Itaconate modulates immune responses via inhibition of peroxiredoxin 5, 2025, Tomas Paulenda et al

V.R.T. said:
By knock down data do you mean like the knock your socks of eureka moment data? Or something else.

Also are you saying that the particular pathway step in your theory involving b cells is likely wrong or the entire thing?
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I meant knock down in the sense of a knock down argument to which there is no rebuttal. Not a knock-down or out mouse! Hopefully knocking your socks off too.

It is the step involving B cells (i.e. antibody) that I think may well be wrong; the rest of it looks to me a fairly good bet - but that draws in lots of ideas we have all been playing with for a while. In a way the hypothesis is an attempt to see if all the pieces can be drawn together with one extra step. That may turn out to be the lime slice in the Corona that you never actually ingest. The solution may turn out to be possible without it but the extra step adds a bit of extra zing to the theorising.
 
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I've searched on PubMed, Scopus, EBSCO and haven't found a relevant publication. In the recent Clarke review of biomarker studies there are these references:
However, the itaconate shunt hypothesis, developed by Phair, Armstrong, and Davis, proposes the itaconate pathway does not turn of in individuals with ME/CFS [74–77]. It is proposed that in ME/CFS patients the itaconate pathway is not turned on in every cell, but perhaps macrophages, monocytes, and muscle cells. Furthermore, the more cells which are activated, the more severe the ME/CFS symptoms [74–77]
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74. Open Medicine Foundation. Rob Phair, PhD, Presents on the Itaconate Shunt Hypothesis for ME/CFS. 2022. p. https://www.youtube.com/watch?v=RiVDNhg4l48.
75. Open Medicine Foundation. NEW Update from Ron Davis: The Itaconate Pathway! In: Open Medicine Foundation, editor. YouTube; 2022. p.15.
76. Open Medicine Foundation. Is ME/CFS Curable? Ronald W. Davis’ Lecture at the 2023 Fatigatio Symposium. 2023. p. 11:29.
77. Open Medicine Foundation. Itaconate Shunt Hypothesis Part 2: Interview with Robert Phair and Janet Dafoe. 2023.
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Jonathan Edwards said:
I meant knock down in the sense of a knock down argument to which there is no rebuttal. Not a knock-down or out mouse! Hopefully knocking your socks off too.

It is the step involving B cells (i.e. antibody) that I think may well be wrong; the rest of it looks to me a fairly good bet - but that draws in lots of ideas we have all been playing with for a while. In a way the hypothesis is an attempt to see if all the pieces can be drawn together with one extra step. That may turn out to be the lime slice in the Corona that you never actually ingest. The solution may turn out to be possible without it but the extra step adds a bit of extra zing to the theorising.
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Very clear thank you. Just one more question - when you say solution here, do you mean the sort of biological-mechanical solution to the 'problem' of ME/CFS, i.e. what the pathway/processes that cause it are, or the solution as in an effective treatment?
 
V.R.T. said:
Very clear thank you. Just one more question - when you say solution here, do you mean the sort of biological-mechanical solution to the 'problem' of ME/CFS, i.e. what the pathway/processes that cause it are, or the solution as in an effective treatment?
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Primarily the first but it is very likely that a first approximation to the first would be enough to inform the second.
 
V.R.T. said:
Very clear thank you. Just one more question - when you say solution here, do you mean the sort of biological-mechanical solution to the 'problem' of ME/CFS, i.e. what the pathway/processes that cause it are, or the solution as in an effective treatment?
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My bad for misleading you @V.R.T.!
 
Braganca said:
I sent him an email w link to this thread.. maybe he’ll come back.
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I did the same a couple of days ago—here is his reply.


JB,
I did not know about this, and I plan to join the Zoom of Max's talk. Because of Tomas' interactions on S4ME, Tomas and Max emailed Ron and me. The result is we are all getting together in another Zoom on Friday. Shows the power of S4ME. :)

Thank you!
Rob
 
Jonathan Edwards said:
Does anyone know if Robert Phair has published his idea on an alpha interferon positive feedback cycle? I have seen the videos but did not hit a published paper on this yet.
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Did you watch the 2023 video from the NIH webcast (post about it)? Testing results showed no difference in Interferon-alpha (at 1 hr 10 mins) but they could have more recent data.

There was another video where Ron Davis talked about the Utah lab work on Zebra-fish and E-coli/yeast modified with the human ACOD1/IRG1 gene that could be activated remotely but that video seems to be no longer available on YouTube (well I couldn't find it). The UTAH researchers used the E-Coli model to screen for drugs.

In the NIH video he gives some data on the drug screening (1 hour 15 mins).
 
I don't know if this thread is the right place or not but @paulendat mentioned that ACOD1/IRG1/Itaconate is highly expressed in microglial cells. Drs Van Elzakker and Younger have both talked numerous times that they believe microglia can become primed by past hits and that this may be the case in ME/CFS. Imaging studies in ME/CFS do highlight microglia but from what I understand the tracer agents also affect other cell types so they can't be sure yet.

