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

That's interesting. I wonder if that would mean, though, that you'd expect the level of the intolerances to be correlated, such that a person who is very intolerant to sensory stimuli would also be very intolerant to meds, and vice versa. I'm completely tolerant to sensory stimuli AFAIK but have huge problems with some meds.
I assume it would just depend which nerves/cells/bits are sensitised. There is a great deal of variation between us. So I wouldn’t expect there to need to be a clear correlation.

I didn’t think I had any medication sensitivities but then found some seem to set me off. Some seems like a more pronounced version of normal stuff people get (nausea etc) which to me is like the body saying ‘new chemical, I may be being poisoned, react’ while others are more clearly neural, like bounceback from certain sleeping meds. I can vaguely get a feel for how it all fits into the overall-responsiveness hypothesis.
 
Can we learn anything from Macrophage Activation Syndrome that might be applicable to the hypothesis? This is a syndrome with positive feedback between macrophages and T cells causing activation and TNF-alpha and INF-gamma release. If NK cells are normal the "inflammation" can be somewhat controlled.

Macrophage activation syndrome: A diagnostic challenge (Review)

From Introduction
Mobile macrophages in the bloodstream are called monocytes. They can migrate into tissues, where their transformation into histiocytes plays a role in phagocytosis. Monocyte recruitment into tissues is mediated by lymphokines: Interferon (INF)-γ and TNF-α. Natural killer (NK) cells secrete INF-γ but do not produce a constant amount capable of sustaining an activated macrophage population. In contrast, T helper 1 (LiTH1) lymphocytes are capable of continuous INF-γ secretion and maintenance of macrophage activation. Macrophage interaction with LiTH1 is essential because it lays the basis for cell-mediated immunity. The proinflammatory cytokines secreted by post-activation macrophages play an important role in defending the host but can also lead to serious injuries if the inflammatory process is not adequately controlled (8,9).

MAS pathophysiology
Primary MAS is triggered by the excessive proliferation of LiTH1 which is caused by the decrease/lack of NK cell cytotoxicity, a decrease due to a mutation in the gene that encodes perforin (a protein that plays a role in the cytotoxicity of NK cells and CD8+ cytotoxic T lymphocytes). Perforin is involved in the apoptosis of tumor or viral infected cells and controls cell proliferation. Due to the decrease in perforin levels and the lack of NK cell activity, lymphocytes are persistently activated and secrete two major macrophage activators: INF-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF). Stimulated by these two mediators, macrophages activate and proliferate uncontrollably (8-17).
 
Can we learn anything from Macrophage Activation Syndrome that might be applicable to the hypothesis?

Very likely, but I am not sure that review is the best place to start. I haven't heard of an immunologist talking about 'histiocytes' for about 50 years. Likewise 'cell-mediated immunity'. These are the conceptual paradigms of my student days.

And i have never been a fan of the TH1-TH2 nomenclature.
 
I sent the paper to a lupus researcher @QUB and she read it!

Thank you very much for sending on the article and sincere apologies for the delayed reply.

I thoroughly enjoyed reading the paper, it offers very interesting insights and I agree there is plenty more to be done around cellular metabolism, tissue resident immune populations and identification of any self-antigens. I'm not aware of any work on Fc-gammaRI variants in the population but this would also be interesting.
We currently have a project investigating sex-related differences in autoantibody responses in lupus and I'm looking forward to learning more in this field.

Thanks again

Best wishes
Dessi
 
I've been wondering how the subgroup with IBS plays into this hypothesis. In some people could the junk IGG antibodies include ones related to food, and that kicks off a chain reaction causing IBS and food sensitivities? Since we found out this week that mast cells have FcGRI receptors, and mast cells are abundant in the gut, as are MAIT T cells which have been highlighted by several research teams as being different in ME/CFS, perhaps there is something there.

The downside is that the American Academy of Allergy Asthma & Immunology and the European Academy of Allergy and Clinical Immunology totally poop on IGG food allergy testing. In fact they say antibodies show tolerance.

However, something in ME/CFS is causing food sensitivities and IBS and often IgE testing is negative.

Thoughts?

