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

@Jonathan Edwards could the learnt molecular signal be acting upon the macrophages which causes them to circulate near places with lots of interferon?

Or could the loop cause macrophages to migrate to certain areas because they interpret some of the byproducts as something they have to deal with?

 

Yes, to clarify, I meant “predisposing conditions” which could be environmental. Though certainly one of the predispositions could be a genetic one that only causes problems with the right cocktail of other things going on

 

Yes, they learn to produce entirely new molecules in the form of antibody or T cell receptor. It is a rather brutal form of learning the kid B and T cells are expected to make new molecules at random to try and guess the answer to their exam question and if they get it wrong (which 99.9% will do) they are 'put to sleep'. If they get it right then the nearby follicular or thymic stromal cells will say 'well done laddie, you can move into the next class'.

If they are allowed to survive and proliferate then their daughter cells will hang around as memory cells potentially for the rest of your life. An interesting question is what keeps B cells alive because they seem to need to see antigen now and again. But we do know that fragments of microbial antigens are held on the surface of follicle stromal cells, which B cells actually live inside for months if to years.

 

Yes, I am still not sure why you need any boots for this but a cocktail of predispositions sounds like the ticket (roll on DecodeME).

But I think this is an example of my hobby horse that you cannot explain disease physiology with normal physiology. If there is a positive feedback alpha IFN/itaconate loop in the normal rules of response that can't explain ME/CFS because it isn't a normal response. The disease must lie in some deviation from this normal positive loop. The loop may very well be involved but it cannot be the explanation.

Just as if molecular mimicry was part of the normal immune response rules it would happen to all of us and it doesn't. So it cannot be part of the normal rules and autoimmunity can only be explained by something else - either something quite different or possibly something that allows mimicry to work, although that has never really been shown to my satisfaction.

And of course the psychologists would say that the normal psychological response to trauma explains ME/CFS but it cannot because ME/CFS isn't the normal response to trauma. If it follows trauma the explanation must be something in addition.

And Jo Cambridge agrees, but then she would because she's my pal.

 

One of those little old positive feedback loops .

 

I agree with you on the logic here—my thought is that the cocktail of predispositions are what prevent the boot from doing a good enough job.

As just one possibility, it’s possible that without further pathogen stimulation, the interferon itaconate loop would continue at low levels, but would eventually be snuffed out by upregulated ROS scavengers (besides PRDX5) which would put a stop on interferon production via HIF-1 pathway.

Now consider that someone has a mutation in a proteasome subunit which mediates HIF-1 degradation in steady state or in the glutathione pathway. Normally this wouldn’t cause problems as the mutation is not deleterious enough to inhibit those pathways, it just makes it slightly less efficient. However, if that pathway has to be upregulated to a certain balance, that would become an issue.

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.

So a mutation that normally causes no problems suddenly becomes a problem when you have the right cocktail. You get a viral infection, it clears, but after-the-fact HIF-1 suppression never quite gets to the level it needs to.

Plus, it’s been shown that chronic stimulation with interferon gamma substantially reduces the amount of stimulus needed to create a runaway itaconate and ROS response, so now you’re in a position where the amount of suppression needed to break the cycle simply can’t be reached.

That’s just one throwaway theory, but presumably the same cumulative effect could be reached by a toxic combination of other factors that only occur at a rate consistent with ME/CFS epidemiology.

 

I can't have all of you writing our new paper for us.
Yes. And yes.

 

This I think is the basis of the ?Dutch guy's idea of focusing on learnt innate immunity. It is conceivable that an epigenetic change occurs in macrophages progressively but we don't have any real evidence for that as far as I know. We do have evidence for progressive clonal changes in B and T cells though.

 

Could this explain worsening through exercise/exertion? As in this itaconate and ROS response is triggered over and over and more frequently each time until it takes very little to trigger it?

Also if this throwaway hypothesis is correct, or just if we're in the right ballpark here, what kind of drugs could get fix this broken signalling loop?

 

Yup, that would be a going concern. I still have my prejudices but sooner or later we are going to find that one of these things can be corroborated by hard data. I am keen to see some FluoroSpot studies on cells talking and signalling. Rob Phair was disappointed he did not find alpha IFN much but people have drawn a blank in other situations - almost certainly because there just isn't much free signal floating about. It is all local.

 

That’s exactly my hunch, but it’s pure speculation at this point so I hope nobody puts too much faith on it until there’s data to back it up.

Unfortunately trying to design and carry out wet lab experiments is not something that can be easily done by someone with ME/CFS who has thus far been completely limited to computational work. Even if you do find a magic supplement that helps a lot. But lord I’m trying!!

I hesitate to speculate on it at this point since the only options I currently see are quite heavy duty drugs and I definitely don’t want to put it out there without evidence. I’d rather have the mechanism be confirmed and jump from there

 

Could they be using one of the self destruct mechanisms with a timer that resets when they encounter antigen?

Or maybe antigen triggers a response to absorb some other sustenance that keeps them alive for a while longer? Some kind of re-fueling response. Or it causes them to expel waste that would otherwise accumulate and kill them? Although that might be a kind of indirect self destruct mechanism.

Local as in just in e.g. the tissue or glial cells, or as in e.g. only a certain part of the body (like the brainstem)?

 

I just read that macrophages are specialised and mostly hang around in their specific type of tissue etc.

Could there be some kind of mix-up of signals where type X gets told by the new molecule to go to place Y, and the local environment of place Y causes the type X macrophage to respond differently than type Y macrophages? That might be the same as I asked about previously.

This would be able to explain the non-normal response to normal feedback loops.

Or maybe the GPS of one type of macrophage becomes faulty for some reason so it believes it’s supposed to turn left instead of right. I believe we had a conversation about the «memory» function of cells a while ago, @Jonathan Edwards . Something related to pain?

 

We did a lot of work on macrophage subsets in the 1990s, some of which seems to have got forgotten by recent reviews. It looked very much as if in humans macrophages become X or Y once they have arrived a t a tissue and got into this or that environment. They respond to the 'writing on the wall' in terms of matrix components and also tissue movement, which is a key factor in RA.

But in a way what I am currently thinking could fit roughly with what you are suggesting. There are lots of possibilities. We are going to focus on just one - for the sake of making the paper comprehensible.

 

I look forward to when someone here can explain your upcoming paper because I’m sure it’s gonna go right over my head.

On which walls is it written? Could the writing have been altered? Or some kind of issue with the translation module in the macrophages where they have learnt to respond differently to X than what they used to?

 

Not to further derail the thread, but it turns out I did read some of your group's work a few years ago when I was working on synovial macrophages, I just didn't realize it was you!

Unfortunately some of that work I was doing might never see the light of day for reasons beyond my control. I was trying to determine if the macrophages that repopulate the joint after STIA resolution are primarily the descendants of the original tissue resident population or BMDM that have shifted into a tissue-resident phenotype.

 

The answer you will find, in ...
'The Windmills of your mind'.

 

I have always assumed they are all bone marrow replaced. That is what I saw in the geometry of the tissue in hundreds of samples just using non-specific esterase doing my doctorate. You can see them looking around and going to the different places from the perivascular region. I never saw anything that looked like cells proliferating. There has always been a lot of dogma and counter-dogma in the area and none of the techniques really prove anything absolutely.

As my then supervisor said "Never mind, 90% of research goes in the bin".