Interferons as mediators in ME/CFS

[jnmaciuch]

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.

I think that’s a question that can really only be solved experimentally, starting with confirmation that either interferon levels or interferon stimulated genes are actually upregulated at baseline in ME/CFS in tissues we can test. Which is my job to find out—as much as I’d like to think the answer for an even more specific mechanism is already in the literature, it might not be.

What we do know from the literature is that it is possible for an ISG signature to persist long term in tissue, per the most recent paper I shared (as well as current projects). And I have a list of possible candidates for which specific players might not be behaving as expected.

So overall the theory based in constitutive interferon-stimulated gene production has more specifics and evidence of that phenomenon actually occurring than any conjecture of potential brain involvement—unless anyone has something substantially more concrete than neuropeptides and synapses. It’s clear you strongly believe that the immune system and brain are the only viable origin places for illness dynamics seen ME/CFS—I can understand how you got there but I personally don’t find the argument strong enough to rule out this other option pre-emptively.

 

[Simon M]

What did you think of the KCL paper on persistent fatigue and interferon alpha @Jonathan Edwards ?

https://www.sciencedirect.com/science/article/pii/S0306453018301963?via%3Dihub

Most of this thread is way over my head, but I thought I'd comment on this approach (not necessarily this paper from the team), which was much discussed at the time.

The study had been years in the making, and I found it a bit disappointing as a model. they used the shoulder fatigue scale to measure fatigue, and the persistent fatigue cases were way less fatigued than the CFS comparison group. I think it was scores of high 20s (ex 31) for CFS cases, and about 10 points lower for those with persistent fatigue. If you add in the relatively short time scale for persistence, didn't seem the most promising model.

And the sample size was quite small (not as many persistent fatigue cases as planned).

But the reason the model went nowhere, and the reason recruitment took so long, was that a curative treatment for hepatitis C have been developed, and interferon alpha therapy was being phased out. Great news for people with HCV, but a shame for us this couldn't be explored further.

But I remember not having a lot of confidence in the findings

 

[Fancymyblood]

I was a member of the old forum, but haven’t posted in over 10 years. Seen everything from the XMRV saga to auto-antibodies, to Ron Davis entering the field and the evidence for all those theories always had a lot of holes in them.

But the one hypothesis (that was mostly discredited by the old forum because the research was related to biological psychiatrists Carmine Parmante and Andrew Miller) that actually did make sense to me is related to Andrew Miller's research on interferon affecting the basal ganglia and dopamine (dys)function.

Cort Johnson has written two great summaries of it, but to me the hypothesis is convincing because:

a) it's the mechanism by which IFN-a therapy in hepatitis C patients cause a similar sickness state as ME/CFS
b) these same changes can be seen in ME/CFS patients
c) a very strong correlation (p<.0001) was found with reduced basal ganglia activity and fatigue
d) the basal ganglia/fatigue findings have been replicated in healthy controls, MS, Parkinson and several other diseases pointing to a common central origin
e) to me it's obvious the brain is involved.

I'm not sure how this is all tied together, but for me any hypothesis should be able to connect basal ganglia dysfunction to its other factors. The evidence for dysfunction is too robust to ignore IMHO

Unrewarding Reward: The Basal Ganglia, Inflammation and Fatigue In Chronic Fatigue Syndrome - Health Rising

Miller finds that basal ganglia problems in ME/CFS are associated with high rates of fatigue, motor slowing, reduced dopamine and inflammation

www.healthrising.org

Dopamine, the Basal Ganglia and Chronic Fatigue Syndrome #II - Treatments - Health Rising

Dopamine production in the brain appears to be reduced in some people with Chronic Fatigue Syndrome. Ways to increase it are explored.

www.healthrising.org

 

[Jonathan Edwards]

The study had been years in the making, and I found it a bit disappointing as a model. they used the shoulder fatigue scale to measure fatigue, and the persistent fatigue cases were way less fatigued than the CFS comparison group. I think it was scores of high 20s (ex 31) for CFS cases, and about 10 points lower for those with persistent fatigue. If you add in the relatively short time scale for persistence, didn't seem the most promising model.

Yes, I was for along time unimpressed by the therapeutic interferon alpha story. But, to be fair, if we assume that in ME/CFS it is being signalling locally and maybe in very specific sites, then the unimpressive scores for infusions are maybe not that worrying. In general these molecules are not designed to work as systemic blood borne signals. Hormones do that, but not cytokines so much.

Andrew Miller's research on interferon affecting the basal ganglia and dopamine

That might be the answer although the signalling might still be indirect and primarily at another brain site. I agree that this sort of model is a lot more plausible than some of the popular ones.

 

[wastwater]

I thought they would have included Rapamycin as a potential treatment.
I used to mention GJa6,so gap junctions are of interest and tonabersat

Tonabersat Prevents Inflammatory Damage in the Central Nervous System by Blocking Connexin43 Hemichannels - PMC

The cis benzopyran compound tonabersat (SB-220453) has previously been reported to inhibit connexin26 expression in the brain by attenuating the p38-mitogen-activated protein kinase pathway. We show here that tonabersat directly inhibits connexin43 ...

pmc.ncbi.nlm.nih.gov

 

[Braganca]

able to connect basal ganglia dysfunction to its other factors. The evidence for dysfunction is too robust to ignore IMHO

Unrewarding Reward: The Basal Ganglia, Inflammation and Fatigue In Chronic Fatigue Syndrome - Health Rising

Miller finds that basal ganglia problems in ME/CFS are associated with high rates of fatigue, motor slowing, reduced dopamine and inflammation

www.healthrising.org

Dopamine, the Basal Ganglia and Chronic Fatigue Syndrome #II - Treatments - Health Rising

Dopamine production in the brain appears to be reduced in some people with Chronic Fatigue Syndrome. Ways to increase it are explored.

www.healthrising.org

That might be the answer although the signalling might still be indirect and primarily at another brain site. I agree that this sort of model is a lot more plausible than some of the popular ones.

Dopamine transporter imaging (DaTscan) has never been looked at as a diagnostic to image brains of people with ME/CFS to look for dopamine dysfunction. Does anyone think that would be a useful study to do? It is a diagnostic used for Parkinson’s but also shows abnormal in Lewy Body Dementia and ADHD.