Invest in ME Conference 12: First Class in Every Way
OverTheHills wraps up our series of articles on this year's 12th Invest in ME International Conference (IIMEC12) in London with some reflections on her experience as a patient attending the conference for the first time.
Discuss the article on the Forums.

ME/CFS and Tregs - confused

Discussion in 'General ME/CFS Discussion' started by adreno, Mar 10, 2015.

  1. adreno

    adreno PR activist

    Messages:
    4,847
    Likes:
    11,067
    Several studies have found increased Tregs in ME/CFS. Simplified, Tregs help to control the immune response, and autoimmunity. So increased Tregs would point to a weaker immune response in ME/CFS.

    However, other evidence point to autoimmunity. The findings of autoantibodies and microglial activation would point to this. Also the fact that rituximabs helps ME/CFS patients (AFAIK, rituximab increases Tregs).

    This blog post gives an overview, (thanks @drob31).

    So I'm confused. Any thoughts?
     
    aaron_c, catly, merylg and 1 other person like this.
  2. Lillybelle

    Lillybelle Senior Member

    Messages:
    110
    Likes:
    89
    Australia
    Great blog on understanding histamine. I actually I understand it now I think:) Thanks
     
  3. Snow Leopard

    Snow Leopard Hibernating

    Messages:
    4,613
    Likes:
    12,424
    South Australia
    Something like the finding of increased Tregs could also be considered not a cause of the disorder, but an adaptive (and helpful) response to an underlying abnormality.
     
  4. anciendaze

    anciendaze Senior Member

    Messages:
    1,786
    Likes:
    4,558
    Part of the confusion here is due to the difference between acute and chronic disease, as found in the Hornig/Lipkin work on cytokines. Most existing work in this area centers on acute infectious disease. The problem we get into is that many markers reverse during the course of prolonged disease. Whether this is due to clearance of pathogens, development of tolerance for them, immunological exhaustion or even immune senescence is still being debated.

    If you look at the data in the Hornig/Lipkin study on cytokines you will see that long-term patients exhibit lower levels of most cytokines than healthy controls. Short term patients are much closer to the conditions found in acute disease, even though those past 6 months duration would not be said to have acute infectious disease. (I'd like to hear someone say what they do have.)

    There is good reason to believe some components of immune response are working at cross purposes to others. My guess is that this is because of infection of some very specific immune cells which are among those depleted by interventions like Rituximab or antivirals. Until we know exactly which cells are responsible only these highly imperfect interventions are available, and they work best in early stages. We simply don't know what is going on past three years, except in very general terms showing deterioration of physical condition.
     
    Valentijn, ukxmrv, SOC and 2 others like this.
  5. adreno

    adreno PR activist

    Messages:
    4,847
    Likes:
    11,067
    According to this paper, natural Treg increase during immunosenescence, while inducible Tregs decline:

    tregs_age.png
     
    melamine and Valentijn like this.
  6. Jonathan Edwards

    Jonathan Edwards "Gibberish"

    Messages:
    5,211
    Likes:
    31,646
    I think we should all be confused - so you are doing fine!
    I am personally doubtful that T regs have much to do with human autoimmunity. Most of the stuff on T regs and autoimmunity relates to mouse disease and particularly inflammatory bowel disease which is more autoinflammatory. There is a mention of RA but I know of no good evidence for T regs being relevant to RA. These stories tend to get very oversimplified. T regs make IL-10 and IL-10 actually helps B cells make antibody - it turns off mostly T cells.

    All that said T regs certainly are thought of as damping down cells and autoimmunity seems to be more flaring up. Which might raise the strange idea that ME is a problem with B cells that are the opposite of autoimmune. That might not seem to make any sense but without saying anything too much there is just a whiff of a suggestion in the lab that ME B cells might be strange in the opposite way to the autoimmune situation. That of course could explain why nobody has worked out what the heck is going on because we are looking in the wrong direction. I think the point about the difference between early and late in the Hornig study is also relevant because again it suggests that if we are not careful we may be looking the wrong way at the wrong point in time.

