OMF/Mark Davis Research Update, June 2018

Indigophoton

Indigophoton

Senior Member (Voting Rights)
The latest update from OMF, about 9 minutes long.



Summary:

Their interest is T lymphocytes, which are prime movers of the immune system and come in several different flavours. They have been studying them for 35 years.

Have seen evidence of major T cell activity in the blood of ME/CFS patients compared to healthy controls, in the form of clonal expansion. Genes are rearranged to create unique sequences for each cloned cell, and the sequence in the chromosome becomes protein which is used for immune response. There are billions of combinations. In the absence of an immunological challenge, you don't see the same clones replicating repeatedly, but this is what they are seeing in ME/CFS, and also other autoimmune diseases like MS.

It means there is a whole set of T cells that is reacting to something in the patients. They hope it might be a pathogen.

If sequences of specific cells are expanding in this clonal way, then you know something's up, and if you can track back this response, you have a chance of figuring out what is causing it.

If the cause is a self-antigen, maybe a neurological antigen, then it would mean an autoimmune disease. Since we don't all get autoimmune disease, the assumption is that there is something that triggers it when it occurs, eg, something genetic or environmental.

One potential is that the T cells see not only a pathogen but that cross-reactivity causes self-antigen reactivity too. They have some candidates for a self-antigen but need a lot more work to see what is going on.

They are hopeful, and think they are on the right track. The art, or the trick, is in sifting the data, and they will keep at it.
 
For anyone else who needs the beginner's guide to clonal expansion, there is a clear, simple, explanation in this video from the Khan Academy (about 10 mins).

Basically, first of all lots of unique T cells are produced in the thymus, and travel to the lymph nodes. When a pathogen comes along, it gets presented to the T cells. The T cell whose receptor matches the pathogen then multiplies: clones, or identical copies, are created to deal with the threat.

Clonal expansion is the name given to the multiplication of the T cell with the receptor that matches the pathogen (ie, the T cell that is able to physically lock on to the pathogen in order to deal with it).

So if clonal expansion is going on, it's a clear sign that the immune system is reacting to something it sees as a threat - either a pathogen, or a bit of self-stuff.
 
Indigophoton said:
Basically, first of all lots of unique T cells are produced in the thymus, and travel to the lymph nodes. When a pathogen comes along, it gets presented to the T cells. The T cell whose receptor matches the pathogen then multiplies: clones, or identical copies, are created to deal with the threat.
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What is the mechanism to prevent self-attack? Does the thymus have a means of not producing self attacking T-cells? If so, does a defect here result in autoimmunity?
 
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@Forbin if it's molecular mimicry, @Jonathan Edwards?

i wonder if t cell clonal expansion could be related to angioedema, or not. i have had more than 50 attacks. google suggests possible t-cell issues.

i finally discovered a trigger: soap. all soap. with a few types of soap there was a sensitization period of 2 weeks or so where i had no symptoms, then i got an attack. no soap, no attack. soap, attack about a day later.

angioedema is life-threatening. i am trying to find out what type of angioedema it is.

the angioedema is delayed by about a day from contact to first noticeable reaction, which occurs within minutes, then spreads, migrates, etc. over several days.

google suggests a t-cell cause, but does not give details or say whether contact dermatitis can present like true angioedema.

the depth, locations, lack of hives, durations, etc. closely match angioedema, with the exception that it might sometimes last 6 days or have back to back attacks. the contact location doesn't necessarily react, or if it does, it can be days after other locations, which were never touched by any soap, react.
 
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@Samuel Well, they attribute it to "molecular mimicry" in this 2005 paper. Whether that explanation has fallen out of favor, I don't know.

Rheumatic fever: how S. pyogenes-primed peripheral T cells trigger heart valve lesions

The pathogenesis of rheumatic fever (RF) is related to autoimmune humoral and cellular responses against human tissues triggered by Streptococcus pyogenes. CD4(+) T cells are the ultimate effectors of chronic heart lesions in rheumatic heart disease (RHD). Heart-infiltrating CD4(+) T cell clones are able to recognize heart tissue and streptococcal antigens by molecular mimicry.

https://www.ncbi.nlm.nih.gov/pubmed/16126952
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ETA: In the video directly below (well worth watching again), Mark Davis uses the term "cross reactivity" to refer to the T-cells going after both the pathogen and "self." I'm not sure if that is the same as "molecular mimicry." The term "mimicry" almost seems to suggest a strategy on the part of the pathogen, though that is probably not the intended meaning.
 
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BruceInOz said:
What is the mechanism to prevent self-attack? Does the thymus have a means of not producing self attacking T-cells? If so, does a defect here result in autoimmunity?
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The mechanism to avoid self-attack is that the thymus has a system for presenting all self peptides to immature T cells and deleting those that recognise self. A defect in this system occurs in the very rare condition where there is a mutation in a gene called AIRE. However, this is an extremely rare cause of autoimmunity and the autoimmunity is not typical.

