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

Hi, Tom. This is a somewhat 'philosophical' post but one that tries to get at how we structure our disease models at a high (overview) level. My background is in rheumatoid arthritis where our identification of switches from negative to positive feedback loops helped me identify the B cell depleting agent rituximab as a useful therapy.

ME/CFS is another acquired disease that seems to switch on and often persist, although, like RA, sometimes it switches off. I think there must be a similar point where a negative feedback loop gets diverted to a positive loop which gets stuck. Robert Phair suggested this might occur at the itaconate level in an 'itaconite trap'. I find that intuitively implausible but I am not exactly sure why.

I think my argument would be that we need a plausible acquired cellular regulatory change that persists. For 'acquired' mitochondrial myopathies I understand that to be cells with abnormal mDNA competing out other cells. For RA the shift seems to be the generation of new recombinations of Ig genes that encode 'subversive' antibodies. For cancer it is a malignant clone. For BSE it is prion polymerisation. For psychosis it may be synaptic rearrangement that leads to cycles of abnormal cognition.

Basically, I see three ways that an acquired cellular change can persist and cause system-wide disease. One is a change in DNA - cancer, and also RA. Another is a change in nerve connections - psychosis maybe. The third is something I think people miss out on and I would call supramolecular pattern propagation. This would include amyloid and BSE. It might be the basis of Alzheimer's. The error is perpetuated by a pattern of repeating molecules that self-propagates, a bit like the 'flyers' in Conway's Life Game. It is conceivable that this can occur in musculoskeletal tissues with things like TGF beta binding - what I call the 'Writing on the Wall' model.

And my problem with an itaconite trap is that I don't see how, in practice, you get propagation of a switch from a negative loop to a positive one within the metabolic machinery of a cell. Where have the railway points been switched over? For sure, if the cell has been infected with a retrovirus the DNA can do the switch, but where would there be switches within the metabolic pathways that could persists and also propagate from cell to cell. So I look for ways signalling between cells could be switched. And I guess that although I understood the interest of thinks like ITIMs and STAT kinases I always focused on the outside signals.

But, as has already come up in the discussion, there is of course powerful information in knowing the intracellular signals both because they might be blocked by drugs and because their time courses and cross-interactions may be crucial to the clinical expression of the story. I like the idea that we might be able to pin down the delay of PEM by working out the time course of mediating steps. PEM may be too variable to make that easy but there is no doubt that we are dealing with a signalling mechanism that can take many hours.

There is also the interesting question, raised by Hutan here, as to whether metabolic shifts cause symptoms such as difficulty using muscles, directly, or through invoking neural or other indirect signals.

What I am increasingly confident of is that somewhere in all this interaction between immune and nerve signals and internal cell metabolic shifts lies the answer to ME/CFS. I personally doubt that anyone 'runs out of ATP'. I think more likely some cells tell other cells to go on strike and refuse to use their ATP. But the evidence remains very hard to interpret. Hopefully we will have some genetic clues soon, so now is the time to really focus in on this problem.

 

If you'd like, I can organize a mass zoom meeting, where I will explain our findings in more detail so that everyone can understand. Would you be interested? We can start a thread to fing out if people like the idea.

 

I'd enjoy eavesdropping on it, but the timings might be tricky—we have members in the UK and Europe, NZ and Australia, and various parts of north America.

 

A live call with many participants unfortunately is also outside the reach of many members due to brainfog and/or their PEM «threshold». But it’s a generous offer!

 

A lot might be interested, though, and able to watch or even just listen passively - and some might also be able to actively engage. And not all here have ME - some are carers or interested scientists, who wouldn't have those limitations. I agree this is a very generous offer.

 

I’ve been having the same line of thought—what is interesting to me is that succinate dehydrogenase (one of the TCA enzymes affected by itaconate in immune cells) is known to be modulated by other regulatory mechanisms, some of which are more well-elucidated than others.

