Unperturbed Cytotoxic Lymphocyte Phenotype and Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients 2017 Theorell et al

John Mac · Mar 2, 2021

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a debilitating disorder linked to diverse intracellular infections as well as physiological stress. Cytotoxic lymphocytes combat intracellular infections. Their function is attenuated by stress. Despite numerous studies, the role of cytotoxic lymphocytes in ME/CFS remains unclear.

Prompted by advances in the understanding of defects in lymphocyte cytotoxicity, the discovery of adaptive natural killer (NK) cell subsets associated with certain viral infections, and compelling links between stress, adrenaline, and cytotoxic lymphocyte function, we reassessed the role of cytotoxic lymphocytes in ME/CFS.
Forty-eight patients from two independent cohorts fulfilling the Canada 2003 criteria for ME/CFS were evaluated with respect to cytotoxic lymphocyte phenotype and function.

Results were compared to values from matched healthy controls.
Reproducible differences between patients and controls were not found in cytotoxic lymphocyte numbers, cytotoxic granule content, activation status, exocytotic capacity, target cell killing, or cytokine production.

One patient expressed low levels of perforin, explained by homozygosity for the PRF1 p.A91V variant. However, overall, this variant was present in a heterozygous state at the expected population frequency among ME/CFS patients. No single patient displayed any pathological patterns of cellular responses.
Increased expansions of adaptive NK cells or deviant cytotoxic lymphocyte adrenaline-mediated inhibition were not observed.
In addition, supervised dimensionality reduction analyses of the full, multidimensional datasets did not reveal any reproducible patient/control discriminators. In summary, employing sensitive assays and analyses for quantification of cytotoxic lymphocyte differentiation and function, cytotoxicity lymphocyte aberrances were not found among ME/CFS patients.
These assessments of cytotoxic lymphocytes therefore do not provide useful biomarkers for the diagnosis of ME/CFS.
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https://www.frontiersin.org/articles/10.3389/fimmu.2017.00723/full

Correction article
https://www.frontiersin.org/articles/10.3389/fimmu.2019.00350/full

Hutan · Mar 2, 2021

I haven't read this paper yet, but, from the abstract, it seems to be evidence against the idea of dysfunctional NK cells.

Reproducible differences between patients and controls were not found in cytotoxic lymphocyte numbers, cytotoxic granule content, activation status, exocytotic capacity, target cell killing, or cytokine production.
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In summary, employing sensitive assays and analyses for quantification of cytotoxic lymphocyte differentiation and function, cytotoxicity lymphocyte aberrances were not found among ME/CFS patients.
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Swedish and Norwegian researchers.

mango · Mar 2, 2021

The result of this study and an experimental follow-up study was discussed at the IIME conference and colloquium in London 2017. That was before the study was published.

At the time, this group of researchers was trying to find out whether it matters if you perform the tests in "whole blood" or with frozen, isolated cells only. They were trying to figure out why they were getting different results than others in the field. They also wanted to make sure the differences weren't just something random (which of course can happen in small studies like this).

Theorell was about to move on to other areas of medicine/research at the time. I'm not sure if any of the others in the group ever performed any formal experiments or studies to compare blood vs frozen, isolated cells?

This is from an email convo with one of the researchers in 2016:

Google Translate said:

there are differences between our assays and those used by Nancy Klimas. She used a whole blood assay, ie cells that were not isolated. Catecholamines, antibodies, and a variety of other soluble factors can affect the activity of cytotoxic lymphocytes.

To find specific defects in immune cells, with a possible genetic or epigenetic cause, we wanted to work with isolated immune cells, as we by analyzing the system as reductionistically as possible hope to better understand disease mechanisms. However, it is possible that soluble factors in blood may provide new insights into ME/CFS, possibly linked to whole blood assays of NK cell activity, but in that case the abnormality is not in the NK cells, but in the soluble factors that affect the NK cells. which is an important difference from a research and treatment perspective.
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Elizabeth Unger, who was involved in CDC's multi-center study, was at the conference too. I wonder if they compared notes on this?

It was also brought to the attention of Dr Avindra Nath in 2017. Someone I know contacted him and suggested that they take this into account when designing the experiments for the NIH Intramural ME/CFS study, and he said they would be looking into it further.

Creekside · Mar 3, 2021

Negative results are useful too.

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Unperturbed Cytotoxic Lymphocyte Phenotype and Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients 2017 Theorell et al

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Unperturbed Cytotoxic Lymphocyte Phenotype and Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients 2017 Theorell et al

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