The great majority of autoimmunity has nothing to do with T cells attacking self as far as we know. Only the B cells attack self. The T cells are tricked into helping but whenever anti-self T cells have been looked for the evidence has been lacking.

The idea of molecular mimicry was invented to explain rheumatic fever in the days when nobody knew much about how the immune system works. Over the net fifty years there have been repeated claims of cross-reactivity with heart tissue and such like but as far as I know none has ever been substantiated. People hang on to old ideas for a remarkably long time. Cross reactivity with tissue specific antigens does not actually make much sense in rheumatic fever since the pathology looks much more like an immune complex deposition problem (with rash, pericarditis and transient arthritis). And there is little or no evidence for the immune reaction continuing after the initial post-infective phase. After that there is simply chronic scarring. The rash and arthritis vanish.

I had the opportunity to talk to Chris Ponting last week. I agree that the possible finding of T cell clonal expansion is very exciting. It would make a lot of sense if a subset of ME involved clonal expansion triggered by an intracellular infection. However, I have to say that the explanation given by Mark Davis looks simplistic to me. This is how people thought autoimmunity worked twenty five years ago. I like to think things have changed a bit!
 
I would add that finding T cell clonal expansion within diseased tissues as in MS or rheumatic fever is a completely different thing from finding clonal expansion in circulating cells. Clonal expansion will occur in diseased tissue simply because the T cells that arrive there divide if activated and they do not need to be activated by an antigen. A lot of local activation is driven by cytokines and other signals.
 
Jonathan Edwards said:
The idea of molecular mimicry was invented to explain rheumatic fever in the days when nobody knew much about how the immune system works. Over the net fifty years there have been repeated claims of cross-reactivity with heart tissue and such like but as far as I know none has ever been substantiated. People hang on to old ideas for a remarkably long time.
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I tend to agree with this observation, but most likely for poor reasons. I have been eager to hear more about Mark Davis research (and I remain so), but in large part due to his background in Lyme. My understanding was that he approached the Lyme conundrum from this autoimmune perch, and I find that interesting if only because of assumptions it possibly embraces.

He well may be right, so I remain eager to get some details.

But this molecular mimicry thing...for those that know Lyme history, it smacks of people like Alan Steere, and it overlaps into the Lyme vaccine debacle. I find it unconvincing - similar to the cobbled and at times almost incoherent argument that Lyme does not persist in a sizable portion of its victims, post-abx. Proponents of an autoimmune theory might have good reasons to embrace this approach, and I would like to parse down on their arguments, but I would imagine, almost by definition, they will have to first discard continued infection by a legion of pathogens set forth by the likes of Lerner and Chia and Steere and Petersen.

Only, I'm not sure proponents really ever adequately do this.

I would think Mark Davis is well-acquainted with the pitfalls of some of the unshored hypotheses such as house Lyme theories, so I am anxious to hear more details from his team relative to ME/CFS (as opposed to, er, chronic fatigue).
 
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Jonathan Edwards said:
I would add that finding T cell clonal expansion within diseased tissues as in MS or rheumatic fever is a completely different thing from finding clonal expansion in circulating cells. Clonal expansion will occur in diseased tissue simply because the T cells that arrive there divide if activated and they do not need to be activated by an antigen. A lot of local activation is driven by cytokines and other signals.
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I didn't know that. But presumably it's still a sign of immune action?

Earlier during the Stanford symposium, Mark Davis showed clonal expansion in CD4 cells for colon carcinoma taken from diseased tissue vs no expansion in adjacent healthy tissue.

But I think the MS results were from blood, same as mecfs. So presumably that means it is more likely to be expansion in response to a specific trigger.

I'd also thought that hard evidence for molecular mimicry was thin on the ground.

Samuel said:
is there anything said in the recent video that was not said in the symposium?
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Not so much, if I remember right. The main thing is that they are expanding and pursuing this work, and it sounds like the antigen-discovery work will take a while.
 
Just wondering if anyone has any recent news about the t-cell clonal expansion finding from Mark Davis, or any news from Chris Ponting about its replication.

@Jonathan Edwards expressed some scepticism about the finding on another thread today, on the basis I think, that there had not been proper controls (although Mark Davis does mention that the finding is from blood samples of people with 'chronic fatigue' vs those from healthy controls @ 1:30 on the video in the first post of this thread) and also that he didn't think anything had been published yet.

The t-cell clonal expansion finding was something that I felt a bit hopeful about. It will be shame if it doesn't pan out; but good to hear any news either way.
 
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