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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. Marco

    Marco Old blackguard

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    Apologies. This isn't news just some musings of my own and I didn't know where else to post it.

    I've not been following ME/CFS research for many years. The XMRV thing brought me back in and I've been trying to get up to speed. One of the PR library papers (Broderick et al) got me doing a little reading on the TH1/TH2 immune imbalance theory which also got me doing a little thinking.

    This is a beautiful paper. If anyone is interested in science for the sake of it this is a peach.

    http://www.forums.aboutmecfs.org/showthread.php?4812-Broderick-2010-A-Formal-Analysis-of-Cytokine-Networks-in-CFS


    I won't even try to explain the basic theory. Others are well versed, in fact its probably old hat to most people. For people like me, this provides a good accessible overview and critique of the limitations of the theory (can't unfortunately vouch for its accuracy) :

    http://docs.google.com/viewer?a=v&q=cache:jE2nP3U1F6gJ:www.adltests.com/assets/files/pdf/Cytokines_Th1_Th2_Kidd.pdf+low+TH1+high+TH2&hl=en&gl=uk&pid=bl&srcid=ADGEESjglKiokexKb0qfb95NbDGM5EHSFmwnPGkq7_Jmetv_dPl7TGcXnw0IBPmnD83fzcMNMz_narNeWq9msAQTFQ1Yu1P1nZ34LMU0pRUlpQMrHPrOxO6c-45uhGKIP-_Z92X8eFih&sig=AHIEtbTOnIk8Qo3930pJJDJFMf-UcdcTCA


    Anyway, we are all too painfully aware that ME/CFS is dogged by the issue of heterogeneity. On one hand there's the 'stating the bleedin' obvious' heterogeneity resulting from loose diagnostic criteria that allow anyone who is frequently tired to be labelled as CFS.

    More substantively, we are all aware that those with 'true' ME/CFS often differ in many ways. Some have sudden onset, some gradual. Some can point to a viral onset, some not. Some cite vaccinations, heavy metals, organophosphates, (the gulf war?) as precipitating factors and some point to overexercise, diet, or stress. While viruses (and retroviruses) have long been proposed as pathogens, none to date have been found in all those diagnosed with ME/CFS. While XMRV may turn out to be the key, PWCs have already been tested negative and it is possible that many of those diagnosed with ME/CFS will be found not to have an active XMRV infection. Some people reportedly make a quick spontaneous recovery while others become chronically ill for many years and fluctuations/relapses are common. Some report that fatigue, the central and sometimes only symptom considered important in CFS, was not a factor in at least a stage of their illness. Finally, regardless of how we view 'therapies' such as CBT/GET or the Gupta Programme, they are reported to be of some help to some people (bear with me of the last point).

    I would like to propose that ME/CFS, in ALL CASES, is caused by a dysregulation of the immune system leading to TH2 dominance. For want of a better title I'll call it Type 2 Immune Dysfunction Syndrome (syndrome to distinguish it from other specific illnesses caused by TH2 dominance).

    Taking this approach I believe avoids the 'problem' of searching for a single etiology, improves diagnosis and clarifies the treatment options.
     
  2. Marco

    Marco Old blackguard

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    I said I wouldn't try to explain the theory but it helps to briefly set out my limited understanding and what I think it might imply. For those of you au fait with this stuff, my apologies. This is simplistic because (a) this is all I can remember and (b) others can explain it better and more fully. There is much more subtlety and upstream/downstream mechanisms than I've presented, but bear with me :

    The human immune system is broadly hypothesised as comprising two arms that are activated as appropriate when confronted with specific pathogens. T helper 1 cells (TH1) lead the attack against intracellular pathogens such as viruses, bacteria and fight cancer cells. T helper 2 (TH2) cells protect against extracellular pathogens such as parasites and toxins.

    TH0 the native unassigned immune cells stand ready to react to whatever pathogens are identified. Cytokines are the chemical messengers that send the appropriate signal for the production, from TH0 cells, of TH1 or TH2 cells depending on the pathogen identified. The cytokine IL12 signals that a TH1 response is required and IL10 signals that TH2 is required. When one system is up regulated the other tends to be down regulated.

