Interferons as mediators in ME/CFS

I’ve also been thinking about location-specific muscle stiffness as something that cannot as easily be explained by a purely neurological issue.

I’ve heard other members describe those experiences, though it may not be universal (and might be something that is less obviously location-specific in less mild cases where any muscle use triggers PEM).

If this theory has any merit, I’m easily convinced that the brain is likely to be involved and mediates most of the relevant symptoms—it just seems worthwhile to check the muscle as well, since a positive finding there could be all the justification needed to get a clinical trial rolling for something that targets this pathway across tissues.

[Edited for conciseness]
 
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Jonathan Edwards said:
This document is totally brainless and could well have been entirely written by AI.
The analysis is so superficial and inaccurate as to be laughable. We can do far better than that here.

The obsession with this being a problem of inflammation is depressing.
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Yes, I agree that's its not a great list. Its that problem of saying 'inflammation' when they mean immune system signalling of some sort.

But my question was whether there had been a trial of ifn alpha-2a in ME/CFS patients in the past, and that was why it was in the list of discontinued treatments as rituximab is. Because if there had been, how the participants responded could be relevant to our theorising in this thread.
 
Utsikt said:
Could it be that the thing that causes PEM is in the brain, but that some of the mechanisms also are present in the muscles so they act up in their own way as well?

So stopping the issues in the muscles might not stop PEM, but stopping the issues in the brain might stop everything?
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Maybe, I think it gets into the realm of not being able to make a good guess until the experiments are actually run. Though to your second point, if this was an issue in the brain and we had a drug that effectively targeted it, it would likely be a circulating drug that would also target the same pathway in muscles anyways.
 
V.R.T. said:
Yes, I agree that's its not a great list. Its that problem of saying 'inflammation' when they mean immune system signalling of some sort.

But my question was whether there had been a trial of ifn alpha-2a in ME/CFS patients in the past, and that was why it was in the list of discontinued treatments as rituximab is. Because if there had been, how the participants responded could be relevant to our theorising in this thread.
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It would be interesting to find out, I’m not aware of any published trials that used it. Recombinant interferon is typically administered to boost anti-viral responses when a viral infection is suspected, so anyone who prescribed it would have been someone who believed in the possibility of viral persistence. Not sure if that narrows it down much.
 
jnmaciuch said:
I think that’s precisely why I’m interested in those findings—an acquired signal that persists in culture is pretty much either epigenetic or a self-perpetuating autocrine/paracrine loop, both of which align perfectly with a mechanism of constitutive interferon signaling. Plus, sorting for myoblasts and culturing accounts for most sampling issues with muscle.
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I find it very hard to believe that a signal loop would persist in the grossly artefactual environment of tissue culture though. We have not seen any follow up on those observations for several years (?10) now I think.
 
jnmaciuch said:
I’ve also been thinking about location-specific muscle stiffness as something that cannot as easily be explained by a purely neurological issue.

I’ve heard other members describe those experiences, though it may not be universal (and might be something that is less obviously location-specific in less mild cases where any muscle use triggers PEM).

If this theory has any merit, I’m easily convinced that the brain is likely to be involved and mediates most of the relevant symptoms—it just seems worthwhile to check the muscle as well, since a positive finding there could be all the justification needed to get a clinical trial rolling for something that targets this pathway across tissues.
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If the muscle finding is negative but we still think ifn signalling in the brain is a good bet, is there any way to check the brain that doesn't involve a theraputic experiment? Assume it will be tricky to get funding for one without that evidence.
 
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jnmaciuch said:
That’s a great point—the one path forward I could see was if muscle and brain tissue are more dependent on some external factor to fully switch over to constitutive interferon signaling after resolution of infection.
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But do we have evidence of muscle being more affected by shifts in interferons than any other tissues? We don't yet have any evidence much for any of them as far as I can see. And I am not sure how this would address my concern. The waxing and waning is the tricky bit. People improve and then relapse - all over it seems. That takes me back to the 2016 Fatigue article and immune and nervous system being the only ones complicated enough to explain this sort of fluctuation.

I think it might be brain. Like migraine perhaps.
 
