A New Decade of ME Research: The 11th Invest in ME International ME Conference 2016
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Big diffs in immune systems of healthy identical twins (so hard to find immune signature in sick?)

Discussion in 'Other Health News and Research' started by Simon, Apr 18, 2015.

  1. Simon

    Simon

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    Interesting blog from Cort about ground-breaking work from Stanford immunologist Mark Davis, who is also running a huge 600-patient study of mecfs immune profiles:

    The Chicken or the Egg? Stanford Study Suggests Immune Problems are Made Not Born - Health Rising
    Normally identical twins look pretty-much the same biologicaly as they have the same set of genes as well as growing up (and in the womb) in very similar environments. But Mark Davis showed this doesn't apply to their immune systems which appear to be very sensitive to their particular environment* and history. For example, where one twin was infected with cytomegalovirus (though showing no symptoms) and the other wasn't, around 60% of the immune factors measured showed a difference. Overall, it appeared that nuture (environment and other non-hereditary factors eg random) trumped nature (genes) in nearly 80% of immune factors measured.

    The idea of this study was to establish a robust baseline for what a healthy immune system looks like, as a benchmark for measuring problems in sick patients. It looks like nailing down what a healthy immune system looks like won't be easy. This could explain why trying to tease out differences in the immune system between patients and healthy controls has proved so hard in mecfs, as well as in other illnesses.

    (* I suspect @Jonathan Edwards would argue stochastic (random) factors play a part too). [edit: correction: the paper itself doesn't argue for only environmental factors]

    here's Mark Davis's original paper in the prestigious journal Cell - nice abstract in pictures:
    Variation in the Human Immune System Is Largely Driven by Non-Heritable Influences: Cell
     
    Last edited: Jun 11, 2015
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  2. A.B.

    A.B. Senior Member

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    Interesting. Perhaps there are disease states where infections are kept under control but at a heavy price.
     
  3. lansbergen

    lansbergen Senior Member

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    It is long known carriers are a danger for public health.
     
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  4. Simon

    Simon

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    It's worth checking out this short video of Mark Davis from Cort's blog - he's an interesting character. highlights:
    • He thinks they should have a healthy immune profile nailed down 'in a few years', though the video is from 2012 ie well before this new paper
    • He likes to stay away from the crowd, believing you won't make a quantum leap breakthrough by following the pack, or making an analogy with art, that he 'wants to paint different pictures, new pictures'
    • He thinks the most important quality of a scientist, is not intelligence, but stubborness, like a pit bull clamping it's jaws around a problem and not letting go


    The paper seems to be arguing that the disease is kept under control at a price, but it's not clear if that's a heavy price, or a lesser one.
     
    Last edited: Apr 18, 2015
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  5. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    It is a pity that we do not get any specific data in the abstract. There are lots of immune parameters, like numbers of cell subsets, that nobody really thinks are very important anyway within a pretty wide range. It is interesting that a lot of these vary more from non-heritable factors (the paper is correctly quite careful not to say environmental) than genes but the interest of that for me would be very much dependent on which measurements we are talking about. Bundling them all together to say '70% of measurements' seems to me unhelpful and a bit naive. The effect of CMV may not be that surprising, since, like EBV, CMV has long been known to produce a permanent change in the general immune repertoire. Nevertheless, the detailed data may be interesting. I have not got to the full paper yet.
     
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  6. anciendaze

    anciendaze Senior Member

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    If you argue that these changes in immunology are not significant you pretty well prove his point about not being able to tell anything about the state of immune function in the vast majority of patients. We can tell that SCID or AIDS involve dramatically altered immune function because of a simple criterion: patients die without treatment. Short of this we remain largely in the dark.

    This work has direct relevance for autoimmune diseases and a number of cancers, where adoptive immune therapy has had some remarkable successes. And, I'm betting that altered immune function will prove to be extremely significant in the serious public health issue of dementia.
     
  7. lansbergen

    lansbergen Senior Member

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    I agree
     
  8. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    My point really was that the 'immune signiatures' of autoimmune and autoinflammatory diseases tend to be much more specific than what he is looking at - like a specific autoantibody or a specific MHC Class I allotype. Numbers of CD4 T cells are not very interesting unless they are very low indeed, as in AIDS. The immune signature of wegener's granulomatosis was completely unknown until about thirty years ago when someone discovered it was antibodies to proteinase 3 in neutrophils. The immune signature of certain ME subtypes might stick out like a sore thumb if we knew what to measure. What I doubt is that you will get far by measuring these standard parameters because they are pretty normal even in lethal autoimmune diseases by and large.

    This is why I am so sceptical about all this stuff about TH1/TH2 balance - it is all just too vague. A chess champion does not win by having more bishops than the other guy. He wins because he makes one really cunning move at a certain point. I have a suspicion that Dr Davis is counting bishops.
     
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  9. Bob

    Bob

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    Note to self (to avoid future confusion): Mark Davis and Ron Davis are different people!
     