    Over-regulation or dominance of the TH1 arm can produce :

    Organ specific autoimmune diseases such as rheumatoid arthritis, MS, type 1 diabetes, Crohn's, Graves Disease etc;

    While over-regulation or dominance of the TH2 arm can produce :

    Allergies and IgE-based disease, systemic autoimmune diseases including asthma and lupus.

    Many with ME/CFS develop a wide range of new allergies/sensitivities which might suggest an over active TH2 arm of the immune system. Additionally PWCs appear to be more prone to cancer, have a high viral load and low Natural Killer (NK) cell toxicity suggesting a complementary down regulation of the TH1 immune arm.

    In addition, to the allergic/inflammatory symptoms associated with TH2 dominance, de Meirleir and others have suggested that many other of the ME/CFS symptoms are caused by a resulting channelopathy (see below).

    Most viruses appear to have the ability to chemically mimic IL10 causing an inappropriate up regulation of the TH2 arm and suppression of the TH1 arm. The TH2 weapons (white cells and antibodies) are produced and TH1 weapons including NK cells are suppressed. With the TH1 arm suppressed previous infections can resurface and new opportunistic infections acquired.

    With the TH1 arm ineffective, the immune system increases production of the anti-viral enzyme RNaseL which can't kill the virus but stops replication. In ME/CFS however the RNaseL produced is a low molecular weight type which is unable to kill infected cells and in fact causes damage to healthy cells. RNaseL fragments, according to de Meirleir, interfere with the functioning of ion channels (channelopathy) causing a range of symptoms. Continued RNaseL production, to provide some sort of anti-viral activity, no matter how ineffective, requires human growth hormone and over time the HGH supply becomes exhausted.

    Low HGH levels have been associated with : Low energy, decreased lean muscle mass, increased abdominal fat, decreased strength and exercise tolerance, feelings or anxiety sadness and social avoidance, dry thin skin, sleep disturbances, decline in bone density, raised cholesterol, low blood sugar, irritability, night sweats etc.


    So an imbalance of the immune system where the TH2 arm is dominant will quickly produce allergic symptoms and new sensitivities (to foods, chemicals, toxins etc) but may also produce a range of other symptoms due to channelopathy.

    TH2 dominance also suppresses the TH1 arm leaving a compromised defence against new opportunistic virus infections, cancer etc. I have not discussed the possible symptoms of any viral infections as they are likely to be many and varied depending on the pathogen.

    Over time, (maybe not that much time depending on the original levels of HGH) the need to replace (defective) RnaseL depletes the body of HGH leading to a range of familiar symptoms.



    ASSUMING TH2 dominance holds true generally, how does this help?
     
  3. Marco

    Marco Old blackguard

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    Heterogeneity, diagnosis and treatment

    TH2 dominance conditions have been shown to be caused by viruses, surgery, blood transfusion, pregnancy, emotional stress, athletic stress, academic stress, malnutrition, heavy metals, organophosphates, vaccinations etc. All frequently suggested triggers for ME/CFS.

    There is no need to identify a single causal agent/factor in all cases to explain the onset of ME/CFS. ME/CFS is clearly identified as a disease of immune dysfunction. The only role for psychological or psychiatric treatments are if needed as an adjunct to treating the immune dysfunction. It also avoids the problem, if XMRV is found to be a major player, of those testing negative who would otherwise be relegated to Reevesville.

    I would suggest that the investigation of all suspected cases of ME/CFS should include :

    • A full medical history to narrow down potential triggers and perpetuating factors;
    • Tests to indicate a TH2 dominant immune state;
    • Tests to indicate total viral load.
    • HGH status.

    If the results suggest :

    (a) Not TH2 dominant and no evidence of virus you do not have ME/CFS perhaps a course of antidepressants might help (in case anyone is offended by this I had severe clinical depression for a number of years and much prefer having ME/CFS in many ways thank you very much so I'm not disparaging the condition or afraid of the stigma!);

    (b) High viral load but not TH2 dominant. By definition you do not have ME/CFS. Your immune system is reacting appropriately to a previously undiagnosed viral infection that should be treated appropriately. HGH supplementation has been shown to enhance the effects of HAART and may enhance the effects of any anti-viral where HGH is shown to be low.

