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

Sasha said:
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.
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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).
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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).
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wigglethemouse said:
Can we learn anything from Macrophage Activation Syndrome that might be applicable to the hypothesis?
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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!
 
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