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Hanson Study: ME/CFS T-Cell Metabolism & Cytokine Associations 2019

Gemini

Senior Member
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East Coast USA
Maureen Hanson's Research Center at Cornell working in collaboration with Dr. Dan Peterson published this study on December 12, 2019 in the Journal of Clinical Investigation.

The work was funded by 2 NIH grants, Simmaron Research, and a private donor.

https://www.ninds.nih.gov/News-Even...eases/energy-use-by-me-cfs-immune-cells-study

Hanson Study image December 2019.JPG
 
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used_to_race

Senior Member
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193
Location
Southern California
Here is a link to the paper which I haven't read.

Looks like three key sets of findings here:
  1. Dr. Hanson and her colleagues did not see significant differences in mitochondrial respiration, the cell’s primary energy-producing method, between healthy and ME/CFS cells at rest or after activation. However, results suggest that glycolysis, a less efficient method of energy production, may be disrupted in ME/CFS. Compared to healthy cells, CD4 and CD8 cells from people with ME/CFS had decreased levels of glycolysis at rest. In addition, ME/CFS CD8 cells had lower levels of glycolysis after activation.
  2. Dr. Hanson’s group also looked at mitochondrial size and membrane potential, which can indicate the health of T cell mitochondria. CD4 cells from healthy controls and people with ME/CFS showed no significant differences in mitochondrial size nor function. CD8 cells from people with ME/CFS showed decreased membrane potential compared to healthy cells during both resting and activated states.
  3. Dr. Hanson’s team examined associations between cytokines, chemical messengers that send instructions from one cell to another, and T cell metabolism. The findings revealed different, and often opposite, patterns between healthy and ME/CFS cells, suggesting changes in the immune system. In addition, the presence of cytokines that cause inflammation unexpectedly correlated with decreased metabolism in T cells.
So it's not the amount of T cells being made (which would be found in a CBC/Differential) or their clonal character (Mark Davis's idea) but rather the metabolic behaviors/requirements of the cells, whether activated or latent (if that's the right word). I'm not sure what the decreased membrane potential means in conjunction with the finding of normal mitochondrial size and function. Maybe the mitochondria appear fine when examined in isolation, but within the cellular milieu they are behaving strangely? Membrane potential would be an electrical property, I wonder how it's measured and if it could be done using a nanoneedle type of device.

The last thing about cytokines is interesting as well. Rather than showing a correlation with patient symptoms/severity, there is a correlation shown with another hard quantitative measure, the T-cell metabolic dysfunction.

I wonder what the follow-up to this would entail. I feel as though we are in the period of ME/CFS research in which scientists are finding obviously measurable stuff by digging a little bit deeper than previous tests would have shown, but the next steps will be harder in terms of how to tease out the causal factors.

Edit: Just skimmed the paper, especially focusing on the discussion section at the end. Found this paragraph at the end to be rather interesting:

It is clear that the immune systemplays a role in ME/CFS. Our data indicate that there are existing reductions in resting T cell metabolism inpatients. In particular,CD8+ T cells have altered mitochondrial membrane potential and an impairment in their metabolic response to activation. Both CD4+ and CD8+ T cells have significant reductions in glycolysis. This hypometabolism in T cells aligns with other findings of hypometabolism in ME/CFScells(50, 51, 59). Furthermore, ME/CFS patients appear to have altered relationships between plasma cytokine abundance and T cell metabolism, where proinflammatory cytokines unexpectedly correlate with hypometabolism. Such a dysregulation may indicate that ME/CFS T cells have lost responsiveness to some proinflammatory cytokines. Along with hypometabolismin immune cells, thisis consistent with a possible ongoing infection (42), though such an agent has not yet been identified. A high priority moving forward will be determiningthe mechanism behind hypometabolism in ME/CFS T cells, as well as howaltered metabolism affectsthe function of these cells.

Would love to have some follow-up here because it seems like almost nobody (not even Ron Davis, exactly) is willing to totally dispense with the idea that ongoing infections play a role in ME/CFS. I would like to know whether the experts think the pathogen is the issue or that something to do with our immune-metabolic response to a common pathogen carried by healthy people is the real issue.
 
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Wishful

Senior Member
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5,684
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Alberta
Since the report includes a contact email, I'll send a suggestion that they look at microglial cells, since from what I've seen, ME seems to be a neurological disorder with secondary effects in the rest of the body. The brain and body have separate immune systems, but they do communicate.
 

Murph

:)
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1,799
I read the paper.

1. If I had to summarise the whole paper I'd say the high level finding is **yes, me/cfs patients definitely do have dodgy immune systems**

A secondary finding might be: **CD8 T-cells work worse than CD4 T-cells**.

They failed more of the tests (glycolysis and membrane potential, resting and activated). This makes them probably a better target for research that tries to distinguish patients from controls.

What's more, If some basic research is ongoing into the difference between these two types of T-cells, that could help explain what's happening. e.g. maybe CD8 T-cells uses a different type of calcium transport method, etc. If we can explain how the T-Cells differ perhaps that provides some insight into mechanisms??

2. There's also another finding, which is weird. The t-cell metabolism correlated with plasma cytokines in patients but not controls. I have nothing to say about this or what it means.

The authors note that some of the correlations are the opposite of what you'd expect, e.g. these cytokines are expected to rise with metabolism and they don't.

"Such a dysregulation may indicate that ME/CFS T cells have lost responsiveness to some proinflammatory cytokines," they write.