    (c) Low/no viral load but TH2 dominant. Likely to apply in cases with gradual onset, early cases and those with non-viral triggers. Therapy might consist of a period of recuperation (if still working or otherwise active), immune support (immune modulators), proper nutrition. HGH supplementation may be useful where levels are low. Light exercise (aimed at enhancing immune function) may be helpful if tolerated and psychological therapies may be appropriate as an adjunct where psychological issues are implicated in stressing the immune system. NOTE : There is no place for CBT or GET in this model. It is a disease of immune dysfunction. There are no illness beliefs to challenge and only exercise that doesn't further stress the immune system should be undertaken.

    (d)High viral load and TH2 dominant. Likely to apply in many cases with a clear viral onset and in many long standing cases where immune dysfunction has allowed for many opportunistic infections. Therapies should include those mentioned in (c) above but excluding exercise until status improves. In addition a general antiviral should be used initially to reduce the overall viral load pending further investigation of specific pathogens. Tests may not be available for all potential pathogens, but reducing the overall viral load and rebalancing the immune system should provide some relief. HGH supplementation is again recommended where levels are found to be low.
     
  4. Marco

    Marco Old blackguard

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    I appreciate that, as set out, this is all very simplistic, but I feel that it represents a much more satisfactory paradigm than the current search for the 'magic bullet' and discussion of sub-sets and heterogeneity. All those with ME/CFS have an immune dysfunction. They only differ on the trigger and duration of illness. The Broderick et al paper, which states that the difference between the structure of cytokine expression in the CFS/ME group compared to the control group is ten times the magnitude of the variability within the groups certainly suggests that there may be a unique pattern of immune dysregulation.

    What role for XMRV?

    XMRV may turn out to be a causal factor in many cases of ME/CFS, may be another opportunistic infection or it may either be THE virus (and detection just needs to be improved) or THE factor which predisposes us to develop ME/CFS when presented with another triggering event. Certainly an explanation is needed as to why some people develop TH2 dominance and others don't when faced with vaccinations, viruses or other triggering events.

    As for CBT/GET and the Gupta Programme and similar. Perhaps they have some benefit for those diagnosed as CFS but who are either no viral load and not TH2 dominant (i.e. they don't have ME:CFS) or those with no viral load but who are TH2 dominant (non viral onset) but at an early stage of illness and have neither acquired opportunistic infections nor HGH depletion. Both 'therapies' might help rebalance the immune system to some extent (or in the case of GET might exacerbate the problem) but neither will treat active virus infections.


    CASE STUDY

    Well what about me?

    Although circumstances might suggest contact with an enterovirus, I have never been tested for viruses and have no evidence of any present or past viral infection.

    Onset was sudden (full health to poor health) but not all of the symptoms were there at the start. My state of health has undergone three distinct step changes downwards over the course of coming up to 25 years.

    I had developed GI problems and anxiety/depression and then collapsed while training. Since then I haven't been able to tolerate any aerobic exercise.

    I then developed dizziness on standing, extreme sensitivity to cold, a wide range of food and chemical intolerances, joint and muscle pains, headaches etc but fatigue as such was not a major issue and I was able to even combine full time working and part time study so no cognitive issues.

    Prior to the onset of illness though I was probably overactive physically, undernourished and under some personal and academic stress.

    To fit it into my suggested schema; I was probably pushed to a TH2 dominant immune response but with no or a low viral load. TH2 dominance would explain the IBS, new intolerances and possible joint and muscle pains. PEM etc I don't know possibly de Meirleir's channelopathy.

    Next step change I suddenly developed a whole raft of new symptoms in addition to those existing. These included rapid unexplained weight gain (abdominally for the first time) loss of strength and muscle tone, rapid greying of hair and apparent ageing, insomnia, anxiety, exacerbated fatigue, profuse sweating, dry skin etc. Strangely enough I have never again experienced real depression since this date. All very suggestive of exhausted HGH. Again circumstances might suggest another enterovirus effect (or vaccine?) as both step changes followed shortly after holidays abroad.

    Finally, after seven years I had to leave work (for the afternoon I thought) and never went back. To the existing symptoms I added extreme fatigue (needing to sleep during the day) and severe cognitive problems. For the first number of months I couldn't walk, think, read or drive and still can't when I have a frequent bad spell.

    I can't identify any specific triggers for the last step change. Perhaps this last stage was viral or perhaps I carried on too long with no relief? Perhaps the last stage was me developing full blown ME and not just part of it?