    Last edited: Apr 18, 2015
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  10. Simon

    Simon

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    Thanks, now corrected above.

    do you think there is merit in his huge study immune profiling mecfs patients?
    I'd assumed this was similar to the Drs Hornig/Lipkin approach but with a bigger sample and more immune paramaters (again, assuming this includes the 51 cytokines in the recent paper from Columbia).
     
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  11. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I think since there is so little to find so far in ME that trawling through these things is worth doing. Even if no clear cut difference from healthy controls is found data like this can yield clues in subtle ways. For instance, the difference between short and long duration disease in the Hornig study looks like a foothold that could make it easier to find something more specific.
     
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  12. anciendaze

    anciendaze Senior Member

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    What Prof. Edwards is describing is admittedly the conventional medical wisdom on the subject, though frankly I confess I have been unimpressed by the success of conventional treatments for e.g. "autoimmune diseases" in people I have known. One person I know who was "borderline for autoimmune disease" was told repeatedly that the treatment would be worse than the disease. This is not a sign of mature medical science or technology.

    I have also repeatedly watched doctors fumble around with different explanations for mysterious diseases until they reach the old cliche "it was just his/her time to die." This is despite considerable evidence that immune senescence is real. To a large extent immunology remains in the dark ages.

    There is also a strong element in circularity to medical reasoning-from-experience. Doctors have recognized diseases which produce highly-specific antibody signatures, which are part of humoral immune response. We scarcely knew many other components of the immune system existed, e.g. dendritic cells, at the time Wegener's Granulamatosis was recognized. This meant it couldn't possibly be connected with much except humoral immunity. This then becomes the paradigm for such diseases, forgetting the ignorance which meant nobody could find anything else at the time.

    In assessing the rate of incidence of mysterious malfunctions of immune systems, I'd have to say that current approaches are losing ground against increasing rates. Even if you have something as specific as Wegener's Granulamatosis your chances of being correctly diagnosed and treated before suffering permanent damage are not great. Typical case histories involve multiple referrals, and a great deal of confusion and head-scratching. I am not sanguine about continuing expansion of the range of diagnostic possibilities with current practice. Your chances of survival would depend on how long it would take to connect you to the right kind of research team. (This works better for professors of medicine than for the rest of the population.) With an expansion to several million possible specific diseases I am not even confident this inside track would be enough. Current approaches simply do not scale. We need the means Dr. Mark Davis talks about to assess immune function, and currently we don't have it.

    I also doubt that "trolling through the same possibilities" will produce anything useful. The same tests, analyzed with the same thinking, will end up with the same useless results, but I believe Mark Davis as well as Hornig and Lipkin are doing something different in examining networks of immune activation. It is time to make the term "immune system" something other than a pair of words.

    Looking at the history of medicine I see considerable evidence that the profession changes at a rate set by mortality of physicians, not patients. What was taken as the consensus 30 years ago will remain a consensus until physicians trained under that paradigm are replaced by those trained in different paradigms. This is not something confined to the "bad old days" when the majority of doctors opposed germ theory, even for such things as cholera and TB. The time scale for innovation remains much the same.
     
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  13. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I think you may have missed some tricks there anciendaze. My views are regarded as seriously heterodox amongst 'conventional' immunologists. And dendritic cells were trendy long before anti-PR3 was discovered. I absolutely agree that the immunology establishment is in the doldrums, but that does not have to be the case on PR. We can have some cutting sedge discussion - but to my mind that means getting down to specifics. 'Networks of immune activation' sounds dreadfully conventional and vague to me. What you find in all that boring immunology literature. If a disease breaks the rules you are not going to find it by assuming the rules of 'networks'. If you look for a dominant seventh and a perfect cadence in Debussy you are likely to miss the ninth that makes the Arabesque hauntingly unique. My experience of these diseases is that the rules in the immunology textbooks do not apply.
     
  14. Bob

    Bob

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    That would definitely be an interesting discussion, but I wonder if it would lead us to any answers about ME?

    Capture 2.JPG Capture 3.JPG Capture 4.JPG

    Sorry, I couldn't help myself - please continue the serious discussions...

    .
     
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  15. anciendaze

    anciendaze Senior Member

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    I'm afraid you may be correct about conventional immunologists. On the other hand the "vast clinical experience" many proclaim does not impress me. I'm familiar with arguments among musicologists, and do not think that is a good model for life-and-death decisions. There is nothing so absurd that some musicologist has not proclaimed it, to paraphrase Cicero and Cato. (Want an example by Karlheinz Stockhausen?) The serious problem, when one is dying, of finding the particular doctor with the right interpretation, as opposed to the large number spouting drivel, is an indication of the failure of such expertise. Such knowledge does not scale, which is what some professionals find desirable -- it keeps the club exclusive.