I've asked the search engines and some AI tools what biomedical action causes the microglia priming to "stick" but all the answers so far are vague and wishy-washy. Is there a possibility that the IRG1/Itaconate pathway can somehow be involved with the priming? Or that transcriptomic changes to genes by past "hits" are enabling this pathway?
 
wigglethemouse said:
I don't know if this thread is the right place or not but @paulendat mentioned that ACOD1/IRG1/Itaconate is highly expressed in microglial cells.
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I was wondering about this. Rob Phair suggests that microglia affected by the taconite shunt might lea to ammonia build up causing brain fog. He also talks about positive feedback in relation to interferon alpha.

My guess about brain fog is that it is likely to be a brainstem effect. Somewhere around the reticular activating system or nucleus caeruleus in the medulla, maybe triggered by hypothalamus. The hypothalamus is open to cytokine signals. Microglia in forebrain are pretty walled off from immune signals normally. My understanding of the data on microglial activation from Nakatomi was of a wider increase in uptake than just hindbrain and moreover, I am not sure that stood up to replication. My thought was that at present we didn't really have evidence for activation anywhere.

Clearly signals are getting to the brain to produce PEM and brain fog. But my guess is that these trigger nerves in hypothalamus which send neurotransmitter signals in medulla on then signals on to thinking areas in the cortex and thalamus. I think it likely that neurotransmitter based signals rather than metabolic shifts are relevant up there. That doesn't stop macrophage shifts being crucial elsewhere but I find it hard to see the adaptive value of flooding your cortex with ammonia even when you have flu.

One reason for thinking this way is that flu-like symptoms can often be significantly relieved instantly by simple counter-stimuli. Overwhelming nausea can be relieved immediately by vomiting. A sense of oppressive heat can be relieved by a cold cloth on the forehead. I think these symptoms are ultimately neural and can be switched off in seconds, if only partially and temporarily, with other neural inputs. The same sort of thing applies to sleepiness and wakefulness (nucleus caeruleus and RAS).
 
The other thought was about positive feedback cycles and 'sticking'.

We spent several months working through feedback routes in RA and came to the conclusion that what is likely to produce an acquired, chronic but unpredictably fluctuating illness is a regulatory system that has 'railway points' between positive and negative feedback loops. Positive feedback that is exhausted by removal of danger signal is everywhere. It is used to amplify but also to localise - to concentrate in one place. But to get the disease dynamics we see we thought you needed a pathway that forked either to positive return or to negative return. Complement and antibody systems do this brilliantly. T cells could do. I still find it hard to think of a way that innate cells will do this, but that may just be that I haven't thought hard enough.
 
I am not well enough to be able to read/study the thread & dont have a science background anyway, but am skimming, & its so heartening to watch you clever people!

But can someone tell me if this summary of the ideas so far by Hutan is accurate please as not seen it confirmed

Hutan said:
So, the cycle is (I think?)

  • Pathogen or damage associated molecular patterns (PAMPs and DAMPs) increase IRG1 expression
  • That increases itaconate levels in the immune cell
  • That reduces levels of PRDX5 (which would normally be mopping up ROS including H2O2)
  • So, there is more H2O2
  • That results in more interferon being released by the cell
  • Interferons can increase itaconate in other immune cells
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Jonathan Edwards said:
The other thought was about positive feedback cycles and 'sticking'.

We spent several months working through feedback routes in RA and came to the conclusion that what is likely to produce an acquired, chronic but unpredictably fluctuating illness is a regulatory system that has 'railway points' between positive and negative feedback loops. Positive feedback that is exhausted by removal of danger signal is everywhere. It is used to amplify but also to localise - to concentrate in one place. But to get the disease dynamics we see we thought you needed a pathway that forked either to positive return or to negative return. Complement and antibody systems do this brilliantly. T cells could do. I still find it hard to think of a way that innate cells will do this, but that may just be that I haven't thought hard enough.
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My intuition keeps pushing me to the idea that metabolic regulation in innate immune cells is precisely that "railway switch". It seems that several TCA cycle metabolites (malate, succinate, citrate, etc.) have dual properties as intermediaries in many of the relevant signaling pathways. It's already been shown that effector function in T cells and activation in macrophages is accompanied by a switch towards increased glycolysis--my question is whether this switch is upstream or downstream of the signaling pathways themselves. And if so, could dysfunction at the metabolic "switch point" maintain the positive feedback loop?
 
JemPD said:
I am not well enough to be able to read/study the thread & dont have a science background anyway, but am skimming, & its so heartening to watch you clever people!

But can someone tell me if this summary of the ideas so far by Hutan is accurate please as not seen it confirmed
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Hutan made a correction after paulendat's comment and it looks like everything else is correct to me
 
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