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

An advantage of this sort of theory where cells are just above a threshold for activation when they should be just below is that any further stimulus might distract the relevant interactions or enhance them according to the way pathways are diverted.

 

The forms of conferences exist but for various reasons you don't get the sort of interest or interactions (depending on the sort) you really want. That should change but to some extent conferences are pretty hopeless for dialogue anyway. The general level of discussion tends to be lower than here.

 

It doesn't look relevant to me. We are not interested in any signalling by FcRI here, just endocytosis. The signalling is from ingested peptides presented on MHC and from the T cells.

 

that’s bleak… but not unexpected i guess.

 

What about a sort of online conference in writing, then? Maybe held here? Where instead of a Zoom call, you'd have back-and-forth in writing, of the sort that has been going on here regarding, for instance, the Zhang et al. paper, but with topics announced ahead of time and discussion scheduled, to make it an event, and with it being advertised, and with people invited?

 

Dunno. My experience is that gossip is much more effective than conferences.

 

If FCRI receptors are involved, would this explain why IVIG therapy is an effective treatment for some/many patients?

Dissecting the mechanism of action of intravenous immunoglobulin in human autoimmune disease: Lessons from therapeutic modalities targeting Fcγ receptors


https://www.sciencedirect.com/science/article/pii/S0091674920310332

 

Interesting stuff about Queios that I didn't know:

If only PACE had been published on Queios!

How interesting that AI seeks reviewers. I wonder how this plays out in ME/CFS. I see lots of good ideas here. I'm looking forward to seeing how @Jonathan Edwards's paper goes down tomorrow.

 

It would be the perfect explanation, if you believe that there is a real effect.

 

I have to agree, vast majority of comments at a conference are “okay, enough about what you just said, how does this relate to [my niche area of interest]?”

I’ve been trying to chase down various researchers at my own institution just to share bits of my ideas and get feedback/criticism on their viability, but the most I’ve tended to get is “sure, might be plausible. I don’t know, did you test it yet?” This forum really is a unique space for back-and-forth

 

I'm wondering if there's any way for us to help make the most of your paper, in terms of generating the kind of interest and high-quality discussion that's likely to move the science forward. My impression of Queios, based on very limited experience, is that it doesn't generate back-and-forth among reviewers - just sometimes between the authors and individual reviewers.

I've suggested upthread a sort of conference-in-writing rather than conference-in-person that could happen on S4ME, but I wonder whether this paper could be the perfect pilot for that - maybe a couple of weeks after tomorrow's publication. A seminar-in-writing, or brainstorming session, or workshop. The reviewers could be invited, and anyone else whose interest you wanted.

Just throwing ideas around but this paper could be where the whole field suddenly shifts gears. I want everybody talking about it, thinking about it, getting their labcoats on and testing it...

 

I think the way things are done every day on S4ME is fine. It is hard to beat. And researchers come here and pinch ideas without us knowing and I am very pleased about that. Ideas belong to everyone and if useful for all, they should be spread and used.

The system on Qeios does in fact allow cross-talk between reviewers and it sometimes happens. Everyone is putting comments up for all to see and a reviewer can easily comment on a comment.

 

Very much agree.

 

Would the remaining 10% capable of understanding this mechanism also easily see how mild exertion or even mere prolonged upright posture is enough to trigger it?

To me this has always been a double hurdle: first you have to make people - or your doctor - understand how sick you feel during crashes, then you have to explain how ridiculously little it takes to trigger them, and the latter is often met with more skepticism, I find.

 

I think the fact that T cells can make their own acetylcholine opens up possibilities for interactions with nerves that could be triggered very easily. But that may take us into the synapse part of the story, which is not really analysed in this paper.

 

Whilst we wait, there's a paper on Qeios about Muslim scholarship.

It's a topic I find fascinating—mathematics and science in the Arabic world was stellar, until it wasn't any more—but the paper's a bit unsatisfying. Still a good find, though, because I hadn't appreciated the breadth of what's published there.

 

I think it also allows for feedback loops that can lock into a state. A subtle shift here, another there, and it gets stuck, without giving a dramatic change in any one part for tests to reveal.

What I'm wondering about is how easy it will be to actually test the theory.

 

To me, a common mistake with a theory of this sort is to try too hard to pin down specific agents or antigens. People love to link MHC alleles to specific peptides from specific microbes. They love to pick out specific antibodies to specific epitopes on antigens. But the reality is that the stereochemistry of immune interaction is so mind-blowingly complicated and unpredictable when you involve millions of possible antibody species, it is unlikely that such specificity would ever generalise.

What to me is more useful is to pin down critical but generalisable events, like ligation of a particular receptor or release of particular cytokines. For RA we found we were looking at FcRIIIa and TNF and IL-6. For ME/CFS we might be looking at FcRI and gamma interferon. We might also be looking specifically at IgG3 binding to FcRI. We might be looking at a role for VH3 heavy chain usage. We might be dealing specifically with CD4 cytotoxic cells. Any of these might be amenable to inhibitory intervention. If one could predict a particular step that ought to be generally necessary for ME/CFS to continue then there is a case for a therapeutic experiment. Fluge and Mella are already well on the way with antibody depletion. I think that may be a blunt instrument in this case but it might be one way in.

 

I read that there are FcGRI receptors in the dorsal root ganglia and they have been shown to regulate pain sensitivity.

Is there anything to learn from studies that transferred IGG from patients with Long Covid and with Fibromyalgia into Mice and observed hypersensitivity?

In this Long Covid study LC3 mice showed increased hypersensitivity. There is also discussion of neuron related findings.
https://s4me.info/threads/transfer-...es-symptomology-in-mice-2024-vidarsson.38759/

In this Fibromyalgia study there were pain sensitivity changes when IGG was transferred. The study has findings in the dorsal root ganglia (one of several locations).
https://s4me.info/threads/passive-t...ce-2021-goebel-et-al.21286/page-7#post-480660

 

If gamma interferon is really the issue, isn't treatment likely to only or mostly work in acute and subacute scenarios?

Secondary pathologies (like 'mitochondrial dysfunction' or persistent glial activation,...) may persist independently of the original trigger?