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Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

Discussion in 'General ME/CFS News' started by Sasha, Jul 30, 2013.

  1. Legendrew

    Legendrew Content team

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    I believe it is a combination of two studies and the varying prevalence shown in each. Yeah I didn't mean to stray from the topic I just noticed it was in the news today and thought it was interesting considering the new white matter abnormalities they're reporting and remembered that migraine is a more common feature in ME/CFS. I think it is most likely that the mechanism of ME serves to simply exacerbate the condition for many.
  2. Snow Leopard

    Snow Leopard Senior Member

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    Hi Jonathan Edwards, thanks for all your thoughtful posts in this thread, your patience and skills as a Professor are definitely showing. :)

    I have a few questions. As you can probably see, many people here have tended to jump in the deep end with trying to see how autoimmunity could be associated with ME, however we tend to have a few gaps in our knowledge due to lack of directed study.
    So my first question is, what would you suggest to be the most straightforward way for people like me to learn more about the latest views on autoimmunity and aspects that may be relevant to ME?

    My second question is what is in a name? Whenever I ask people (including scientists) who are unfamiliar with CFS (as it is known over here) why they think there is a lack of research, one of the first things they usually mention is the name and they suggest that it trivialises the condition and makes others less interested in tackling it. Both CFS and ME are unfortunate historical accidents that we seem to be stuck with due to a lack of leadership within the field to change the name. The thing is, that other diseases have slightly inappropriate names, Lupus for example, but others are named after the individuals who first characterised the condition, which at the very least seems more tasteful. The latter may be much more appropriate when the aetiology is not well understood and other names (like ME or CFS) mischaracterise the condition.
    What were your first impressions of the names CFS and ME? Do you believe they should be changed and what sort of name should we push towards?

    Getting everyone in the community to agree on a particular name would be another matter, however many in the community are calling for this at the moment.

    My third question is more technical. There have been a number of studies attempting to detect antibodies in fluid samples from CFS patients, however the panels used have been very limited. There have been some findings that have been replicated by four or more independent research groups (eg a strong association with antiphospholipid antibodies). The meaning of this is not at all clear and may well be a coincidence or a secondary consequence of immunological events. What is interesting is that anti-CRP autoantibodies have also been found in those with anti-phospholipid syndrome (interfering with the idea of CRP as a marker for inflammation). Perhaps the picture in ME or CFS is similarly complex?

    Disappointingly however, there has not yet been a study using comprehensive autoantibody profiling techniques. I guess the main limitations are knowing what to profile for, since there are thousands of options and the difficulty in gaining funding, since the idea of CFS as an autoimmune condition goes well against the established dogma and were unlikely to gain funding until there was a shift in perspective.

    I'm not aware of any groups explicitly doing this right now (Columbia University perhaps? someone can correct me if I am wrong), do you think this is an idea worth floating in the research community? I'm also curious (because it's a tricky question) about what kind of heuristic could be used to select potential targets in such a study.
  3. Marco

    Marco Old blackguard

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    To be fair Snow Leopard, you don't have to be 100% convinced that autoimmunity does underpin ME/CFS to engage in a conversation on mechanisms that might be compatible with autoimmunity and what we currently understand about the condition.

    Similarly, if you like, to the current debate in the UK House of Commons regarding what steps 'in principle' should be taken in response to the alleged regime use of chemical weapons in Syria. In both cases there is currently no 'smoking gun'. Thankfully the discussion we are having is unlikely to have such wide ranging consequences.


    Not only is there little harm in these discussions but they may also generate useful leads that could substantially narrow down the range of potential targets that as you state represents a major limitation to any 'unguided' search for autoantibodies.

