Interferons as mediators in ME/CFS

Why does exertion, mental or physical, provoke a delayed symptom aggravation?

If exercise leads to an interferon response that leads to PEM, why do all the other things that cause an interferon response not cause PEM? Presumably exercise doesn't even lead to a particularly pronounced interferon response in comparison to say, infections. It seems that some PWME even feel better during some infections. There has to be something much more specific going on, related to exertion.
 
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Utsikt said:
This popped up in social media today. Don’t know if it’s relevant? I don’t have access.

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It might actually have an interesting application, though for the opposite reasons than what it is used for here. It seems that the main justification of injecting mRNA of just interferon-stimulated 10 genes is because the actual interferon response induces a suite of anti-viral genes and a suite of genes that serve to downregulate the interferon response. The latter is basically an in-built self regulatory mechanism to try to tamp things down lest the interferon response gets out of control and causes tissue damage. So what they're doing is directly inducing 10 interferon-stimulated genes with strong anti-viral properties, but not any of the counteracting genes, leading to a more robust response.

(I can't access the paper either, but I'd be curious to read about any detected side effects. It's possible they could have bypassed the negative effects of too much interferon as well, since that mostly seems to be caused by interferon calling in other immune cells that cause the tissue damage.)

It would be interesting if the opposite strategy could work in ME/CFS--an mRNA injection of ISG15, USP18, and other negative regulators of the interferon response. Ideally, if ME/CFS was caused by a failure to re-instate certain "brakes" on constant basal interferon production, and the specific missing "brakes" could be identified, it might be a viable strategy to just deliver those via mRNA rather than go the route of lifelong JAK inhibitor treatment leaving someone immunocompromised.
 
Hoopoe said:
Why does exertion, mental or physical, provoke a delayed symptom aggravation?

If exercise leads to an interferon response that leads to PEM, why do all the other things that cause an interferon response not cause PEM? Presumably exercise doesn't even lead to a particularly pronounced interferon response in comparison to say, infections. It seems that some PWME even feel better during some infections. There has to be something much more specific going on, related to exertion.

It seems to make more sense to evoke some sort of problem in the brain, where interferon could be playing a part, but not the main role.
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I'm not sure I understand the question--do you mean why all the other things that cause an interferon response don't cause PEM in healthy people? Or why viruses don't trigger PEM in pwME?

For the latter, viruses do trigger immune responses with symptoms overlapping, but not identical to, PEM. A large part of the difference would be driven by the suite of pathogen-specific immune responses mediated by TLR signaling and adaptive pathogen recognition which would cause new symptoms not seen in PEM (or in response to exercise in healthy people). Many of those immune responses actually counteract interferon to an extent (prostaglandins and IL-1B come to mind), and as I've said elsewhere, many viruses have the ability to counteract the host interferon response during early infection. There would also be differences in location specificity of where the primary interferon response is triggered.

Plus I think it wouldn't be a one-to-one comparison to interferon response in healthy people. Interferon is a self-sensitizer--if there was a baseline difference in interferon levels, that would directly translate to a different magnitude of response to an exercise trigger.

I don't discount the potential role of the brain--I think it's absolutely possible for this phenomenon to occur in multiple tissues, with brain-specific interferon signaling driving a large portion of ME/CFS symptoms. But I do think there is reason to look in the muscle as well, since it presents an easy explanation for PEM triggered by muscle use, it would fit with existing muscle findings (inconsistent though they are), and it's certainly way more accessible than brain tissue.
 
jnmaciuch said:
I'm not sure I understand the question--do you mean why all the other things that cause an interferon response not cause PEM in healthy people? Or why viruses don't trigger PEM in pwME?
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If exercise leads to an interferon response and an interferon response resembles PEM, why do healthy people not report PEM from exercise?
 
Hoopoe said:
If exercise leads to an interferon response and an interferon response resembles PEM, why do healthy people not report PEM from exercise?
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Does this help?:
jnmaciuch said:
Plus I think it wouldn't be a one-to-one comparison to interferon response in healthy people. Interferon is a self-sensitizer--if there was a baseline difference in interferon levels, that would directly translate to a different magnitude of response to an exercise trigger.
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To add on--let's suppose that the issue in ME/CFS is insufficiently regulated basal interferon signaling in the muscle and brain. That would mean an outsized response to triggers specifically in the muscle and brain (and potentially a sliiightly increased sensitivity in other tissues if there is any low-level leakage into the blood stream), since pre-existing interferon exposure both:
1) increases the concentration and sensitivity of cytosolic DNA sensors that trigger an interferon response to mtDNA in exercise and
2) serves to amplify the positive feedback loop used by interferon.

