Review Advocating the role of trained immunity in the pathogenesis of ME/CFS; a mini review, 2025, Humer et al

[SNT Gatchaman]

Now published.

Having read through, the first question I have would be whether persistent overactivity of the innate immune system could explain the observed markers of T cell exhaustion and reduction in switched B cells.

I.e. it wouldn't be persistent viral antigen (that many groups are chasing) triggering T cells, but instead the monocytes, macrophages, dendritic cells having been primed via their marrow progenitors and now "too touchy" are responding to endogenous stimuli.

Innate immune cells have a limited lifespan, suggesting that trained immunity is engraved deeper within the hematopoietic system. Studies investigating this have shown that long-term effects of trained immunity are retained by changes in hematopoietic stem cells in the bone marrow.

Besides exogenous ligands, endogenous ligands and cytokines are also capable of inducing immunological memory in innate immune cells. Examples of such endogenous stimuli are lipoprotein(a), oxidized low density lipoproteins, aldosterone, catecholamines, cytokines, and uric acid. This data suggests that also naturally occurring substances may invoke the secondary response in trained cells.

 

[Jonathan Edwards]

I.e. it wouldn't be persistent viral antigen (that many groups are chasing) triggering T cells, but instead the monocytes, macrophages, dendritic cells having been primed via their marrow progenitors and now "too touchy" are responding to endogenous stimuli.

I agree. Very much my line of thought. Except that I doubt this is priming in marrow. I think the 'learning' may reflect self-perpetuating changes in peripheral lymphoid organs. A bit like the kids at school all being on social media and distracting each other from homework by gossiping about each other. Or the 'exhausted T cells' may simply be all the exhausted neighbours wandering around in their pyjamas who cannot sleep because the kids are having a rave in an empty house, posted on Facebook. Or they may just be cells told not to respond by the TGFbeta police responding to the noise of the rave. And so on.

We need to invoke specific pathways. My experience with RA makes me think that we need to identify pathways that are vulnerable to very particular malfunctions - like antibodies that are just big enough to cross link Fc-gamma-RIII but not C1q or tissues where VCAM-1 is normally used for control monocyte traffic having it misused for B cell proliferation. One thing that I have wondered about is whether there might be a weak link in the way the body handles foreign antigen by fighting it but the gut handles foreign antigen by ignoring it. There might be a way that 'normal junk' keeps tripping the monocyte alarm system when it should be ignored.

I think it is good that people like Humer are exploring these ideas. I just think that more focus on specifics and less use of loaded terms like 'cell exhaustion' would be good. And probably much more focus on tissue micro-environments, which is where the RA story showed itself.

 

[Creekside]

Some of the possible theories of immune memory causing ME fail my "Does this fit experiences of abrupt switching from full ME to full non-ME and back again?" test. Some probably could, due to blocking/removal of whatever the primed cells are responding to. The "can switch abruptly" requirement should at least reduce the number of theories to consider.

 

[Jonathan Edwards]

The "can switch abruptly" requirement should at least reduce the number of theories to consider.

I think that is an excellent point.

 

[Sasha]

Some of the possible theories of immune memory causing ME fail my "Does this fit experiences of abrupt switching from full ME to full non-ME and back again?" test. Some probably could, due to blocking/removal of whatever the primed cells are responding to. The "can switch abruptly" requirement should at least reduce the number of theories to consider.

But is that a reasonable test? I'd have thought that that experience was extremely rare among PwME, but we have heard a few examples.

 

[Utsikt]

But is that a reasonable test? I'd have thought that that experience was extremely rare among PwME, but we have heard a few examples.

It’s not a test to see if something is the ME/CFS mechanism(s). It’s a test to see if it can be the ME/CFS mechanism(s), because whatever it is, it has to be able to explain the features we’ve observed.

 

[Sasha]

It’s not a test to see if something is the ME/CFS mechanism(s). It’s a test to see if it can be the ME/CFS mechanism(s), because whatever it is, it has to be able to explain the features we’ve observed.

But does it have to explain features that are so rare that it raises the question of whether that person is so unusual that it may be something else very rare about them that allows their ME/CFS to behave in that way, rather than it being a feature of the ME/CFS itself? (I'm trying to think of an analogy to illustrate my point but I don't have the brains for it at this point in the evening!)

 

[Utsikt]

But does it have to explain features that are so rare that it raises the question of whether that person is so unusual that it may be something else very rare about them that allows their ME/CFS to behave in that way, rather than it being a feature of the ME/CFS itself? (I'm trying to think of an analogy to illustrate my point but I don't have the brains for it at this point in the evening!)

That’s a good point that I don’t know how to answer!

 

[Sasha]

That’s a good point that I don’t know how to answer!

It might not look like such a good point in the morning!

 

[Jonathan Edwards]

But is that a reasonable test?