Background : I came across someone whose ME/CFS has improved in the last year and they have comparison before and after IgG food allergy test results also showing improvement. That is what made me wonder if it could relate to the hypothesis.
 
I think the allergy tests related to IgE would not be linked . FcgR1 binds IgG. But if there are allergy tests looking at igG the hypothesis does not predict these would be correlated with symptoms. It specifically invokes antibodies that only mediate interactions in the context of FcR1and would not show up on standard ELISAs.

I also don't think this is likely to be an issue of immune responses to foodstuffs. The junk antigens are more likely to be microbial I think. How that relates to specific food intolerances I amnotsure butI am not convinced that those are immunological.

All in all I am not sure we can draw any clear conclusion!
 
This may be really silly, but I can’t remember if you mentioned if breaking the feedback loop you’d think the body would find homeostasis?

I was wondering if the new OX40L antibody target class (amlitelimab not out yet) would be enough to break this feedback loop. This also may be a silly question…
 
However, something in ME/CFS is causing food sensitivities and IBS and often IgE testing is negative.

My ten bob is on losing the ability to digest sugars or proteins.

When I became lactose intolerant I noticed my clothes and sheets smelt funny when I took them out of the basket to wash. I didn't know what it was, but I recognised it; I'd smelt it before on cats.

Same thing when I lost potato starch. Different smell and I hadn't come across it before, but it was definitely there.

For all the fashionable talk about the 'gut microbiome', it might still be a reasonable bet.
 
I am curious how well you think your hypothesis stands up post DecodeME?

DecodeME did not come up with anything that would strongly favour an autoantibody theory (an HLA-DR or maybe complement gene variant). So it is consistent with our idea that there is nothing particularly wrong with the antibodies in people with ME/CFS, but that normal differences in antibody repertoire between men and women might still explain the sex ratio.

DecodeME might confirm a role for an innate-type T cell population, as we suggested, perhaps gamma delta T cells with the butyrophillin gene coming up.

But more than anything DecodeME tends to shift attention to possible neural mechanisms, which we deliberately set to one side in our paper, to keep our focus.

I think DecodeME leaves investigation of priming of innate T cell populations a very valid target. It may further support an interest in interferon signalling, although that might be one of several interferons. I think it emphasises the need to think about hind brain control mechanisms that might interact with immune signals.

I have never been very sold on the FcR1 story, but I thought it was a useful thing to analyse in the context of the sex ratio. I think the laying out of arguments there remains to my liking. Chris Ponting read the article and disagreed about the absence of inflammation, but maybe he will come round to the view of a veteran inflammation scientist in the end.

Independently of DecodeME I have thought more about the possibility that the female predominance might reflect an increased sensitivity of neural tissue to some signal in women - it might even be through interferon receptors. That would bypass the need for involving antibody (as we point out briefly in the paper), leaving the story otherwise much the same - T cells and neurons.
 
Chris Ponting read the article and disagreed about the absence of inflammation
What was the evidence put forward in favour of inflammation?

Do you think this frequent source of disagreement is an issue of language specificity? My sense is that use of the word inflammation has drifted (whether appropriately or not) away from its classical definitions.
 
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What was the evidence put forward in favour of inflammation?

Do you think this frequent source of disagreement is an issue of language specificity? My sense is that use of the word inflammation has drifted (whether appropriately or not) away from its classical definitions.

I think Chris mentioned the elevated CRP levels in the Beentjes paper and also the Nakatomi study on glial activation.

The source of disagreement is definitely related to a shift in usage. I personally think that the slight statistical shift in CRP in the Beentjes paper has to be seen in the context of persistent evidence of absence of an acute phase response in MECFS patients selected for biological studies (and hopefully without the noise acknowledgeed in recruitment for the Beentjes paper). And Nakatomi's study did not replicate. So I would disagree that there is even evidence for events often associated with inflammation, but the key problem for me is that neither a CRP rise nor microglial activity are inflammation as such.

