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

Actually, wouldn't DecodeME have this data for 25k people?

@Simon M

 

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.

 

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.

 

Might there are also be a case for also looking at a group aged 15 – 21 at onset, to see if it suggests there could be a link with late acquired EBV?

 

Yes, but I think very early cases are most likely to give a clear signal.

 

Ha! I woke up with the exact same line of thought based on my earlier comment:

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.

 

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.

 

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!

 

I can’t understand any of it, but this thread is making me so happy.

Thanks to all you smart peeps for trying to figure us out..

 

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…)

 

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...

 

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?

 

Thanks for your involvement here @paulendat it’s been great following the discussion. Is there a way more of us can get access to the paper and/or is there a recording of the talk from last week available anywhere?

 

I don't know, but I watched it go out live and the red "recording" icon was on. So if it's not already accessible somewhere, it hopefully will be.

 

Thanks Kitty, I hope so too. I had a look around the Wednesday Seminar Series website and Harvard Medical School youtube channel but couldn’t find anything