Notice about a forthcoming paper: A Proposed Mechanism for ME/CFS Invoking Macrophage Fc-gamma-RI and Interferon Gamma

Link to the thread on the preprint - 27 May 2025:
A Proposed Mechanism for ME/CFS Invoking Macrophage Fc-gamma-RI and Interferon Gamma, 2025, Edwards, Cambridge and Cliff
******


I am hoping that the paper I have been writing with Jo Cambridge and Jackie Cliff will appear on Qeios tomorrow. If there are glitches it may be Monday.

There is nothing in this that should be too unexpected for S4ME members. I have suggested a possible mechanistic framework for ME/CFS that includes a role for both antibodies and T cells. Those roles are rather different from typical autoimmunity but then each autoimmune disease is a bit different. We focus on a receptor called FcRI. That could well be wrong but it provides a story that seems to make sense.

Jo Cambridge has been involved in the evolution of this for a long time. Jackie Cliff was asked to help on the T cell side and did a great job pulling that aspect together. This isn't specifically her preferred theory, but then I wouldn't say it was for Jo and I either. It is an exercise in seeing how one could make a testable theory that accounted for all the salient facts.

We have deliberately put this out with a reference to DecodeME results being expected soon. The idea is to stimulate debate by seeing to what extent those results fit with or test existing ideas.

Sorry not to actually post the paper here but this is to reassure people that it really is about to appear!

 

Looking forward to reading this.

It is 36 years since SW suggested “a little more psychology and a little less T cells would be welcome” in a review of books about ME/CFS (BMJ, June 1989: https://www.simonwessely.com/Downloads/Publications/CFS/3.pdf).

I would be delighted if any hypothesis about the mechanism of ME/CFS proves to be correct, but it would be particularly pleasing if T cells prove to be involved.

 

If anyone can help, it would be helpful to have a "Janet and John" or "Ladybird" explanation of what an FcRI receptor is and does. Internet searches get mixed up and give explanations for Fc receptors and FcεRI receptors. Thank you.

 

Looking forward to reading this and greatly appreciate all of your efforts to solve this awful puzzle of a disease.

 

I think FC Gamma RI (also called CD64 amongst other things) is a type of FC receptor
Wikipedia entry
Genecard

Also see the wikipedia description of Fc gamma receptors

 

36 years can be a short time in immunology as they say. But I was a little naughty with the opening of this paper - adding a non-existent quotation to 'anon':

Summary: Evidence bearing on possible mechanisms for the clinical syndrome of ME/CFS is reviewed. The evidence is used to argue for a hypothesis that centres on a form of persistent, inappropriate, ‘neuroimmune hypervigilance’ mediated primarily by T lymphocyte-macrophage interaction but influenced by IgG antibody binding to the gamma interferon-inducible high affinity immunoglobulin receptor FcgRI. This proposed mechanism could explain why the illness resembles post-infective T cell-mediated autoinflammatory syndromes in age of onset and time course but has a female preponderance similar to autoantibody-mediated disease.

‘A little more T cells …’. Anon

 

I don't know either, there are 3 main ones:
FcγRI (CD64)
FcαRI (CD89)
FcεRI

https://en.wikipedia.org/wiki/Fc_receptor

Probably the former, but we'll need the manuscript or JE to clarify.
https://en.wikipedia.org/wiki/CD64_(biology)

 

Does this proposed mechanism explain ME/CFS arising from exposure to organophosphates ?

 

Antibody molecules are like crayfish, with two (variable) antigen binding claws and a constant body (fragment C = Fc). Fc is not inert. It signals to cells when the variable Fv regions have bound, either by binding to and activating soluble complement proteins or by binding to receptors specific for Fc on white blood cells and endothelial cells.

There are at least four classes of Fc receptor, each with different binding affinity and response function, which are present each on a different range of cells. We first had FcRI, FcRII and FcRIII but now have at least FcRI, FcRIIa, FcRIIb, FcRIIc, FcRIIIa, FcRIIIb and FcRN (N for neonatal). Most of these activate the cell carrying them but some inhibit.

FcRIIIa is present on macrophages in only a few tissues - including joint lining synovium. It binds small immune complexes and the cell responds by producing TNF. That is what we worked out happens in RA - hence it is an arthritis.

FcRI is present on quite a lot of mature macrophage but is increased in response to the T cell cytokine gamma interferon. It also binds immune complexes but can also hold on to uncompleted antibody (IgG) so it can sit there with antibody already on it, waiting for antigen.

