Abnormal T-Cell Activation And Cytotoxic T-Cell Frequency Discriminates Symptom Severity In [ME/CFS],2026, Lee, Cliff et al

[hotblack]

So for you, Jacqueline Cliff is now one of your biobabblers as well? Interesting—you seemed to hold her in very high regard.

Nobody has said that. To me it’s an unhelpful misinterpretation or misrepresentation of what has been said.

I think it’s also misinterpretation of the results to make the claims you have. I don’t know what the studies tell us about the causes but I can see that the papers are not saying that.

Maybe someone will show what you claim in the future, who knows. But these papers are not and those who have made that claim up until now have never been able to back it up.

 

[Andy]

An immune system with very-good self-repair powers (we see that in the young patients who often go into full remission), rest and pacing. What explanation do you have?

That your theory isn't supported by the evidence.

 

[hotblack]

An immune system with very-good self-repair powers (we see that in the young patients who often go into full remission), rest and pacing. What explanation do you have?

Luck, chance, underlying genetic predisposition, something unknown. There’s lots of possibilities.

Plenty of young people who rest and pace become severe.

 

[PageofME]

That your theory isn't supported by the evidence.

I'm not quite sure what you mean by "theory"—do you mean the herpes virus theory, or my idea about why some (particularly young) patients go into full remission?

 

[Andy]

Does she talk of hyperinflammation?

Not in the published paper this thread is about. And as far as I can see the paper doesn't even talk about inflammation, let alone hyperinflammation.

 

[hotblack]

As its been referenced here I’ve posted a link to the CureME email in the updates thread so others can read it first hand including the mentions of this paper and the HHV6 project.

 

[PageofME]

Not in the published paper this thread is about. And as far as I can see the paper doesn't even talk about inflammation, let alone hyperinflammation.

My question was whether my summary of the findings by Cliff and her team—describing the immune system of severe patients as hyper-inflammatory and aberrant—is correct. I didn't claim that Cliff used this exact description. How would you summarize the state of the immune system in severe patients according to her findings?

 

[Jonathan Edwards]

A simpler explanation is that the immune system gets so pathological and dysfunctional that it doesn't look like fighting this/these virus(es) anymore, or has lost these capacities.

What is simple about a proposal so vague that it could mean anything?
We have no evidence for anything being wrong with the immune system, in the way that we do in leukaemia or graft versus host disease or lupus or whatever.
Couching things in these teleological terms gets us nowhere.

 

[PageofME]

What is simple about a proposal so vague that it could mean anything?
We have no evidence for anything being wrong with the immune system, in the way that we do in leukaemia or graft versus host disease or lupus or whatever.
Couching things in these teleological terms gets us nowhere.

Could you elaborate: why do you believe that the work of Jacqueline Cliff, Liisa Selin, and other researchers on the immune system in ME/CFS—particularly regarding T-cells—isn't "evidence for anything being wrong"?

When leukaemia and the other diseases you mentioned above were first being researched, was it the first handful of promising studies that proved the whole point, or wasn't it rather a slow process where one study after another built strong evidence over many years?

 

[Trish]

What do you all think?

I have read your post and the abstract. I'm not well enough to read the whole paper.

I can't see anything in the abstract suggesting the immune system is 'fighting a virus' or that the immune system of severe patients is
"so pathological and dysfunctional that it doesn't look like fighting this/these virus(es) anymore".

Can you quote the specific points in the paper that talk about fighting viruses that support your comments?

 

[PageofME]

I have read your post and the abstract. I'm not well enough to read the whole paper.

I can't see anything in the abstract suggesting the immune system is 'fighting a virus' or that the immune system of severe patients is
"so pathological and dysfunctional that it doesn't look like fighting this/these virus(es) anymore".

Can you quote the specific points in the paper that talk about fighting viruses that support your comments?

I'm not interested in social media ancedotes about treatment in this context. They are not useful scientific information.

RESULTS
People with mild/moderate ME/CFS had increased expression of cytotoxic effector molecules alongside enhanced proportions of early-immunosenescence cells, determined by the CD28-CD57- phenotype, indicative of persistent viral infection. In contrast, people with severe ME/CFS had higher proportions of activated circulating lymphocytes, determined by CD69+ and CD38+ expression, and expressed more pro-inflammatory cytokines, including interferon-γ, tumour necrosis factor and interleukin-17, following stimulation in vitro, indicative of prolonged non-specific inflammation. These changes were consistent across different cell types including CD8+ T cells, mucosal associated invariant T cells and Natural Killer cells, indicating generalised altered cytotoxic responses across the innate and adaptive immune system.

