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

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wigglethemouse said:
I read that there are FcGRI receptors in the dorsal root ganglia and they have been shown to regulate pain sensitivity.
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That would be interesting, especially if their expression was gamma interferon sensitive. Were they on macrophages or on neurons? I wonder what would then trigger them and mediate sensitisation?

wigglethemouse said:
Is there anything to learn from studies that transferred IGG from patients with Long Covid and with Fibromyalgia into Mice and observed hypersensitivity?
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I am fairly sceptical about studies like that. To be convincing you would need to show a chronic state truly analogous to the human over a period of time with repeated infusion. Since human proteins are foreign to mice that is pretty hard to do without all sorts of problems and complications.
 
butter. said:
If gamma interferon is really the issue, isn't treatment likely to only or mostly work in acute and subacute scenarios?
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Gamma interferon isn't the only 'issue'. It is one mediator in a long causal chain. There may be options to interrupt that chain at multiple points - as we do at at leat four points in RA, which is also chronic. Not sure I get the argument here.

butter. said:
Secondary pathologies (like 'mitochondrial dysfunction' or persistent glial activation,...) may persist independently of the original trigger?
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But are they actually there? We don't have clear evidence of either of those as far as I know, and they are not part of my theory.

Moreover, why should they persist if they are? I can see why gamma interferon might persist if the adaptive immune system had 'learnt' to persistently make too much by giving rise to unhelpful T cell populations that would persist. But metabolic processes in cells should return to normal unless those cells have similarly 'learnt' something'. There have been suggestions of epigenetic learning in macrophages but, as I point out in the paper, we do not yet have clear examples of that in human disease.
 
Snow Leopard said:
There are numerous studies, but it is FcγRI on the neurons themselves
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Well that would fit rather nicely - amazing!! We must have been telepathic.
That paper is rat neurons. FcR are different in humans but not that much different.

The only problem is that a direct effect of antibody complexes on DRG would not seem to make much sense temporally in terms of PEM without some other signal. But things are likely to be complicated.
 
Jonathan Edwards said:
The only problem is that a direct effect of antibody complexes on DRG would not seem to make much sense temporally in terms of PEM without some other signal. But things are likely to be complicated.
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It's only an excitatory effect, so it still requires regular afferent signalling for nociception. It remains to be seen if other afferent sensory pathways are affected.
 
Looking into the FcRI on neurons - this is something raised in 2012 by Qu, which does not seem to have been taken up by others since. The staining pattern is not quite what I would expect but could be bona fide.

I am puzzled as to quite what function FcRI would have on these cells. It would be very important to know if real and it is perhaps odd that there is little published in the last 3 years as far as I can see - but I may have missed stuff.

The really interesting thing would be if this is a mechanism for epigenetic control of nociceptor sensitivity over a period of days or weeks during illness that fails to get turned off.
 
rvallee said:
Sometimes, just being sincerely interested in something beats years of training and experience on related skills and knowledge.

It's so easy to misapply years of training and experiencing bouncing a dead cat, something that sincere motivation usually easily avoids doing in the first place.
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That actually makes so much sense.

8 years of French literature lessons during my education and you couldn’t tell I’d taken a single year. Never was my thing. Just studied to scrape by.

While I’m able to pretty much understand and do most things my friends with Bsc in Computer Science do, mostly because I was quite a nerd during my teenage years and spent my free time coding and contributing to FOSS projects for fun.
 
Jonathan Edwards said:
That would be interesting, especially if their expression was gamma interferon sensitive. Were they on macrophages or on neurons? I wonder what would then trigger them and mediate sensitisation?
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They were on DRG neurons. There are a number of papers, here are two I looked at yesterday.
(213) IgG-Immune Complex Directly Activates Joint Sensory Neurons through Neuronal FcγRI to Induce Arthritis Pain

Neuronal Fc-gamma Receptor I Mediated Excitatory Effects of IgG Immune Complex on Rat Dorsal Root Ganglion Neurons
 
Jonathan Edwards said:
It would be very important to know if real and it is perhaps odd that there is little published in the last 3 years as far as I can see - but I may have missed stuff.
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Here are two more recent studies looking into FcGRI receptors in sensory neurons in neuropathic pain.

B cells drive neuropathic pain–related behaviors in mice through IgG–Fc gamma receptor signaling, 2024
(Paywall, Abstract does not detail type of FcGR)

Neuronal C-Reactive Protein/FcγRI Positive Feedback Proinflammatory Signaling Contributes to Nerve Injury Induced Neuropathic Pain, 2023
 
Rather a rag-bag of papers, some of which, in my field, I don't really believe. And a lot in animal models.

Nerve endings in joints are a very different story from DRG cell bodies and very different again from neuropathic pain situations.
This is probably an area that has got a bit trendy and people are messing about with animal systems to generate papers on neuropathic pain and stuff.

And few of these situations would seem to fit ME/CFS very well, so I am not sure where it takes us. Effects in DRG would interesting, if I could see how they fit into a more general story.
 
dave30th said:
What bank holiday?
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It used to be the Monday after Whit Sunday but the UK has gone a bit atheist. Surprised you didn't have it in the US with all your evangelists - speaking in tongues and what not.

But the editorial office of Qeios is probably in Italy and as it says in the old Silly Song:

"When it's midnight in Italy it's Wednesday over here."

So the Italians may well have a bank holiday yesterday or 'ayer', as they say in Spanish.

It all goes to show that we live in a bewildering virtual age where nothing is quite what it seems - no less than the Age of Qeios (the Greek word for chaos).
 
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