Decreased Expression of the CD57 Molecule in T Lymphocytes of Patients with Chronic Fatigue Syndrome. (Espinosa, 2019)

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Mol Neurobiol. 2019 Sep;56(9):6581-6585. doi: 10.1007/s12035-019-1549-7. Epub 2019 Mar 21.
Decreased Expression of the CD57 Molecule in T Lymphocytes of Patients with Chronic Fatigue Syndrome.
Espinosa P1, Urra JM2,3.
Author information
1Immunology, Hospital General Universitario de Ciudad Real, 13005, Ciudad Real, Spain.

Abstract
The chronic fatigue syndrome (CFS) is characterized by a prolonged incapacitating fatigue, headaches, sleep disturbances, and decreases in cognition, besides alterations in other physiological functions. At present, no specific biological markers have been described in this pathology. In the present study, we analyzed in lymphocytes the CD57 expression for the diagnosis of CFS, evaluating both the percentage of blood lymphocytes expressing CD57 and the average amount of the molecule expressed per cell.

The study demonstrated a marked and significant decrease in the expression of CD57 in lymphocytes of CFS patients regarding healthy controls. In T lymphocytes, the decrease was significant both in the percentage of cells expressing CD57 (7.5 ± 1.2 vs 13.3 ± 1.6, p = 0.024) and in a more relevant way in the amount of CD57 molecule expressed per cell (331 ± 59 vs 1003 ± 104, p ≤ 0.0001). In non-T lymphocytes, the decrease was significant only in the amount of CD57 expressed per cell (379 ± 114 vs 691 ± 95, p = 0.007). The study of CD57 antigen in blood lymphocytes is a useful marker that could cooperate in the diagnosis of CFS patients. Its decrease in T lymphocytes provides most valuable results than the results in other lymphocyte subpopulations.

KEYWORDS:
CD57; Chronic fatigue syndrome
PMID: 30895436 DOI: 10.1007/s12035-019-1549-7
 
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22 patients (canadia criteria) and 25 controls, which is not bad. Here's your scatterplot.
Screen Shot 2019-08-08 at 9.36.25 am.png


In the discussion section they talk about using this as a biomarker. It could be part of a biomarker suite I think.

Incidientally they also talk a bit about overlap with Lyme. That discussion is pleasing to me because as per this thread...

https://forums.phoenixrising.me/threads/any-recent-mecfs-outbreaks.62859/page-4

...I'm increasingly convinced that we have the same thing as post-Q fever patients and post-Lyme patients, etc, it's just that their onset is defined by reference to a specific infection.
 

ljimbo423

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I'm increasingly convinced that we have the same thing as post-Q fever patients and post-Lyme patients, etc, it's just that their onset is defined by reference to a specific infection.
I don't know much about Q-fever but I also think CFS and post-Lyme are the same beast for most people. I wouldn't be a bit surprised if it were true for Q-fever and other illnesses too. Ron Davis has said this too.
 

Markus83

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I didn't read the paper. But in Lyme there are CD57+ NK cells in discussion which is not the same as CD57+ T- cells. But the above shown CD3-CD57+ cells could be equal to CD57+ Nk cells. Maybe someone knows? However, normal range for the CD57+ Nk cells is typically thought to be in the range of 60-360 /ul. The numbers in the figure posted by Murph seem to be much higher.
 

Markus83

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@Murph: Do you have a full text of the paper?

I took a deeper look at your posted figure. The Cd57+Nk cells discussed by some to be lowered in Lyme would probably equal the "%CD3-/CD57+" figure (second line, left figure). Seems that there is no statistical significant difference between controls and patients in this respect.
 

lauluce

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Sorry about such simple analysis, but after 20 years of reading about ME/CFS research, what I get is this: small or medium sized studies find anomalies in chemistry, cell popullations, blood vessels, brain anatomy, etc, etc etc... all seems to point to an actual physical disease being behind the constellation of symptoms that is ME/CFS, but THERE'S NEVER FOUND ANYTHING THAT CAN REALLY DIFFERENTIATE BETWEEN ILL AND HEALTHY PEOPLE, THERE'S NEVER A BIOMARKER. What's going on??? I just can't keep thinking about that, why is the fabled biomarker so elusive? is the task of finding it beyond the capabilities of conventional medical research? do we perhaps need to feed all this HUGE amount of data to a more capable than us Artificial Inteligence in order to find the patttern that we couldn't find?
 

pattismith

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@Murph: Do you have a full text of the paper?

I took a deeper look at your posted figure. The Cd57+Nk cells discussed by some to be lowered in Lyme would probably equal the "%CD3-/CD57+" figure (second line, left figure). Seems that there is no statistical significant difference between controls and patients in this respect.
CD3-CD56+CD57+ (activated NK cells) are believed low in lyme as seen in Arminlab website,
I just received mine that is 83/mm3;

According to Armilab interpretation, my number is too low (min 100/mm3).

