Genetics: OLFM4

[jnmaciuch]

Could it also be that this state 2 is doing something new and different it doesn’t in healthy people, rather than just a how much it’s turned up or suppressed?

Maybe--I'll admit I can't really imagine how that works. In all other immune-mediated diseases, the signaling pathways themselves do what they're supposed to do, it's mostly just a matter of getting triggered when we don't want them to be. Though I suppose there's room for ME/CFS to be different!

Or how about it being fairly normal in itself but something else mediating or intermittently activating it, maybe along with some T cells, perhaps MAIT cells that have learned some new tricks?

MAIT cells interest me because of well, the mucosal aspect. And because I onky recently learned about them so recency and novelty bias! But I certainly experience and others talk of issues with eyes, nose, mouth, throat, even chest as well as gut.

Potentially! For what it's worth, I think that constitutive interferon would still result in intermittent bursts of even more interferon signaling in PEM through mtDNA release--something that already occurs during activity for healthy people, which is known to trigger a type I interferon response. If you have a higher basal interferon response, that would just mean a more exacerbated response to the mtDNA release during activity, because interferon is self-priming.

Plus there's the effects of interferon on metabolism, which happens to align quite well with what has been shown, albeit inconsistently, in muscle cells, and which might substantially lower the threshold of activity that triggers mtDNA release. But that's a whole other rabbit hole. Though all that wouldn't be T cells--that's coming from the interferon response that every tissue cell can maintain on its own, but it might include calling in some T cells through interferon-stimulated genes.

The range of symptoms in other tissues may also be explained by interferons as well--interestingly, type III interferon signaling predominates in all those tissues you listed, and type I/type III use basically the same set of mediators (whereas type II/interferon gamma has a little less overlap). But that's only one potential explanation, if MAIT cells turn out to be relevant that would be interesting too. The trick with implicating MAIT, or any specific immune cell, would be explaining exactly what it is about activity that triggers them that wouldn't also trigger them at seemingly random times not explained by activity (for mild/moderate pwME at least).

 

[bobbler]

If they're standard assays, it might not be unsurmountable for moderately affected people with access to a general hospital.

I have to have bloods taken every fortnight at the moment, so I drive 15 minutes to the hospital, park next to it, wheel in to the phlebotomy dept next to the reception desk, take a ticket and wait for my number to come up. The whole thing (waiting included) never takes more than 10 minutes.

It's so streamlined I could do it in pretty nasty PEM. You don't even have to talk to anyone except for giving your DoB; I swear they get paid by the number of vials they fill, they never even look up from what they're doing.

Just seen this. On a special car that has blood testing machines and X-rays etc

Another link if fb doesn’t work

What’s the likelihood of this sort of thing access wise becoming possible?

 

[AliceLily]

I really hope you all continue investigating and not forget the MAIT side. I really think it is part of my set up ME.
Thanks for bringing it up and thanks to Jonathan Edwards for making me aware of it years ago within his postings. I understand very little of the science but I really do think you all will work it out eventually.

 

[hotblack]

The trick with implicating MAIT, or any specific immune cell, would be explaining exactly what it is about activity that triggers them that wouldn't also trigger them at seemingly random times not explained by activity (for mild/moderate pwME at least).

The problem I see without having something else is that the mechanism described seems very muscle/metabolism heavy and doesn’t seem to account for a lot of what we (maybe particularly moderate/severely affected) describe? Although I may well be missing something as I only have a shallow and patchy understanding of all this.

That MAIT cells seem to crossover innate and adaptive and pop up in places like nerves seems a possibly route to explaining a few more things though.

 

[Kitty]

2) a constitutive state, where a low basal amount of interferon and interferon-stimulated genes are constantly produced but actively kept in check by several mechanisms. This pathway always has to be a little bit active, because it's a self-perpetuating feedback loop. If the "active" response is mediated by a game of telephone across signaling molecules, this is basically making sure that someone is always at the switchboard to enable that lightning fast non-specific antipathogenic response.

What interests me about this sort of approach is the fact that a developing infection damps down or switches off the response in some of us. A reduction in symptoms when ill isn't universal, but enough people with ME/CFS experience it for it to need explaining.

The AZ Covid vaccine switched it off altogether for me and a few others. It lasted about a week after the first jab and a few days after the second, but it was incredible to feel as well and energetic as I did—gave me a glimpse of what life could be like if a treatment is found.

It's as if the process can't run under certain conditions, and is only restored once the first part of the immune response to infection has been mounted.

 

[hotblack]

The AZ Covid vaccine switched it off altogether for me and a few others.

I know we’ve talked about it on here before but the lack of curiosity from the scientific world in the quite dramatic (both positive and negative) impacts of these vaccines on some people with ME/CFS has been equally surprising and disappointing. I agree there must be some really useful information to glean about the disease and possibly the vaccines and our immune systems in general.

