Dr. Amy Proal interviews Dr. Liisa Selin about T cell exhaustion and viral activity in ME/CFS

Shanti1

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Dr. Liisa Selin is a professor of pathology at the University of Massachusetts Medical School. In her work as a viral immunologist, she and her colleague Dr. Anna Gil recently received an NIH grant to study the role of viral infection and T-cell exhaustion in the development of ME/CFS. She has had ME/CFS since 1974.

 

Shanti1

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Here are some of my notes on Dr. Selin's talk, my notes don't capture all of the minutia, so worth watching if you are interested.

ME/CFS involves a dysregulated immune response to viral infection
Long-COVID-19 creates a similar dysregulated immune response
CD8 T-cell exhaustion is a feature of post-viral syndromes like ME/CFS
In order to get CD8 T-cell exhaustion, you have to have a viral antigen that doesn’t clear
Some people become ill after the flu, this may be because their latent viruses reactivate
The most common latent viruses include the herpes viruses, HHV-6, CMV, and Zoster (for you enterovirus fans, Dr. Poal brought them into the mix too). One of the challenges is that it is hard to measure viral activity/load, but so much research is pointing to it.

Features of CD8 T-cell exhaustion
  • Inhibitory receptor expression on CD8 cells, leading to further CD8 T-cell exhaustion
  • The innate immune system continues to be activated and present viral antigen to get an adaptive (T-cell) response leading to increased INF-1
  • The body tries to shut down the over-activation of the innate immune system, leading to elevated inhibitory cytokines IL-10 and TGF-b1
  • The resulting cytokine soup dysregulates our metabolism and increases oxidative stress, leading to symptoms
  • The brain is full of cytokine receptors and neurological symptoms are often present
  • CD8 and NK cells are low in number in ME/CFS
  • Most T-Cells express either CD4 or CD8, but not both (once they have left the thymus). In ME/CFS there is increased CD4/CD8 + cells in peripheral blood compared to healthy controls. This is also seen following some viral infections and in MS (there is a link between MS and EBV).
  • T-cell exhaustion leads to vulnerability to new infections and responses to infections that deviate from normal
  • CD8-T cell exhaustion may be preceded by a heterologous immune response that has gone awry.

Some people who get long-COVID had asymptomatic COVID, this points to the possibility that some people who get ME/CFS may not have been aware of the triggering infection.

Dr. Selin reported benefit in herself with use of Inspiritol, which is a new investigational drug that combines 5 antioxidants in a nebulized formula, particularly to alleviate her severe reaction to the COVID vaccine. Working with Nancy Klimas to start a study. She says she has seen reversal of T-cell exhaustion in the data they have so far.
 
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Here are some of my notes on Dr. Selin's talk, my notes don't capture all of the minutia, so worth watching if you are interested.

ME/CFS involves a dysregulated immune response to viral infection
Long-COVID-19 creates a similar dysregulated immune response
CD8 T-cell exhaustion is a feature of post-viral syndromes like ME/CFS
In order to get CD8 T-cell exhaustion, you have to have a viral antigen that doesn’t clear
Some people become ill after the flu, this may be because their latent viruses reactivate
The most common latent viruses include the herpes viruses, HHV-6, CMV, and Zoster (for you enterovirus fans, Dr. Poal brought them into the mix too). One of the challenges is that it is hard to measure viral activity/load, but so much research is pointing to it.

Features of CD8 T-cell exhaustion
  • Inhibitory receptor expression on CD8 cells, leading to further CD8 T-cell exhaustion
  • The innate immune system continues to be activated and present viral antigen to get an adaptive (T-cell) response leading to increased INF-1
  • The body tries to shut down the over-activation of the innate immune system, leading to elevated inhibitory cytokines IL-10 and TGF-b1
  • The resulting cytokine soup dysregulates our metabolism and increases oxidative stress, leading to symptoms
  • The brain is full of cytokine receptors and neurological symptoms are often present
  • CD8 and NK cells are low in number in ME/CFS
  • Most T-Cells express either CD4 or CD8, but not both (once they have left the thymus). In ME/CFS there is increased CD4/CD8 + cells in peripheral blood compared to healthy controls. This is also seen following some viral infections and in MS (there is a link between MS and EBV).
  • T-cell exhaustion leads to vulnerability to new infections and responses to infections that deviate from normal
  • CD8-T cell exhaustion may be preceded by a heterologous immune response that has gone awry.

