ME/CFS Science Blog article - Immune findings in ME/CFS

[ME/CFS Science Blog]

In this article, we have made a comprehensive overview of research findings on the immune system in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In contrast to what is frequently claimed, current data do not suggest that (low-grade) inflammation is a key driver of ME/CFS symptoms. There have been major studies into viral persistence, antibodies, and cytokines, but with mostly null results. The most consistent findings in the ME/CFS literature on the immune system over the past 40 years are reduced natural killer cell cytotoxicity and increased levels of the signalling molecule TGF-beta.

We have divided this overview into separate chapters, so can you read one at a time and come back to read the rest later. There are chapters on:

• viral persistence
• cytokines
• neuroinflammation
• autoantibodies
• immune cells such as Natural Killer cells, T-cells, and B-cells.

Although we took great care in dissecting and interpreting research findings, we do not have a professional background in medicine or immunology. We are therefore interested in hearing comments and feedback from professionals in the field. If you think we missed an important study or replicated finding, feel free to post them in the comments section below.

Link to the article:

The immune system in ME/CFS - ME/CFS Science

In this article, we have made a comprehensive overview of research findings on the immuneContinue readingThe immune system in ME/CFS

mecfsscience.org

 

[ME/CFS Science Blog]

We've made this social media summary of the article but for if you want to engage with the content or find references to the studies, it's best to look at the full article.



1) New article: we've made a comprehensive overview of the immune system in ME/CFS, analyzing major studies of the past 40 years.

A longread with separate chapters on:

- viral persistence
- cytokines
- neuroinflammation
- antibodies
- immune cells such as NK, B, and T cells

2) One of the major findings is that current evidence in blood does not point to (low-grade) inflammation as driving ME/CFS symptoms.

This probably means that it’s either hidden in tissue or involves an entirely different immune pathway.

3) This may come as a surprise because numerous studies talk about (low-grade) inflammation as being key in ME/CFS. We found that there’s a contradiction between what papers claim in this regard and what the actual evidence shows.

4) Studies show no consistent elevation of inflammatory cytokines in ME/CFS, even after an exercise test, and there’s no increase in inflammatory markers such as ESR and CRP.

5) There have also been high-quality studies into viral persistence, for example, by Ian Lipkin’s team, which studied blood, feces, and saliva but found null results. Same with studies on severe ME/CFS patients or with well-matched twin controls.

6) That doesn’t mean the viral persistence hypothesis is dead, but it has to be a very unusual virus, one that is exceptionally good at hiding itself, causes no obvious tissue damage, leaves no traces in blood or saliva, and induces no systemic immune activation.

7) Next chapter: antibodies. In a major study, Scheibenbogen’s group found increased autoantibodies against adrenergic and muscarinic cholinergic receptors in ME/CFS.

But the differences were small and do not correlate well with symptoms.

8) Questions were also raised about the CellTrend assay used, and its findings were not replicated by a major antibody study published last year.

The most interesting results on antibodies come from treatment trials (Rituximab, Daratumumab, immunoadsorption, etc.)

9) Two results to look forward to are the HLA analysis from the genetic study DecodeME and the RESETME trial on daratumumab.

If both are negative, the antibody theory would take a big hit. If any do find an effect, it would be the biggest breakthrough in ME/CFS thus far.

10) The most consistent immune finding in ME/CFS research is reduced cytotoxicity of natural killer (NK) cells. Although some big studies didn’t find an effect, the majority did.

NK cytotoxicity is not a very specific finding, though. It’s found in multiple other conditions.

11) It’s also unclear why NK cytotoxicity is reduced in ME/CFS. Our favorite explanation is TGF-beta: the cytokine most consistently found to be increased in ME/CFS, and also a potent inhibitor of NK cell cytotoxicity.

Perhaps there’s a connection between the two?

12) There’s no evidence for clonal expansion in ME/CFS, but a Cornell study found reduced lower glycolysis in T-cells despite normal mitochondrial respiration. Could mean they have a slightly different metabolism.

13) In B-cells, the most replicated finding is a skew in the building blocks of their receptors. IGHV3-30 is used more often in B-cell receptors of ME/CFS patients than in controls.

14) Overall, the immune abnormalities we in ME/CFS are relatively subtle. They are likely just an echo or side-effect of the core pathology. We have seen surprisingly little immune activation for such a debilitating disease triggered by viral infections.

15) This has important implications for future research. New immune hypotheses on ME/CFS will need to account for these negative findings. Focus should be on innovative methods and research targeting the gut, brain, or other tissues that have been difficult to sample

16) We’re looking for an immune signal that is potent enough to produce extremely debilitating symptoms yet produces no systemic immune activation visible in blood.

The answer to this question may have implications in medicine that go far beyond ME/CFS.