V.R.T. said:
But my question was whether there had been a trial of ifn alpha-2a in ME/CFS patients in the past, and that was why it was in the list of discontinued treatments as rituximab is. Because if there had been, how the participants responded could be relevant to our theorising in this thread.
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Sure, I was just commenting on the list. If interferon alpha has been used we ought to know what happened. I just wonder if someone has got muddled about Pariente's alpha interferon study designed to shed light on ME/CFS, which was not a study of treating ME/CFS.
 
Going back to the discussion of switching railway points we had with Robert Phair I am just wondering if, in the Hornby train set analogy, interferons are mediating the loop round the bedroom floor but that what we really need to pin down is at the switch point by the window that keeps flipping the train back on the interferon line. Maybe that is something like a neuropeptide - CGRP, CCK or whatever? Just a passing thought. (And maybe the points are synapses.)
 
Jonathan Edwards said:
Sure, I was just commenting on the list. If interferon alpha has been used we ought to know what happened. I just wonder if someone has got muddled about Pariente's alpha interferon study designed to shed light on ME/CFS, which was not a study of treating ME/CFS.
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Haven't had a chance to dig properly through this but this MEpedia page refers to Dr Chia trialling interferon (not sure which kind), and Google turned this 1996 trial of alpha interferon on CDC-criteria PwCFS up. There may be more, sorry for the rubbish searching, not sure if even these are any good...
 
Jonathan Edwards said:
I find it very hard to believe that a signal loop would persist in the grossly artefactual environment of tissue culture though. We have not seen any follow up on those observations for several years (?10) now I think.
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Unfortunately I am unable to share relevant details that might address this concern. The lack of follow-up, however, would be because no one else besides the Newton group (as far as I know) was both interested in muscle cells and had the ability to culture myoblasts to replicate (the Newton group lost funding). And no one has done studies of muscle cells that would have specifically detected an interferon signature.

Jonathan Edwards said:
But do we have evidence of muscle being more affected by shifts in interferons than any other tissues? We don't yet have any evidence much for any of them as far as I can see.
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Could you explain what you meant specifically by “affected by shifts in interferon”? What I’m hypothesizing is not sensitivity but rather the specific machinery involved in regulating constitutive signaling and returning to an appropriate baseline after elevated systemic interferon levels. If all that machinery is working correctly in healthy individuals or any other context, you wouldn’t expect to see a difference in those tissues. Unfortunately it’s an understudied mechanism overall so I just don’t have the ability to speculate about specific candidates beyond what I’ve already put forward.
 
V.R.T. said:
If the muscle finding is negative but we still think ifn signalling in the brain is a good bet, is there any way to check the brain that doesn't involve a theraputic experiment? Assume it will be tricky to get funding for one without that evidence.
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That’s something I’d have to ask others with more expertise. Cerebrospinal fluid may or may not show anything—I know other studies have looked at CSF but didnt do the types of screens that would detect anything relevant here.
 
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Jonathan Edwards said:
Going back to the discussion of switching railway points we had with Robert Phair I am just wondering if, in the Hornby train set analogy, interferons are mediating the loop round the bedroom floor but that what we really need to pin down is at the switch point by the window that keeps flipping the train back on the interferon line. Maybe that is something like a neuropeptide - CGRP, CCK or whatever? Just a passing thought. (And maybe the points are synapses.)
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But the beauty of interferon is that it doesn’t follow the same dynamics as any other immune feedback loop that requires continuous stimulation. It has a robust constitutively active state already, just with additional suppressive mechanisms meant to keep it under control.

And some of those repressing mechanisms are not constantly active themselves, but a one-time thing that got put in place after resolution of infection (per the epigenetic regulation of interferon beta study I shared earlier in the thread). Perfect opportunity for something to get thrown out of place after infection and stay broken, but perhaps get spontaneously resolved if another infection gives another chance for the right cascade of epigenetic regulation to fall into place.
 
Sasha said:
Haven't had a chance to dig properly through this but this MEpedia page refers to Dr Chia trialling interferon (not sure which kind), and Google turned this 1996 trial of alpha interferon on CDC-criteria PwCFS up. There may be more, sorry for the rubbish searching, not sure if even these are any good...
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This reminds me that over at Phoenix Rising a couple years back a group of them got Peginterferon Lamda manufactured and tried it on themselves.