    A guided 'Bayesian' search is one such heuristic to narrow the search space.
  4. Mark

    Mark Acting CEO

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    Glad to see migraines mentioned here. Prof Baraniuk stressed this issue at his presentation at IiME 2012. 80% is what I recall, and the highest proportion of any individual symptom in the long list of symptoms (most symptoms are mentioned by 60% or less) though I can't remember where any of that data is coming from and in a heterogeneous population it still begs the question of cluster analysis. But anyway, the prevalence of headaches - specifically, headaches of a new type around the time of onset (which was true in my case also) - to me points at the low blood volume and vascular issues (eg neuropathies?), and that's a big focus of my thinking in the last few months: I think that low blood volume, and the Orthostatic Intolerance, seem to suggest a key aspect of the pathophysiology. Just vague impressions of an amateur though...:)
    vli, Legendrew and Valentijn like this.
  5. Valentijn

    Valentijn Activity Level: 3

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    My OI is pretty well treated now, but the otherwise Unending Headache is still around if I stop taking fish oil (omega 3). Since it's responding to an anti-inflammatory, this all seems to suggest that my Headache is inflammatory rather than OI related.

    Though I can get an OI headache as well, it's more of a normal thing and will go away after a while when laying down.
  6. Bob

    Bob

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    I've just remembered a comment made by Ian Lipkin a couple of years ago:
    "Two thirds to three quarters of the individuals whom we studied had polyclonal B cell activation."

    I can't identify or find the study that Lipkin might be referring to.

    Doing a Google search, a number of studies seem to suggest that there is an increase in the number of B cells in the CFS patient population. And a number of studies suggest B cell dysfunction.
  7. Sasha

    Sasha Fine, thank you

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    Was it the study he referred to during the press conference to announce that XMRV was no-go? I vaguely seem to remember it was something to do with Japan (not sure if I've made that up).
  8. Bob

    Bob

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    Yes, that's right. Here's longer quote:
    "The one thing that did impress me was that there was an enormous amount of immuno-activity that appeared to be non-specific in these individuals.
    So at a time when people were saying that this was a psycho-somatic disorder, I said:
    Two thirds to three quarters of the individuals whom we studied had polyclonal B cell activation.
    They're sick. We don't know why, but they are sick."

    The original source of the text appears to have been deleted now:
    http://cii.columbia.edu/blog.htm?cid=tM5E7V
    Sasha and heapsreal like this.
  9. Purple

    Purple Bundle of purpliness

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    I may be wrong but I seem to remember that Ian Lipkin worked on a study that disproved the involvement of the Borna virus in ME (I have a vague memory that this was a study of Swedish patients even) and the B-cell findings may have been part of that study. Perhaps someone can find out more about this?
  10. Bob

    Bob

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    I did come across that paper, but I couldn't find any specific results re polyclonal B cell activation in it.

    Absence of evidence of Borna disease virus infection in Swedish patients with Chronic Fatigue Syndrome
    1999, Vol. 5, No. 5 , Pages 495-499
    Birgitte EvengÄrd, Thomas Briese, Gudrun Lindh, Shaun Lee and W Ian Lipkin
    http://informahealthcare.com/doi/abs/10.3109/13550289909045378

    Full PDF version:
    http://www.researchgate.net/publica..._Fatigue_Syndrome/file/79e4150de0ab81fea7.pdf

    This is the only reference to B cells that I can find in this paper, unless I've missed something:

    "Although serum immunoreactivity to BDV proteins observed in Swedish CFS patients by ELISA may reflect infection with related microbial agents that induce cross-reactivity with conformational determinants on BDV proteins (Kliche et al, 1996) and b-galactosidase, the serologic findings are also consistent with nonspecific polyclonal B-cell activation. Indeed, increased levels of antibodies against different microbial agents and other viruses, such as EBV, have previously been shown in sera from CFS patients (Jones et al, 1985; Straus et al, 1985) and interpreted as evidence of polyclonal activation.
    In summary, we find no serologic or molecular evidence for BDV infection in Swedish CFS patients. Absence of evidence is not equivalent to evidence of absence. Nonetheless, our findings do not support the hypothesis that BDV can be implicated in the pathogenesis of CFS in Swedish patients."


    These are the two references cited in the above text (Perhaps this is where the answer to Lipkin's quote lies, but I don't think I've read these papers, because I don't have access to them):

    Jones JF, Ray CG, Minnich LL, Hicks MJ, Kibler R, Lucas DO (1985). Evidence of active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: Elevated anti-early antigen antibodies. AnnIntern Med 102: 1 - 7.
    http://annals.org/article.aspx?articleid=699346

    Straus SE, Tosato G, Armstrong G, Lawley T, Preble O, Henle W, Davey R, Pearson G, Epstein J, Brus I, Blese RM (1985). Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med 102: 7 - 16.
    http://annals.org/article.aspx?articleid=699347
  11. FancyMyBlood

    FancyMyBlood Senior Member

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    I'm pretty sure the Lipkin comment was made at a lecture at the WPI. It was the same lecture where he mentioned what ME/CFS research he would if someone donated $1 million.
    He has to be referring to the paper posted above by Bob. That was his only ME/CFS research before the XMRV saga. No sure if the B-cell findings are described in the full text or remained unpublished though.

