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

Yes, I was.

I am not sure I can answer that. I was thinking of one approach, maybe among many potential therapeutic strategies. Unwinding the whole process to get permanent remission would clearly be ideal but some people may be so genetically susceptible that relapse would be hard to prevent entirely.

 

Well in simple terms if there is an interaction leading to continuing fluctuating signalling through interferon gamma (downstream of the FcRI interaction), which influences lots of tissues and makes you feel poorly.

Don't follow that. It may to matter much where the binding to FcRI is if T cells interact with the receptor bearing cell and then wander off and release signals in other tissues. That could include muscle. The DRG idea came along since uploading this.

Yes. But it doesn't have to be any very special IgG. With the right genetic background and some unknown shift in T cell populations any old IgG from long lived plasma cells may feed the process - but perhaps of a sort that women tend to make more of. Until we understand why unhelpful IgG is made more commonly by women it is hard to know what that sort might be. It might even have something to do with skewing of heavy chain usage.

 

Thanks for the prompt response.

I am still a little unclear on the exact implications of what you say.

Are you saying that it may be hard work to find effective treatment for those of us who have been sick more than a couple of years?

Or are you saying that it may be hard to treat the longer term sick with one particular treatment strategy you had in mind?

 

I haven't got around to reading the full study yet and I probably won't get around to reading everything written here in this thread too quickly, as I expect this thread to blow up even more, but I wanted to thank all the three authors for a piece that is surprisingly readable and of course the humorous first quote. I recall that one of the authors struggled with ill health quite recently and can only hope that things are looking brighter, for the many patients and of course for herself as well!

 

So am I. I am only speculating on general strategies. I was not relating it to any specific treatment.

 

Do the T-cells become resident in those tissues, is that why we don't consistently see interferon gamma turning up in cytokine studies?

The Lipkin study (10.1126/sciadv.1400121) found higher levels in the early group, but lower interferon gamma than in controls for the >3 year illness group so one could argue that it is not a perpetuating factor. Other studies found no difference eg https://link.springer.com/article/10.1186/1479-5876-7-96.

 

Yes, I've been wondering that.

To go back to psoriasis again, once you've got it you tend to keep getting it. But first line treatments often help in a flare, and there are heavier duty options for severely affected people. The aim's managing it so you can live with it.

The thing that might be overlooked is that in a disease that tends to flare, early intervention could make a substantial difference in how bad an episode is. Like the way people who get migraines start hunting for their meds at the first warning sign, because it can mean the worst of the symptoms never develop.

We currently don't have that option, so we've no sense of what it might look like in the context of ME/CFS. All the same, even if some of us have a genetic predisposition that makes it likely we'll get flares, a treatment would leave us a lot better off than we are now.

 

They probably do not become resident. They pass through constantly, maybe releasing signals if they disapprove of what is going on or are already annoyed from talking to some macrophages in spleen or lymph node. Which would mean that the number of T cells in tissue may not be different from normal.

 

What I think might be part of the story is that a 'malaise' response is engineered by the immune system using cells and mediators that we tend to think of as acting in an inflammation context but which can also operate in a non-inflammatory way. The malaise response may be cunningly designed to stop us from being too active and spreading our germs or wasting our energy and may highjack signals used in other ways at other times. When I have a cold my lumbar spine, where I have a worn out disc, starts hurting. As far as I know nothing has changed in the disc but my immune system is sensitising tissue slightly dodgy tissues to produce pain. Muscles, being slightly dodgy all the time, in terms of micro damage and repair on a daily basis, may bear the brunt of that. But they might be tuned up to receive gamma interferon signals from wandering annoyed T cells simply because it is a good way to make people stop running around.

 

I suppose what I'm getting at is, if your speculation is correct, what is it about pwME who have a longer time sick that might make it harder for them to be treated than pwME who have been sick a short time? If there is no detectable damage, as you have emphasised before? Some change in immune signalling that occurs later in the disease? Do we have evidence for anything like this?

I have read a fair bit of the paper but I haven't come across anything explaining that.

 

I thought the Prusty Fibronectin paper finding that patient IGG caused cell fragmentation and control IGG did not was a remarkable finding, one I'd like to see replicated.

 

Nothing specific. I am just basing it on the general systems dynamics principle that if you have a bistable situation where dynamics can either lodge in a normal feedback loop or drift off into an abnormal cycle the longer that goes on the more likely you are to recruit changes that entrench the abnormal cycle. The immune system has millions of options for shifting control loops to a slightly different position with B and T cell subpopulations changing.

 

"Our data show altered active immune complexes, immunoglobulin-mediated mitochondrial fragmentation as well as adaptive IgM production in ME/CFS patients."

None of that sentence makes much sense to me as an immunologist.

The paper does not appear to have been formally published after 2 years.

 

The hot dog buns, surprisingly, got me all the way to the synthesis where things fell apart considerably but I know now that I can build on the buns! I may be some time...

 

Shh... Don't let on.

 

For me! For me! Not for the paper!

 

Who or what is vigilant?

And what is the «learnt» neuroplasticity?

I know it’s not your fault that neuroplasticity has become a favoured term in the pseudoscientific circles, but might the term benefit from being explained in a way that makes it less likely to be misinterpreted?

 

Is this an 'in joke' at a patient's expense. Hideous if so! Explain?

 

Not at all! It’s a silly reference to a previous silly exchange between Sasha and Jonathan about Sasha’s recent adventure into trying to learn about the immune system in anticipation of this paper.

 

No, not at all! It's a joke about how I've been mugging up frantically in preparation for publication of this paper by reading the Kurzgesagt book, 'Immune', in which Major Histocompatability Complex Class II molecules are compared to hot-dog buns that present antigens (the 'sausages' in the buns) to immune cells.