Preprint A Proposed Mechanism for ME/CFS Invoking Macrophage Fc-gamma-RI and Interferon Gamma, 2025, Edwards, Cambridge and Cliff

rapidboson said:
Yes, from what I've seen - and I haven't looked into it too deeply - it did seem to broadly affect lymphocyte proliferation. And was just wondering how, based on your hypothesis and isoprinosine's mechanism of action, you'd expect this to affect pwME.
Click to expand...

I would guess it would do nothing because any general leaning on lymphocytes to do a bit more of this is likely to immediately get offset by mechanisms to ensure a bit more of the other. If you poison lymphocytes in people with RA a bit, mostly nothing happens. You need to interfere in a very precise way. My guess is that ME/CFS will be the same. You will need to interfere in a precise way in the a specific pathway.

And there will be hundreds of people who have ME/CFS or Long Covid who have been exposed to these agents and we don't hear of many miracle cures.
 
Jonathan Edwards said:
I would guess it would do nothing because any general leaning on lymphocytes to do a bit more of this is likely to immediately get offset by mechanisms to ensure a bit more of the other. If you poison lymphocytes in people with RA a bit, mostly nothing happens. You need to interfere in a very precise way. My guess is that ME/CFS will be the same. You will need to interfere in a precise way in the a specific pathway.
Click to expand...
Very interesting, thank you!

Jonathan Edwards said:
we don't hear of many miracle cures.
Click to expand...
Oh, I didn't want to imply that this could be a miracle cure. Just trying to wrap my head around potential consequences. E.g. as gamma IFN had been found increased in some studies. If I understand your hypothesis correctly, this would/should promote the vicious cycle you describe. But I suppose it's much more complex.
 
The paper has been viewed over 8,000 times and downloaded over 1,200 times now, and it's occurred to me to wonder who has been reading it. The ME/CFS field of researchers is tiny. Do we think the paper has pulled in a far wider audience of scientists, or is it likely that most of the interest is coming from interested PwME?
 
I suspect not many in the ME/CFS field have the expertise to comment on the hypothesis itself. They'd be picking at the descriptions, the epidemiology, etc.

Which isn't irrelevant, but it'd be good to have immunologists' thoughts on the model or the mechanism. It sounds like there's still a lot to understand about immune mediated disease and why we struggle to switch off errant processes for good, so surely new thinking is of interest.
 
Jonathan Edwards said:
No idea @Sasha, but I suspect quite a lot of downloads will be PWMECFS.
It would be nice to have a third review, even some criticism of the model, but maybe nobody can find anything to criticise!;)
Click to expand...
I think you said that Qeios has some AI thing that automatically sends papers out to reviewers it thinks would be appropriate. Is it worth doing something a bit more hands-on, not necessarily to elicit reviews but just to dangle this interesting carrot in front of some useful people who might want to get involved?
 
Andy said:
In an ideal world who would you want to take notice of it? Especially who outside the current ME/CFS research field?
Click to expand...

I would like people like interest from peopple like Matt Brown, the senior author of a paper recently posted on T cell clonality research. The vast majority of researchers in the autoimmunity/ autoinflammatory disease field seem to have no real aspiration to understand exactly how each one goes wrong. My hope is that with genetic data we will not only have a key to understanding exactly why things are going wrong in ME/CFS but that will have major knock on effects on understanding of diseases like lupus, ankylosing spondylitis and narcolepsy/cataplexy.

But that conversation, which Jo C and I tried to start with our 1999 Immunology paper on autoimmune disease in general has never got started in 25 years. Why that is continues to puzzle me but maybe the time has come for that to change.

Closer to ME/CFS, I would hope people like Andreas Goeber might take an interest because I think he may be on to something in severe fibromyalgia but may need to consider variations on the standard theme.

And of course I would like people like Danny Altmann to take an interest, since he is already on the DecodeME board and in a position to start thinking about what the results might mean. And people like Andreas Radbruch, who has a detailed understanding of plasma cell dynamics in disease.
 