    I'm sure a video of that lecture is still floating around.
    Bob likes this.
  12. Gemini

    Gemini Senior Member

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    CFIDS Assn Summer 2013 Newsletter indicates Columbia U, Univ of Oklahoma & Michael Cooperstock will be looking for CNS autoantibodies in patient blood samples from the SolveCFS BioBank, antibodies that may attack the brain & neurotransmitters.

    http://www.cfids.org/solvecfs/summer2013.pdf
  13. voner

    voner Senior Member

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    bob,

    I did a search and found this Lipkin quote from a TWIV Podcast transcript where Dr Lipkin is talking with Dr. Vincent Raceniellio:

    .......At that point the one thing that struck me was that many of these individuals, I think it was close to two-thirds, something like 67%, were reactive with borna-virus proteins and lysates but negative in western blot. They were also reactive with flag and beta-galactosidase and I was left to conclude that they had polyclonal B cell activation.

    At the very end of this paper, which appears in the Journal of Neurovirology, I said, you know, these patients are clearly sick in some way, they have some immunological activation, I don't know why, but it's not borna virus......

    the The transcript is here,

    http://www.twiv.tv/TWiV-Special-XMRV-091812.pdf

    someone want to Enlighten us as to what "Reactive with flag and beta-galactosidase ", etc. means?
  14. Gemini

    Gemini Senior Member

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    Professor, your description of the abundance of antibodies generated is clearly reflected in a recent study where protein microarrays were utilized to "count" them in normal controls and persons with various diseases. The researchers were surprised by the magnitude found! And, as you pointed out early on in this thread the number of antibodies varies by age, gender & disease state. Are you aware of any research group that might consider using microarray technology to determine antibody levels in ME/CFS patients? I'm referring to Open access article...

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617628/
    voner likes this.
  15. lansbergen

    lansbergen Senior Member

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  16. Gemini

    Gemini Senior Member

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    An interesting follow-up two-part question for Dr. Lipkin's Sept 10 Conference Call would be one, whether his lab is studying B cell activation in ME/CFS, and two, how the intramural work in Dr. Fauci's Immunoregulation Lab which has been studying B cell activation in chronic infections such as HIV & Hep C as well as autoimmune diseases such as Sjogren's & Lupus for the past five years could be broadened to encompass ME/CFS.
    Sasha, Marco and voner like this.
  17. Jonathan Edwards

    Jonathan Edwards Senior Member

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    Probably keep logging in to PR! One of the reasons I quit medical research, maybe, sort of, or at least a symptom of why I decided to do something new (solve the mind-brain problem and the nature of time - that sort of thing - which turned out to be easier), was that the received wisdom, or fashionable stuff written in 'erudite' review articles and textbooks, was mostly second rate nonsense written by people who just wanted to have 700 papers on their CV. Science has become fairly much like Hello magazine - very suddenly since about 1990. Very few people have any idea about autoimmunity - they stick to the old genetic and environmental and molecular mimicry ideas and think T cells are in charge. As long as everyone on the grant giving committees sticks to the same story and shares out the money between themselves it will carry on. But life was always so - and it didn't stop new ideas winning out in the end. And things have moved on. I keep my finger on the pulse with Google and Wikipedia (seriously) rather than PubMed now. Exciting stuff gets onto the net. Peer reviewed journals are largely redundant. But, you may ask, how do you tell what is good stuff and what rubbish. Sadly, I think the answer is thirty years experience so I am not being much help. Maybe what is most useful is batting ideas back and forth - so yes, keep logging on!

