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

[Marky90]

Sorry but what exactly is clonal expansion? I had a big percentage of double positive expression of CDRO something on t-cells found on tests, so this makes me wonder if t-cells could be involved (in subsets?) after all.

 

[Snow Leopard]

View attachment 23149 View attachment 23150

Proposal to change our disease name to "Charlie Brown Disease".

 

[cigana]

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.

Why would clonal expansion in ME make sense if it didn't indicate a trigger antigen?
From what you say about skewed Vh gene usage, does that mean that clonal expansion of T cells could occur but as a kind of indirect result of B cell disease?
Are there examples of diseases where clonal expansion occurs but there is no associated 'inflammation' picked up with the usual activation markers?

 

[Snow Leopard]

Why would clonal expansion in ME make sense if it didn't indicate a trigger antigen?

It implies the activation/expansion process is in some way broken.

 

[A.B.]

It implies the activation/expansion process is in some way broken.

A bit like cancerous immune cells? Is this nonsense or could it be happening in some limited form? The metabolic changes seem to be somewhat similar (thinking about that scientist who reported higher energy production in immune cells, and compared it to cancer).

 

[Sean]

It implies the activation/expansion process is in some way broken.

Which presumably would classify it as an autoimmune disorder. Yes?

 

[Forbin]

Could be that the charts are difficult to interpret because this is pre-publication data, the details of which they want to keep vague.

Now, in the closed sessions, that's where you get to see the charts.

 

[A.B.]

@Jonathan Edwards Would elevated CD8%, low CD4% and low CD4/CD8 Ratio be in line with these preliminary findings if they indeed hold true?

The CD4/CD8 ratio is a reflection of immune system health. A normal ratio is between 1 and 4. People without HIV infection generally have a greater number of CD4 cells than they have of CD8 cells. As people get older, the immune system's defence against pathogens is weaker and the CD4/CD8 ratio tends to decrease. People with autoimmune diseases tend to have an increased CD4/CD8 ratio, while those with viral infections have a decreased ratio.

Source http://www.aidsmap.com/CD4CD8-ratio/page/1733224/

My CD4/CD8 ratio was 2.8 when tested (range 1-3).

 

[aimossy]

Mark Davis goes on to answer some questions during the panel discussion at the end - which is here on the video.

 

[redo]

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.

Fascinating. T-cells.

Have anyone heard of ME patients that have tried Campath (Alemtuzumab)?

Studies show MS patients get better by both Rituximab and Campath. They have completely different mechanisms of action. No-one knows why both help.

Quote about Campath: "Alemtuzumab is a drug used in the treatment of chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL)"

 

[cigana]

It implies the activation/expansion process is in some way broken.

But why would that "make sense in ME"? Do we have some reason to expect that the expansion process is broken?

 

[AndyPR]

Sorry but what exactly is clonal expansion?

It is when a particular cell produces exact copies of itself. The idea here is that T cells are being prompted to use clonal expansion to create copies of themselves due to an immune system activation - the reason for the activation is currently unknown.

 

[AndyPR]

But why would that "make sense in ME"? Do we have some reason to expect that the expansion process is broken?

I get the impression that it's more likely to be the activation process to be "broken", in the sense that ME could be an autoimmune condition and is therefore being activated by some part of us, rather than some part of an invader.

 

[Gemini]

I get the impression that it's more likely to be the activation process to be "broken", in the sense that ME could be an autoimmune condition and is therefore being activated by some part of us, rather than some part of an invader.

Agree, @AndyPR Davis' seemed to say tracing back to a "trigger" would hopefully identify a pathogen or autoantibody.

As per @Simon's excellent blog: “Basically, researchers take one of the clonally-expanded T cell receptors and use those to go fishing in a vast pond of possible protein fragments to try to find the antigen.”

So I’m really looking forward to learning more about Davis’ “Computational Immunology” techniques given Wikipedia lists 31 molecular and immunological data bases containing some very impressive data.
https://en.wikipedia.org/wiki/Computational_immunology

Again from @Simon :“Identifying the offending antigen or antigens could potentially provide a target for drug treatment.” This goal ties in nicely with Dr. Naviaux’s multi-staged treatment strategy especially the first stage, removal of the Cell Danger Response trigger, as summarized in his keynote address. (18.00-38.25 on the Symposium video)

 

[RogerBlack]

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.

I wish it was computationally plausible to run the anomolous dots receptor shapes (not sequences) through in-silica binding assays to the whole human proteome.
There is probably some reason (other than it being computationally impossible) why this wouldn't be a magic bullet for determining autoimmunity effects.

 

[Woolie]

Oh, if anyone is like me, and needs the various immune system components (re)explained to them in simple terms, this book is for you!

Our Immune System

Its a free kids' picture book - definitely pitched at just the right level for me!

Here's a frame from the book:

 

[GreyOwl]

Thank you @Woolie, that is at the right level for me too

 

[Woolie]

Oh, if anyone is like me, and needs the various immune system components (re)explained to them in simple terms, this book is for you!

Our Immune System

Its a free kids' picture book - definitely pitched at just the right level for me!

I should give credit where its due. The book was written by the US Immune Deficiency Foundation to help kids diagnosed with an immune deficiency disorder (ID).

https://primaryimmune.org/

The foundation want to support their members, but they also want to spread awareness, so its only fair that I do so, since I enjoyed their book.

IDs are comparatively rare as diseases go, and to make things worse, there are many subtypes. Some IDs don't become evident till adulthood, and these types are underdiagnosed. Some patients suffer from symptoms for decades before they get a diagnosis. In the interim, they could easily end up with a diagnosis of CFS.

 

[Jonathan Edwards]

I wish it was computationally plausible to run the anomolous dots receptor shapes (not sequences) through in-silica binding assays to the whole human proteome.
There is probably some reason (other than it being computationally impossible) why this wouldn't be a magic bullet for determining autoimmunity effects.

I think it is computationally impossible because we are talking about recognising something like decamer peptides with 20 amino acid options at each point ( peptide alternatives = 100,000,000,000,000,000,000). What is much worse is that we need to know the binding affinity window involved. Too high binding kills T cells as much as too low bores them. And the peptide has to be recognised in the context of not just the right MHC class II 'tongs' but also CD3, CD4 and all sorts of other co-factors.

My problem is that over a period of 30 years in immunology labs I watched T cell enthusiasts fail consistently in finding any evidence for specific T cell receptor bindings relate to autoimmunity.Either the problem is too difficult or, to my mind more likely, they are irrelevant. Unfortunately many hundreds of millions of dollars have been invested in the idea that T cell receptors are worth exploring.

My sense is that what specific clones recognise may not be very interesting. What may be much more important is skewing of T cell behaviour in a more non-specific way. That might give rise to clonal expansion. But I am still confused about what this paper is about. Clonal expansion is something quite specific about lots of T cells having identical receptors. Lots of T cells having rather similar receptors is something quite different. And lots of T cells recognising the same peptide is again quite different. I am afraid I have not had time to look at the presentation itself but I am confused.

 

[Gemini]

And this is for T cell receptors; I'm not sure how well the approach would adapt for B cells/antibodies that can also lead to autoimmunity

@Simon I was very pleased to hear Mark Davis say the techniques they are using can be applied to T and B cells.

In fact I listened twice to make sure I heard him correctly! Would love to hear more about B cells, i.e.,might B cell clonal expansion occur concurrently with the T cell expansion?