CONCLUSIONS
These immunological differences likely reflect different disease pathogenesis mechanisms occurring in the two clinical groups, opening up opportunities for the development of prognostic markers and stratified treatments.

 

[PageofME]

i was responding directly to the text you posted as 'your argument'

My argument was that if there is indeed an immune system fighting a virus in mild/moderate patients—as Cliff and her team have shown in this study—and an aberrant, hyper-inflammatory immune system in severe patients, why conclude that there are two different subgroups? I think it is more compelling to consider that the immune system simply loses its capacity for a targeted fight against the virus or viruses when deteriorating.

 

[EndME]

My argument was that if there is indeed an immune system fighting a virus in mild/moderate patients—as Cliff and her team have shown in this study—and an aberrant, hyper-inflammatory immune system in severe patients.

To me this is pure interpretation of data and I don't see that the data we have supports this intepretation.

 

[PageofME]

To me this is pure interpretation of data and I don't see that the data we have supports this intepretation. And I'd even guess that GPT-Astra with the "appropriate" harnesses to prevent a reiteration of "social media trends" would not support that argument either.

What I referenced and what you quote here is from the results section. Then the abstract suggests in the conclusion that there are two subgroups with different pathomechanisms. One of my questions is why they came up with this. Completely legitimate question, I believe.

Are you not convinced that Cliff's results are sound?

In the results they say: people with severe ME/CFS had higher proportions of activated circulating lymphocytes, determined by CD69+ and CD38+ expression, and expressed more pro-inflammatory cytokines, including interferon-γ, tumour necrosis factor and interleukin-17, following stimulation in vitro, indicative of prolonged non-specific inflammation. These changes were consistent across different cell types including CD8+ T cells, mucosal associated invariant T cells and Natural Killer cells, indicating generalised altered cytotoxic responses across the innate and adaptive immune system.

Or do you disagree with my summary of that abstract that severe patients show an "aberrant, hyper-inflammatory" immune system.

 

[PageofME]

I wonder whether there is so much confusion because this thread was launched when the pre-print was published. The abstract of the final study which I base my argument and questions on you find here on page three of the thread.

 

[jnmaciuch]

Just to situate the interpretation of this paper, these are the figures that the claim of possible indirect evidence of chronic antigen stimulation are drawing from. Each panel is missing one T cell subset that would have been tested (likely not shown because of lack of group differences). CD28-CD57- is also a weird population to zoom in on—the one typically associated with chronic antigen is CD28-CD57+, since CD57 increases as CD28 decreases.

The text claims that CD28-CD57- represents an “early senescence” phenotype, but found no difference in the classic “senescence” phenotype. Which doesnt particularly fit with a story of chronic antigen stimulation. These are long-lived T cell populations. If this is a real difference and not a chance artifact, why would only the small subpopulation of a subpopulation of cells just barely starting to reflect signs of chronic stimulation show a difference in number? We also don’t know the antigen specificity of these subsets: a virus-specific population of these T cells would only skew overall population numbers if they were a significant proportion of the memory T cells, which would happen downstream of clonal expansion, which we don’t have strong evidence of in ME/CFS.

When you look through the whole text, figures, and supplemental figures you get a sense of the sheer scale of different subpopulations measured and compared between groups. What isnt shown in this figure is the comparisons across CD4 and CD8 CMs, EMs, and TEMRAs for all the other combinations of CD57 and CD28. Which is a very large number of things to check with no p-value correction for multiple testing. And that’s just for one figure.

Even if these findings are real and not the result of random chance (being extremely generous I might say they somewhat fit with the “increased markers of exhaustion” line from the Grimson lab) this is not strong evidence of chronic antigen stimulation from a persistent virus. These T cell markers respond to all kinds of things, including other transient immune signaling that has nothing to do with a hidden virus.

And no, none of this is evidence of a “hyperinflammatory” or even an “inflammatory” state. You can’t define that from T cell populations alone.

 

[V.R.T.]