This paper follows previous experiments showing that itaconate’s actions on succinate dehydrogenase do not completely explain its phenotypic effect on macrophages.

However, something similar in other cells would create the malate-aspartate shuttle impairment that I’ve been hypothesizing.

So the question is: if the TCA cycle is involved in ME/CFS pathology at all, is it only mediated by itaconate in immune cells which has a knock on effect through immune signaling, or is there a global impairment driving the more constant symptoms of ME which results in a similar (or perhaps worsened, if itaconate compounds the effect) phenotype in macrophages during activity.

In the latter, macrophage signaling would only explain PEM.

[edit: for my part, I am thinking it might be the latter, as part of my evidence for malate-aspartate shuttle impairment comes from reduced levels of NADPH-dependent metabolites, which would be synthesized in the liver, adrenals, and gonads]

 

I understand, you make a good point here. But, what can be done is to record the meeting and people can come back to it and listen to it in bite sized portions on their own pace if interested.
I don't have any proffesional recording equipment, so I wouldn't be able to do production to be published on youtube. But putting it here on the forum for people to listen to would be fine. And I can imagine, there will be lot of common questions. coming from pepople. So, even those not able to join, may get their questions answered.

 

For what it’s worth, some of my literature search turned up that the itaconate response can be triggered by interferon gamma as well. Meaning that if there was a higher than normal level of interferon gamma, it might have the same effect as pre-treating with itaconic acid in these experiments, resulting in an exaggerated response to stimulus (this is where I’m thinking activity itself might be a stimulus).

Interferon gamma production in T cells seems to be dependent on TCA cycle metabolites (citrate/COA) and at least one epigenetic marker (H3K9ac). I have yet to work out the details, but since modulating succinate dehydrogenase has already been shown to affect interferon production, I am trying to see if an induced global TCA cycle abnormality (or perhaps an failure to turn “off” an epigenetic switch) would result in abnormal interferon gamma production, leading to itaconate upregulation in macrophages and macrophage signaling in response to activity leading to PEM

 

If you zoom in, there are error bars very tight to the LPS dots.

 

For scheduling a Zoom, if you are in St. Louis, probably some time between 9am and 2pm your time would work for most of the people on here (US, UK, West Europe) most of the people on this forum are not working—so don’t worry about avoiding scheduling during normal “working hours”.

 

It'd probably be the middle of the night for our members in Australia and New Zealand, though. They must be something like 15 hours ahead of Central time.

 

Timeanddate.com has a meeting planner for different timezones.
https://www.timeanddate.com/worldclock/meeting.html

 

Sorry, I'd missed @paulendat's idea about recording it.

It wouldn't be quite the same for members in the wrong time zone (or just in the wrong sleep cycle!) as they wouldn't be able to ask questions live, but still really interesting.

 

Excellent idea! And thanks so much again to @paulendat for this offer.

 

Thank you! Let me know if there is more I can explain.

 

I like this idea. Since ME/CFS is mostly self reported (correct me if I'm wrong, please) this would be a key step in understanding and categorizing people in a study. We can talk about this in a more detail.

 

That's correct, ME/CFS is diagnosed on the basis of patients reporting symptoms - there is no diagnostic test.

 

@paulendat @Sasha

we have those CCC, ICC and other diagnostic criteria but no doctors use it. if you get ME/CFS diagnosis it´s mostly after exclusion of all other similar diagnosis.
You go from one doctor to another one, nobody knows what to do and then finally a doctor write that it´s probably ME/CFS and then the other doctors start to write it also. SO it´s something like this how it works here.
But I am sure you will find something smart how to do it. Just let me know if you want me to help to connect with patients communities.

 

or I dont know where @paulendat is doing his research but maybe you can use a ME/CFS biobank or to cooperate with a ME/CFS doctor.
How I already said in our country there is no ME/CFS doctor but just few dozens of kilometers from our border is Wien and there are several ME/CFS doctors. So maybe this is an option.