Some people who get long-COVID had asymptomatic COVID, this points to the possibility that some people who get ME/CFS may not have been aware of the triggering infection.

Dr. Selin reported benefit in herself with use of Inspiritol, which is a new investigational drug that combines 5 antioxidants in a nebulized formula, particularly to alleviate her severe reaction to the COVID vaccine. Working with Nancy Klimas to start a study. She says she has seen reversal of T-cell exhaustion in the data they have so far.

This is very interesting, but I don't seem to be represented by this phenotype at all. I have the following features:

- highly elevated IL-6, mildly elevated IL-8, TNF-a and TNF-b (all pro-inflammatory)
- borderline low TGF-b, all anti-inflammatory cytokines mid-range (including IL-10)
- CD4/CD8+ ratio 1.8 (CD4 0.69, CD8 0.38) - so maybe slightly less than ideal? Or indicative of an infection/pathogenic issue
- normal NK cell count 0.31 (range 0.07 - 0.60) - all of these cell markers are number x 10^9/L

I do want to redo both of these tests as the lymphocyte subsets were tested in Dec 2019 and the cytokines are through a third party lab so not sure of their accuracy/reproducibility.

Does the above show I don't have T cell exhaustion? I have successfully fought around 30-50 viruses in the last 2 years as our then-baby started daycare and got us sick endlessly. Aside from becoming worn out and easier to crash during a virus, I seem to have a normal response (sore throat to fever, to runny nose, to more solid sinus discharge, to finally resolution).
 

Shanti1

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@Rufous McKinney I hear you. Inspiritrol is also still pretty mysterious. I would like to know what the 5 antioxidants are, I'm sure one is glutathione. I have my doubts that it would be helpful for me, given that most antioxidants make me feel worse, but I would give it a try if it were available. I think Dr. Selin would it to be available to more people now, but since the developers are going for drug status, they have to go through the FDA hoops.
 

Shanti1

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@GlassCannonLife I wish I knew the answer to your question. I had the impression that Dr. Selin was referencing some of her unpublished research in addition to published research, and that cytokine/immune behavior is more complicated than what she was able to speak to in the interview.
You might find this chart on ME-Peida interesting, it gives the cytokines levels in ME/CFS from various studies.
https://me-pedia.org/wiki/Cytokine
As you can see, the research is quite conflicting. I will be interested to see where Dr. Selin's research leads as she is well respected in the field and also personally connected with ME/CFS.
 
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@GlassCannonLife I wish I knew the answer to your question. I had the impression that Dr. Selin was referencing some of her unpublished research in addition to published research, and that cytokine/immune behavior is complicated than what she was able to speak to in the interview.
You might find this chart on ME-Peida interesting, it gives the cytokines levels in ME/CFS from various studies.
https://me-pedia.org/wiki/Cytokine
As you can see, the research is quite conflicting. I will be interested to see where Dr. Selin's research leads as she is well respected in the field and also personally connected with ME/CFS.
Thanks @Shanti1. I often forget about that site, I'll take a look.
 

Learner1

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This is very interesting, but I don't seem to be represented by this phenotype at all. I have the following features:

- highly elevated IL-6, mildly elevated IL-8, TNF-a and TNF-b (all pro-inflammatory)
- borderline low TGF-b, all anti-inflammatory cytokines mid-range (including IL-10)
- CD4/CD8+ ratio 1.8 (CD4 0.69, CD8 0.38) - so maybe slightly less than ideal? Or indicative of an infection/pathogenic issue
- normal NK cell count 0.31 (range 0.07 - 0.60) - all of these cell markers are number x 10^9/L

I do want to redo both of these tests as the lymphocyte subsets were tested in Dec 2019 and the cytokines are through a third party lab so not sure of their accuracy/reproducibility.

Does the above show I don't have T cell exhaustion? I have successfully fought around 30-50 viruses in the last 2 years as our then-baby started daycare and got us sick endlessly. Aside from becoming worn out and easier to crash during a virus, I seem to have a normal response (sore throat to fever, to runny nose, to more solid sinus discharge, to finally resolution).
A lot can change in 2 years especially With what you're saying has been going on. It would definitely be worthwhile to update your labs. You might also look into the CytoDX profile.
 