What I referenced and what you quote here is from the results section. Then the abstract suggests in the conclusion that there are two subgroups with different pathomechanisms. One of my questions is why they came up with this. Completely legitimate question, I believe.

Are you not convinced that Cliff's results are sound?

In the results they say: people with severe ME/CFS had higher proportions of activated circulating lymphocytes, determined by CD69+ and CD38+ expression, and expressed more pro-inflammatory cytokines, including interferon-γ, tumour necrosis factor and interleukin-17, following stimulation in vitro, indicative of prolonged non-specific inflammation. These changes were consistent across different cell types including CD8+ T cells, mucosal associated invariant T cells and Natural Killer cells, indicating generalised altered cytotoxic responses across the innate and adaptive immune system.

Or do you disagree with my summary of that abstract that severe patients show an "aberrant, hyper-inflammatory" immune system that I took from Gemini?

If JCs results are sound (and we should know fairly soon as her studies continue and as we saw upthread Dmissa has a study in analysis phase which may replicate this if I understood correctly), then we cannot assume that they are due to viral reactivation as opposed to some kind of signalling issue.

I do agree with you that Cliffs interpretation of mild/moderate and severe being two different diseases makes little sense. I emailed her about this last year and recieved no response sadly.

The severe ME results line up with two recent studies showing increased CD38 and IFNy in pwME and long covid respectively.

Edit: Cross posted with a much more detailed and knowledgeable analysis by @jnmaciuch

Edit 2: The CD38 expression in the Mensah/Armstrong/Cambridge paper was from B cells after stimulation iirc as opposed to T cells like here.

 

[Mij]

I wonder about that framing around different subgroups in the conclusion. Why did they come up with this?

I think we might find some answers if EBV as a prerequisite for the development of MS (which has 4 official subgroups) has similarities to ME onset and progression that contributes to immune dysregulation.

My close friend who was a patient of Dr. John Chia tried the medications that you are taking and continued to worsen after 18yrs of illness.

 

[PageofME]

View attachment 34487
Just to situate the interpretation of this paper, these are the figures that the claim of possible indirect evidence of chronic antigen stimulation are drawing from. Each panel is missing one T cell subset that would have been tested (likely not shown because of lack of group differences). CD28-CD57- is also a weird population to zoom in on—the one typically associated with chronic antigen is CD28-CD57+, since CD57 increases as CD28 decreases.

The text claims that CD28-CD57- represents an “early senescence” phenotype, but found no difference in the classic “senescence” phenotype. Which doesnt particularly fit with a story of chronic antigen stimulation. These are long-lived T cell populations. If this is a real difference and not a chance artifact, why would only the small subpopulation of a subpopulation of cells just barely starting to reflect signs of chronic stimulation show a difference in number? We also don’t know the antigen specificity of these subsets: a virus-specific population of these T cells would only skew overall population numbers if they were a significant proportion of the memory T cells, which would happen downstream of clonal expansion, which we don’t have strong evidence of in ME/CFS.

When you look through the whole text, figures, and supplemental figures you get a sense of the sheer scale of different subpopulations measured and compared between groups. What isnt shown in this figure is the comparisons across CD4 and CD8 CMs, EMs, and TEMRAs for all the other combinations of CD57 and CD28. Which is a very large number of things to check with no p-value correction for multiple testing. And that’s just for one figure.

Even if these findings are real and not the result of random chance (being extremely generous I might say they somewhat fit with the “increased markers of exhaustion” line from the Grimson lab) this is not strong evidence of chronic antigen stimulation from a persistent virus. These T cell markers respond to all kinds of things, including other transient immune signaling that has nothing to do with a hidden virus.

And no, none of this is evidence of a “hyperinflammatory” or even an “inflammatory” state. You can’t define that from T cell populations alone.

So you'd say that what Cliff and her team state in their results section is baseless, or at least completely exaggerated? And why do you claim that one can't make these inferences from T-cells alone, given that they measured so many other markers?

 

[jnmaciuch]

So you'd say that what Cliff and her team state in their results section is baseless, or at least completely exaggerated?

I would say that the line “indicative of persistent viral infection” is not well supported by the presented evidence.

And why do you claim that one can't make these inferences from T-cells alone, given that they measured so many other markers?

All the markers they reported were on T/NK cells.