 

[hotblack]

Clearly a huge amount of work here @ME/CFS Science Blog thank you! I’ll be going through this properly in the coming days. Looks like a really good resource to have.

 

[DHagen]

Looks like amazing work here - thank you @ME/CFS Science Blog!

 

[butter.]

I can't read the whole text, but just judging from the thread, I am sure it's great and it must have been a lot of work. Thank you! I just wanted to say that, 1. to assume that there must be a detectable and ongoing immune signal in chronic patients under current stratification and 2. to not mention that inflammation might be an important early disease feature that we currently miss due to the six months diagnostic criteria cutoff, might be a missed opportunity that could reinforce current blindspots potentially?

 

[forestglip]

This is so impressive, and looks like a ton of work. You do a great job describing complex topics for non-experts.

---

Would it maybe be good to use links to your Bluesky posts instead of Twitter posts? For people that don't have accounts, only the first post in a thread is visible on Twitter.

For example, these links:

Michael VanElzakker from Tufts University reported similar results in Long Covid and ME/CFS patients during a conference presentation. Michelle James from Stanford shared images where it was not the brain but the muscles of ME/CFS patients that lit up on a whole-body TSPO scan.

Typo (suggested changes in bold):

These have been studied in ME/CFS patients by immunologist[ s] Amolak Bansal at [and] Geraldine Cambridge, but there wasn’t much that stood out.

 

[jnmaciuch]

Great article!

Just a tangential thought about TGF-b:
As you note, direct measurement of TGF-b can be confounded by quite a few things. In some assays it even requires a different protocol than other cytokines.

One way to determine if the differences in TGF-b are a result of differential release when measured from an assay or whether there’s actually differential TGF-b signaling in-vivo is via transcriptomics of TGF-b-responsive cells (such as PBMCs). The genes induced in response to receptor activation are pretty well defined and relevant pathways would almost certainly have been included in any major study that performed pathway analysis. I just looked back over Vu et al. (The Grimson/Hanson transcriptomics study) and didnt see any mention—I also don’t recall it being mentioned in other studies, but my memory definitely isn’t perfect.

Obviously the lack of mention of a particular pathway doesn’t necessarily mean there was no difference—it may just have been a weak signal and didn’t pass multiple testing correction. But to me, the discrepancy in TGF-b being a relatively consistent signal in cytokine assays and not a repeated finding in transcriptomics is a decent hint that the relevant difference in ME/CFS probably is more platelet-related (or something else that would result in higher levels after sample processing) rather than actually a reflection of TGF-b signaling.

 

[Kitty]

Thank you so much to all involved, this is a fantastic piece of work.

 

[Creekside]

While there don't seem to be significant immune signals, another possibility is abnormal response to even slight elevation of chemokines. That's probably more difficult to study.

Some PWME do suffer elevated severity of symptoms when some cytokines rise, from viral infection or other causes. So, while persistent elevated cytokines can be ruled out, the ME mechanism is still affected by them, so that might be a worthwhile pathway to study. Maybe inject a safe dose (no more than what you'd generate from a cold) of each cytokine, and see which affect ME symptoms?

 

[Jacob Deasy]

Hello, first time posting. To the authors, thank you for this detailed article.
Can someone help me understand the statement in the article
‘Data from the UK Biobank also showed that having persistent DNA of EBV in blood is not associated with (self-reported) ME/CFS, while it is linked to several autoimmune diseases.’
When the UKBB paper mentions a significant association in the image attached.
Maybe I am missing something?

 

[forestglip]

Welcome @Jacob Deasy, thanks for posting!

When the UKBB paper mentions a significant association in the image attached.
Maybe I am missing something?

They report an association with fatigue, but as noted in this thread, they did not find a similar association with ME/CFS: https://www.s4me.info/threads/popul...-of-persistent-ebv-dna-2026-nyeo-et-al.45162/

This is from Chris Ponting's comment on Science Media Centre:

Nevertheless, ME/CFS is not classified under R53 (rather, under G93.3), so this interesting association is not clearly relevant to ME/CFS (which has many other symptoms beyond fatigue), but rather is relevant to asthenia, debility, general physical deterioration, lethargy and tiredness. From their supplementary data, ME/CFS (G93.3) had the opposite effect (i.e., was correlated negatively with EBV DNA levels), albeit not significantly.

 

[ChronicallyOverIt]

Thank you for this. Shared with my local groups. It’s great to be able to have something to communicate the general ideas I’ve read hear over the last year in such a concise way.

 

[Peter T]

It will take time for me to read the full article, but it does feel that this article is an important analysis of this area of research. I have long thought that we need clear overviews of what feels like fragmented and incomplete research into the biology of ME/CFS.

 

[MrMagoo]

This is great! As “not a scientist” I’ve reduced this down to “it’s not inflammation” for the “not a scientist yet feel qualified to opine on my illness” people in my life.