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

[V.R.T.]

And this summary, written by our friend, is truly devastating for those hoping for a quick treatment or a major breakthrough in the coming years. We are still a long way off.

I've gotten the distinct impression over the last year or so that the researchers and clinicians on this forum are not nearly so pessimistic. There is a lot of talk about how a breakthrough could happen soon. But I don't need to tell you that at this point.

I think there's a middle ground between believing Ron Davis is going to save us all tomorrow and a sort of fatalistic pessimism thinking it's going to be ages and we are very far off of any sort of breakthrough. I don't think either are a realistic reflection of the reality of the situation.

 

[bscheurle]

Thank you so much for your post. I'm French, and your article has really shaken things up for patients, especially those with severe cases, because it's realistic, dispassionate, and factual.

Many believe that Carmen Scheibenbogen and Klaus Wirth have the solution and are making progress toward a treatment.
They think Ron Davis is a genius in MECFS research, that his story about the Itaconate Shunt is well-supported, and that OMF only needs the funding to find the solution (OMF is wasting a lot of resources, in my opinion)...
Polybio has hundreds of millions of dollars and has lost a lot, but they are clearly finally going to target tissues, especially intestinal tissue.

Are there other Ponting, Edwards, Fluge and Mella etc.? I think Lipkin will be releasing a study soon too? In any case, you've shattered a lot of hope, but it had to be done. Well done on your work.

My experiences talking with patients on various social media sites have taught me that for many folks, citing a single (often poor quality) paper is sufficient for them to feel as if they have demonstrated something apodictically. They aren’t open to the fact that lots of other research challenges their preferred paper. They almost never investigate whether the evidence within a given paper even supports its claims.

I can only guess that this is because, at least in the USA, high school students are taught that this is what it looks like to provide evidence. We were taught that we’ll get a good grade as long as we cite claims with a single study. We also learn about the history of science as if it is constituted by a series of famous experiments that each alone demonstrated their findings, and I think people conclude that every paper is like this. Of course there are other explanations for why people cling to individual headlines, but I think a general lack of understanding of how science moves forward is ultimately to blame.

 

[neophyte32]

I've gotten the distinct impression over the last year or so that the researchers and clinicians on this forum are not nearly so pessimistic. There is a lot of talk about how a breakthrough could happen soon. But I don't need to tell you that at this point.

I think there's a middle ground between believing Ron Davis is going to save us all tomorrow and a sort of fatalistic pessimism thinking it's going to be ages and we are very far off of any sort of breakthrough. I don't think either are a realistic reflection of the reality of the situation.

Yes, you're right, my friend. I'm in PEM, and very pessimistic when I'm in this state...
To get back to the blog post, it rightly points out the multitude of small cohort studies, poorly conducted and, in fact, useless.
As it specifies, "Large-scale studies on viral persistence, antibodies, and cytokines have not yielded any significant results. The current hypothesis of low-grade inflammation is very poorly supported. These results have important implications for future research. Immune hypotheses concerning ME/CFS will have to explain and take these negative results into account."
But will they take these negative results into account? No, they'll keep going and going...
I know there's optimism on this forum, but I'm not currently aware of any scientists conducting a very thorough study with funding and a large patient cohort on the brain and the central nervous system (SequencEM ?). Polybio will focus on tissues, particularly the gut, finally. But the brain?
Then again, there might be researchers on the right track working quietly... Nobody knows.

 

[Dolphin]

It is trending on X

These summaries are created by AI:

Why Advocates Champion Long COVID Without Having It

Last updated 18 hours ago

A post sparked open talk in chronic illness circles about motivations for supporting Long COVID patients, with replies highlighting personal risks like shielding disabled loved ones since 2020 and parallels to conditions such as ME/CFS and chronic Lyme. Amid this, a new ME/CFS review summarized 40 years of immune research, finding no consistent inflammation or viral persistence but noting reduced NK cell function and subtle shifts that echo Long COVID puzzles. Advocates stress prevention and deeper studies into tissues like the gut or brain to benefit everyone facing these post-viral challenges.

https://x.com/i/trending/2035398665448087798

 

[poetinsf]

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

One possibility is that the hypersensitivity to low-grade inflammation, not the inflammation itself, is driving the symptoms, possibly triggering neuroinflammation flareup. Something, most likely the brain, could've become conditioned to overreact after chronic/acute immune stress.

As one review concluded: “Exercise does not result in abnormally higher levels of pro- or anti-inflammatory cytokines in patients with CFS.” Another review stated that “following physical exercise, there were no differences in circulating cytokine levels between cases and controls.”

Same thing here. One study I've seen mentions 100x spike after a maximal exertion on stationary bike. But it's pretty conclusive at this point that there is no difference in cytokine levels between the cases and controls. The difference in the sensitivity (to tiny spikes after minimal exertion), however, could explain the different response to minimal exertion.

