Preprint Abnormal T-Cell Activation And Cytotoxic T-Cell Frequency Discriminates Symptom Severity In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome,'25,Lee

[Dolphin]

https://www.medrxiv.org/content/10.1101/2025.01.02.24319359v1

Abnormal T-Cell Activation And Cytotoxic T-Cell Frequency Discriminates Symptom Severity In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Ji-Sook Lee1,3, Eliana Lacerda2, Caroline Kingdon 2, Giada Susannini1, Hazel M Dockrell1, Luis Nacul2*, Jacqueline M Cliff3*

*These authors contributed equally to this work.

1Department of Infection Biology and 2Clinical Research Department, Faculty of Infectious and Topical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT. 3Centre for Inflammation Research and Translational Medicine, and Division of Biosciences, Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, Kingston Lane, Uxbridge, UB8 3PH. Corresponding Author: Dr Jacqueline Cliff, Division of Biosciences, Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, Kingston Lane, Uxbridge, UB8 3PH, United Kingdom, +44 (0) 1895 268803


Abstract

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

In this study, we examined immunological profiles of people living with ME/CFS 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.

We found that 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.

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 IFNγ, TNF and IL-17, following stimulation in vitro.

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 .

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

https://twitter.com/user/status/1876639897525837908

 

[Dolphin]

https://twitter.com/user/status/1876641561242484975

 

[Creekside]

Could the differences be due to different lifestyles (activity, diet, etc) and different exposure to pathogens? I'm guessing that someone with mild ME would encounter more variety of microbes than a bedridden person, and thus have different immune system challenges.

 

[Yann04]

post-exertional disease exacerbation

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

 

[Yann04]

to determine whether people with mild/moderate (n= 43) or severe ME/CFS (n=53) expressed different immunological markers.

I know this isn’t a massive sample size but it’s refreshingly large compared to the 5-10 patients in most studies.

I'm guessing that someone with mild ME would encounter more variety of microbes than a bedridden person, and thus have different immune system challenges.

Interesting hypothesis. Sounds like a possible confounding factor. Although pwSevere ME still often have quite a bit of pathogen spread due to interaction with caregivers, in fact, a severe person requiring a caregiver might end up having more human (=pathogen) contact that a mostly housebound mild/moderate person who lives on their own.

 

[Jonathan Edwards]

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

Except that if we don't know what the 'disease' is or whether there is one or two or six it doesn't mean much does it? The paper is making an argument for there being two routes to symptoms (moderate and severe being different) or, if you like, two different diseases.

 

[Sean]

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

Does have the somewhat problematic acronym of PEDE.

 

[SNT Gatchaman]

Glad they didn't go with overactivation.

 

[Yann04]

Does have the somewhat problematic acronym of PEDE.

Certainly doesn’t work in french, but to be fair translating the underlying words gives EMPE.

I’m not aware of what PEDE could mean in english? In French “Pede” is a really derogatory word for queer people, but I don’t think I’ve ever heard that in english?

 

[Peter T]

Certainly doesn’t work in french, but to be fair translating the underlying words gives EMPE.

I’m not aware of what PEDE could mean in english? In French “Pede” is a really derogatory word for queer people, but I don’t think I’ve ever heard that in english?

Who knows what it might be taken for in the UK, if ignorance is willing. One thinks of the lady doctor here in the UK who was targeted some years back because a small group of people confused ‘paediatrician’ with ‘pedophile’.

 

[Sean]

One thinks of the lady doctor here in the UK who was targeted some years back because a small group of people confused ‘paediatrician’ with ‘pedophile’.

Yep.

Some brains cannot comprehend the critical difference between PEDE, paed, and pedo.

 

[Yann04]

paed, and pedo.

To be fair paed has the same root as ped in pedophile, which comes from ancient greek “paid” meaning children.

But yeah it’s kind of baffling people will confuse words with pedophile.

 

[V.R.T.]

So is this paper arguing for two entirely separate diseases? Or is this another situation with different stages or states being proposed as we discussed in the thread about the Ryback paper?

My experience of mild ME for three and a half years before getting worse and hundreds of other stories like mine I've read over the last four years strongly suggest the latter.

I suppose another possibility is that severe ME is a disease you are more likely to get or trigger if you have mild/moderate? But again I'm not sure I buy this.

This raises the spectre of different treatment pathways...

Does anyone know if the Lee team plan to follow up this paper?

 

[wigglethemouse]

This is a very technical paper that I find very hard to understand. This study is ONLY ME/CFS mild/moderate vs severe to show the differences in T cell behaviour between the two groups.

