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

I see your point here. Though the more I personally experiment with supplements that affect metabolic function, and see their unique effects (nearly all of which I would not have been able to predict ahead of time) on my experience of brain fog, feverishness, etc., the more I'm convinced that metabolism has to be playing a role. Whether it's mediated through microglia specifically, I'm not sure.

 

That's what I suspect, since as Hutan noted earlier, people who are treated with interferon for other infections often report very similar symptoms. However, it remains to be confirmed

 

Does someone have a link to the post and its correction. I see this is a popular thread and want to understand the basics but with the complexity of these messages I can only read one at a time before I need to take a PEM break so this thread is kind of unreadable to me.

 

Is it possible it is playing some role, but a short term supportive one that doesn't address the underlying problem?

I get positive effects from nicotinamide, but it doesn't change anything. It makes my leg muscles more responsive and less painful, but they'll be burning and full of grit again the next day.

 

@Yann04

Hutan's original summary of the talk (corrected at point #2):

paulendat's correction that prompted Hutan to modify #2 above:

Hutan's updated summary:

 

At this point, my sense is that it is both a cell metabolism and an immune signaling problem at the same time. E.g. immune stimuli cause metabolic reprogramming which enables immune signaling from those cells, which in turn might be able to shift metabolic pathways in other cells, which might somehow maintain that immune signaling in the absence of a "stop" that is normally present in healthy people.

That's just a long sentence to say "all of the above, maybe?" There are a lot of if's and maybe's at this point, but I see several potential ways that all the various puzzle pieces can fit together. Other people much smarter than me seem to already be ahead of me on that

Nicotinamide would also only be one small part of cellular metabolism--I suspect that taking it might help counteract one of the many downstream issues, but I doubt that any potential issue in cellular metabolism in ME is solely driven by NAD levels.

 

It may not be relevant, but sometime around 2010/2011 ish, there was some ringfenced funding from the MRC for research for us. I remember that there was to be a study using interferon.

I remember it because given my ME experince is identical to the experience of having an infection, a study looking into drug that produced flu like symptoms as a side effect seemed a useful idea.

I dont know whatever became of that study & a number of others done using the same funding (it wasnt much - maybe 1.5 million but there were high hopes for it at the time. If i remember correctly it may have involved Hep C patients too but that may be wrong. I know Charles Shephard would definitely remember it, & likely its in the MEA purple book.
May be irrelevant but just thought id mention it just in case it useful

Edited for sense

 

That was the alpha interferon study with Carmine Parente. My memory is that it showed much what was expected - that alpha interferon produces fatigue. It seems that both alpha and gamma interferons make you fell lousy. The question is whether either is what is making people with ME/CFS feel lousy. We still don't know. (I am not sure if beta interferon does this too.)

 

Thank you.

is this cycle what was discovered in the paper?
or a theory to do with me/cfs?
or both?

 

I am happy that the switch point is in a metabolic pathway that mediates signalling.

My thought is that the positive feedback loop options that we have programmed in must all come with spring loaded railway points so that when there is no longer something pulling the points over to the positive loop they flop back to homeostasis. If that was not the case flu would last a lifetime. Rob Phair notes that alpha interferon has a positive loop option but to me that is not enough. There are lots of positive feedback options but they shut off when the acquired stimulus that pulled the poets against the spring is no longer present.

In infection the story is easy. Tuberculosis continues as a positive loop of granuloma formation because the bacterium thrives in the granuloma. Autoimmunity is easy enough. If you expand B clones with certain Ig gene rearrangements that code for 'subversive' antibodies like rheumatoid factors that bind at certain Cgamma2/3 junction points or anti C1q antibodies then they keep the points forced over to positive. T cell diseases presumably depend on T clone expansions.

Rob doesn't mention what keeps pushing against the spring for the a-IFN loop. That is what I would like to track down - what keeps the points over to positive? I don't think the small molecules of the metabolic pathways can do that on their own.

 

If I’m not mistaken, I think the positive feedback loop Phair is proposing is itaconate -> interferon alpha -> itaconate. I know that interferon gamma also stimulates itaconate production in combination with LPS, and paulendat’s comments seem to suggest that interferon alpha can also upregulate itaconate.

