Avindra Nath finds T-cell exhaustion in ME/CFS, which weakens immunity, and is possibly caused by the persistent remnants of a viral infection

[RYO]

Can anyone clarify? It seems Nath found increased expression of PD1 in T cells of CSF. In previous studies from Dr Mark Davis and Maureen Hansen did they not find evidence of T cell exhaustion from peripheral blood draws? Any significance of this disparity?

 

[Hip]

Can anyone clarify? It seems Nath found increased expression of PD1 in T cells of CSF. In previous studies from Dr Mark Davis and Maureen Hansen did they not find evidence of T cell exhaustion from peripheral blood draws? Any significance of this disparity?

I have not seen these studies from Mark Davis and Maureen Hansen, but this present study by Avindra Nath et al did not find increased PD-1 on T-cells in the blood, they only found reduced CD226 on blood T-cells (a protein that boosts the proliferation and activity of T-cells). It was only in the cerebrospinal fluid that Nath's study found increased PD-1, which causes T-cell exhaustion.

This is according to the Scientific American article about Nath's study.

 

[Hip]

Some discouraging findings about PD-1 inhibition: seems it does not work that well for chronic viral infection:

Programmed cell death-1 (PD-1) blockade therapies have been shown to improve CD8 T cell responses during chronic viral infections. These therapies have been licensed to treat cancers in humans, but they have not yet been licensed to treat chronic viral infections because limited benefit is seen in pre-clinical animal models of chronic infection.

Source: here

 

[junkcrap50]

Some discouraging findings about PD-1 inhibition: seems it does not work that well for chronic viral infection:

Source: here

Later says:

We utilized a model of chronic viral infection to evaluate if bacterial lipopolysaccharide (LPS), a major constituent of the microbiome, influences the efficacy of PD-1 therapy. Interestingly, we demonstrate that TLR4 triggering with low doses of LPS combined with PD-1 blockade induced a synergistic rescue of exhausted virus-specific CD8 T cell responses.

So maybe, if our leaky guts are releasing LPS in us, our guts will help with the PD1 blockade. Lol.

More seriously, from what it seems about their chronic viral model, these mice had widespread, active, raging infection throughout their body, which is not exactly occurring in ME/CFS based on our current hypotheses. So maybe PD1 blockade may still be effective in ME/CFS in rescuing T-cells, which absent active infection is enough (though I'm not optimistic).

 

[Hip]

So maybe PD1 blockade may still be effective in ME/CFS in rescuing T-cells

In terms of an experimental ME/CFS treatment, I am currently thinking in terms of addressing the factors which lead to T-cell exhaustion, rather than blocking PD-1.

Blocking PD-1 with the current generation of monoclonal antibody drugs is very risky anyway, as when used in cancer patients, these checkpoint inhibitor drugs cause death in 0.3% to 1.3% of patients, it says here. Though small molecule checkpoint inhibitors I read are much safer (but not yet available, apart from the methylene blue mentioned earlier).

Factors which lead to T-cell exhaustion include:

• High levels of the viral antigen (which you get with the widespread viral infections in ME/CFS)
• Hypoxia (found in ME/CFS, due to poor brain blow flow)
• Reactive oxygen species (there is high oxidative stress in ME/CFS)
• Reactive nitrogen species (there is high nitrosative stress in ME/CFS)
• High TGF-β (this cytokine is usually high in ME/CFS)
• Hyperactivation of the sympathetic nervous system activation (often found in ME/CFS)

Most of the above can be addressed with the right supplements and drugs. So if all these factors were dealt with, it is possible you might reduce T-cell exhaustion, and then in turn eliminate the viral infections which may be underpinning ME/CFS.

 

[BrightCandle]

Factors which lead to T-cell exhaustion include:

• High levels of the viral antigen (which you get with the widespread viral infections in ME/CFS)
• Hypoxia (found in ME/CFS, due to poor brain blow flow)
• Reactive oxygen species (there is high oxidative stress in ME/CFS)
• Reactive nitrogen species (there is high nitrosative stress in ME/CFS)
• High TGF-β (this cytokine is usually high in ME/CFS)
• Hyperactivation of the sympathetic nervous system activation (often found in ME/CFS)

Most of the above can be addressed with the right supplements and drugs. So if all these factors were dealt with, it is possible you might reduce T-cell exhaustion, and then in turn eliminate the viral infections which may be underpinning ME/CFS.

