August 8th, 2016: Understanding and Remembrance Day for Severe Myalgic Encephalomyelitis
Jody Smith joins with other ME voices in honor of Understanding and Remembrance Day for Severe Myalgic Encephalomyelitis.
Discuss the article on the Forums.

Simon McGrath blogs: Mark Davis finds the strongest evidence yet for ME/CFS immune activation..

Discussion in 'General ME/CFS News' started by AndyPR, Aug 18, 2017.

  1. AndyPR

    AndyPR Tired Sam ate all the cookies!

    Read more at https://www.facebook.com/notes/simo...s-immune-activation-and-hunt/343163262805297/

    Thanks for the write-up @Simon :thumbsup:
     
  2. Simon

    Simon

    Messages:
    1,913
    Likes:
    14,348
    Monmouth, UK
    Thanks, Andy. Seriously, this research was so impressive I had to come out of blogging retirement :)



     
    moosie, Jennifer J, justy and 51 others like this.
  3. A.B.

    A.B. Senior Member

    Messages:
    3,583
    Likes:
    21,735
    I find this picture confusing. Is the immune activation occurring only in a subset? There are more than 50 dots on both sides, with 50 patients. In the red circle alone there are 28 dots. So what do these dots mean exactly?

    [​IMG]
     
    Manganus, Barry53, Hutan and 3 others like this.
  4. aimossy

    aimossy Senior Member

    Messages:
    1,076
    Likes:
    3,694
    So stoked you did. Excellent blog on this @Simon thank you!
     
    RL_sparky, simeyss, barbc56 and 7 others like this.
  5. unicorn7

    unicorn7

    Messages:
    36
    Likes:
    196
    I'm really getting a lot of hope from posts like this, keep em coming!:woot::woot:

    As I understand the graph, it's the number of T-cells that have undergone clonal expansion in the patient population. The other graphs (the comparison to lyme disease and MS patients) are more clear.
     
  6. dangermouse

    dangermouse Senior Member

    Messages:
    406
    Likes:
    2,244
    Thank you for posting this :thumbsup:
     
  7. NL93

    NL93 Senior Member

    Messages:
    139
    Likes:
    845
    The Netherlands
    Super interesting!
     
  8. alex3619

    alex3619 Senior Member

    Messages:
    12,283
    Likes:
    33,787
    Logan, Queensland, Australia
    I think the first row of dots on the right might be callibration controls. They are almost identical in both groups, and highly structured. Its the other cluster on both sides that matters.
     
  9. AndyPR

    AndyPR Tired Sam ate all the cookies!

    OK, I'll take a stab at answering this. I believe, but don't know for certain, that each dot is a specific T-Cell Receptor. The higher they are in the graph, the more "activated' they are, and why is the big question obviously. My guess would be the graph shows the averaged results of both cohorts, controls and patients.

    Does this make sense to anybody else? I think it's logical but more than happy for an expert to jump in. :)
     
  10. Old Bones

    Old Bones Senior Member

    Messages:
    800
    Likes:
    4,764
    CANADA
    I'm so glad you did. Thanks @Simon , and @AndyPR , for posting. I was intrigued by Mark Davis' presentation in the context of what was happening with me prior to the upper respiratory infection I've always perceived as my triggering event.

    Approximately 20 months pre-ME, my ophthalmologist diagnosed me as having a problem with what he called "Killer T-cells". He explained I had a proliferation of T-cells that had identified my contact lenses as foreign (after many years of successful use). His advice was to stop wearing them for six months. Based on experience in other patients, he was confident the T-cells would settle down and I'd be able to wear my lenses again.

    Desperately wanting to be without glasses for our wedding in six months, I followed his advice scrupulously. And it worked -- but only for about two weeks, by which time the T-cells were back in full force, again causing severe eye irritation. Based on this experience, I've often wondered if something was already going wrong with my immune system when the ME symptoms started. This research seems to provide proof there was. Because . . .

    From Simon's blog, (T-cells) "come in many forms, but the relevant ones here are called cytotoxic (CD8) T cells." I Googled cytotoxic T-cells, and found that they are also called "T-killer cells" -- the exact same type the eye doctor said was causing my problem more than 30 years ago.

    Has anyone else experienced something similar?
     
    fireflymd, leokitten, Simon and 11 others like this.
  11. Marco

    Marco Grrrrrrr!

    Messages:
    2,360
    Likes:
    3,103
    Near Cognac, France
    @Simon

    We need to bear in mind that both Davis' findings and the Ritux findings are preliminary. But assuming both pan out is there any way of explaining both i.e. does B cell ablation impact on T cell clonal expansion?

    One paper suggests it does in vitro but for CD4+ and not CD8 T cells :

    Therapeutic B cell depletion impairs adaptive and autoreactive CD4 T cell activation in mice

    http://www.pnas.org/content/104/52/20878.full.pdf

    (It's and old paper - maybe things have moved on).
     
    simeyss, Murph and Hutan like this.
  12. Simon

    Simon

    Messages:
    1,913
    Likes:
    14,348
    Monmouth, UK
    [​IMG]

    This isn't easy - I had a chat with a researcher pal figuring this out. The dots represent groups of T cell receptors with similar receptor sequences (not identical) - so these are not dots of patients at all. As you can see from the scale on the left, there are many thousands of TCRs represented by each dot.

    Imagine patient 1 has a clonally expanded T cell. that might contribute 50 or so copies. The same patient might well have other clonally expanded T cells with very similar but not identical sequences that would be in there too. And patient 2 might also have some clonally expanded T cells with very similar sequences, all contributing to the same point. The chances of two T cells from the same or diffferent patients having identical TCR sequeces - unless they are clones - is about 0. Tjhat's why they are looking at similar sequences, not identical ones. Similar sequences are likely to be targeting the same or very similar antigens.