    Any thoughts/criticisms would be much appreciated.
     
  5. slayadragon

    slayadragon Senior Member

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    I really want to discuss this. It seems really important, and I've yet to figure out exactly how it fits in with the rest of how I personally am looking at this illness right now.

    First, Th2 is supposed to "protect against extracellular pathogens and toxins."

    Does this pertain to all toxins? Or just some of them?

    In what way does Th2 protect us against those toxins? What are the immune system components that do this work?

    Thanks, Lisa
     
  6. Countrygirl

    Countrygirl Senior Member

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  7. Marco

    Marco Old blackguard

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    C.G.

    I can't comment on what Dr Mikovits said but everything Nancy Klimas has said about XMRV describes immune dysregulation and suppression (or at least ineffectiveness) of the TH1 side?
     
  8. Marco

    Marco Old blackguard

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    Slayadragon

    I'd need to dig around to get a concise description of the TH2 components that 'protect us from toxins'.

    In the meantime, I think the key point is that when the TH2 arm becomes overactivated, the immune system has a constant message that there is a toxin out there and actively searches out anything that is "not-self" or even in some cases starts attacking our own cells.

    Things that were previously tolerated are now treated as toxic (e.g. food in the stomach and bowel is morphologically speaking 'outside the body' but if large food molecules escape into the body through a leaky gut they are toxic). I believe that this is how we develop new sensitivities/intolerances to common foods, chemicals, dental amalgam etc. We have previously been exposed to them and tolerated these substances, but the overactive TH2 arm is driven to identify the toxin it 'believes' is there and starts to identify previously innocuous substances as toxins.
     
  9. dannybex

    dannybex Senior Member

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  10. guest

    guest Guest

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    Great post, Marco. I always wondered if there is anything good about a Th2 dominance, now it seems there is (lower incidence of MS, diabetes etc.). Thanks for posting it!
     
  11. Mark

    Mark Acting CEO

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    Then there are those handful of people with atypical MS and XMRV+ to fit in...
     
  12. Mark

    Mark Acting CEO

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    i agree, d.
    ok, marco?
     
  13. helsbells

    helsbells Senior Member

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    I deffinately identify with your three distinct downward slides, this is completely what happened to me, also the first step where I developed massive anxiety literally out of no where and something the DR called malaise :rolleyes:, actually I never fully returned to work but over time went back to study as at that a point I had no brain fog. But differ in that virus's, infections, sore throats et al came thick and fast until the point of the first down turn and when I became more or less housebound with brain fog (which I still have no reading, drawing etc or thinking or rememebring) BUT Viruss, colds stopped dead allergies flowered on the other hand. the third phase were I became so intolerant to food it was difficult to eat for a while and developed interstitial cystytis plus loads of other additional diagnosis's so my case history I think would fit in very well with what you are positing. What is HGH by the way - sorry if its obvious - I have said all along my immune system is dysfunctional because altho it rarely happenes I get any colds, virus's etc on the rare occasion I do the day before is the best I ever feel and even during feel better than normal in some ways and can deffinately get away with more foods and meds. MCS is now a massive problem for now too
     
  14. Marco

    Marco Old blackguard

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    I'm glad people are getting something out of my musings!

    Mark - were you asking me a question??

    Helsbells. HGH is human growth hormone - very important stuff to stop you feeling like - well what we do actually. Sorry to hear about your food intolerance problems - they sound horrendous. Food intolerances and GI problems/IBS have been my most long standing and consistent problems which is why I wouldn't be surprised if there was an enterovirus issue. I often think, if I could change one symptom, it would be to be able to eat without worrying about the consequences hours and days later. On the other hand I'd also like to be able to think straight for more than an hour at a time!


    As I said - TH2 dominance is old news.

    But it seems to me that ME/CFS researchers have identified a dysregulated immune system and have posited X,Y or Z virus as the pathogen. They typically test their patients and find A% have the virus an publish on the basis that virus X causes ME/CFS in a subset of patients.

    Researcher B tries to replicate the results and finds low of no evidence of virus X and declares that virus X is not the cause of ME/CFS.

    Researcher C then proposes that virus Y is the pathogen, or if they are a psych its bedwetting.