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A lot can change in 2 years especially With what you're saying has been going on. It would definitely be worthwhile to update your labs. You might also look into the CytoDX profile.
Thanks, I'll see if I can get it done somehow.

Edit: just looked it up - looks very similar to the one I had done through the private lab here (Nutripath cytokine panel). A retest of that should be ok it seems
 

lenora

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Hello @Shanti1......Thanks for posting this info and the follow-up explanation(s). Your hard work is very much appreciated.

If it's of any comfort to most of you out there, we seem to be making rather fast research fast at the moment, compared to decades of the past. Fingers crossed.....Yours, Lenora
Hi Shanti....One other point: Where is Dr. Nancy Klimas practicing at the moment? Yours, Lenora.
 

Shanti1

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Hi @lenora She is at the Institute for NeuroImmune Medicine in Miami, FL. Yes, it is good to see research moving forward. I am so thankful to all the researchers and doctors who have chosen not to forget about us and are dedicating their life and work to finding answers, even when they face uphill battles against antiquated ideas. They are all heroes and angels in my book.
 
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Dr. Liisa Selin is a professor of pathology at the University of Massachusetts Medical School. In her work as a viral immunologist, she and her colleague Dr. Anna Gil recently received an NIH grant to study the role of viral infection and T-cell exhaustion in the development of ME/CFS. She has had ME/CFS since 1974.

This was an excellent interview and wonderful to hear the perspective of Dr Seliin, who is has an advantage of connecting some dots since she had ME herself. I would try inspiritol if I had the chance, despite its somewhat cheesy name 🤓
 

lenora

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Thanks to all involved in both the videos and the explanations. Unfortunately it's hard to understand some of it, thus we rely heavily on those of you who understand more about how these viruses affect the body.

Now we have a new variant of COVID....one that seems to be more dangerous (early reports). Things are happening and changing very quickly....research among them. We are hopeful. Thanks to @Shanti, @GlassCannonLife & the many others trying to help us understand. Yours, Lenora.
 

halcyon

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Does the above show I don't have T cell exhaustion?
No, not really. None of those tests are designed to show the presence of T cell exhaustion, nor is there (to my knowledge) any clinically available tests to do so.

T cell exhaustion is defined by the presence of specific populations of T cells expressing very specific exhaustion-associated proteins, and in the extreme case it's defined by the total absence of specific effector T cells (but only those that recognize the specific antigen that produced the exhaustion in the first place). My understanding is that this type of abnormality would be basically invisible to any cytometry tools because the population of cells we're talking about, relative to the total pool of lymphocytes, is extremely small.

The only clinical condition where this presently has any relevance is in certain cancers, and while the experimental treatments being used there are supposed to reverse T cell exhaustion, I don't think they really monitor that aspect, but rather just monitor the cancer instead.
 
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No, not really. None of those tests are designed to show the presence of T cell exhaustion, nor is there (to my knowledge) any clinically available tests to do so.

T cell exhaustion is defined by the presence of specific populations of T cells expressing very specific exhaustion-associated proteins, and in the extreme case it's defined by the total absence of specific effector T cells (but only those that recognize the specific antigen that produced the exhaustion in the first place). My understanding is that this type of abnormality would be basically invisible to any cytometry tools because the population of cells we're talking about, relative to the total pool of lymphocytes, is extremely small.

The only clinical condition where this presently has any relevance is in certain cancers, and while the experimental treatments being used there are supposed to reverse T cell exhaustion, I don't think they really monitor that aspect, but rather just monitor the cancer instead.
Thanks, that's very interesting.

I had some T cell interferon gamma EliSpot testing done a while back (Arminlabs), looking at response to EBV and CMV. EBV came back negative (0 on the index), while CMV was 28 (positive is greater than 3).

It seems that T cell exhaustion towards EBV could be a possible interpretation of this result based on what you said? But even with this very antigen specific test, it does not appear possible to deduce whether that is the case, or whether there is just a very limited response as I was exposed to EBV when I was 17 (currently 31, ME/CFS started gradually at 28). They did test both latent and lytic antigen and I had the same response.

Overall the test is very inconclusive as it somewhat indicates an analogue of memory cell immunity just in a T cell context, but your post made me think of the results so I thought I'd share them.