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

But I suppose there would be all sorts of confounders in a cross-sectional study so we'd need a prospective one.

Anyway, I think I may be derailing the thread. Maybe we should start another one if we want to discuss this particular sub-topic.
 
Sasha said:
Actually, wouldn't DecodeME have this data for 25k people?
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My thought is that if DecodeME comes up with genetic links it would be very useful to look at patients presenting under 15 to see if the link was enriched. If nothing else it would be a way to strengthen the significance of the data. At leat some genetic links should be enriched I early inset cases but they might be rare allele ones that need while genome screening.
 
Jonathan Edwards said:
Yes, but I think very early cases are most likely to give a clear signal.
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Ha! I woke up with the exact same line of thought based on my earlier comment:

jnmaciuch said:
Which would then prompt you to ask why someone with these mutations is not getting ME/CFS at their first viral infection in childhood. The answer would be that whatever mutation exists, its effect is modulated through a variety of other factors, such as sex hormone levels, the effects of chronic poor sleep quality, etc. etc. etc.
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It would make sense that more deleterious mutations in the same pathways would end up rare in the population if they severely affect children at earlier stages.

The recent rare variant WGS results might actually be quite helpful in that regard then—it’s why I was thinking proteasome in the first place in my throwaway “boot” theory. Glutathione levels also came up as predictive in Leonard Jason’s prospective EBV cohort.

At risk of flattering myself too much I’ll take that as a “great minds think alike” moment.
 
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Jonathan Edwards said:
I eventually became a professional immunologist having been a rheumatologist, macrophage and stromal cell biologist, histopathologist, embryologist and fluid physiologist along the way! That might make me a Jack of all trades but I think it taught me to have a group of people with lots of different knowledge bases - redox, antibody, macrophages, tissue mechanics, whatever. (Macrophage FcgammaRIIIa is induced by mechanical forces, which is why RA is an arthritis.) I suspect @jnmaciuch may be picking up the same vibes from a similarly diverse track.

I can see what Tom and Max may be saying, and it is related to my own concerns, but I don't think it is as simple as that. There is no independent innate immune response. Even newborn infants use antibody to forearm their macrophages and NK cells. As Donne said 'No cell is an island, unto itself'.

Coming from a histological and tissue structure training I tend to see everything situated in this context and I don't think we have thought enough about where we think the bad cell events really are in ME/CFS. I am writing something with Jo Cambridge and Jackie Cliff and both of them came back with the first comment - 'where is it?' I think it very plausible that metabolic shifts inside macrophages are crucial to the bad signalling that makes people feel ill but this bad signalling might be hidden away in places we have never looked. I don't think we even need muscle cells to be involved at all, although they may be.

Where I suspect I agree with Tom and Max is in that it is hard to see innate immune cells getting stuck on the wrong fork of a bistable pathway without some outside help. And especially if this problem is supposed to spread to cells all over. I think the evolutionary argument must be that a pathway that is bistable and can flip into a hypo metabolic state entirely without external help will not survive. Non-linear bistable pathways are everywhere in haematology and immunology but they all have switch points that have external control I think.

The counter to this argument would be the pyrin gene allele for familial Mediterranean fever perhaps. It may have advantages as a heterozygous allele but produces bouts of fever when homozygous. It might be that people with early onset ME/CFS have something analogous - a gene variant that allows a purely innate immune cell bistable pathway to stuck flipped. It is just that the dynamics of ME/CFS seem very odd for that. It is not a paroxysmal disorder, nor a purely progressive one. It seems that other forces must be having a variable permissive effect on a flip over very long periods. That looks to me like an 'adaptive' immune response, with the caveat that you can get learnt clonal expansion of T cells that work more on innate signals than antigen recondition.

So I like the basic idea of invoking a positive loop and I like the idea of interferons because they modulate ell behaviour without necessarily being directly pre-inflammatory. I am drawn intuitively to gamma interferon but I have an open mind.
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Hi Jonathan,

I completely agree, that we can't presume purely myeloid compartment playing a role. This simply doesn't exist in the body. Everything is interconnected. What is really needed now is systemic analysis of immune system. I think what I've seen so far that this analysis is warranted. We need to see how both innate and adaptive immune responses are changing in patients.

The most crucial are timing and location where we look. It is possible that in most severe cases the differences will be profound enough to manifest systemically and can be observed even from PBMCs.

We are currently looking into obtaining patient samples to analyze.