The shift has been going on a long time with an acute phase response being called 'systemic inflammation' when it isn't. The shift has to be inappropriate because it leads to nonsense arguments. If presence of a 'pro-inflammatory' factor, such as a cytokine, is regarded as 'inflammation' you have a causal nonsense. Something that causes X is called X. If gravity causes an apple to fall gravity is not a falling apple. It gets even worse if something that causes X may also cause Y and Y is then called X (e.g. CRP rise). And if you start thinking like that you end up with garbage biology - which is what we have most of the time these days.
 
DecodeME did not come up with anything that would strongly favour an autoantibody theory (an HLA-DR or maybe complement gene variant). So it is consistent with our idea that there is nothing particularly wrong with the antibodies in people with ME/CFS, but that normal differences in antibody repertoire between men and women might still explain the sex ratio.

DecodeME might confirm a role for an innate-type T cell population, as we suggested, perhaps gamma delta T cells with the butyrophillin gene coming up.

But more than anything DecodeME tends to shift attention to possible neural mechanisms, which we deliberately set to one side in our paper, to keep our focus.

I think DecodeME leaves investigation of priming of innate T cell populations a very valid target. It may further support an interest in interferon signalling, although that might be one of several interferons. I think it emphasises the need to think about hind brain control mechanisms that might interact with immune signals.

I have never been very sold on the FcR1 story, but I thought it was a useful thing to analyse in the context of the sex ratio. I think the laying out of arguments there remains to my liking. Chris Ponting read the article and disagreed about the absence of inflammation, but maybe he will come round to the view of a veteran inflammation scientist in the end.

Independently of DecodeME I have thought more about the possibility that the female predominance might reflect an increased sensitivity of neural tissue to some signal in women - it might even be through interferon receptors. That would bypass the need for involving antibody (as we point out briefly in the paper), leaving the story otherwise much the same - T cells and neurons.
Thanks for your reply. It's interesting that you think that some central elements of the hypothesis are somewhat strengthened by DecodeME.

I am waiting for the HLA element of DecodeME with interest. I don't know if you saw Chris Ponting's reply to me in the DecodeME thread a week or two ago, but essentially he said the Manhattan plot published with initial DecodeME results has had nothing removed from it. So I'm interested to know what happened to the big HLA signal you saw a few months back.

No timeframe for completion of the HLA analysis. The Manhattan plot in the preprint includes all variants including those in the HLA. But note that in the HLA analyses we do not test each DNA variant, rather we test combinations of variants that are commonly coinherited, i.e. "HLA alleles". So even if there isn't a "signal" in the Manhattan plot this does not immediately mean that we won't see association to an HLA allele.


If the HLA-DQ link was confirmed, would that solidify any aspects of your hypothesis? And what would it mean more generally?
 
If the HLA-DQ link was confirmed, would that solidify any aspects of your hypothesis? And what would it mean more generally?

DQ is a bit of a mystery. It does not seem to be regularly used for restricting/mediating T cell helper responses to peptides that might facilitate antibody production in the way DR does. There are suggestions that DQ has more to do with innate T populations that may not be involved in specific help to B cells. (I guess they might give non-specific help.) I think it would tend to swing things towards an innate T cell step mediating T cell cytokine signalling rather than antibody production.
 
@DMissa can you give any update on the potential projects mentioned in this post?


Would be very interested to hear whats occuring on that front.
I have not designed anything in this space yet. I have just finished a proposal to check for dysfunction in processes relating to one of the DecodeME genes. I will have to design a “basic science” project later in the year which I may use to try to fill holes in our fundamental knowledge that are important to Jonathan’s hypothesis, but this depends on a few things and I don’t yet know what the project will look like. I can’t make promises, it’s just my hope.
 
I have not designed anything in this space yet. I have just finished a proposal to check for dysfunction in processes relating to one of the DecodeME genes. I will have to design a “basic science” project later in the year which I may use to try to fill holes in our fundamental knowledge that are important to Jonathan’s hypothesis, but this depends on a few things and I don’t yet know what the project will look like. I can’t make promises, it’s just my hope.
Thanks for your response, that all sounds intriguing. Filling holes in our fundamental knowledge is really vital. I hope your project related to the DecodeME gene is able to go ahead, it sounds like a worthwhile endeavour.
 
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