    Hopefully that has confused things even more.
     
    aaron_c, Marky90, Valentijn and 16 others like this.
  7. lansbergen

    lansbergen Senior Member

    Messages:
    2,467
    Likes:
    2,639
    Do you mean il10 turns off Tcells?
     
  8. Jonathan Edwards

    Jonathan Edwards "Gibberish"

    Messages:
    5,211
    Likes:
    31,646
    To a first approximation, and mostly TH1 I think if you believe humans have such things. IL-10 tends to downregulate TNF alpha.
     
    melamine, MEMum and aimossy like this.
  9. justy

    justy Donate Advocate Demonstrate

    Messages:
    5,227
    Likes:
    11,737
    U.K
    I wish there was a brain exploding emoticon - this is the closest I can find :eek::wide-eyed::jaw-drop:

    Sounds intriguing...
     
    melamine, Valentijn, MEMum and 4 others like this.
  10. Snow Leopard

    Snow Leopard Hibernating

    Messages:
    4,613
    Likes:
    12,424
    South Australia
    Um, is it possible for you to be more specific for what you mean by this? The opposite of autoimmunity could be considered immunodeficiency, or at least normal functioning.

    I know there have been quite a few discussions here and elsewhere how ME does not fit the classical inflammatory autoimmune picture (eg build up of immune complexes, leading to inflammation). But I'm not sure how an 'opposite of autoimmune' B-cell dysregulation would self-perpetuate, nor what it would look like.

    Likewise, there is some interesting discussion in the literature about anti-cytokine autoantibodies, though not sure if that could be at all relevant in ME.
     
    Last edited: Mar 10, 2015
    Hutan, Valentijn, justy and 1 other person like this.
  11. bambi

    bambi Guest

    Messages:
    56
    Likes:
    59
    @JonathanEdwards

    Didn't you co-author with Michael R. Ehrenstein the paper Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis ?

    Since you disregard all the thousands of papers by reputable scientist on the role of Tregs in various settings and what an increase or decrease of Treg cells indicate , maybe you are more inclined to acknowledge a review of your former co-author Michael R.Ehrenstein on this topic.

    Restoring the balance: Harnessing regulatory T cells for therapy in rheumatoid arthritis
    Fabian Flores-Borja, Claudia Mauri and Michael R. Ehrenstein

    "Treg play a vital role in the maintenance of tolerance to self antigens, thereby preventing disease through the active suppression of proliferation and pro-inflammatory cytokine production by autoreactive T cells. Here we discuss strategies aimed at enhancing Treg function in patients with rheumatoid arthritis with the ultimate aim of restoring lasting tolerance but without increasing the risk of infections or cancer."



    To look at Tregs in isolation will not tell you much and no one is saying they are the sole cause of any disease. However, the are an important player on the immune field and in combination with other immune markers or cytokines they are a good indicator of what is going on in a disease.
     
    Last edited: Mar 10, 2015
  12. bambi

    bambi Guest

    Messages:
    56
    Likes:
    59
    @adreno

    Here is an analogy I made up for friends who had difficulty understudying the role of Tregs.

    Imagen a socker game on a playing field.

    So one team are players from the T- cells team. Some players are the first line of defenders, for example NK cells, than there are effector T- cells which you could compare with stormers and than you have T -helper cells and so forth. There is a subset on this whole field which are very important and those are the T- regulatory cells -- Tregs. They are the referees.

    They control the other cells and check that the game is not getting out of control. Meaning, if there is a pathogen invading the field, all immune cells go into full action. If this action gets to much, the game could get out of hand and the immune cells go basically into overkill mode. That would cause damage to the host, could kill us, and it can happen that the effector immune cells could attack the bodies own tissue-- that is what is commonly understood as autoimmune reaction (auto reactive T cells). So Tregs control that by damping (regulating) the immune response of other cells.