I still believe it is possible for itaconate to play a role. You may say I'm biased and it will be true. It is my favorite molecule. But regardless of itaconate, there are gaps that need to be answered before any conclusions can be drawn.
 
paulendat said:
I still believe it is possible for itaconate to play a role. You may say I'm biased and it will be true. It is my favorite molecule.
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Don't worry, @paulendat you can easily sell me some shares in itaconatePLC. But yes, we need to know where and when and we need the whole picture. I think now is the time to be looking at this. Things are funelling in to a plausible story. And if my past experience is anything to go by we may have already done the clincher experiment, if only we could see which one it was!
 
paulendat said:
Hi Jonathan,

I completely agree, that we can't presume purely myeloid compartment playing a role. This simply doesn't exist in the body. Everything is interconnected. What is really needed now is systemic analysis of immune system. I think what I've seen so far that this analysis is warranted. We need to see how both innate and adaptive immune responses are changing in patients.

The most crucial are timing and location where we look. It is possible that in most severe cases the differences will be profound enough to manifest systemically and can be observed even from PBMCs.

We are currently looking into obtaining patient samples to analyze.

I still believe it is possible for itaconate to play a role. You may say I'm biased and it will be true. It is my favorite molecule. But regardless of itaconate, there are gaps that need to be answered before any conclusions can be drawn.
Click to expand...
I love that there is a such a thing as a favourite molecule. To a layman like me it sounds kind of ridiculous but I guess it makes a lot of sense. Anyways, the idea of everyone having a favourite molecule makes me giggle :)

(if this message reads like insomniac gibberish, that’s because it is…)
 
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paulendat said:
I would suggest Caution with relation of itaconate and inhibition of type I interferon (IFNa and IFNb).
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A side story, but the severity of COVID-19 was largely linked to impairment of type I interferon responses during the initial period of the infection and one study found lower itaconate was associated with increased COVID-19 severity. https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30317-X

Unfortunately I haven't been able to read your primary study because it's paywalled...
 
paulendat said:
We are currently looking into obtaining patient samples to analyze.

I still believe it is possible for itaconate to play a role. You may say I'm biased and it will be true. It is my favorite molecule. But regardless of itaconate, there are gaps that need to be answered before any conclusions can be drawn.
Click to expand...


Thank you for your dedicated, hard work and participation in the discussion on s4me!!
A fool can ask more than 10 wise people can answer. I don't mind being that fool. Due to 34 years of ME/CFS out of 68, I have no reputation to protect.

I was never tested on itaconate, but I had a 24-hour urine test that might come close to a shunt/trap, at least that's what my non-scientific brainfogged brain tells me.

All measured from creatine in mmol/mol

pyruvic acid was 0.07, lactic was 14.11. Can I conclude that's the Krebs cycle down?

succinic was high 63 Is that SDG very low performance?

Fumaric 0.17
Malic was 0.03 Both not doing much?

All messured in 1997, only once.

Is this at all connected to itaconate? Or just me being a scientific fool?
 
I think I spent an hour snd a half tryong to understand the frist two pages and gave up when ghe thread balloon to loads of pages. But does sound rather interesting. And I did learn a little about cell metabolism, ROS, interferon, and itaconate.

Very mucj appreciate @Hutan 's summary thanks yo that I'm pretty sure I atleast understand the papers mechanism.
 
Yann04 said:
I think I spent an hour snd a half tryong to understand the frist two pages and gave up when ghe thread balloon to loads of pages. But does sound rather interesting. And I did learn a little about cell metabolism, ROS, interferon, and itaconate.

Very mucj appreciate @Hutan 's summary thanks yo that I'm pretty sure I atleast understand the papers mechanism.
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May I give my non-scientist takeaway?

a) interferons IFN make people feel lousy

b) pathogen --> IFN secretion by macrophages
... some pathogen stimulates macrophages (eg microglial cells in the hypothalamus?) to produce itaconate (by expressing IRG1/ACOD1 enzyme)
... this occurs mainly in activated macrophages (also in monocytes, neutrophils and to some extent dendritic cells)
... this itaconate inhibits a mitochondrial peroxide-detoxifying enzyme PRDX5 (peroxiredoxin5) allowing ROS to increase
... this ROS enables IFNb secretion (upregulates STING (Stimulator of Interferon Genes) pathway in cytosol)

c) this secreted IFN binds to bystander macrophage IFNa-receptors, generating more IFN (JAK/STAT1&2 pathways activate many interferon signalling genes “ISGs” including IRG1/ACOD1 producing itaconate)

d) this itaconate/IFN positive-feedback loop persists somehow in PWME
... normally, adaptive/innate immunity eventually destroys the pathogen, and the loop stops
... in PWME might there be a chronic supply of pathogen from reactivated HHV/EBV virus miRNAs, or leaky-gut, etc?

