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

[hotblack]

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.

 

[hotblack]

@Jonathan Edwards would the elispot/co-culture experiments proposed be possible on already collected blood samples, like those in the CureME biobank? Those are what Jackie was using for previous studies of T cells iirc, but I think they were using flow cytometry and I have no idea about these different methods or their requirements.

 

[wigglethemouse]

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).

 

[Jonathan Edwards]

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.