    I think we need two names. One for the symptom complex - which would be something like chronic fatigue syndrome but a bit punchier and without the 'syndrome' which sort of implies that it is one disease. I have no idea really but I wonder about something like GIMIF - Group of Illnesses with Myalgia and Inappropriate Fatigue. The 'Group of Illnesses' forces everyone's thinking away from 'he thinks he's got that disease' mindset. It could include the fatigue of Sjogren's or thyroid disease or type 1 diabetes together with the new diseases we are looking for.

    Then we want a name for what we think is a specific disease - or several. I have sympathy with the suggestion, not popular with all, that myalgic encephalopathy is a much better name than myalgic encephalomyelitis. I doubt that most people have true 'itis' of either brain or cord. But it does seem that the brain is not working properly. You want precision without overstatement. But we would want to link that to various pathogenic mechanisms. So maybe when the next slice of research has got sorted we might have BME and NKME for B cell related and NK cell related myalgic encephalopathies.

    That would be my train of thought just now but I think the thing is to wait until there is hard evidence for some pathophysiology. The Norwegian work is very suggestive but needs nailing. I would hope that in maybe two years time there will be a good argument for sorting out names a bit.

    Yes, I think you are on the right track. I know of at least two other groups looking for antibodies in different areas. It is a needle in haystack job but different groups seem to be picking sensible places to try. I think the idea has got about that it is worth looking and I suspect there is a reasonable chance that once the attention is focused something will turn up in the next year or two.
    Sidereal, aimossy, vli and 8 others like this.
  18. Jonathan Edwards

    Jonathan Edwards Senior Member

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    This could be a good micro-tutorial. The 'number of antibodies' in the study quoted is something different. They found binding of antibodies to a thousand different self proteins. When I was talking about a hundred sorts of antibody I was talking about a hundred different antibody proteins (mostly the same but different in their 'variable' regions) all binding to the same self protein - each one produced by a different B cell. If you like they are talking about baits that will catch 1000 different fish whereas I am talking about 100 different types of fly-hook that will catch a trout.

    The problem with this study is that it suggests that the authors have not really considered the significance of what they are looking for before they started doing high tech microarrays. We all have antibodies to everything in a sense. Antibodies stick to other proteins like any protein sticks to other proteins. So if you look for antibodies sticking to 5000 proteins you will find a few antibody molecules stuck to all of them. To be of any interest the binding of an antibody has to be very tight and good assays are set so that nothing is registered until you have really tight binding. So the binding they are reporting, everyone has known about for decades but takes no notice of - at least that is my interpretation. Anyone who has done a western blot looking for antibodies to self proteins in serum will have found scores of bands but ignored them. That is not to say that there might not be an important antibody hidden amongst all that but since you find lots of bands in normal people's serum it seems likely that most of the binding is of no significance in real life.

    I have a feeling that microarrays of all sorts are a very quick way to go nowhere. If you go out looking for anything you can find you are bound to find something - and then what do you do? I go for a more focused approach.
    merylg, MeSci and Valentijn like this.
  19. lansbergen

    lansbergen Senior Member

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    But wouldn't one need to know the trout for that?
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  20. Jonathan Edwards

    Jonathan Edwards Senior Member

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    Yes. In theory you could stock 5000 ponds each with a pure species of fish without knowing their names and do some fishing and then when you find you have 120 hooks in your bag that catch fish 3986 you can look up in the book and see they are trout. But in reality, to find out how many antibodies you have to a particular antigen you have to work with antibody forming cells (they have antibodies on their surface so will bind to antigen like the individual hooks do). You have to see how many different cells stick to the antigen and then clone their antibody genes from their messenger RNA, and see how many different sequences you have. To do that you need more than just a microarray, you need a big panning plate coated with antigen or something similar.

    Knowing how many types of antibody you have to a particular antigen is not that helpful in practice. The main reason for studying it is to try to get a better understanding of how antibodies change or 'affinity mature' over time and how that relates to regulatory pathways.

    The real problem, as I think you are suggesting, is how you find any antibodies unless you know what they are going to bind to. This has always been a problem and it is not clear that newer techniques are that much better than the old way of pouring serum on to slices of tissue and looking for binding down a microscope using fluorescent tag dyes. Newer array systems should be helpful but you have to be sure you know how to interpret them.
    voner, merylg, MeSci and 3 others like this.

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