Viral antigen - an antiviral might reduce this somewhat.
Hypoxia - no clue what we can do about that.
High oxidative stress- lots of antioxidants, many of us take a number.
High TGF-β - acetylcholine, vitamin D. From what I gather its also high platelet count so in theory platelet reduction via Grape seed extract might work too.
Hyperactivation of the sympathetic nervous system - Calming measures like blocking light, sound, binaural beats, anything that gets you to a yawning state.

Any other ideas? I think largely its a group of stuff I have taken or do take already.

 

[Treeman]

Hypoxia - no clue what we can do about that.

Hypobaric oxygen therapy (HBOT)

 

[Hip]

Any other ideas? I think largely its a group of stuff I have taken or do take already.

I am currently trying to work out what supplements and drugs could counter the above factors which induce T-cell exhaustion. This is what I have so far:


➤ Viral antigen overexposure causes T-cell exhaustion. 1

So if it were possible to reduce viral levels with antivirals or immunomodulators, this might be beneficial.

In the case of enterovirus ME/CFS, in theory it might be good to begin with interferon treatment, to reduce viral load in the body sells. But of course this is extremely expensive, and also Dr Chia says many patients cannot tolerate the side effects, so he does not use interferon much now.

But I believe Dr Chia does give some of his severe hospitalised patients a few weeks of interferon beta therapy, which he says can allow bedbound patients to be able to walk again, at least for short walks.

Dr Chia also uses oxymatrine to treat enterovirus ME/CFS. This boosts the antiviral Th1 CD4 T-cells. But oxymatrine only seems to work for a small percentage of patients. However, I wonder if its failure to work might be caused by CD4 and CD8 T-cell exhaustion? If so, then taking oxymatrine along with an anti-T-cell exhaustion protocol might be more effective.

For herpesvirus ME/CFS, antivirals such as Valtrex and Valcyte could be considered, but these are slow acting, taking a year before any benefits they can offer manifest.


➤ Hypoxia causes T-cell exhaustion. 1 One study found that T-cells maintained functionality under hypoxia or continuous antigen stimulation alone, but combination of both triggered exhaustion. 1

In the brain, I believe hypoxia in ME/CFS arises from low blood flow. The counter this, taking a few breaths of carbon dioxide (made in a plastic bag from mixing sodium bicarbonate and citric acid, as detailed in this post) may be helpful, as CO2 is a potent cerebral vasodilator. I've found a few breaths of pure CO2 will reduce my brain fog for the next fours or so, which I assume is from its vasodilation effects.

Also, increased CO2 levels causes the haemoglobin in red blood cells to more readily release its oxygen (this is the Bohr effect), so that's another way breathing CO2 may improve brain (and body) oxygenation.

If you have an oxygen concentrator machine, then breathing 90% oxygen for a few hours each day might help raise tissue oxygen levels. But decent machines like the Philips EverFlo (which can supply the necessary 5 litres per minute of 90% oxygen) are expensive; although second hand EverFlo can be bought for about £300.

Oxygen multistep therapy could also be considered; this is touted to permanently reverse hypoxia. See this article, this book and this thread.

Daily mild HBOT at 1.3 atmospheres in a home soft chamber might be better, but even second hand soft chambers in the US cost about $6000.

Dr Leslie Simpson found that in ME/CFS, red blood cells are often the wrong shape: he discovered that in ME/CFS there are too many cup-shaped red blood cells (called stomatocytes), and this shape makes the cell more rigid and less deformable. When they are the wrong shape and cannot be deformed, these oxygen-carrying red blood cells may not get through the blood capillaries, and this in turn can lead to low oxygen in the tissues and organs. 1 2

Dr Simpson suggested evening primrose oil 4 grams daily may make these cell more deformable, so that they can more easily pass through tiny capillaries. He also thought omega 3 fish oil should also help improve deformability, and he found B12 hydroxocobalamin injections helped improve deformability in some patients.

Brain Blood Vessel Vasodilators:

• Vinpocetine increases cerebral microcirculation. 1
• Ginkgo biloba increases microcirculation 1 and increases brain blood flow. 1
• Huperzine A increases brain blood flow. 1
• Bacopa monnieri increases brain blood flow. 1
• Korean ginseng is a microcirculation vasodilator. 1

Nimodipine is a cerebral vasodilator through a calcium channel blocker mechanism; a gentler over-the-counter calcium channel blocker and antihistamine is cinnarizine, which one ME/CFS patient found moved her from moderate to near remission.

For vasodilation in the entire body, supplements such as citrulline, arginine and nitrate can help. The drug nicorandil improves microcirculation.