Sasha said:
I think you said that Qeios has some AI thing that automatically sends papers out to reviewers it thinks would be appropriate. Is it worth doing something a bit more hands-on, not necessarily to elicit reviews but just to dangle this interesting carrot in front of some useful people who might want to get involved?
Click to expand...

It might be, but there is a sense in which this paper was deliberately written to be read alongside the results of DecodeME, even if we did not know what those were going to be at the time. As we say at the beginning, the DecodeME results will provide tests of any model framework such as this.
 
Holinger said:
Response from Pio Conti
www.qeios.com

Review of: "A Proposed Mechanism for ME/CFS Invoking Macrophage FcγRI and Interferon Gamma"

Title: A Proposed Mechanism for ME/CFS Invoking Macrophage FcγRI and Interferon Gamma [https://www.qeios.com/read/8GI3CT.2] In this paper, evidence for possible mechanisms of the clinical syndrome of ME/CFS is reviewed. The authors propose a novel m...
www.qeios.com www.qeios.com
Click to expand...
The paper should clarify whether the authors' hypotheses are supported by their scientific data.
Click to expand...
I thought it was pretty clear that these are ideas based on the literature, not based on experiments they’ve conducted on this specifically.
mTOR (mechanistic Target of Rapamycin) plays a key role in cellular energy balance, autophagy, and inflammation—and emerging evidence suggests it's significantly implicated in the pathogenesis of ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome). Studies show chronically elevated activity of mTORC1 in lymphoblasts (immune precursor cells) from ME/CFS patients, evidenced by increased phosphorylation of 4E‑BP1, a hallmark of mTORC1 activation.

In light of these concepts, to make this paper more interesting for the readers of this important journal, the authors should expand the discussion (or introduction) a bit. Below, I report an interesting article that should be studied, incorporated in meaning, and reported briefly in the discussion and in the list of references.

Avivar-Valderas A. Inhibition of PI3Kβ and mTOR influence the immune response and the defense mechanism against pathogens. International Journal of Infection. 2023;7(2):46-49. (www.biolife-publisher.it).
Click to expand...
@DMissa is the first paragraph a reference to your findings (thread)?
Interleukin‑37 (IL‑37) is an anti-inflammatory cytokine that broadly suppresses innate immune responses—especially by inhibiting IL‑1β, IFN‑γ, IL‑6, and TNF, etc. ME/CFS patients exhibit elevated pro-inflammatory cytokines, and preclinical evidence suggests that IL‑37 reduces inflammation and restores energy metabolism in mice—directly targeting fatigue mechanisms.

Again, in this context, to make this paper more interesting, the authors should expand the discussion (or introduction) a bit. Below, I report an interesting article that should be studied, incorporated in meaning, and reported in the list of references.

Toniato E. IL-37 is an inhibitory cytokine that could be useful for treating infections . International Journal of Infection. 2024;8(1):1-2. (www.biolife-publisher.it).
Click to expand...
How relevant is a discussion of fatigue to the mechanisms of ME/CFS?

And aren’t cytokines notorious for doing all kinds of stuff depending on the context (and often nothing at all)?
I don't see any figures or tables. For better presentation, a figure and a table should be added.
Click to expand...
Better presentation of what?
 
Hutan said:
Putting those two things together, there was one case report of the removal of a spleen, and subsequent recovery from 'CFS'. It wasn't a very good case report. But, I wonder if there are any more cases of this happening.




The thermodynamics of binding events - that's an interesting thought. The core temperature of the person might affect the rate of all sorts of biochemical reactions, or even whether a reaction occurs at all. As far as I can see, the core temperature of women tends to be a bit higher than in men. Perhaps that tendency is enough to increase the chance of antibodies binding to receptors, or something else? Exercise can significantly increase core temperature (although the idea of that being significant falls down a bit if we are trying to explain why simply brushing teeth can cause PEM).
Click to expand...
That spleen bit is pretty interesting

I remember it perhaps being mentioned in old times or maybe that us just because of having glandular fever that being aware of the spleen etc from laypersons (but no medical I came across ever cared or looked at it despite how bad my glandular fever was). I assumed it was either actually inconsequential (or those in GP etc were told that) or it was a body part they knew nothing about.