Screen Shot 2019-12-15 at 8.25.53 am.png


Figure 6. Plasma cytokines are uniquely correlated with T cell metabolism in ME/CFS patients. Significant correlations between plasma cytokines and cellular metabolism in patients and non-significant correlations in healthy controls.
Correlations between resting CD8+ T cell basal glycolysis and:
(A) IL-2 (n=19 patients/21 controls),
(B) IL-8 (n=18 patients/19 controls),
(C) IL-10 (n=19 patients/21 controls),
(D) IL-12 p70 (n=19 patients/21 controls), (
E) SCGFβ (n=19 patients/20 controls),
(F) and IL-9 (n=19 patients/21 controls), between resting CD8+ T cell compensatory glycolysis and
(G) M-CSF (n=12 patients/12 controls), (H) and TNF⍺ (n=12 patients/12 controls),
(I) between activated CD8+ T post-2DG acidification and M-CSF (n=9 patients/13 controls),
(J) between activated CD8+ T cell glycolytic capacity and M-CSF (n=10 patients/14 controls).


All correlations tested by Spearman correlation test with multiple testing correction (false discovery rate), with q<0.01 considered significant.
 

sb4

Senior Member
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1,654
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United Kingdom
Dr. Hanson and her colleagues did not see significant differences in mitochondrial respiration, the cell’s primary energy-producing method, between healthy and ME/CFS cells at rest or after activation. However, results suggest that glycolysis, a less efficient method of energy production, may be disrupted in ME/CFS. Compared to healthy cells, CD4 and CD8 cells from people with ME/CFS had decreased levels of glycolysis at rest. In addition, ME/CFS CD8 cells had lower levels of glycolysis after activation.
If I am reading this right, it goes against other studies showing poor mito respiration and increased glycolysis. Makes me think about what Ron found with RBC deformability only showing when in the same serum as patient. Does anyone know if this study accounts for this?

If RBC do not release O2 as well in sick patients due to something in the serum, this would lead to more glycolysis, and less mito respiration. If you took these sells out and put them in some kind of experimental medium then the O2 might be free to release again causing normal looking mito and glycolysis. Does anyone know if this is true?
 

Wishful

Senior Member
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5,684
Location
Alberta
I did send an email to the contact, and did get a reply (within minutes actually). They do want to study more types of cells, but it's a matter of funding. She was interested in how I discovered that cumin blocked my PEM, which I replied to.

I did suggest that they think about whether the results could be caused by downstream effects of abnormal microglial function. T-cell activation activates microglial cells, but I don't know what kind of reverse communication exists.
 

Hufsamor

Senior Member
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2,768
Location
Norway
https://www.nih.gov/news-events/nih...sDvOo_64ndbnf8bL5EwnYQOK2YpuT7GPicnCM8F62uyPc

Immune cell metabolism altered in ME/CFS

At a Glance


  • Some immune cells in people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) show disruptions in the way they produce and use energy.
  • More research is needed to understand how these metabolic changes affect the way immune cells work in people with the disease.

20200107-tcell.jpg
Colorized scanning electron micrograph of a T cell. The study focused on T cells in people with ME/CFS. NIAID
ME/CFS is a complex, poorly understood disease. Symptoms can include fatigue, chronic pain, problems thinking and concentrating, poor sleep, and gut problems. These symptoms often worsen after physical or mental activity that wouldn’t have caused a problem before the illness. This is known as post-exertional malaise.
About a quarter of people with ME/CFS become house- or bed-bound at some point. Scientists don’t know what causes the disease. This has prevented the development of effective treatments.
Whether or not specific microbes—such as a virus—may play a role in ME/CFS is not well understood. Recent research suggests that the immune system is involved in ME/CFS. In particular, researchers are interested in metabolism—how energy is produced and used—within immune cells.
To look more closely at immune-cell metabolism in ME/CFS, researchers led by Drs. Alexandra Mandarano and Maureen Hanson at Cornell University collected blood samples from 53 people with ME/CFS and 45 people without the disease. They tested specific types of immune cells in the blood for changes in metabolism, both at rest and after being activated by signals that indicate a danger to the body.
The team focused on CD4+ and CD8+ T cells. CD4+ T cells alert other immune cells about invading pathogens. CD8+ T cells attack infected cells in the body. The study was funded in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of Allergy and Infectious Diseases (NIAID). Results were published on December 12, 2019, in the Journal of Clinical Investigation.
Most aspects of immune-cell metabolism measured by the researchers did not differ between samples taken from people with ME/CFS and those without the disease. But there were exceptions.
CD8+ T cells from people with ME/CFS showed a decrease in energy production after activation. Notably, they had changes in their mitochondria—the structures that produce most of the cell’s energy.
Compared to cells taken from people without the disease, both CD4+ and CD8+ cells from people with ME/CFS had reduced glycolosis at rest. Glycolosis is another pathway that cells use to produce energy. CD8+ cells from people with ME/CFS also had reduced glycolysis after activation.
The team found different patterns of cytokines in the blood of people with ME/CFS as well. Cytokines play important signaling roles in the immune system. Although many of these cytokines would normally promote immune activity, they correlated with reduced metabolism in CD8+ T cells in people with the disease.

More work is needed to understand whether altered cytokine production and reduced T-cell metabolism play a role in ME/CSF. “Additional studies focusing on specific cell types will be important to unravel what’s gone wrong with immune defenses in ME/CFS,” Hanson says.
 
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