 

[Robert 1973]

Really good article. Thank you @ME/CFS Science Blog.

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.

Have you consider doing submitting a review paper based on this article for publication, perhaps in collaboration with any professionals in the field or others who offer feedback?

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

As far as I’m aware Jo Cambridge isn’t an immunologist. She is emeritus professor in rheumatology and inflammation but I don’t think she is a medical doctor. @Jonathan Edwards will know.

 

[poetinsf]

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.

I've been wondering if there is a way to artificially increase cytokine levels to test this hypothesis. A quick search didn't turn up any answer. It seems all medicine/research are directed on reducing, not increasing, inflammatory cytokine level. If you can increase the cytokine level somehow without exertion, it could conclusively tell if the cytokine-hypersensitivity is the driver in ME/CFS.

 

[jnmaciuch]

I've been wondering if there is a way to artificially increase cytokine levels to test this hypothesis. A quick search didn't turn up any answer. It seems all medicine/research are directed on reducing, not increasing, inflammatory cytokine level. If you can increase the cytokine level somehow without exertion, it could conclusively tell if the cytokine-hypersensitivity is the driver in ME/CFS.

Artificial forms of many cytokines exist and some are even used as treatments, but to do this in a study outside of the context of treatment and with no sense of how it might harm pwME who suffer from an unknown mechanism, it would be incredibly hard to get ethical approval (and I think most conscientious scientists wouldnt even want to propose it)

 

[poetinsf]

I think there's a middle ground between believing Ron Davis is going to save us all tomorrow and a sort of fatalistic pessimism thinking it's going to be ages and we are very far off of any sort of breakthrough.

One of my beef about ME/CFS research has been the random nature of it. Science tends to converge towards common solutions after decades. ME/CFS, however, has been all over the map as if it's taking a random walk. It seems that every decade or so a new crop of second-rate minds come onboard and rehash what's been covered. Virus, muscle, metabolism, sickness behavior, kindling, you name it. Yet, none of them even fully explain the phenomena. This random trajectory makes me think that ME/CFS is unlike any other diseases. (I don't have to tell you that, of course).

Hopefully, the something significant and credible will happen within a year or so and the science converge. Whoever makes that happen should be awarded a Novel prize as it will make difference to millions of people around the world.

 

[poetinsf]

Artificial forms of many cytokines exist and some are even used as treatments, but to do this in a study outside of the context of treatment and with no sense of how it might harm pwME who suffer from an unknown mechanism, it would be incredibly hard to get ethical approval.

Even tiny amount? We do allergy test all the time. Raise the level by the amount no more than typical flu shots do and they could consider it an allergy test. But, yes, there are unknowns in ME/CFS, so I get it.

 

[jnmaciuch]

Even tiny amount? We do allergy test all the time. Raise the level by the amount no more than typical flu shots do and they could consider it an allergy test. But, yes, there are unknowns in ME/CFS, so I get it.

If you propose a study that involves unknown potential harm to a human subject, it needs to have a benefit for the patient that outweighs the risk. For pwME the obvious benefit would be learning something about the disease, but thats also a perspective that is skewed by decades of no real answers. That argument would be an extremely tough sell to a IRB panel of largely scientists and administrators (with one layperson).

At most you might be very lucky and get approval to do something like that in healthy subjects with the argument that it’s no more harmful than what they would experience in normal infections. But if I’m proposing a study where the premise is “I think pwME will overreact to this stimulus to an unknown degree” that argument kind of goes out the window.

 

[obeat]

apodictically

I have learned a new word thank you.

 

[Jonathan Edwards]

As far as I’m aware Jo Cambridge isn’t an immunologist. She is emeritus professor in rheumatology and inflammation but I don’t think she is a medical doctor. @Jonathan Edwards will know.

Jo Cambridge is the one real Immunologist here. She is emeritus professor, probably of immunology. She is not a rheumatologist but worked alongside me in a department of rheumatology at UCL.

I am emeritus professor in connective tissue medicine and was a clinical physician/rheumatologist.

Amolak Bansal was a physician working in immunology and infectious disease at St Helier.

 

[Peter T]

I have learned a new word thank you.

Me too: apodictically = clearly established or beyond dispute

 

[Creekside]

"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."

That sounds unlikely to me. To me it's much more likely that ME is triggered by a normal elevation of some immune signals, and may--in some PWME--be followed by an exaggerated response to normal fluctuations in immune signals. There's no need to postulate an undiscovered immune signal with a magical ability to avoid previous testing technologies.

For researchers whose "hammer" is blood measurement, I suppose everything looks like something to be found in the blood.

 

[Creekside]

But if I’m proposing a study where the premise is “I think pwME will overreact to this stimulus to an unknown degree” that argument kind of goes out the window.