My thought is that, in normal individuals, this loop is not maintained by constant positive stimulus. Rather, I suspect that it is a rare example of a self-perpetuating positive feedback loop that was allowed to evolve only because it can usually be stomped out by a separate “heavy boot” once the insulting stimulus clears.

Such a feedback loop would be extremely volatile, I’m quite aware of that, so it would only be allowed to persist evolutionarily if the “heavy boot” was very consistent at doing its job.

If I’m not mistaken, Phair suspected some miRNAs that block STAT signaling as a potential candidate. I for one have my suspicions that it might be a metabolic block (e.g. controls on ROS-mediated signaling such as the proteasome or glutathione), or perhaps one of the many metabolites dependent on proper metabolic function to be produced (e.g. cortisol).

Could be other explanations, certainly, but I’m at the “throwing things at the wall to see what makes many of the puzzle pieces fit” stage.

 

My previous work makes me think otherwise though. Positive feedback loops are everywhere in the immune response. Our rheumatoid model made use of four of them - all normal plus loops. Both complement and coagulation cascades are autocatalytic. Neutrophil chemotaxis is self-enhancing. And, as far as I know they nearly all turn off just because danger is dealt with. There is a major industry trying to blame diseases like RA on failure of some 'turning off mechanism' - I guess your heavy boot. But I never came across any need for that. Give antibiotics and the CRP levels drops within hours. Remove the microbes and everything happily goes back to normal service.

Evolution of a positive feedback loop that doesn't have a spring loaded return mechanism seems to me implausible. Since we all get stimulation of these pathways why isn't a 'stuck on' situation the norm?

 

It does seem odd that it can get stuck and there's apparently no rescue mechanism. Or if there is, it doesn't work in some people.

Unless it's like ecological competition, where a species functions well in its niche until its numbers are suppressed by the increased presence of another. It should be easy to see, but with so many natural fluctuations it isn't always.

 

It is odd but almost certainly what is happening in rheumatoid, lupus, scleroderma, Wegener's... most of the autoimmune diseases I came across. And there are plausible explanations. Instead of the spring being kept open by a microbe, it is kept open by the immune response itself. But for that to happen suddenly at an unpredictable time in life and only in a tiny proportion of people I think it has to be a learnt response involving some new molecular signals that most people do not have. The cells that make those are B and T.

 

If my speculation is correct, it would be because it requires a hefty cocktail of predispositions before the heavy boot becomes inadequate at its job.

In my case, the only thing I can point to as a triggering event for my ME/CFS is pre-existing Hashimoto’s coupled with a period of intense stress from trying to do an intense school workload with undiagnosed ADHD and relying on my panic response for months to get by.

I suspect that some other combinations of generic predispositions plus a viral infection plus another lifestyle factor might end up with a similar effect, since the commonality between a lot of those factors is effects on metabolism.

 

By learnt and new, do you mean that the B or T cells somehow «learn» to produce a molecule that didn’t exist in the body previously?

What maintains the production of the molecule?

 

The relationship between itaconate, interferon beta, and ROS/PRDX5 is what was found in the paper.

A prior paper showed that natural itaconate had different properties than itaconate derivatives commonly used in experiments—a fact that confused our understanding of what itaconate actually does in the body.

This paper is following up on that with an explanation for why natural itaconate has different effects on immune signaling.

At the moment, any connections to ME/CFS is speculation and discussion on the forum drawing from the itaconate shunt hypothesis

 

It's winning the slots with the right combination. Or perhaps more appropriately, the trifecta. I'm not convinced it involves predispositions, though. I would not rule out a combination of the right microbes, one or two of which fall beneath most radar.

 

Bone marrow derived macrophage levels typically fluctuate in response to some insult, but there are also tissue resident macrophages (e.g. the ones in the brain are called microglia) that are constantly present. There’s also evidence from single cell studies of higher chemotactic signaling in monocytes, meaning that there could be higher constant numbers of BMDM to begin with.

[edit: I suspect the latter might be due to chronic signaling from tissue-resident cells. Tissue-resident immune cells are often the first line of defense for pathogen recognition, and one of their jobs is calling in reinforcements.

Typically this is accompanied by histological inflammation, which we don’t see here, so that’s the mystery. It might be that if there is chronic aberrant signaling among the tissue residents, that is enough to trigger some, but not all, of the typical immune response cascades]