    The claim that they are dealing with hard facts and specific data is another one that generally bothers me about doctors. There was a time in the 1980s when I was impressed by work on the dynamics of the heart. I watched as cardiologists continued to do the same things and make the same mistakes for years afterward. Their idea of specific information was to give the Latin name of a particular nerve, vessel or muscle causing the trouble. They were completely impervious to real mathematical facts about dynamics unless these fit that kind of a causes b causes c reasoning with appropriate Greco-Latin labels. Dynamics seldom works that way. The vagueness was not in the mathematics, which really works in the case of implanted defibrillators, but in the minds of cardiologists. Most have still not noticed the change.

    During the time when various doctors were doing uncontrolled experiments on me with antidepressants, I was reading the research literature. At some point I discovered that the vast majority actually believed the nonsense they were telling patients about how these worked (in cases other than mine). When your understanding of where in the body most of a particular class of receptors may be found is completely wrong, how much does your specific information about the physiological effect of particular molecules matter?

    Medical education gives one a great deal of the Greco-Latin material to memorize, which goes a long way to making you think you really know something. The actual utility of such knowledge is quite low, except for communicating with other M.D.s (Perhaps you have experience with colleagues who have been upset by what a new graduate did while "doing a locum" at their practice.) Time and again I find that doctors are behaving like rule-based expert systems, simply matching patterns and producing a stereotyped response. (A friend, trained as a behaviorist, calls this "stimulus bound".) I am no longer surprised to discover in many cases they have no mental model at all for the physiology they are dealing with.

    A correspondent of mine has traced the course of medical opposition to diabetic patients testing blood sugar themselves. Dr. Richard Bernstein was originally an engineer, and had to take a medical degree before doctors would listen. It still took a long time, even though he could show that diabetic mice with well-controlled blood sugar levels did not suffer the complications and lost limbs common in human diabetics. If the doctors who opposed this change had any mental model of blood sugar regulation I can't imagine what it was.

    The dynamic behavior of blood sugar is a great deal simpler than the dynamics of almost any part of the immune system.
     
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  16. alex3619

    alex3619 Senior Member

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    On a slightly different topic, the brains of identical twins are not identical either. No two brains develop the same way. They will be similar but not have identical structure.
     
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  17. Snow Leopard

    Snow Leopard Hibernating

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    To be honest, from what we know of say, gene expression or SNP studies in ME or other dieseases, is that it takes a keen eye to see what is going on. Too many irrelevant positive results.

    The most interesting part about these studies is lets just say that someone else did make what they believed to be a key breakthrough, they can go back to these studies and see if the expected pattern exists - they are potential confirmations, but it can't always be seen until we have additional clues.
     
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  18. IreneF

    IreneF Senior Member

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    Since the immune system is designed to respond to threats, and no two people are going to experience exactly the same antigens, for example, you would expect the immune systems of even identical twins to differ.
     
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  19. lansbergen

    lansbergen Senior Member

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    Yep
     
  20. anciendaze

    anciendaze Senior Member

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    Prof. Edwards could not possibly know the personal loss which caused me to lose patience with an entire profession. If I have said anything personally abusive or intemperate, I apologize.

    What I would like to do is focus on a positive aspect of this study correcting a lack which has maddened me in discussions with immunologists. In my experience it was Dr. Paul Cheney who pointed out that most patients with real ME/CFS have low cardiac output, and that cardiac output plays a crucial role in immune function.

    Once this was pointed out the realization was blinding: cardiac output controls the rate at which immune cells reach tissues, and the rate at which information from infected tissues reaches other parts of the immune system. Many immune processes require multiple trips on this transport system. The delay between initial immune stimulus and a powerful response determines a great deal about the effect of infectious agents. The expectation that patients with low output would have immune problems is confirmed in the case of recognized heart failure. This insight also caused a number of things I've seen over a lifetime of visiting those who are ill to fall into place.

    Now, my experience in dealing with immunologists has been discouraging. Generally, they don't know a patient's cardiac output, or a proxy for same. Worse, they are not particularly curious. You can get responses ranging from disputing objective measures, to denying relevance, to insisting "we knew this all along". There was a time when I thought this was simply because I was only dealing with practitioners who were small cogs in a larger system. Research literature disabused me of this notion.

    (I'm still wondering what goes on in the minds of most practitioners. My impression is of a flotsam of disparate facts drifting about in a kind of Sargasso, and forming random constellations on which some kind of pattern-matching takes place. Expertize in reading tea leaves might help one to delve deeper.)

    Consider a patient with low cardiac output whose immune system is doing the best it can with limited resources. Now, consider a patient with good cardiac output whose immune system is barely handling ordinary challenges because of defects confined to that system. They may both exhibit the same poor overall effectiveness in immune response, but for very different reasons. If you conduct research which lumps the two together you can expect the result to be confusion.

    By comparing healthy identical (homozygous) twins this study finally matches immune behavior in people with the same cardiac output. What took so long?
     
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