    This was my attempt at explaining it more simply in the blog:
     
  13. Jonathan Edwards

    Jonathan Edwards Senior Member

    Messages:
    5,070
    Likes:
    29,596
    I agree,it is puzzling, and I do not think these are calibration dots. I think Andy and Simon are probably right. I have to say that as an immunologist I cannot really understand any of these slides. They do not have clear enough titles and axis labels.

    I think the finding of CD8 T cell expansions in ME/CFS would be hugely significant and make a good deal of sense. However, I would not equate this to T cell activation. If there was activation I think that would have been picked up on activation markers on all the previous studies. In disease a finding like clonal expansion does not necessarily mean what it means in a normal immune response. But clonal expansion of CD8 would fit with something like the post infective problems of Reiter's syndrome or psoriasis.

    I am a bit puzzled by the reference to autoimmune peptides as I am not sure we have evidence that such things exist in human disease.

    I do not think you can easily put together a story that involves both B cells and CD8 T cells. They are about as separate arms of the immune response as you can get. If we look at fatigue in a rheumatology clinic, though, you will probably find 80% of it is due to autoantibody B cell disease and mostly women and 20% is T cell driven (likely CD8) disease commoner in men. I have thought for a long time that ME may also be a mixture of two quite different immune responses. If CD8 T cells were the key thing in ME I would expect ME to be more common in men. However, we do not know from the figures as far as I can see how many patients showed expansions. Maybe it was only 25%.

    Another point I am a bit uncertain about is that talk of 'similar' T cell receptor sequences. If that means identical then that is clonality. But similar in the sense of nearly the same does not mean that at all and may tell us nothing about antigen drive. A single amino acid change in a T cell receptor may mean it binds to completely different antigens. In B cell disease we see skewing of B cell receptors (antibodies in effect) with lots of similar ones because of skewed Vh gene usage. That may not mean much to people but it means that the antibodies look similar but not because they see the same antigen, just because they us the same framework sequence. Something like that might be true here - the similar TCRs might be overusing a framework region (my knowledge of TCR splicing is limited). That might be very useful to know but it would not point to a trigger antigen. I am a bit sceptical that this approach will point to trigger antigens because that has never panned out in other situations.
     
    snowathlete, MeSci, Jill and 24 others like this.
  14. duncan

    duncan Senior Member

    Messages:
    1,935
    Likes:
    4,196
    Excellent Blog.

    T cell mediated severity in Lyme disease has long been established, with at least murine models discussed as far back as the mid 90's. It may or may not be relevant to this conversation that in cases of late stage or chronic Lyme, there is frequently the added variable of immune deficiency, e.g.an IgG subclass.

    I would be curious to know what if any portion of the ME/CFS patients studied for Mark Davis's study had immune deficiencies.
     
    justy, Murph and Gemini like this.
  15. Simon

    Simon

    Messages:
    1,913
    Likes:
    14,348
    Monmouth, UK
    So if I've got this right, you are saying that the clonal expansion in Lyme patients (actute), MS and cancer are different to what's going on here? I'd have to check back on the video, but Mark Davis talked more about clonal expansion than immune activation - possibly he didn't talk about immune activation at all so it could be my mistake but I'm pretty sure that what was driving this work was trying to figure out how to spot signs of immune issues.

    He talked about molecular mimicry too (I know how keen you are on that, and why) and the title of the talk was "Is mecfs an autoimmune diseases" though that wasn't answered and no evidence of autoimmunity was presented. However, this same data was shown in April at another symposium and then he only mentioned pathogens - I wonder if he has a match for the antigen to both pathogen and self-protein? I'm as puzzled as you by this (I put the quote in for other reasons and had missed the 'autoimmune' bit!)

    The numbers look too high for clonality and it does say 'similar'. But I think it does mean similar in antigenic-binding terms, using this approach, I believe: Identifying specificity groups in the T cell receptor repertoire : Nature
     
    snowathlete, MeSci, perrier and 8 others like this.
  16. Marco

    Marco Grrrrrrr!

    Messages:
    2,360
    Likes:
    3,103
    Near Cognac, France
    Mmmm. The devil is most definitely in the detail.
     
    RL_sparky likes this.
  17. Jonathan Edwards

    Jonathan Edwards Senior Member

    Messages:
    5,070
    Likes:
    29,596
    Trawling for signs of immune issues makes a lot of sense. However, immunologists then tend to pigeonhole what they find into some rather dubious received dogma. To my mind the raw observation is often much more interesting. Clonal expansion in ME would make sense to me but not because it indicated some trigger antigen.

    I cannot quite see how he can be measuring similarity of specificity. I had assumed he had extracted RNA and made acDNA library of all the receptors and then looked for sequence similarity. The paper you quote seems to suggest that this may correlate with specificity but I would be pretty cautious about that.
     
  18. Simon

    Simon

    Messages:
    1,913
    Likes:
    14,348
    Monmouth, UK
    The paper is very technical and I can't claim to understand it all, but it looks like they went to great lengths to validate the specificity claim - including mutagenesis and de novo TCR design. Davis seems to be the person who cracked TCRs in the 1980s and it's been a focus of his research ever since so he looks well-qualified to take on such an ambitious piece of work. Of course, the acid test will be actually finding antigens with this method.
     
    justy, Gemini, Vicki Cole and 8 others like this.
  19. Darach

    Darach

    Messages:
    7
    Likes:
    54
  20. tudiemoore

    tudiemoore Senior Member

    Messages:
    112
    Likes:
    221
    Southeast U.S.
    Yes!
    Well, at least I'm not hanging out there by myself....
    But I don't think I want to say, "Great minds run in the same, etc."
    T.
     

See more popular forum discussions.

Share This Page