My CD8 are too low as well (171/mm3 versus 181/mm3 two years ago), so I guess my CD8+CD57+ (activated cytotoxic T lymphocytes) are low as well.

These T Lymphocytes are supposed to fight intracellular infections and tumorous cells. So what can we do to improve these numbers?

I wonder if Histone Deacetylase Inhibitors may be interesting drugs for us?

Epigenetic Manipulation Restores Functions of Defective CD8(+) T Cells From Chronic Viral Infection
Article (PDF Available)inMolecular Therapy 22(9) · May 2014

Abstract
Functional exhaustion of antigen-specific T cells is a defining characteristic of many chronic infections, but the underlying mechanisms of T cell dysfunction are not well understood.

Epigenetics plays an important role in the control of T cell development, differentiation and function.

To examine if epigenetics also plays a role in T cell exhaustion, we analyzed chromatin remodeling in CD8(+) T cells from mice with chronic lymphocytic choriomeningitis virus infection.

We observed down-regulation of diAcH3 in both virus-specific and total CD8(+) T cells, and functional defects not only in virus-specific CD8(+) T cells but also within the total CD8(+) T cell population.

In vitro treatment of these exhausted CD8(+) T cells with histone deacetylase inhibitors restored diAcH3 levels, and improved their immune functions.

Upon adoptive transfer, these treated CD8(+) T cells developed into functional memory T cells in vivo that enhanced protective immunity.

These results define a role of epigenetics in T cell exhaustion and suggest epigenetic manipulation as a novel molecular therapy to restore immune functions.Molecular Therapy (2014); doi:10.1038/mt.2014.91.
 
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Pyrrhus

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And here is a 2011 review that notes that CD8+CD57+ T cells are not necessarily senescent, as they still possess some proliferative capacity:

CD8+ CD28− and CD8+ CD57+ T cells and their role in health and disease
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173691/

The review also describes how HIGH levels of CD8+CD57+ T cells can mean a chronic infection or cancer.

But no mention of LOW levels of CD8+CD57+ T cells.
 

Pyrrhus

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The LOW levels of fully activated CD8+CD57+ T cells might be explained by dysautonomia!


The sympathetic nervous system may prevent naive CD8+ T cells (CD8+CD57-) from becoming fully activated CD8+ T cells (CD8+CD57+), by stimulating β2 receptors on the T cells:
Reference 1 said:
Rather, additional findings suggest that the sympathetic nervous system tempers the capacity of antigen-presenting cells to activate naïve CD8+ T cells. We also show that antiviral CD8+ T cell responses are enhanced by administration of a β2 (but not β1 or α) adrenergic antagonist. These findings demonstrate a critical role for the sympathetic nervous system in limiting CD8+ T cell responses and indicate that CD8+ T cell responses may be altered in patients using β-blockers, one of the most widely prescribed classes of drugs.

This is similar to how the sympathetic nervous system might reduce NK cell activity, by stimulating β2 receptors on the NK cells:
Reference 2 said:
However, the control of NK cell IFN-γ production was not cell intrinsic, revealing a cell-extrinsic downregulation of the antiviral NK cell response by adrenergic neuroendocrine signals. This pathway reduces host immune defense, suggesting that the blockade of the β2-AR signaling could be used to increase resistance to infectious diseases.

References:
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664017/
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144531/

@Hubris
 
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sometexan84

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All of my documentation on CD57 expression in ME/CFS involves NK cells (minus possibly the 1991 study). Though, there does seem to be enough overlap for possible significance.

(1991) A comprehensive immunological analysis in chronic fatigue syndrome
  • Decreased CD16+, CD56+, and CD57+ Lymphocytes
(1993) Clinical and Immunologic Study of 205 Patients With Chronic Fatigue Syndrome: A Case Series From Italy
  • Decrease in CD3 -/CD16+, CD56+/CD57+ cells
(1994) Immunological Abnormalities in Patients with Chronic Fatigue Syndrome
  • Reduction of CD3−/CD16+ and CD57+/CD56+ NK lymphocytes
(2015) Pilot Study of Natural Killer Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis
  • Co‐expression of CD57 and perforin was significantly increased on CD56dimCD16+ NK cells
 
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The LOW levels of fully activated CD8+CD57+ T cells might be explained by dysautonomia!


The sympathetic nervous system may prevent naive CD8+ T cells (CD8+CD57-) from becoming fully activated CD8+ T cells (CD8+CD57+), by stimulating β2 receptors on the T cells:



This is similar to how the sympathetic nervous system might reduce NK cell activity, by stimulating β2 receptors on the NK cells:



References:
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664017/
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144531/

@Hubris
Amazing find! So it would end up being some sort of minor immunodeficiency right?