➤ High oxidative stress promotes T-cell exhaustion. 1

So a cocktail of antioxidants may help counter this, which might include the following:

• Vitamin C 1000 mg
• Vitamin E 400 IU
• Acetyl-L-carnitine 1000 mg
• Alpha lipoic acid 200 mg
• N-acetyl cysteine 600 mg
• Q10 100 mg
• Grape seed extract 100 mg
• SOD-gliadin (GliSODin) 500 mg

➤ High nitrosative stress promotes T-cell exhaustion; 1 peroxynitrite promotes T-cell exhaustion. 1

So to counter this, some peroxynitrite scavengers may help:

• Methylfolate 250 mcg (potent) 1
• Ellagic acid 50 mg 1 2
• Lycopene 10 mg or beta-carotene 1000 IU 1

Ellagic acid though causes me weird vivid dreams and lightheadedness all day, so I don't like to take it. I have a pomegranate extract with 90% ellagic acid that I bought from PureBulk.


➤ High TGF-beta causes T-cell exhaustion. 1 And this cytokine is high in ME/CFS. 1

Dr Ritchie Shoemaker uses the blood pressure drug losartan 25 mg twice daily to reduce TGF-beta in his CIRS (mould illness) patients. One of Shoemaker's other treatments, VIP nasal spray (vasoactive intestinal peptide), also lowers TGF-beta. 1 2 Oxymatrine also lowers TGF-beta. 1 Lots of herbs that lower TGF-beta are listed here (but I am not sure how their potency compares to losartan).


➤ Sympathetic nervous system activation causes T-cell exhaustion by activating the β1-adrenergic receptors of T-cells. 1

This study (see also this article) found that the beta blocker propranolol could counter this exhaustion, and improve the cancer fighting abilities of T-cells. The study also tried a selective β1 blocker, but this did not prevent T-cell exhaustion; but the non-selective β1 and β2 blocker propranolol did.

So one could also try calming and relaxing therapies to try to reduce sympathetic activation; but propranolol might provide more guarantees.


➤ Staphylococcus alpha toxin induces CD8 T-cell deactivation. 1

So the anti-Staphylococcus probiotic (Bacillus subtilis MB40 or HU58) detailed in this thread might be worthwhile. Staphylococcus vaccines might also be worthwhile (indeed, the CD8 cell exhaustion caused by Staphylococcus alpha toxin could explain Prof Gottfries findings that anti-alpha toxin vaccines improve ME/CFS).



So a multimodal approach taking many of the above treatments might reverse T-cell exhaustion. However, just how long you would have to take this cocktail of treatments before improvements in ME/CFS symptoms were observed is an open question.

I find I am happy to take a protocol for a month or so, but if I don't see any improvements by then, I tend to lose enthusiasm, and may drop the treatment.

 

[Forummember9922]

I think if they're doing a trial of PD-1 inhibitors at UCSF that's a green arrow pointing towards something.

Easy to criticize that rationale but when something is this unsolved and unactionable you kind of need to value even weaker leads.

 

[Bobby Peru]

In long covid we have seen that many people undergoing H E L P apheresis which removes clots and some other particles etc. can help them recover. Additionally hyperbaric oxygen therapy also helps some people with long covid. Both allow oxygens back to the cells which is claimed allows the mitochondria to function more efficiently and divide, so support the required bodily functions.

I would like to see some research on the above in a connected way.

Does this study get close to what you are after? It discusses how Mitochondrial respiration controls the functional exhaustion of T cells. Attachment #2 is the actual study (Sept. 2023) which was geared towards cancer rather than ME/CFS. Attachment #1 is an article on the study in laymen's terms.
"Here, we provide genetic evidence that impaired mitochondrial respiration is not merely a consequence of T cell dysfunction but, instead, is sufficient to elicit the transcriptional, phenotypic, and functional hallmarks of T cell exhaustion."

 

[Dakota15]

Speaking of Dr. Nath:

Sharing from today. Healio: '‘There must be a persistent antigen’: NIH researcher discusses new PI-ME/CFS data’

https://www.healio.com/news/rheumat...gen-nih-researcher-discusses-new-pimecfs-data

 

[Dakota15]

Some excerpts:

'“It all points to the hypothesis that there must be persistent antigen,” co-author Avindra Nath, MD’

'we still do not know why that is happening. In my mind, that is the next important immunological question to ask.’

'Normally when we face a foreign antigen, the B cells will recognize it. They will go from a naïve state, producing IgM, and switch to a mature state producing IgG. This maturity of the B cell can occur in a T-cell dependent or independent manner. If the B cells fail to switch to the mature or memory B cells, the ability to clear the antigen is going to be impaired. If it is impaired, the immune system would have to depend on T cells for antigen clearance. This creates exhaustion in the T cells from persistent antigen stimulation.