It really needs to be interpreted together with their 2019 paper (link to thread) which included T cell analysis of controls and MS as well as ME/CFS mild/moderate and severe. I wish they had provided some commentary that included the findings of that paper as a comparison.

For example in the 2019 paper

However, modest differences were observed in several differentiation populations in the CD8+ T cell compartment (Figure 5B) with a small increase in the proportion of EM cells (CCR7-CD45RA-CD28-CD57-) and a reduction in the proportion of terminally differentiated cytotoxic effector TEMRA cells (CCR7-CD45RA+CD28–CD57+) in people living with ME/CFS.

But this paper states

Moreover, a similar pattern was also seen in CD8+ T cells, with the frequency of CD57-CD28- cells in the CD8+ EM and CD8+ TEMRA T cell subsets being significantly elevated in ME-MM compared to ME-SA

With no reference to to HC or MS I don't know whats up and whats down compared to HC for mild/moderate & severe. The 2019 plot of data for this is really tiny and illegible.

It also means I don't know how to interpret the conclusions as no reference is given to healthy controls. For example what is given as "pro-inflammatory" in one group means nothing to me in comparison to healthy control as it could be perfectly normal compared to HC for all I know.

In conclusion, our results elucidate that people with ME/CFS with different symptom severity had different immune profiles in T cells in aspects of activation, differentiation and cytotoxic effector molecule expression.

These immunological differences open up the possibility of different disease aetiology and pathogenesis mechanisms in the two groups.

These findings may suggest that people with ME-MM have frequent antigen exposure, likely related to persistent viral infection and frequent reactivation, leading to the appearance of early senescence memory T cells and MAIT cells, and also the expression of more cytotoxic effector molecules in cytotoxic cells with diminished CD8 molecules on CD8+T cells.

In contrast, people with ME-SA had an ongoing uncontrolled pro-inflammatory immune system activation, with more activated T cells in blood, and higher cell activation and pro-inflammatory cytokine production in response to stimulation.

The sustained activation and inflammatory cytokine production in ME-SA may be a cause or result of symptom exacerbation, and may contribute to symptom severity.

These differences support the importance of careful patient stratification in the clinical management of ME/CFS, and also in the development of new diagnostic tools and treatments.

It is still a preprint so I guess there is time to make this paper more understandable with relation to a HC population and an MS disease comparison if sufficient data is available to do so.

 

[wigglethemouse]

It is interesting though that there is such a difference between mild moderate and severe. The conclusions are that these could be two different diseases.

I was mild/moderate for decades until what seemed like a switch flipped to severe. Did I have two different diseases or did some mechanism flip? I'd be interested to here about others who are severe and did they experience a long mild/moderate phase or straight into severe quite quickly.

Has such a survey ever been carried out? I don't believe the mega ME Action survey has published as there might be data in there somewhere.

 

[V.R.T.]

It is interesting though that there is such a difference between mild moderate and severe. The conclusions are that these could be two different diseases.

I was mild/moderate for decades until what seemed like a switch flipped to severe. Did I have two different diseases or did some mechanism flip? I'd be interested to here about others who are severe and did they experience a long mild/moderate phase or straight into severe quite quickly.

Has such a survey ever been carried out? I don't believe the mega ME Action survey has published as there might be data in there somewhere.

I find this line of inquiry extremely concerning. The idea that mild and severe are different diseases seems totally illogical to me. You would have to discount a lot of patient testimony to even consider it.

Personally, I was mild for three and a half years before becoming severe. I slowly deteriorated over the course of a year from exercise and other overexertion, and a covid infection that demolished me when i was already couchbound.

I did email Jackie Cliff with detailed concerns about drawing such conclusions when she did the webinar earlier this year but she never emailed back.

 

[V.R.T.]

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 IFNγ, TNF and IL-17, following stimulation in vitro.

It is interesting that they found CD38 and IFNy in severe and not in milder patients..

 

[DMissa]

The idea that mild and severe are different diseases seems totally illogical to me. You would have to discount a lot of patient testimony to even consider it.

I would not refer to it as different diseases, but if something is progressing there may be different components of the contributing processes becoming more or less deranged or consequential as things get worse.

 

[Sean]

I too see no reason to conclude they are different diseases. Could just as easily be due to different levels of severity.

 

[Peter T]

People with severe ME/CFS have a very different life to people with a mild form, so how do we know whether the differences measured are a down stream effect of the behavioural differences or are inherently part of the underlying condition(s).

(The old chestnut, association is not the same as causation.)