I like that all this could happen in a location with system-wide reach like the hypothalamus.
 
paulendat said:
Hi Jonathan,

I completely agree, that we can't presume purely myeloid compartment playing a role. This simply doesn't exist in the body. Everything is interconnected. What is really needed now is systemic analysis of immune system. I think what I've seen so far that this analysis is warranted. We need to see how both innate and adaptive immune responses are changing in patients.

The most crucial are timing and location where we look. It is possible that in most severe cases the differences will be profound enough to manifest systemically and can be observed even from PBMCs.

We are currently looking into obtaining patient samples to analyze.

I still believe it is possible for itaconate to play a role. You may say I'm biased and it will be true. It is my favorite molecule. But regardless of itaconate, there are gaps that need to be answered before any conclusions can be drawn.
Click to expand...

Tom and Jonathan,

Just a point of clarification: The innate immune response I'm invoking is the response of parenchymal cells to infection, not a response of the myeloid lineage. The itaconate shunt hypothesis is not about professional immune cells. Instead, it is an extension of the idea that every nucleated cell is an (innate) immune cell. I agree with Jonathan's earlier point that most blood immune cells are too short-lived to explain a chronic disease. If I see a disease phenotype in PBMCs, I assume the environment producing that phenotype is in the generative tissue, not in blood plasma. Do you agree with this point?

We're studying PBMCs only because they are available. It's nice to find a phenotype in ME PBMCs, but it surprised me. What our field needs most is a supply of ME cells that are known to express the underlying ME disease mechanism. Too often, we assume that any cell from a patient meets this criterion. But multiple lines of evidence suggest otherwise. Somewhere on S4ME I repeated my argument, based on oxygen consumption, that the fraction of patient cells that are sick may be as small as 10-15%. I'm asserting this disease is cell-autonomous. If that's true, it's an important confounder for every negative result.

Returning to the itaconate shunt, the hypothesis is that the ME trigger infection induces expression of ACOD1/CAD in parenchymal cells that happen to express a cell surface receptor for that virus. This mechanism evolved to defend parenchymal cells from acute infection by limiting host-cell resources for viral replication. ACOD1 expression should be transient. But if the normal off-switch fails for any reason, then the infected cell and its neighbors can be trapped in a pathological steady state that produces too few reducing equivalents to sustain the electron transport chain. ME symptoms then devolve from what cell types are trapped and how many are trapped and thus cannot perform their normal physiological functions. Do you think this hypothesis is too far-fetched?
 
RDP said:
Returning to the itaconate shunt, the hypothesis is that the ME trigger infection induces expression of ACOD1/CAD in parenchymal cells that happen to express a cell surface receptor for that virus. This mechanism evolved to defend parenchymal cells from acute infection by limiting host-cell resources for viral replication. ACOD1 expression should be transient. But if the normal off-switch fails for any reason, then the infected cell and its neighbors can be trapped in a pathological steady state that produces too few reducing equivalents to sustain the electron transport chain. ME symptoms then devolve from what cell types are trapped and how many are trapped and thus cannot perform their normal physiological functions. Do you think this hypothesis is too far-fetched?
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This certainly fits with other threads that I have been running down in my own research. However, the main concern would be whether non-myeloid cells actually upregulate IRG1 to a sufficient extent to cause the level of TCA cycle dysregulation you hypothesize.

Tomas noted that other findings from his lab showed itaconate to be a weak SDH inhibitor, which may not be expected to have a strong physiological effect at all in neighboring cells (I will not speak for him further than this, as he has also mentioned follow-up experiments that would confirm or deny this point). This may not be a problem for e.g. macrophages, where the sheer level of itaconate produced is high enough to be locally bactericidal, and therefore are more likely to be able to affect neighboring cells than any other celltype. The question then remains as to whether non-myeloid cells are able to produce enough itaconate to sufficiently alter their own metabolism, let alone their neighbors. And even if they do, the follow-up question is whether a mild auto-inhibition in 10% of cells would be sufficient to produce the level of dysfunction seen in ME/CFS. Looking through the literature, so far it seems that only cancer cells have been shown to reach a high capacity of itaconate production. Though, as you note, we might just not have looked in the right places yet.

I am currently in the process of meeting with collaborators to discuss how my own theories might be addressed through tissue samples. If I am successful in arranging a study, it may also address parts of what you propose.
 
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