Basically it’s been something hanging around this stuff and at least for some of us for years. And I had strange symptoms like something feeling it didn’t ‘fit’ under my left ribs for years but which was never taken seriously (just ten second replies of ‘that will be something else’ poo poo from any medical person I mentioned it to) and I was trained into not mentioning that way. It’s strange because it wasn’t ever present but was that way for years at a time then less present and then present again and I’ll never know as not once did anyone look at or reply to me in it.

So I don’t know enough to even think whether it was and what a symptom of it being involved would or wouldn’t be.

Could we have a thread on what is the spleen and what would it even feel like if it is involved at all type thing?
 
Utsikt said:
@DMissa is the first paragraph a reference to your findings (thread)?
Click to expand...
Probably, I can't recall anybody else measuring 4EBP1 and he mentioned "lymphoblasts". There is a terminology problem here, though. The lab I worked in at the time was a microbiology lab that had adopted human cell culture recently. So what we now call LCLs (and are commonly called LCLs) we used to casually call lymphoblasts in the lab, and so that's what made it into the paper title which has been an endless source of frustration to me since.

They are immortalised B cells, not immune precursor cells. So the individual probably didn't read the paper too carefully is my guess.

As to the relevance to Jonathan's paper... yes it's relevant to a part of the story but I'm not sure it needs to be specifically dealt with. Jonathan touches on B cell metabolism and proliferation and mTORC1 in B cells is clearly relevant to this in a loose sense. One problem is that we don't know enough about specific and fundamental biology in this space to establish a confident and detailed mechanistic proposal here. Second is that the evidence being seen in a subset of transformed lines without accompanying causal investigation is not exactly mature evidence of "pathogenesis".
 
Jonathan Edwards said:
I will make some replies tomorrow.
Click to expand...
The author of the comment has published a lot on IL-37 so I'm not surprised he suggested IL-37. (Link)

Regarding MTORC1 it may be interesting to look into data for diseases that have elevated MTORC1 action in B cells to see if there is something that can be used to refine the hypothesis. I don't know if MTORC1 is elevated in B cells in ME/CFS but it is in LCL cell lines derived from ME/CFS patient B cells.
DMissa said:
In terms of plausibility, lupus and MS (particularly EAE model) feature elevated mTORC1 activity in B cells as well so there is precedent for its activity being shifted in diseases with some overlapping characteristics.
Click to expand...
 
DMissa said:
As to the relevance to Jonathan's paper... yes it's relevant to a part of the story but I'm not sure it needs to be specifically dealt with. Jonathan touches on B cell metabolism and proliferation and mTORC1 in B cells is clearly relevant to this in a loose sense. One problem is that we don't know enough about specific and fundamental biology in this space to establish a confident and detailed mechanistic proposal here. Second is that the evidence being seen in a subset of transformed lines without accompanying causal investigation is not exactly mature evidence of "pathogenesis".
Click to expand...

May I quote you on this @DMissa when responding to Dr Conti? It matches my own interpretation of the study. I think you have also made the point that you did not find a similar effect in other cell types more recently.
 
wigglethemouse said:
The author of the comment has published a lot on IL-37 so I'm not surprised he suggested IL-37.
Click to expand...

I found four papers on pubmed searching IL-37 and chronic fatigue. Two are reviews by Conti that look much the same and focus on mast cells in fibromyalgia. One includes the rather strange statement:

"Here, we propose IL-37 as a cytokine that contributes to improve the pathogenesis of FM by blocking IL-1 family members."
 
You must log in or register to reply here.
Back
Top Bottom