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

Mark Davis finds the strongest evidence yet for ME/CFS immune activation and hunts for the trigger.

This is one of the most significant findings since the results from the first rituximab trial.

Using a completely new, cutting-edge approach Stanford’s Professor Mark M Davis has produced the most dramatic evidence yet of immune activation in ME/CFS. At the recent OMF Stanford Symposium, he showed unpublished evidence that the immune activation in ME/CFS, in the form of activated T cells, is on a par with that seen in cancer, MS and infection. That's a much bigger effect than has been seen in ME/CFS cytokine studies where the changes are altogether more subtle.

Davis is already looking for the specific antigens (small proteins recognised by the immune system) that are triggering the immune activation, again using new technology. So far, he says he's found one candidate from the new work, but he wants to verify the findings before revealing more details. Identifying the offending antigen or antigens could potentially provide a target for drug treatments.

Davis is pretty new to the field of ME/CFS, but he is a researcher with a remarkable reputation: an immunologist and professor at Stanford whose work is widely quoted by other researchers.
Read more at https://www.facebook.com/notes/simo...s-immune-activation-and-hunt/343163262805297/

Thanks for the write-up @Simon :thumbsup:
 

A.B.

Senior Member
Messages
3,780
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?

20882271_343166636138293_1569210243825021120_n.png
 

unicorn7

Senior Member
Messages
180
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.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
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?

20882271_343166636138293_1569210243825021120_n.png
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.
 
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?

20882271_343166636138293_1569210243825021120_n.png
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. :)
 

Old Bones

Senior Member
Messages
808
Seriously, this research was so impressive I had to come out of blogging retirement :)

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?
 

Marco

Grrrrrrr!
Messages
2,386
Location
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).
 

Simon

Senior Member
Messages
3,789
Location
Monmouth, UK
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?
20882271_343166636138293_1569210243825021120_n.png


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:
I said:
For both patients and controls most of the points group towards the bottom of the graph. Each point represents the number of TCRs with similar sequences, and those at the bottom are present in relatively small numbers. These represent non-activated T cells that haven't gone through clonal expansion in response to an antigen: “all is well”.
However, for the group of 50 patients, there’s a cluster higher up the graph showing high numbers of similar TCRs, indicating clonal expansion in response to antigens: the signature of a fight going on.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
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?

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.
 

duncan

Senior Member
Messages
2,240
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.
 

Simon

Senior Member
Messages
3,789
Location
Monmouth, UK
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.
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.

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.
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!)

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.
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
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
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.

Mmmm. The devil is most definitely in the detail.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
I'm pretty sure that what was driving this work was trying to figure out how to spot signs of immune issues.

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

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.
 

Simon

Senior Member
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Location
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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.
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.