It would be the difference between setting off a single fire alarm (healthy) vs. a fire alarm that is already linked up with every other fire alarm in the building (ME/CFS).
 
jnmaciuch said:
Does this help?:

To add on--let's suppose that the issue in ME/CFS is insufficiently regulated basal interferon signaling in the muscle and brain. That would mean an outsized response to triggers specifically in the muscle and brain (and potentially a sliiightly increased sensitivity in other tissues if there is any low-level leakage into the blood stream), since pre-existing interferon exposure both:
1) increases the concentration and sensitivity of cytosolic DNA sensors that trigger an interferon response to mtDNA in exercise and
2) serves to amplify the positive feedback loop used by interferon.

It would be the difference between setting off a single fire alarm (healthy) vs. a fire alarm that is already linked up with every other fire alarm in the building (ME/CFS).
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Could it instead be that it’s the neruons that are sensitised to interferon so they react more than they would normally do interferon within «healthy» ranges? Or that the T cells react that way?

Do we even need abnormal interferon if that’s the case? Maybe abnormal interferon is just something that makes it even worse, but it’s not stricrly required to achieve ME/CFS.
 
I came across this paper earlier in the week when looking for the anaphylaxis paper from Northwestern and it stuck in my head because of the mention of Lupus, but it has Interferons too, and a thread here already

SNT Gatchaman

Thread 'Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus, 2024, Law et al.'

Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus
Law, Calvin; Wacleche, Vanessa Sue; Cao, Ye; Pillai, Arundhati; Sowerby, John; Hancock, Brandon; Horisberger, Alice; Bracero, Sabrina; Skidanova, Viktoriya; Li, Zhihan; Adejoorin, Ifeoluwakiisi; Dillon, Eilish; Benque, Isaac J.; Nunez, Diana Pena; Simmons, Daimon P.; Keegan, Joshua; Chen, Lin; Baker, Tina; Brohawn, Phillip Z.; Al-Mossawi, Hussein; Hao, Ling-Yang; Jones, Brian; Rao, Navin; Qu, Yujie; Alves, Stephen E.; Jonsson, A. Helena; Shaw, Katharina S.; Vleugels, Ruth Ann; Massarotti, Elena; Costenbader...
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Thanks for the other links @jnmaciuch I have new tabs and bookmarks and lots of reading/listening!
 
jnmaciuch said:
Also may or may not be relevant, but I happened across this paper on neurological features in mouse models of lupus that mentioned several synaptic adhesion genes (NLGN1 and 2 specifically mentioned, which came up in the Zhang et al. paper) being interferon stimulated genes in neurons.

Spatial enrichment of the type 1 interferon signature in the brain of a neuropsychiatric lupus murine model - PMC

Among systemic lupus erythematosus (SLE) patients, neuropsychiatric symptoms are highly prevalent, being observed in up to 80% of adult and 95% of pediatric patients. Type 1 interferons, particularly interferon alpha (IFNα), have been implicated in ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov

Honestly not sure how it relates but something interesting to note nonetheless.
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Interesting, in that study neuroligins and neurexins appear to be down in various CNS cells which express batteries of inteferon stimulated genes. That would suggest an inhibition of stable connections between synapses. That would match the direction of the loss of function NLGN I believe seen in Zhang et al, maybe also fits with lower ARFGEF2 from decode. I haven't worked out whether the decode CA10 hit - which supposedly directly modulates neuroligin and neurexin interaction at synapses - would increase or decrease this connection.

cited paper: We observe an almost uniform decrease in components of the type 1 interferon-regulated Neuroligin (Nlgn) – Neurexin (Nrxn) synapse adhesion module across hindbrain astrocytes, hippocampal oligodendrocytes, and most major neuronal clusters, except for the Excitatory Neuron 1 cluster in the hindbrain, and the DG cluster in the hippocampus
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Utsikt said:
Could it instead be that it’s the neruons that are sensitised to interferon so they react more than they would normally do interferon within «healthy» ranges? Or that the T cells react that way?

Do we even need abnormal interferon if that’s the case? Maybe abnormal interferon is just something that makes it even worse, but it’s not stricrly required to achieve ME/CFS.
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I think a lot of things could theoretically be possible--but my goal here isn't so much to think of all the possible things that could be going wrong. It's more to find a specific mechanism that both explains the symptoms of ME/CFS (at least partially) and explains how it could possibly break in a way that maintains a long-term disease state. That's most likely to lead to a worthwhile testable hypothesis.

That's also why I'm interested in looking at the muscle first--it's easiest and fastest to find out if I'm wrong and need to go back to the drawing board.
 
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