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

Advocating the role of trained immunity in the pathogenesis of ME/CFS; a mini review

Bart Humer, Willem A. Dik, Marjan A. Versnel

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Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic disease of which the underlying (molecular) mechanisms are mostly unknown. An estimated 0.89% of the global population is affected by ME/CFS. Most patients experience a multitude of symptoms that severely affect their lives. These symptoms include post-exertional malaise, chronic fatigue, sleep disorder, impaired cognitive functions, flu-like symptoms, and chronic immune activation. Therapy focusses on symptom management, as there are no drugs available.

Approximately 60% of patients develop ME/CFS following an acute infection. Such a preceding infection may induce a state of trained immunity; defined as acquired, nonspecific, immunological memory of innate immune cells. Trained immune cells undergo long term epigenetic reprogramming, which leads to changes in chromatin accessibility, metabolism, and results in a hyperresponsive phenotype.

Initially, trained immunity has only been demonstrated in peripheral blood monocytes and macrophages. However, more recent findings indicate that hematopoietic stem cells in the bone marrow are required for long-term persistence of trained immunity.

While trained immunity is beneficial to combat infections, a disproportionate response may cause disease. We hypothesize that pronounced hyperresponsiveness of innate immune cells to stimuli could account for the aberrant activation of various immune pathways, thereby contributing to the pathophysiology of ME/CFS.

In this mini review, we elaborate on the concept of trained immunity as a factor involved in the pathogenesis of ME/CFS by presenting evidence from other post-infectious diseases with symptoms that closely resemble those of ME/CFS.

Link (Frontiers in Immunology) [Provisionally accepted, currently only abstract]

 

I noted that another thread "Defining trained immunity and its role in health and disease, 2020, Netea et al." elicited little response. Is "trained immunity" unlikely to be relevant to ME, and if so does anyone know of a good resource that explains/highlights why?

Thanks so much.

 

How do they account for the other 40 %? If almost half of ME/CFS isn’t caused by an acute infection, how can trained immunity be a key element? Are they suggesting that there are different subgroups?

 

This mini-review is presumably part of the work that Wim Dik is doing on ME/CFS after having gotten a ZonMW grant.

 

As far as I can tell they aren't suggesting that "trained immunity" only occurs due to infections and presumably it includes all sorts of effects.

 

I only went by this:

I might be missing something, I have no knowledge on this topic in general.

 

Could "trained immunity" not be triggered also by autoimmune disorders?

 

Does cognitive exertion triggering PEM involve innate immune cell activation?

Do immune cells of PWME hyperrespond? Isn't that easily testable? Put some immune cells from PWME in a tube, and apply an appropriate antigen and measure the response. Compare with responses from cells from healthy (and maybe unhealthy) controls. Basic science.

 

"trained immunity; defined as acquired, nonspecific, immunological memory of innate immune cells."

Would be the definition, which seems rather general to me. Possibly even too general to be meaningful any way or at least working out the details is what matters here. The question is whether someone would also be commited enough to work out the important details or whether it's more along the lines of thought "maybe the BCG vaccine reduces the risk of getting LC, maybe it doesn't".

These links describe the work that Willem Dik planed to do with his grant:
https://projecten.zonmw.nl/nl/project/immuunhandtekeningen-mecvs
https://www.zonmw.nl/nl/artikel/blog-een-behandeling-op-maat-met-immuunhandtekeningen-voor-mecvs

I don't remember if he also got some Long-Covid grants.

 

That was my thought. I don't think new buzzwords like 'trained immunity' get us any further. The mechanisms they are proposing are reasonably plausible but in realise most innate immune cells like monocytes die pretty quickly so their training would be forgotten. I get the impression the authors realise that and so talk of stem cells. I think it then all begins to get too vague and likely based on inappropriate in vitro or animal models.

Which was my other thought. And fortunately I am doing just that this week. I have hit on a way of getting together virtually all the information of ME/CFS, including the paradoxical things about B cells, T cells, cytokines, remissions and relapses and so on. My proposed answer will give detailed specifics of pathways, cells and tissues. It will take a few more days though.

 

Wow! Can't wait to see that (well, see it soaring over my head, anyway).

Exciting!

 

Sorry about the typing:

I have hit on a way of getting together virtually all the information of ME/CFS, including the paradoxical things about B cells, T cells, cytokines, remissions and relapses and so on.

 

As I understand it trained immunity is not adaptive immunity - i.e. it is not a response to a particular antigen or infection. And we don't know that infection causes any ME/CFS. It might just reveal it.
Trained immunity seems to imply an acquired hypersensitivity of innate immune cells to stimuli in general.

 

This is intriguing! Do you plan on posting this framework on here or will it just be shared within the research community at present?

 

I am pretty certain this is what happened to me. At 19 I developed a sleep disorder, depression, DPDR, blood sugar issues, lost my youthful energy, and experienced lots of strange unquantifiable neuropsychiatric symptoms and frequent debilitating panic attacks.

All this taken together had a massive impact on my life and limited it majorly. But I don't remember ever experiencing PEM like exhaustion until I got strep at the start of 2017.

I have seen a lot of people on the long covid subs who report no PEM but have many or all of the symptoms I had pre 2017.

 

If I can get my act together I may publish it open access on Qeios by about May. It can be linked in here.

 

I look forward to reading it when it's published! And to the discussion on here which always helps me make sense of scientific papers.