I'm still not totally sure what CD8+CD57+ cells represent. In some studies, like this one, they are thought to represent senescent T cells, which cannot replicate anymore and are thus not really that efficient anymore at fighting pathogens, but they are also recognized as being the most potent type of cell for fighting chronic viral infections. source

"Expression of CD57 is also found on T‐lineage lymphocytes, where it is currently considered a marker‐replicative senescence (“clonal exhaustion” [15]), i.e., a high susceptibility to activation‐induced cell death and the inability to undergo new cell‐division cycles despite preserved ability to secrete cytokines upon encounter with their cognate antigen"

Many studies talk about these cells being high in chronic viral infections/autoimmune disorders, but no studies talk about what these cells being low might mean (mine are very low). One could say well it could mean that your immune system is very efficient, but i know that in m ycase that doesnt make sense given my history of recurrent infections and chronic immune activation.
 
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heapsreal

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I have to laugh when these studies say there are no specific biological markers in cfsme. They only been researching and finding low nk function in cfsme patients at griffith university australia since about 2009.

Dr Nancy Klimas has found low nk function in cfsers since the mid 80s.

Really! This is something they should be chasing down the dam rabitt hole. Stands out like dog nuggets and could easily be responsible for the onset of cfsme but also could make cfsme a chronic illness as we no longer have a healthy immune system to suppress viruses that normal people can.

The only genuine immune drug helpful for cfs, ampligen, not only improved ohysical symptoms like general wellbeing, aerobic capacity and suprise suprise, it increased NK function.
See said the blind man.

Slightly different subject, but are they testing the nk function of the covid long hallers?
 

Wishful

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My question is: are the controls matching the patients in terms of reduced physical activity and possible diet changes and sleep changes? Could the findings just be: "Lifestyle changes due to illness may cause alteration in immune function"? They should compare the PWME to people with similarly disabling viral infections or other health problems.
 

Pyrrhus

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Amazing find! So it would end up being some sort of minor immunodeficiency right
I would call it dysautonomia since it is due to a dysfunction of the autonomic nervous system. But yes, prolonged activation of the sympathetic nervous system, whether due to chronic stress or dysautonomia, can suppress the immune system.

I'm still not totally sure what CD8+CD57+ cells represent. In some studies, like this one, they are thought to represent senescent T cells, which cannot replicate anymore and are thus not really that efficient anymore at fighting pathogens, but
When a CD8+ T cell encounters an antigen, such as a virus, it becomes activated and is then capable of destroying the antigen. If a CD8+ T cell encounters the same type of antigen many times, such as multiple copies of a virus, it becomes re-activated many times. If a CD8+ T cell becomes activated many times, it becomes a CD8+CD57+ T cell. So it's an old cell, but it is still an active cell.

Dr Nancy Klimas has found low nk function in cfsers since the mid 80s.

Really! This is something they should be chasing down the dam rabitt hole. Stands out like dog nuggets and could easily be responsible for the onset of cfsme but also could make cfsme a chronic illness as we no longer have a healthy immune system to suppress viruses that normal people can.
This discussion is mainly about CD8+CD57+ T cells, but a similar situation may explain the reduction in function of NK cells. I'm not sure that the reduction in NK cell function can explain the onset of ME, but it can definitely explain the reactivations of herpesviruses such as EBV, CMV, HHV6, etc.

Strong NK cell function is the most effective immune defense against reactivations of herpesviruses.[1] So, when NK cell function is suppressed by the autonomic nervous system, it may just be a matter of time before latent herpesviruses are reactivated. In this case, reactivations of herpesviruses can be considered a symptom of dysautonomia!

P.S. The β2 adrenergic receptors found on the surface of these T cells and NK cells are the same β2 receptors that are sometimes implicated in Orthostatic Intolerance, another type of dysautonomia.

Reference:
[1] https://www.frontiersin.org/articles/10.3389/fmicb.2019.02297/full
 
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Pyrrhus

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I believe CD57 is a marker for Natural Killer T (NKT) Cells, which is different from "Natural Killer Cells" or regular "T cells".

Attached is a "T Cell Quick Guide" I refer to sometimes. Mainly pages 4-5
https://www.miltenyibiotec.com/_Resources/Persistent/321261780bc5f2b6e4257bd90cfa8c54a9500c10/T Cell Quick Guide.pdf
CD8+CD57+ T cells may be a heterogeneous group, but we're generally talking about Cytotoxic T cells here, not about Natural Killer T cells.

From page 7 of your very helpful guide:
CF4E09D6-57B1-4901-BEC3-E17AD356C19C.jpeg

Hope this helps.