Iirc there were very mixed results.

Possibly not relevant as a different kind of interferon to alpha/beta/gamma but thought it was worth mentioning.
 
Potentially relevant to this discussion:

A paper discussing constitutive production of interferon-stimulated genes in multiple cell lines and cultured organoids from primary cells without detectable interferon, suggesting that the signal is primarily maintained by downstream mediators of the interferon response and that this can persist long term.

jnmaciuch

Thread 'Unphosphorylated ISGF3 drives constitutive expression of interferon-stimulated genes to protect against viral infections, Wang et al. (2017)'

Unphosphorylated ISGF3 drives constitutive expression of interferon-stimulated genes to protect against viral infections​

Wenshi Wang, Yuebang Yin, Lei Xu, Junhong Su, Fen Huang, Yijin Wang, Patrick P. C. Boor, Kan Chen, Wenhui Wang, Wanlu Cao, Xinying Zhou, Pengyu Liu, Luc J. W. van der Laan, Jaap Kwekkeboom, Maikel P. Peppelenbosch, and Qiuwei Pan

An interferon-independent antiviral defense​

Virally infected cells produce type I interferons (IFNs), which stimulate the phosphorylation and activation of the STAT1 and STAT2 transcription factors. When combined with the...
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V.R.T. said:
This reminds me that over at Phoenix Rising a couple years back a group of them got Peginterferon Lamda manufactured and tried it on themselves.

Iirc there were very mixed results.

Possibly not relevant as a different kind of interferon to alpha/beta/gamma but thought it was worth mentioning.
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That's interesting--interferon lambda receptors are pretty much only expressed on epithelial cells. Anyone's guess what effect that would have in ME/CFS. If anything, it might be expected to lead to more mucus production in the respiratory tract.
 
jnmaciuch said:
Unfortunately I am unable to share relevant details that might address this concern. The lack of follow-up, however, would be because no one else besides the Newton group (as far as I know) was both interested in muscle cells and had the ability to culture myoblasts to replicate (the Newton group lost funding). And no one has done studies of muscle cells that would have specifically detected an interferon signature.


Could you explain what you meant specifically by “affected by shifts in interferon”? What I’m hypothesizing is not sensitivity but rather the specific machinery involved in regulating constitutive signaling and returning to an appropriate baseline after elevated systemic interferon levels. If all that machinery is working correctly in healthy individuals or any other context, you wouldn’t expect to see a difference in those tissues. Unfortunately it’s an understudied mechanism overall so I just don’t have the ability to speculate about specific candidates beyond what I’ve already put forward.
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Deficient oxygen supply can impact production and response to interferon.
BNIP3 (hypoxia-induced) and NIX should be regulated by FBXL4 to restrain mitophagy. DecodeME said not enough FBXL4

@SNT Gatchaman recently posted about it, in FBXL4. Sorry I'm no good at copy, paste.

When I go upstairs in a normal tempo I pant heavily, heart pounding and head throbbing, not enough oxygen?
When I go s t e p by s t e p, real Turtle slow, I'm fine on top, just enough oxygen?
 
I have a bunch of questions, apologies if they don't contribute.

Can genetic interferonopathies tell us anything useful? Maybe one exists that resembles ME/CFS. From what I understood, it's a broad category and often associated with tissue damage or other obvious problems, but perhaps there is one that is a bit like ME/CFS.

I understand that the illness starts with an immune response... but from the DecodeME results, genetic vulnerabilities in the brain seem similarly important. In the chronic phase where the illness is firmly established, maybe more so. I'm getting the impression that people are exploring the idea of some self-sustaining dysfunction involving interferon. Why is that?

Does increased interferon count as inflammation or not?
 
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jnmaciuch said:
But the beauty of interferon is that it doesn’t follow the same dynamics as any other immune feedback loop that requires continuous stimulation. It has a robust constitutively active state already, just with additional suppressive mechanisms meant to keep it under control.
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I don't get that. Lots of processes within the immune system have a constitutively active steady state, with suppressive mechanisms. I am still not seeing a clear picture of how you think an abnormal loop works and persists, with fluctuations.
 
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