Audio/Transcript of NIH Telebriefing July 10 Available

[Gemini]

NIH has posted an Audio/Transcript of their July 10, 2017 Telebriefing:

https://www.nih.gov/research-traini...ives/mecfs/nih-me/cfs-advocacy-call-july-2017

Dr. Breen, NIAID, indicates Mark Davis' immunological research may be "groundbreaking:"

And then we heard some of the work that’s supported by Mark Davis at Stanford. And Mark has really pioneered the way to go from how the immune system senses either an external or internal antigen and then actually how that response is generated.

And it’s very groundbreaking work in that he can go from not knowing what the body is responding to, to actually doing detective work and tracking back to find where the original response was. For example, in a large cohort of chronic fatigue patients he has now found a number of new antigens that correlate with disease. And he hasn’t published this yet, and he’s not ready to tell us because he needs to be 100 percent certain of what these antigens are, but I think the approach itself is really groundbreaking. It was published about a month ago for TB. [my bold]

 

[Simon]

And then we heard some of the work that’s supported by Mark Davis at Stanford. And Mark has really pioneered the way to go from how the immune system senses either an external or internal antigen and then actually how that response is generated.

And it’s very groundbreaking work in that he can go from not knowing what the body is responding to, to actually doing detective work and tracking back to find where the original response was. For example, in a large cohort of chronic fatigue patients he has now found a number of new antigens that correlate with disease. And he hasn’t published this yet, and he’s not ready to tell us because he needs to be 100 percent certain of what these antigens are, but I think the approach itself is really groundbreaking. It was published about a month ago for TB.

I'm not totally sure this is directly about antigens, for a couple of reasons
1. I know Mark Davis was looking at T-Cell receptors (TCR) for the big data study (or linked to that). T-cell receptors are antibody-like molecules bound to their surface that T-cells use for recognising antigens. But the study was of the receptors as opposed to looking at antigens - though you can deduce much about antigens by deducing what TCRs will bind to.
2. This is the same approach used in the TB study from Mark Davis published in Nature last month: Identifying specificity groups in the T cell receptor repertoire : Nature

[we developed an algorithm that] can analyse large numbers of TCR sequences and define TCR specificity groups shared by TCRs and individuals, which should greatly accelerate the analysis of T cell responses and expedite the identification of specific ligands [antigens, or parts of them].

That said, Davis published another paper in PNAS that looks like it is using antigens directly, though not identifying them.

If anyone can throw more light on this, I'd be grateful

Assuming its the same approach as the last month's TB paper in Nature, the work on TCRs would definitely help track down antigens (possibly groups of). And I'm pretty sure it would be possible to say that antigens with particular characteristics (identified by analysing the TCRs they bind to) were associated with mecfs.

Congratulations if you followed all that. I'm not sure I did.

 

[Research 1st]

For example, in a large cohort of chronic fatigue patients he has now found a number of new antigens that correlate with disease.

When you say ''Chronic Fatigue'' do you mean CF or Fukuda Criteria CFS?

CF is a symptom and CFS is an unrelated syndrome involving every body system going.

If the finding is indeed in a symptom only it's possibly not relevant to the CDC syndrome and certainly not ME which involves PEM/O.I/Inflammation.

Certainly no researcher should find molecule X in a symptom and then declare I've found a key finding in the syndrome or disease.

As that wouldn't accurate if one diminishes the core symptoms of ME to a single symptom - CF.

 

[alex3619]

We need the study to be published. Only then can we find out what is actually going on.

Given this is at Stanford there is a good chance this is well characterized patients, and so it might be very important. We just don't know enough yet.

 

[Gemini]

Assuming its the same approach as the last month's TB paper in Nature, the work on TCRs would definitely help track down antigens (possibly groups of). And I'm pretty sure it would be possible to say that antigens with particular characteristics (identified by analysing the TCRs they bind to) were associated with mecfs.

So glad to read your encouraging analysis @Simon!

Would it be too much of a stretch to take this a step further--If Davis' TCR approach is capable of identifying antigens, might those long sought after antigens be the "linchpins" driving the chronic immune activation in ME/CFS discovered by immunologist Dr. Jay Levy 30 years ago? Interested in your thoughts....

 

[Gemini]

NIH has posted an Audio/Transcript of their July 10, 2017 Telebriefing:

https://www.nih.gov/research-traini...ives/mecfs/nih-me/cfs-advocacy-call-july-2017

Dr. Breen also reported on Dr. Montoya's current ME/CFS research involving subgrouping:

And finally we had Jose Montoya from Stanford who has developed a way to look at the immunological characteristics of a chronic fatigue cohort that he runs actually at Stanford. And he’s actually able to subtype patients into more severe and less severe clinical types based on some of the immunology. And that data is again unpublished but he said he’s writing it up. And so we’re hoping to see it in press certainly in the coming months.[my bold]

NIH indicated it's going to propose the topic of "subgroups" be taken up by the CFSAC at its December 13-14, 2017 meeting. Besides Dr. Montoya, Drs. Peterson, Lipkin, and Younger have recently identified interesting subgroups.