I suppose I’m thinking at it from the ‘having a way to reproduce something helps you understand it’ viewpoint. And I guess we have that already with activity and PEM. But the vaccine/infection aspect seems different, in modifying something more fundamental than ‘just’ inducing PEM.

 

[Evergreen]

What interests me about this sort of approach is the fact that a developing infection damps down or switches off the response in some of us. A reduction in symptoms when ill isn't universal, but enough people with ME/CFS experience it for it to need explaining.

The AZ Covid vaccine switched it off altogether for me and a few others. It lasted about a week after the first jab and a few days after the second, but it was incredible to feel as well and energetic as I did—gave me a glimpse of what life could be like if a treatment is found.

It's as if the process can't run under certain conditions, and is only restored once the first part of the immune response to infection has been mounted.

I've only experienced this once - my pain, and only my pain, was turned off by a tummy bug. It was glorious, as I had been in the middle of a pain flare.

But I do wonder if it's actually part of a normal process - because something similar happened to me when I was healthy (albeit someone who would go on to get ME/CFS). I had a bad cold and had to get a flight. So I took an over-the-counter remedy, in the hope of stemming the incessant sneezing and general germ-factoriness while beside so many people. I did not know, however, that I could not tolerate one of the ingredients (a decongestant, I think). So mid-flight, there was an abrupt change from incessant sneezing and nose-blowing to fainting and puking. And the puking stopped the cold/flu in its tracks. As the guy beside me remarked "Your puking really scared that cold away." The cold was in full flow and it stopped, and didn't get going again. It just vanished.

That has always made me wonder if there's just a limit to what the body can do.

And whether we could harness it to fix ME/CFS. (I have read some anecdotes where people get an infection and their ME/CFS goes away.)

And also just how nice people can be.

 

[Hoopoe]

The AZ Covid vaccine switched it off altogether for me and a few others. It lasted about a week after the first jab and a few days after the second, but it was incredible to feel as well and energetic as I did—gave me a glimpse of what life could be like if a treatment is found.

It sometimes feels like an ordinary infection will reset something in the body for a few days, during which I feel better... that background feeling of sickness improves. It's not all infections, just some.

The staphylococcus toxoid vaccine was allegedly also effective as treatment for ME/CFS.

 

[Kitty]

It sometimes feels like an ordinary infection will reset something in the body for a few days

Yep.

Either that, or it has to take the brake off in order to do something different/of greater priority.

 

[jnmaciuch]

The problem I see without having something else is that the mechanism described seems very muscle/metabolism heavy and doesn’t seem to account for a lot of what we (maybe particularly moderate/severely affected) describe? Although I may well be missing something as I only have a shallow and patchy understanding of all this.

It’s definitely a good thing to be aware of! For what it’s worth, mtDNA certainly isnt the only thing that triggers an interferon response—it can be kicked off in innate cells by recognition of bacteria in the gut for example. It just normally doesn’t in healthy people because there’s a concert of counter measures to keep things in check—but interferon tends to swing the pendulum quite a bit across the board for different immune cells.

There very well may be MAIT involvement or some other part of the immune system in severe. It just might be a case where they only get involved in the first place because basal interferon production is high enough to allow it.

 

[jnmaciuch]

What interests me about this sort of approach is the fact that a developing infection damps down or switches off the response in some of us. A reduction in symptoms when ill isn't universal, but enough people with ME/CFS experience it for it to need explaining.

The AZ Covid vaccine switched it off altogether for me and a few others. It lasted about a week after the first jab and a few days after the second, but it was incredible to feel as well and energetic as I did—gave me a glimpse of what life could be like if a treatment is found.

It's as if the process can't run under certain conditions, and is only restored once the first part of the immune response to infection has been mounted.

That is actually one of the things that led me to thinking about the switch between “active” and “constitutive” interferon production. It’s a switch that involves multiple steps—degrading interferon and the transcription factors that keep amplifying its transcription, epigenetic changes that close off the genes encoding interferon, etc. There’s basically two parts to that changeover—the guards coming in to wrangle the dragon, and then the set of chains that they put in place so they can clock out.

So my thought was “what happens if you get a system reset on calling the guards back in, but one of the important brakes doesn’t get put in place?” That would probably look like an initial reduction in interferon signaling, and then a slow ramping back up as whatever manages to escape suppression kickstarts the loop all over again. Some pwME may get lucky and all the important brakes got put in place this time, but most will not.

Plus there’s also the fact that most common viruses have now evolved to counteract the host interferon response themselves, which might somewhat account for the improvement people report at the start of infection.

It’s all just speculation, I might be way off the mark here, but you and others are right that a good theory should be able to account for many of the big fluctuations pwME report.