Abnormal T-Cell Activation And Cytotoxic T-Cell Frequency Discriminates Symptom Severity In [ME/CFS],2025, Lee, Cliff et al

[hotblack]

I’ve been back over the webinar and parts of the paper and it certainly raises lots of thoughts or half formed questions, particularly in light of the paper Jackie contributed to with @Jonathan Edwards and Jo. That would seem to fit the severe or ‘over sensitive’ ‘over reactive’ immune subtype well. But I also don’t see any clear reason here that it couldn’t fit the mild/moderate too?

Maybe the ‘aging cells’ or ‘viral persistence’ vs ‘heightened activation’ or ‘pro inflammatory’ is only narrative and the differences are subtle and not causative?

Rather than being different mechanisms could there be the same core mechanism but different pathways on this? Or responding to the same thing in slightly differing ways?

It would be interesting to hear more about how these papers and ideas tie together from the authors/experts in this field.

 

[hotblack]

I went back and watched Dr. Cliff's CureME webinar presentation and I realised that there is an awful lot of overlap between mild/moderate and severe ME/CFS despite there being group differences.

Yes, looking over the paper there seems to be a lot of similarities outside of these very specific differences too.

For instance:

Firstly, we compared the frequencies of T cells (identified as CD3+) and T cell subsets (CD4+ T cells, CD8+ T cells, CD4-CD8- Double Negative (DN) T cells, CD4+CD8+ Double Positive (DP) T cells, CD3+CD56+ NKT-like cells), as well as NK cells (identified as CD3-CD56+) and CD8+CD56+NK cells (“NK8 cells”) in ex vivo PBMCs from people with ME-MM or ME-SA, and found there were no differences between the two clinical groups (Supplemental Figure 2A-2H).

There was no significant difference in CD4+CD8+MAIT frequency between the two groups.

There were no significant differences in frequencies of naïve/memory subsets in CD4+ or CD8+ T cells between the ME-MM and ME-SA groups, nor were there any differences in the frequencies of CD57-CD28+, CD57-CD28-, CD57+CD28-or CD57+CD28+ subsets (Supplemental Figure 4).

I like the questions @wigglethemouse has been been raising.

Hopefully things will make more sense with greater context and information, maybe even after DecodeME, but if not then after other studies of T cell populations. But for now it seems it’s difficult for those of us not deep into immunology, and perhaps also for those who are, to draw too many conclusions, especially on mechanisms or correlation/causation.

It seems like these results are telling us something. But what that something is I’m not sure and it seems quite open to interpretation.

 

[wigglethemouse]

Yes, looking over the paper there seems to be a lot of similarities outside of these very specific differences too.

For instance:

When I asked Drs Selin/Gil about double positive CD4+CD8+ cells they said that you need to sort the cells first before analysing and that is why the CureME immune paper did not detect differences.

This was the post where I provided more information

https://www.s4me.info/threads/identification-of-cd8-t-cell-dysfunction-associated-with-symptoms-in-me-cfs-and-long-covid-and-treatment-with-a-nebulized-2023-gil-et-al.36702/post-509630

 

[wigglethemouse]

This was the tweet contents by @Susan K in case you can't access:

Standard flow cytometry doesn't involve cell sorting like the magnet sort FACS. So the latter isolates a much more specific population, & allows sorted cells for further analysis like cytokine secretion Video describing difference, begin at 1 hour, 2 min



The power of the LSHTM study is they had so many samples from criteria-defined #pwme. The downside is they had to use frozen PBMCs, & multiple folks doing sample prep. An intractable problem with the big studies

 

[hotblack]

Thanks for the links @wigglethemouse really interesting

 

[SNT Gatchaman]

Now published (early access) —

Abnormal T-Cell activation and cytotoxic T-Cell frequency discriminate symptom severity in myalgic encephalomyelitis/chronic fatigue syndrome

Spoiler: Authors

Lee, Ji-Sook; Lacerda, Eliana; Kingdon, Caroline; Abken, Ella; Susannini, Giada; Dockrell, Hazel M; Nacul, Luis; Cliff, Jacqueline M

BACKGROUND
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating but poorly-understood disease. ME/CFS symptoms include immune system effects alongside incapacitating fatigue and post-exertional disease exacerbation. Symptom severity can range from mild to severe and whilst symptoms can fluctuate, few people fully recover.

METHODS
Immunological profiles of people living with ME/CFS were analysed by flow cytometry, focusing on cytotoxic cells, to determine whether people with mild/moderate (n = 43) or severe ME/CFS (n = 53) expressed different immunological markers. Flow cytometry data were tested for normality and the two clinical groups were compared by t-test or Mann-Whitney U-test as appropriate.

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.

Web | DOI | PDF | Journal of Translational Medicine | Open Access

 

[Ravn]

Has anyone looked at this study again in light of the DecodeMe results?

 

[Mij]

Did the study factor in or include the length of time pwME were ill?

 

[bobbler]

This is really interesting phrasing for PEM, and I have to say, as a severe person, it encompasses my experience far better than “PEM”.

Agreed I think it is an interesting point for us to consider on as I think we don’t emphasise enough that it’s not just a ‘being under the weather for x days of pain etc’ issue but that ‘deteriorating as long as the cumulative commitments and exertion keep being over threshold ‘in a certain way’’ as the illness but with these strange PEM patterns and cycles feeling like clues as to mechanisms going on

 

[DMissa]

I gave 100 samples to a collaborating T cell lab a week or two ago, will have some interesting results to follow this up with maybe next year