 

[dreampop]

RFAs should be given in September (if I read the correctly)

 

[Gemini]

RFAs should be given in September (if I read the correctly)

You did @deampop, Dr. Vicky Whittemore reported:

Just to give you an update on the timeline for the RFAs, they will be meeting and reviewers have been invited and the study section will be meeting at the end of July to do the review.

And then the Working Group will come together in August to look at the reviews and determine the funding plan and the recommendations for funding then will be taken to the appropriate NIH Institute Council meetings in September,
with the hope that we can then get the Notice of Awards out by the end of September, which is the end of our fiscal year.

And so then our goal would be to have a meeting of the investigators and the groups involved in the funded applications, including those people funded for the Data Management Coordinating Center, in the fall to really launch the project and get things moving in the right direction right from the get-go. [my underlining and bold]

 

[Simon]

I'm still a bit confused by Dr Breen on the one hand saying Mark Davis has identified antigens, and on the other saying it's the same method used in a recent paper on TB, which seems to use a method that doesn't directly identify antigens, but helps find them.

So I've emailed Joseph Breen and will post here if I get a reply.

Would it be too much of a stretch to take this a step further--If Davis' TCR approach is capable of identifying antigens, might those long sought after antigens be the "linchpins" driving the chronic immune activation in ME/CFS discovered by immunologist Dr. Jay Levy 30 years ago? Interested in your thoughts....

Well, that would be the interesting prospect, or if the antigens themselves are not the problem directly, they might be from infectious agents that are driving the illness in other ways.

 

[Gemini]

I've emailed Joseph Breen and will post here if I get a reply.

Well, that would be the interesting prospect, or if the antigens themselves are not the problem directly, they might be from infectious agents that are driving the illness in other ways.

Thanks @Simon. Am looking forward to learning more about Mark Davis' work.

 

[Simon]

Update: this is looking good:

So I've emailed Joseph Breen and will post here if I get a reply.

Dr Joseph Breen actually replied promptly but it got stuck in my spam filters.

The fuller story is this: Mark Davis did indeed use the method in his recent Nature paper on TB to identify possible types of antigens in ME/CFS patients (that is, identifying them indirectly by sequencing T-cell receptors (TCRs) and seeing what they should be able to bind). However, he then did additional work to try to directly identify antigens (effectively, test tube experiments to see what the receptors did bind), following up the clues in the TCR work. He's still working on confirming those findings.

If he has found an antigen associated with mecfs that could be a huge clue. Early days still, and even if this comes to naught its great to have such a cuting edge approach applied to our illness.

 

[Gemini]

If he has found an antigen associated with mecfs that could be a huge clue.

Huge, indeed!

Thank you @Simon for following up with Dr. Breen and keeping us updated.

Wonder if Mark Davis will present this work at the upcoming Symposium?

https://www.omf.ngo/community-symposium/

Chronic Fatigue Syndrome Research Center at Stanford University

Community Symposium on the Molecular Basis of ME/CFS
Sponsored by Open Medicine Foundation (OMF)

Saturday, August 12, 2017

Come hear from our amazing team in person!A unique and unprecedented opportunity to learn from and interact with these world-class scientists.

 

[Snow Leopard]

If he has found an antigen associated with mecfs that could be a huge clue. Early days still, and even if this comes to naught its great to have such a cuting edge approach applied to our illness.

How are they targeting activated T-cells, that are likely to be in some way associated with this disease, rather than just random T-cell receptors? Otherwise you simply end up identifying the structure of random TCR (and correspondingly, random antigens).

Also, given JE's theory of autoimmunity, it seems it would be more useful to target B-cells rather than T-cells (at least in suspected autoimmune conditions)

 

[Gemini]

How are they targeting activated T-cells, rather than just random T-cell receptors? Otherwise you simply end up identifying the structure of random antigens.

Also, given JE's theory of autoimmunity, it seems it would be more useful to target B-cells rather than T-cells (at least in suspected autoimmune conditions)

Mark Davis' upcoming talk at the August 12th Symposium is titled "Is ME/CFS an Autoimmune Disease?"

Looking forward to learning more about his research & perhaps answers to your questions, @Snow Leopard!

https://www.omf.ngo/2017/07/02/agenda/

 

[Simon]

How are they targeting activated T-cells, that are likely to be in some way associated with this disease, rather than just random T-cell receptors? Otherwise you simply end up identifying the structure of random TCR (and correspondingly, random antigens).

Also, given JE's theory of autoimmunity, it seems it would be more useful to target B-cells rather than T-cells (at least in suspected autoimmune conditions)

Good question, and I'm not sure as I haven't read the Nature paper. I'd assumed that even if he just looked at circulating T-cells they would be enriched with those active against current threats.

I'm guessing he wasn't pursuing an autoimmune hypothesis exclusively since he used a technique developed for TB to home in on antigens, though that may be what he found. My understanding is that T-cells can play a role in autoimmunity too as they are needed to allow b-cells to mature into plasmocytes.

 

[RL_sparky]

My understanding is that T-cells can play a role in autoimmunity too as they are needed to allow b-cells to mature into plasmocytes.

Maybe that is why Drs. Fluge & Mella said that Cyclophosphamide would turn out to be the drug of choice for ME/CFS since it also works on T-cells.