    Perhaps I'm being unfair but the focus is always on the virus or other trigger. Did researcher A,B or C consider the possibility that the immune dysfunction IS the disease and the specific trigger of lesser importance (if you can call a potentially deadly retrovirus of lesser importance).

    I was actually hoping that some scientifically minded bods could chip in and tell me why I'm obviously wrong??
     
  15. helsbells

    helsbells Senior Member

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    Marco would TH2 dominance explain why I would feel relatively better just prior to getting a bug? I totally know I have immune dysfunction as you say is it chicken or egg? Problem being for me (and please bear in mind my biology/chem understanding was poor even prior to 12 years of virtual altzeimers) I have developed such sensitivity to anything that is chemically active (inc foods vits or seemingly oft times the air, in my case!!) if it was XMRV I don't know if I would survive treatement but equally if I have XMRV and do stem cells would the original problem, left untreated, take me down again (assuming SC therapy worked in the first place. )
     
  16. Marco

    Marco Old blackguard

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    Hi again Helsbels

    I'm afraid I can't answer your questions -I don't have the science background either. I just pick up a basic understanding of things and then start piecing things together.

    If is any comfort I don't personally think the sensitivities are particularly dangerous in themselves. Its think its just like the symptoms you get with a flu virus are not due to the virus itself but our immune reaction to it - all to do with neutralising and expelling the bug from the body before it can get inside the cells and multiply.

    In the same way I think our reactions to food and chemicals are that our overactive T2 arm identifies them as toxins, produces flu like symptoms and tries to .. er .. expell them as quickly as possible - hence the IBS. The foods and chemicals themselves are usually pretty innocuous.

    Please bear in mind I'm just a PWC trying to make sense of all of this :Retro redface:
     
  17. helsbells

    helsbells Senior Member

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    Trouble is Marco I have had some pretty bad reactions - it isn't like a standard allergy but I have lost consciousness and doxy left me with permanent Interstital cystitis so I am very very wary. Don't worry I appreciate you trying to make sense of this, I know I find some of the science actually pretty difficult to grasp although I am always grateful to the boffins for keeping tabs on things for us. As someone with ASD I like things to be black or white and the more I learn about medicine seems as if it is all a can of worms - you know something written clearly on a page becaming a three dimensional object and understanding that the perspective changes from all angles it is viewed, mind boggling for someone with very moderate brain :D
     
  18. Mark

    Mark Acting CEO

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    Whoops looks like I never posted this in the end, must have got sidetracked...

    Marco I think the theory you've set out is really good, I think some categorisation very similar to yours is emerging.

    I think if we talk about a "2-hit" condition, then we have to consider that multiple hits are possible, and also that people who've had one or the other half might have some but not all of the problems too.

    Also that our histories might vary as we progress from 1-hit to 2-hit to 3-hit.

    I see a big distinction between people who always catch colds and people who never do (there are two separate threads on that). Also between people sensitive to sunlight, sound etc, and those who are not. I thought the first was TH1 dominance vs TH2 dominance, so I'm wondering where that particular distinction fits in your analysis because I think I'm seeing what look like two quite distinct groups there. I suspect they are your (c) and (d), perhaps?

    Marco as a quick guess fwiw, your own personal description sounds to me like, over the course of years, you battled as hard as you could to keep going and your body's strength and inertia kept you going for a while, then just sheer will-power, and then when you could do no more you were forced to stop, then got a massive version of the cold everyone overworked gets as soon as the first day of holiday relaxation starts. I also wonder if changes in environment circumstance, diet could have played a role. The biggest guess - and it is a guess - that I can make is: try different beds, bedding and sleeping arrangements. Experiment to find a way to sleep effectively (ie deeply) rather than for a long time. And different clothes, environmental control, diet etc are all always worth working on. Mold, of course...

    btw there is masses on TH1 and TH2 in the archives, way over my head some of it, perhaps you've dug away through that a bit?

    Anyway: thanks for a great thread Marco, really excellent stuff. I look forward to the forthcoming analysis.
     
  19. slayadragon

    slayadragon Senior Member

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    "The Straw That Broke the Camel's Back"

     
  20. HopingSince88

    HopingSince88 Senior Member

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    How does this all jive with the folks that have Crohn's and/or Interstitial Cystitis, which I thought were common in ME/CFS?
     

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