The significance of the difference between the FcR classes lies in the thermodynamics of their binding to single antibody and multiple antibodies bound to antigen. This is too complicated to explain easily and probably not very well understood.

The interest in FcRI is partly because it is induced by T cells and partly because it is the strongest binder and can therefore mediate interactions in which the binding of the antibody to antigen is weaker or less specific. It will allow the cell to take up antigen and present peptide fragments to T cells to recognise. The T cell can then further increase the FcRI expression through gamma interferon. This means that it is likely to be involved in getting together in a pow-wow with T cells in order to sort out which dubious-looking antigens need an immune response to and which not

The reason for invoking FcRI is very complicated but I think reasonable. It is a way of explaining how antibody may be involved without having any direct effect on tissue in itself - only indirectly as part of an interaction with T cells. This could explain why ME/CFS is common in women and also why it is one syndrome rather than twenty - because it doesn't actually matter what the antigen is. The response is a general T cell activation response.

I fear that is too complicated but unfortunately the case is based on very subtle functional properties of FcRI and equally subtle arguments about how disease patterns emerge from the cell interactions. 90% of immunologists will probably not understand it - certainly not the ones we see posting on X. But it is all based on ideas that people here can grasp if they want to get stuck in to it. All a bit like locks and keys that fit together with variably strong magnetic attraction. It can get a bit like Chinese wire puzzles but once you see how things fit I think it is intelligible.

 

Just to add - I have just mentioned Fc gamma receptors for IgG. As Snow points out there are also Fc alpha and epsilon receptors for IgA and IgE.

Fc gamma receptors are surface proteins that have CD numbers. It seems that a committee decided to entertain itself by numbering by powers of two in reverse so that

FcRI = CD64
FcRII = CD32
FcRIII = CD16

 

If organophosphates annoy T cells and macrophages, which they probably do, then yes. An important part of the theory is that ME/CFS is not a response to a specific antigen in the way that Hashimoto's disease is due to a response to a thyroid protein. It is a general pattern of T cell over activation like Reiter's syndrome or ankylosing spondylitis or Crohn's disease. Just about anything that got T cells annoyed could start it off.

More specifically we have mentioned organophosphates because several bits of evidence about ME/CFS might point to acetylcholine and its receptors. T cells have muscrainic ACh receptors so that is a way of linking it all up.

Acetyl choline is also a key neurotransmitter of course. The paper does not attempt to go into the neurological side of the illness - which the Zhang paper highlights. But we discuss the need to think of a 'neurological half' to the story and this may include acetylcholine.

 

Would we expect to be able to pragmatically test this hypothesis with a drug like fostamatinib?

 

Probably not in that this drug blocks SYK kinase. SYK kinase mediates the macrophage activation response to Fc receptors but we are thinking more in terms of the receptors as mediators of internalisation of antigen and peptide presentation. SYK probably mediates the TNF response from FcRIII and there doesn't seem to be a TNF response in ME/CFS.

 

Alright! I was hoping blocking SYK as a downstream mediator of (among others) FcyRI might be able to block some feedback loop or further downstream mediators.

Looking forward to reading the full hypothesis once its out! Thank you for your work

 

Just starting it off or also aggravating them some more? Would or could this theory explain why some immune triggers (illness or vaccination for example) also trigger worsening for some people?

 

Certainly.

 

Do we have published research suggesting this ? If not how can we find out for certain ?

 

This rings bells from my study 30 years ago of the nervous system. Can't remember it all now.

So this could be what adds to triggering PEM in muscle? The alarm system in play?

 

Organophosphates inhibit acetylcholinesterase and thereby raise levels of ACh by preventing its breakdown.

I discovered yesterday that interestingly nerves supplying lymphoid tissues cannot make acetylcholine in their terminal branches. But T cells make it instead. And have receptors for it.

Demonstrating that organophosphates have an effect on lymphocyte interactions in vivo might be pretty tricky, but it is certainly very plausible and if it was possible to do, worth testing. But I would be wary of animal experiments and giving humans organophosphates is not easy.

Of course there might be a suggestion that mestinon might make the problem worse, but it might not be relevant to the lymphoid environment.

 

I don't think what we are suggesting would predict that. ACh interaction with nicotinic receptors on muscle cells would not be affected.