It depends on the magnitude of "overreact". For subjects who have suffered many incidents that resulted in months-long debilitating crashes, it qualifies as "harm". For subjects who just feel worse for a day, it's merely an inconvenience, and they might judge it worth the chance of discovering something that leads to genuine understanding of ME's mechanism. I'd participate in such testing, since the expected "worst case" is only a day of inconvenience.

 

[jnmaciuch]

It depends on the magnitude of "overreact". For subjects who have suffered many incidents that resulted in months-long debilitating crashes, it qualifies as "harm". For subjects who just feel worse for a day, it's merely an inconvenience, and they might judge it worth the chance of discovering something that leads to genuine understanding of ME's mechanism. I'd participate in such testing, since the expected "worst case" is only a day of inconvenience.

If I’m explicitly stating that I expect pwME to have an exaggerated response that hasn’t been quantified yet, the ethics committee is going to seriously doubt whether I can just pull a dosage out of thin air that guarantees only “mild inconvenience.” Setting up a study where I start with tiny amounts and ramp up until I get a dose that elicits a response—where the only benefit to participants is “maybe we learn something interesting”—is similarly a non starter both on the ethical and logistical fronts. It’s done in trials for promising drugs where all the phase 1 participants can be adequately compensated, not for exploratory studies.

And the calculations of the participants don’t really matter so much as the view of the entire ethics committee, of which there will usually only be one patient representative if that.

 

[ME/CFS Science Blog]

Thanks for all the comments and feedback.

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.

The big cytokine studies also tested a (small) selection of chemokines (CXCL1 CXCL5 CXCL9 CXCL10, CCL2, etc.)

Would it maybe be good to use links to your Bluesky posts instead of Twitter posts?

Done, thanks.

In any case, you've shattered a lot of hope, but it had to be done.

It does trouble me that I might have shattered people's hope, certainly not my intention.

I used to write more about the problems with GET/CBT and the history of psychosomatic medicine, but have changed to more biomedical research because the findings are becoming more interesting.

The DecodeME study gave valuable clues into the pathology of ME/CFS and the COVID-19 pandemic confirmed the existence of ME/CFS as a syndrome. This was quite important to me. The diagnostic boundaries might not be ideally drawn yet but the pandemic showed that there is a particular illness triggered by infection and characterised by symptoms such as OI, PEM, light and sound sensitivity, extreme exhaustion etc.

Negative results on immune activation, antibodies or viral persistence might be disappointing but they help us pin down what type of pathology we're looking for. So I have a feeling that we're laying more pieces of the puzzle and closing in on our target. Hopefully this gives others hope for the future as well.

 

[ME/CFS Science Blog]

Have you consider doing submitting a review paper based on this article for publication, perhaps in collaboration with any professionals in the field or others who offer feedback?

Have no plans in that direction myself but always happy to help if there are researchers who plan to write a review or paper along the same lines.

To me it's much more likely that ME is triggered by a normal elevation of some immune signals, and may--in some PWME--be followed by an exaggerated response to normal fluctuations in immune signals.

One possibility is that the hypersensitivity to low-grade inflammation, not the inflammation itself, is driving the symptoms, possibly triggering neuroinflammation flareup. Something, most likely the brain, could've become conditioned to overreact after chronic/acute immune stress.

But in that case, dampening that normal immune response with for example anakinra or IL-6 inhibitors should actually help to reduce symptoms?

 

[bscheurle]

Thanks for all the comments and feedback.

The big cytokine studies also tested a (small) selection of chemokines (CXCL1 CXCL5 CXCL9 CXCL10, CCL2, etc.)


Done, thanks.


It does trouble that it might have shattered people's hope, certainly not my intention.

I used to write more about the problems with GET/CBT and the history of psychosomatic medicine, but have changed to more biomedical research because the findings are becoming more interesting.

The DecodeME study gave valuable clues into the pathology of ME/CFS and the COVID-19 pandemic confirmed the existence of ME/CFS as a syndrome. This was quite important to me. The diagnostic boundaries might not be ideally drawn yet but the pandemic showed that there is a particular illness triggered by infection and characterised by symptoms such as OI, PEM, light and sound sensitivity, extreme exhaustion etc.

Negative results on immune activation, antibodies or viral persistence might be disappointing but they help us pin down what type of pathology we're looking for. So I have a feeling that we're laying more pieces of the puzzle and closing in on our target. Hopefully this gives others hope for the future as well.

I think if you have shattered hope, you have only shattered ungrounded hope. And although ungrounded hope might help make someone feel better for a bit, it can only coincidentally lead to long term satisfaction (more often than not, it leads to disappointment).

You haven’t shattered any well-placed hope. Your summary isn’t overly pessimistic or anything. You’ve just pointed out that, even if we might be somewhat close to having a good understanding of ME/CFS, we aren’t all the way there yet. That still leaves plenty of room for hope!