    That is a very simplified explanation, because of course the immune system is very complex with lots of more players at different times and in different settings.

    So the continued expression of increased Treg do not necessarily indicate a weaker immune response. But as I said elsewhere, in combination with other markers, for example low NKcell activity and a decrease CD8+CD28+ cells, increased CD8+CD28- would indicate a continued long term antigen stimulation and immune exhaustion. Hence, chronic infection which leads over time to immune exhaustion.
     
    Last edited: Mar 10, 2015
  13. Jonathan Edwards

    Jonathan Edwards "Gibberish"

    Messages:
    5,211
    Likes:
    31,646
    Not really, Mike Ehrenstein was a junior member of the team when we did the B cell repopulation study. I am not aware that he and his colleagues actually have any evidence for T regs being of importance. Everyone who wants grant money writes about T regs these days. Il-10 therapy did sweet FA for RA - made the nodules worse I think.

    I agree we should have zero tolerance for psychobabble, but immunobabble deserves the same. I don't judge scientists by their reputation, more by whether they have something sensible to say.
     
    Valentijn, aimossy, rosie26 and 5 others like this.
  14. Jonathan Edwards

    Jonathan Edwards "Gibberish"

    Messages:
    5,211
    Likes:
    31,646
    I read the paper. It provides no evidence for T regs being important in RA. There is a lot of stuff about mouse arthritis which is irrelevant because it is a different disease. There is mention of the fact that T regs seem to be suffering from the effects of TNF in RA but that is hardly surprising since the whole immune system is suffering from the effects of TNF, which as far as we know has nothing to do with T regs being defective (there are lots of them). It adds up to nothing. I have been in immunology too long to get caught up in the latest fad of this or that T cell. As far as we know the T cells in RA are perfectly normal!
     
    Valentijn, aimossy, Sherlock and 2 others like this.
  15. bambi

    bambi Guest

    Messages:
    56
    Likes:
    59
    Well here we are again. Now you are telling us your former co-author is an immunobabbler. Sweet !
     
  16. Jonathan Edwards

    Jonathan Edwards "Gibberish"

    Messages:
    5,211
    Likes:
    31,646
    Not really, it is work going through, which is not ready for public discussion because it needs thinking about and more controls. Maybe I could say that autoimmune B cells tend to have a certain flavour to the way they behave, or signature, and in ME one aspect of this goes in the opposite direction. It has to do with the way the immune response to an antigen evolves and changes character with time. I cannot say more without raising hares.
     
    justy, aimossy and rosie26 like this.
  17. Sherlock

    Sherlock tart cherry etc. for joints, insomnia

    Messages:
    1,229
    Likes:
    678
    Czechosherlockia, USA
    That's your answer?
     
  18. Jonathan Edwards

    Jonathan Edwards "Gibberish"

    Messages:
    5,211
    Likes:
    31,646
    Where on earth did you get that idea from?

    Human autoimmune diseases are those with autoantibodies - lupus, RA, thyroid disease, pernicious anaemia, myasthenia. People have often thought there must be autoreactive T cells but can you point me in the direction of any consistent evidence? In all the diseases I have been involved in nobody can find any.

    Sorry, but this to me is toy immunology. Very popular, but not based on any evidence that I am aware of.
     
    melamine, Valentijn, aimossy and 2 others like this.
  19. bambi

    bambi Guest

    Messages:
    56
    Likes:
    59
    Nope, that is the answer of PROFESSOR Edwards to his co-authors review.
     
  20. bambi

    bambi Guest

    Messages:
    56
    Likes:
    59
    Yep, very popular:

    "Medical definition of Merriam-Webster"

    Definition of AUTOREACTIVE
    : produced by an organism and acting against its own cells or tissues <autoreactive T cells>

    http://www.merriam-webster.com/medical/autoreactive
     

See more popular forum discussions.

Share This Page