I think is a pretty good test. It means that permanent shift due to bine marrow cells learning something cannot account for ME/CFS in every case. There must be cases with different mechanism. William of Ockham would then say most likely it's all just the one different mechanism.

 

[Kitty]

I'd have thought that that experience was extremely rare among PwME

Maybe it doesn't necessarily have to be? It's true I haven't come across many who experienced rapid remissions, but there are far more who first became ill very quickly.

Some will have felt ill with whatever virus is assumed to have triggered their ME/CFS. But we've no way of knowing when that "not going to recover" switch was thrown. It could just as easily have been on Day 1 as any other.

That would mean it's at least possible to switch it one way quickly, which in turn makes it more plausible—especially as no destructive disease process seems to be involved—that it could go the other way too.

 

[Trish]

There must be cases with different mechanism.

Or perhaps the are misdiagnoses, given that we repeatedly hear of people diagnosed with ME/CFS who are found to have something else instead.

 

[SNT Gatchaman]

I'd be cautious about the idea of rapid on-off as it relates to evaluating putative mechanisms. I think it's entirely possible that slow changes in cells and their signalling (including marrow precursors) could set-up and potentially revert over many weeks, but that the recognisable expression of disease is mitigated by compensations, right up until it isn't.

My onset was characterised by an initial, completely unexpected crash for a few days, then recovery. It was only in hindsight that I realised I'd been going off over the prior 6-8 weeks. Then a couple of months of very weird "things are definitely not right" vs "things are completely normal" (odd fatigue, fast heart rate) with a three week cycle, repeated 3x. However, as things slowly progressed from there I continued to work and walk around until one day I didn't and was bed-bound for the next six months or so. The morning that second and definitive crash happened the last thing I did was a liver transplant biopsy, so I was clearly still able to stand for 30 minutes in a warm OR, interact with the anaesthetic and nursing teams and maintain precision bilateral hand-eye coordination of imaging tech and instruments.

 

[Jonathan Edwards]

Or perhaps they are misdiagnoses, given that we repeatedly hear of people diagnosed with ME/CFS who are found to have something else instead.

Trouble is, that is sort of circular if ME/CFS is at present simply the group of people who have a symptom pattern.

 

[Sasha]

Trouble is, that is sort of circular if ME/CFS is at present simply the group of people who have a symptom pattern.

I agree, but with misdiagnosis so common, and this 'switching off' phenomenon so rare, can we be sure that the people showing it really have the symptom pattern that we would call ME/CFS?

And if they did, what if, out of (imaginary number) 10 million PwME worldwide, only one showed this switching phenomenon? Would that change your argument? (I'm thinking it shouldn't, as opposed to what I thought yesterday)?

 

[Sasha]

We talked about 'Rosetta stone' people a while back, whose ME/CFS switches on and off sometime, and whose biology could tell us a lot if we caught them at the switching point. I guess that's what we're talking about now and I don't know why I seem to have suddenly become resistant to the idea!

 

[Utsikt]

We talked about 'Rosetta stone' people a while back, whose ME/CFS switches on and off sometime, and whose biology could tell us a lot if we caught them at the switching point. I guess that's what we're talking about now and I don't know why I seem to have suddenly become resistant to the idea!

Regularly questioning your assumptions is probably a good quality when trying to figure out something difficult!

 

[Jonathan Edwards]

I agree, but with misdiagnosis so common, and this 'switching off' phenomenon so rare, can we be sure that the people showing it really have the symptom pattern that we would call ME/CFS?

I don't get the impression it is that rare. I have read accounts of people suddenly feeling better dozens of times on the forum. Some people have sudden good days. Some report suddenly feeling better and staying well for a good while. Some attribute it to treatments, others not.

And in fact the 'trained immunity' idea based on shifts in bone marrow stem cells doesn't really help explain PEM in the first place.

I think bringing in different ideas about regulation like this (epigenetic changes in innate immune cells) is very useful but my main point would be that we are looking for explanations for quite sudden shifts one way or another and long term change in bone marrow precursors doesn't seem that good a way to do that.

 

[Utsikt]

I think bringing in different ideas about regulation like this (epigenetic changes in innate immune cells) is very useful but my main point would be that we are looking for explanations for quite sudden shifts one way or another and long term change in bone marrow precursors doesn't seem that good a way to do that.

Would we have to account for the anecdotes of LP recoveries as well?

 

[Jonathan Edwards]

Would we have to account for the anecdotes of LP recoveries as well?

Yes.
Which makes the point that there isn't going to be a single answer that fits all.
It looks as if we are looking for multiple interacting control mechanisms with different dominance in different cases. The weakness of trained bone marrow as a story there I see as being too fixed. Adaptive immune changes can change back. Maybe epigenetic marrow stem cell changes can too but it would alb very speculative.