Two-stage metabolic remodelling in macrophages in response to lipopolysaccharide and interferon-γ stimulation, 2020, Seim et al.

[Murph]

I'm always interested to see theories where LPS can trigger PEM-like symptoms. I have poor digestion and often digestive disturbances can leave me exhausted and very brainfogged.

I've come to think of that as leaky gut pushing LPS into the blood.

Duration is usually not as bad as PEM from exericse. The two can stack though.

 

[Creekside]

Perhaps it’s not really important to narrow it down

It might not identify the mechanism, but a reliable response from the majority of PWME would be valuable, if for nothing more than verifying that ME is biological rather than psychological. It needn't be a cytokine; I just think it's likely that a cytokine would affect ME symptoms. That's just my experience with immune activation of various types worsening my ME symptoms.

 

[AliceLily]

We already know the effect of the interferon used for treating hepatitis, and it sounds very close to PEM (at least the experience of it, not the fact that it’s triggered by exertion afaik), but signaling molecules trigger other signaling molecules so you can’t really zero it down. Perhaps it’s not really important to narrow it down in the first place if it is likely a cumulative effect anyways

A close relative was having interferon treatment for Hep. C the same year of my very severe ME onset. His symptoms sounded like mine. I remember thinking that his symptoms would be turned off eventually, but mine were uncontrolled and no help in sight. I did post about this year's ago on PR.

 

[Hutan]

I am wondering if something about the stimulant allows that initial TNF-a and IL-6 response to go through whereas it normally would be blocked in ME. I’m also wondering if something about that early stage actually helps counteract that later response provided that I don’t keep stimulating it through activity, so that I don’t end up with general malaise delayed PEM anymore.

Do we need to posit an early TNF and IL-6 response?

What led you to wondering whether an initial TNF-a and IL-6 response is protective against PEM, jnmaciuch?

My son, also doing his PhD with ME/CFS, gets by on coffee. He has a mug that says 'But first, coffee'. On the days when I have very long zoom calls or meetings, I drink a lot of coffee. I think it helps me not get as much PEM as I would otherwise expect from the exertion. I see that coffee seems to increase adrenalin, and I've speculated before whether adrenalin during exertion might protect against PEM.

Studies have shown that caffeine supplementation, particularly in athletes, can lead to increased IL-6 and IL-10 levels in response to exercise. This increase is thought to be related to a decrease in IL-6 clearance by the liver due to adrenaline-induced changes.

Caffeine supplementation induced higher adrenaline levels in the supplemented participants after exercise (257.3 ± 53.2 vs. 134.0 ± 25.7 pg·mL− 1, p = 0.03) and higher cortisol levels after recovery (46.4 ± 8.5 vs. 32.3 ± 5.6 pg·mL− 1, p = 0.007), but it did not influence plasma cAMP levels (p = 0.327). The exercise test induced significant increases in IL-10, IL-6, IL-1ra, IL-4, IL-8, IL-12 and IFN-γ plasma levels, with IL-6 and IL-10 levels remaining high after recovery.

(studies have also shown the opposite effect of caffeine, but.. anyway)

Only problem is that to confirm it, I’d need to be able to run to someone’s home exactly when they’re experiencing it to do a blood draw.

Have you seen that @MelbME Chris Armstrong is doing good day bad day studies? I think participants might be providing blood spot samples on cards on bad days - my memory is hazy.

It might not identify the mechanism, but a reliable response from the majority of PWME would be valuable, if for nothing more than verifying that ME is biological rather than psychological.

BPS people don't deny that there can be a biological component to ME/CFS (an initial biological trigger, and/or a downstream effect of some faulty thinking or inactivity). An unusual biological response would not be a hindrance to their theories.

 

[jnmaciuch]

What led you to wondering whether an initial TNF-a and IL-6 response is protective against PEM, jnmaciuch?

It was mostly due to the fact that since starting a stimulant, I reliably experience an immediate, primarily muscle pain, stiffness, and feverishness “PEM” that lasts for ~24 hours, and I very rarely experience the typical delayed flu-like PEM. I know that the immediate PEM is at least partially mediated by prostaglandins since NSAIDs have an effect on the muscle pain and stiffness, but very little effect on delayed PEM.

I’ve also read that prostaglandin release inhibits interferon production. I’m definitely not sure it’s TNFa and IL-6, they just happen to fit with the timeline and a study into viral myalgia (unfortunately I can’t find the link now, it was posted by someone else on another thread) reported that injecting a mix of cytokines, including those two, triggered reports of myalgia.

That’s interesting corroboration from your son, thank you!

Have you seen that @MelbME Chris Armstrong is doing good day bad day studies? I think participants might be providing blood spot samples on cards on bad days - my memory is hazy.

I haven’t heard of that but thanks for letting me know! That sounds promising. I’ve reached out to Chris a little while ago but haven’t gotten a response, I assume he’s just very busy.

[Edited for grammar]

 

[sneyz]

There was a trial by the Fluge/Mella team in Bergen on TNFa inhibition along with Rituximab. It got terminated, and I haven't come across any published data. Might be worth the try reaching out to ask about their experience with it.
( @jnmaciuch )

 

[jnmaciuch]

There was a trial by the Fluge/Mella team in Bergen on TNFa inhibition along with Rituximab. It got terminated, and I haven't come across any published data. Might be worth the try reaching out to ask about their experience with it.
( @jnmaciuch )

Thanks!

 

[Utsikt]

There was a trial by the Fluge/Mella team in Bergen on TNFa inhibition along with Rituximab. It got terminated, and I haven't come across any published data. Might be worth the try reaching out to ask about their experience with it.
( @jnmaciuch )

The page says this at the top:

After inclusion of four patients, two experienced moderate worsening of symptoms.

 

[Trish]

Some off topic posts discussing experimentation with treatments related to cytokines have been moved to:
The ethics of experimentation with treatments based on unevidenced hypotheses - discussion thread

 

[AliceLily]

A close relative was having interferon treatment for Hep. C the same year of my very severe ME onset. His symptoms sounded like mine. I remember thinking that his symptoms would be turned off eventually, but mine were uncontrolled and no help in sight. I did post about this year's ago on PR.

I've just been talking to my relative who had been on interferon and asked if he could remember whether he had worsening of symptoms while working full time during his treatment. He said he didn't think he did. He said his symptoms had felt just the same, awful. I remember how hard it was for him to be working while on treatment and had wondered recently about whether he experienced PEM. So I had a chance today to ask.

So it sounds like maybe not regarding PEM the way we experience it. So not a definite yes

 

[Creekside]

I've just been talking to my relative who had been on interferon

It might depend on which interferon. ME symptoms not responding to IFN-a doesn't mean they don't respond to IFN-g.