating the production of the "bright" NK cells.

    Sorry I can't give you more information about this. Immunology is still a developing field. I have the most recent editions of two of the best texts, and they don't even mention the "bright" NK cells.

    Best regards,

    Rich
     
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  10. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    i think interleukin 2 was a common cytokine found elevated in bond/cfs study, which is an inflammatory cytokine. i dont know anymore then that. how do we control cytokines, this might help me get some sleep, lol.

    cheers!!!
     
    Xandoff likes this.
  11. richvank

    richvank Senior Member

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    Hi, heaps.

    The best I can do now is to advise lifting the partial methylation cycle block so that glutathione can come up to normal. I think that has the best chance of normalizing the function of the immune system, including the cytokines.

    As far as I can tell, none of the immunological researchers have totally figured out what the cytokine patterns mean or how they come about in ME/CFS in any detail. It's kind of a hodge podge, and they vary with time. So I think we have to get at the root cause of the immune dysfunction and fix that, rather than trying to manipulate the cytokines. It's a very complex and interactive system, the immune system!

    Best regards,

    Rich
     
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  12. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    I have tried the methylation treatment in the past with no noticeable effects. I still use the odd injection of hydroxy b12 and use NAC and lipoic acid. Now things have improved some with antivirals i will add methyl b12 and methylfolate and see what happens. I believe in retrying treatments as we can be in a different biochemical state when previously trying something before.

    cheers!!!
     
    Little Bluestem likes this.
  13. seanpaul

    seanpaul

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    Hi All

    I am massively interested in this area, I am about to start a Masters Research Dissertation in Medicinal Chemistry and Im looking for a topic to study and I am looking at neuropharmacology which links into immune responses in ME/CFS:

    I want to follow up on a previously mentioned phenomenon, that of constant inflammation being felt in the body without often catching colds and flu's. Like a mini-Einstein I have sat in my bedroom feeling all the body sensations of ME and trying to work out, using my medical knowknowledge, whats going on here: I speculate

    1. what systems are being afflicted, =(answer seems neural tissue, base of brain, maybe brain stem, basal ganglia, also throat tissue, down sternum, around heart) - thus thoughts, its pathogenic bacteria or virus that might be spreading along nerves, or perhaps just in upper respiratory system then spreads outward towards brain and heart /

    2. whats causing the inflammation =(answer, well there has to be an internal mechanism at work here, the cells detecting some pathogen, or perhaps pathogen has passed, I think the former, pathogen is alive and spreading if and when it can, thus constant back and forth immune respones, with hyper inflammation sometimes esp if run down, and less inflammation when feeling well. Inflammation for me is the worse symptom and is most likely damaging neural tissue, stressing vascular tissue, causing changes in blood pressure and heart rate, interfering with hormonal homeostatis, and draining the body of energy, not to mention the effort needed to produce immune cells and vitamins and so on that are being depleted at a rapid rate by this hyper-immune reaction.

    the question is, whats causing this type of immune reaction? Ive been reading that viruses can knock out interleukin-21 which is needed for cross talk between immune cells. I think this ME virus /bacteria has been around so long its found a way to evade standard immune response. I think the above is right, the body compensates by changing the immune system (Th1 to Th2 if you will), using alternative means to contain and attack pathogen --- the problem with this is, the immune response is the thing casing most of the bad body sensations and stress (TNF, histamine, cytokines, pain chemistry, IL's) and this type of intra-cellular immunity generates cellular level stress (NO, free radicals, and bi-products that stress the cell). Basically, the immune response is killing us. thats my theory.

    Here is the million dollar question: whats causing it?.... who knows, but we can understand the mechanisms

    here is the sub question I think we should be able to asnwer: can we say using our knowledge of immunology whether its bacterial or viral e.g increases in cellular B-interferon from Mast Cells should indicate a viral attack, hence am I right in assuming the reverse is true - low BetaInterferon indicates bacterial infection????
    http://www.sciencedaily.com/releases/2010/06/100607111308.htm

    As C-reative protein is never elevated, we are talking about tissue level reactions, not systemic

    The increase in chemical sensitives leads me to think Mast cells and tissue level immunity is key here - before ME I never had any allergies, I still think I dont have true allergies, but often when I eat things I get a type of alergic reaction, showing me at least there is some change in immunity, over response to normal chemicials, hyper-altert over-reaction status.

    Understand this and you get ME!

    Thoughts please......
     
  14. valentinelynx

    valentinelynx Senior Member

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    "As C-reative protein is never elevated, we are talking about tissue level reactions, not systemic."

    Says who? My CRP is consistently elevated. Also one of the most common findings in ME/CFS. Sorry don't have energy to dig up sources at moment.
     
  15. seanpaul

    seanpaul

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    Hi, from my readings for the majority of ME/CFS patients C-reactive protein levels are within normal ranges - if you have raised C-reactive protein you should contact your physician because it is a sign of inflammation, it should really be actue, however there are some chronic conditions that may evlevate it.

    I dont think in ME/CFS there is actue inflammatory responses in the normal blood work, like raised white cell count, raised neutrophil count, or raised c-reactive protein: in my own case they have always been normal, despite the fact Ive been very unwell for a good long while. I personally believe the inflammation I experience is tissue level, ie there is an inflammatory process happening that is not triggered in the usual systemic way - more localised to cells infected with what ever pathogen is in there.

    C-reactive protein is a sort of side line issue to my main offering about differentiating between bacterial and viral infections given what we already know about immunology?
     
  16. Valentijn

    Valentijn Activity Level: 3

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    My (marginally) elevated CRP was the only abnormal result on the normal screening tests I got when I first got diagnosed.
     
  17. Gestalt

    Gestalt Senior Member

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    I am trying to understand this better. Does NAC help with boosting glutathione level temporarily? Or does NAC not work at all?
     
  18. richvank

    richvank Senior Member

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    Hi, Gestalt.

    For people for whom lack of cysteine is the limiting factor for glutathione synthesis, NAC should help the liver to make glutathione, and should raise it on a temporary basis. The dosage should be limited to about 1 gram (1,000 milligrams) per day to avoid causing a pro-oxidant, rather than an antioxidant effect. If there is a high body burden of mercury, Dr. David Quig has recommended limiting the dosage to 300 mg per day, to avoid moving mercury into the brain. If something else is limiting glutathione synthesis, such as very low glycine, which some PWMEs have, supplementing NAC won't help. To raise glutathione on a permanent basis in ME/CFS, it is necessary to lift the partial methylation cycle block, which is upstream of glutathione synthesis in the sulfur metabolism.

    Best regards,

    Rich
     
  19. xrayspex

    xrayspex Senior Member

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    keith, I can relate to some of what you say, i didnt have elevated crp the one time we checked few years ago. but main thing is as a kid I wasnt allergic or asthmatic but since CFS over time have gotten super reactive to a lot of foods and chemicals, but I rarely get colds, dont seem sick in the classic way in winter but will have periods of feeling more pain and malaise that I think is my way of having a bug, I used to get my share of those sorts of colds and flus but the longer this goes on the less likely for me to get "sick". I found out have autoimmune issue going on, sjogrens.
     
  20. Daffodil

    Daffodil Senior Member

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    my perforin mRNA expression was 468, which is in normal range, before treatment. yet my NK cell function has always been in the single digits. what can this mean?
     

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