Natural killer cytotoxicity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a multi-site,.., of ME/CFS (MCAM) sub-study 2023

Sly Saint

Sly Saint

Senior Member (Voting Rights)
authors:
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Abstract
Background

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem illness characterized by substantial reduction in function accompanied by profound unexplained fatigue not significantly relieved by rest, post-exertional malaise, and other symptoms. Reduced natural killer (NK) cell count and cytotoxicity has been investigated as a biomarker for ME/CFS, but few clinical laboratories offer the test and multi-site verification studies have not been conducted.

Methods
We determined NK cell counts and cytotoxicity in 174 (65%) ME/CFS, 86 (32%) healthy control (HC) and 10 (3.7%) participants with other fatigue associated conditions (ill control [IC]) from the Multi-Site Clinical Assessment of ME/CFS (MCAM) study using an assay validated for samples shipped overnight instead of testing on day of venipuncture.

Results
We found a large variation in percent cytotoxicity [mean and (IQR) for ME/CFS and HC respectively, 34.1% (IQR 22.4–44.3%) and 33.6% (IQR 22.9–43.7%)] and no statistically significant differences between patients with ME/CFS and HC (p-value = 0.79). Analysis stratified on illness domain measured with standardized questionnaires did not identify an association of NK cytotoxicity with domain scores. Among all participants, NK cytotoxicity was not associated with survey results of physical and mental well-being, or health factors such as history of infection, obesity, smoking, and co-morbid conditions.

Conclusion
These results indicate this assay is not ready for clinical implementation and studies are needed to further explore immune parameters that may be involved in the pathophysiology of ME/CFS.

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-03958-2
 
Sly Saint said:
These results indicate this assay is not ready for clinical implementation
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It is time that ME researchers actually said it how it is.
It is not that the assay is not ready for clinical use. It has no apparent relevance to ME.
A - value of 0.79 is impressive - you could bet on getting a result like this by chance and go home rich.

cassava7 said:
A nail in the coffin.
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More the laying of the turf over the filled in hole.



At least they did the replication. That is one step forward.
 
I am not saying the study is not valid. However I note that their conclusion is

In conclusion, these results indicate this natural killer cell assay is not ready for clinical implementation and studies are needed to further explore immune parameters that may be involved in the pathophysiology of ME/CFS
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So they assessed this one assay, from next day delivery and testing. I would have been curious to see whether results were exactly the same comparing to commercial lab (I believe it is Quest lab) or Dr Fletcher's lab (Linked to Dr Klimas) ?

Does this one assay find any differences with healthy control with any other disease?
 
They also looked for abnormal values of NK cytotoxicity in subgroups such as patients with severe ME/CFS or sudden onset ME/CFS but found nothing. There was also no significant correlation between NK cytotoxicity and symptom questionnaires such as subscale scores of SF-36, MFI-20, CDC-SI and PROMIS.
 
Could lower NK cell cytotoxicity in ME/CFS be due to increased TGF-beta (the cytokine found to be most consistently increased in ME/CFS). Think these are the two immune findings with most consistency across studies (although there is still quite some inconsistency).

There are several studies that report that TGF-beta is an important cytokine in reducing NK cytotoxicity.
TGF-β signalling limits effector function capacity of NK cell anti-tumour immunity in human bladder cancer - eBioMedicine
TGF-β Decreases NK Cell Mobility and Cytotoxic Efficacy in Complex in vitro Models of the Leukemia Microenvironment - PMC
Enhancing human NK cell antitumor function by knocking out SMAD4 to counteract TGFβ and activin A suppression | Nature Immunology
 
Looks like low NK cell cytotoxicity has also been reported in systemic sclerosis where increased TGF-beta is a hallmark feature.
Abnormal Natural Killer Cell Function in Systemic Sclerosis: Altered Cytokine Production and Defective Killing Activity - ScienceDirect

There are lots of things that influence NK cell cytotoxicity though: stress, smoking, obesity. The latter might also be interesting because leptin seems to play a role there in influencing NK function. Leptin is not consistently increased in ME/CFS but it has come up repeated in several more complex analyses.
 
Jonathan Edwards said:
And nobody really knows what the assays mean in clinical terms.
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Perhaps not much as there doesn't seem any immune deficiency or notable susceptibility to cancer in ME/CFS. A risk factor for ME/CFS also doesn't seem likely. So it's presumably some innocuous downstream side-effect of the hidden immune process that is relevant to ME/CFS pathology?

When I look up at possible reasons for reduced NK cytotoxicity, TGF-beta comes up quite prominently so perhaps it isn't a coincidence that these come up repeatedly in ME/CFS? Does anyone know if this been discussed before on the forum?
 
ME/CFS Science Blog said:
When I look up at possible reasons for reduced NK cytotoxicity, TGF-beta comes up quite prominently so perhaps it isn't a coincidence that these come up repeatedly in ME/CFS? Does anyone know if this been discussed before on the forum?
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I know that I raised it as a plausible-sounding connection ages back but i had no evidence base. We might even have mentioned it in the FcR1 paper but probably not.
 
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