'So, now you have a combination of exhausted T cells and B cells that are unable to switch. This leads to reliance on the innate immune system, activation of which can be detrimental to the host. This is not a good way to fight infectious processes.’

'Nath: I am a neuroimmunologist, so I think in terms of immune targets. In the paper, you will see that we discovered a number of targets which include the autonomic nervous system, metabolites, microbiome and others. If there is antigen persistence and T cells are exhausted, one could consider using checkpoint inhibitors. If you have T-cell activation and they are not exhausted, we have plenty of drugs to block T-cell activation. For B-cell activation you can use immunotherapies that block B cells. For issues with innate immunity, you can use an interleukin (IL)-1, IL-6, or TNF inhibitor.'

'Healio: Do you have thoughts on how to go about conducting those trials? Nath: You can’t try one after another because it would take too long. Investigators should consider doing a platform study, with multiple arms and multiple agents at the same time.'

 

[Treeman]

Does this study get close to what you are after? It discusses how Mitochondrial respiration controls the functional exhaustion of T cells. Attachment #2 is the actual study (Sept. 2023) which was geared towards cancer rather than ME/CFS. Attachment #1 is an article on the study in laymen's terms.
"Here, we provide genetic evidence that impaired mitochondrial respiration is not merely a consequence of T cell dysfunction but, instead, is sufficient to elicit the transcriptional, phenotypic, and functional hallmarks of T cell exhaustion."

It's moving in the right direction, I think.

ME/CFS is described as a multi system disease, therefore a way to investigate this is with a multi discipline team looking for a root cause. The NIH and RECOVER have a $1.15 billion budget for Long Covid, this would have been a great way to bring together a multi discipline team.

Many have said including OMF it's something in the blood. Prusty has demonstrated in the lab putting infected ME/CFS blood on to uninfected cells the mitochondria fragment so lowering energy production. Systrom discovered that blood returning to the heart contained more oxygen than it should do, hypothesising that it was an auto immune disease. Pretorius found in LC and researches looking at ME/CS that the blood is dark, thick, sticky so forming clots and preventing oxygen getting into the cells.

It's already been established that viral infections stop the body absorbing nutrients from food, many ME/CFS sufferers find relief from adding some nutrients, possibly because of the former after the body is unable to produce enough energy to successfully support the immune system and fight infections?

Additionally, I'm aware that there are a known 120 auto antibodies however, its estimated that there could be up to 3000, many still to be discovered. Could it be theses undiscovered auto antibodies produced by a dysfunctional immune system struggling with low oxygen, energy production, are significant problems?

It's known the body in some "overreacts". Could this over reaction cause a cascade as above and lead to ME/CFS?

I think a multi system disease needs a multi discipline team of experts.

 

[unto]

Hello, I am convinced that the cause of ME/cfs is of unknown and persistent viral origin undetectable by testing, and I think researchers need to look in those tissues more affected as heart, brain, spinal cord, lungs, pelvic floor and urinary tract, we patients when we have to operate donate our tissues for their research.
The research of Dr.'s group Nath has taken a notable step forward.
Good night

 

[junkcrap50]

Hello, I am convinced that the cause of ME/cfs is of unknown and persistent viral origin undetectable by testing, and I think researchers need to look in those tissues more affected as heart, brain, spinal cord, lungs, pelvic floor and urinary tract, we patients when we have to operate donate our tissues for their research.
The research of Dr.'s group Nath has taken a notable step forward.
Good night

It would be very worthwhile to be able to donate our bodies to a ME/CFS research. For autopsy research studies or biopsy/tissue samples for biobanks. Unfortunately, this isn't discussed more or has much support because it may encourage suicides. Of course, lack of funding is also a huge prohibitive reason. At the very least, we should be able to send any independent biopsies we do/have to a biobank for ME/CFS research. For instance, I could have forwarded a small intestinal biopsy (for celiacs) & skin punch biopsy (for SFN). Other examples could be commonly donated are muscle biopsy, CSF, etc. A significant portion of the cost is in the collection & procedure to acquire the biopsy, which would already be done/paid for.

It'd be great if any CFS patient had a bone marrow biopsy done for some reason could save it in a biobank. I'm interesting in seeing if there's a persistent antigen there since some research's pointing to something there being dysfunctional possibly creating the "something in the blood."

 

[Wishful]

Of course, lack of funding is also a huge prohibitive reason.

Cost is definitely a factor, but I think the biggest hurdle to collecting samples is the legal paperwork. Getting permission from survivors is probably quite expensive, with sending someone to meet with the people, maybe requiring witnesses too, and whatever other procedures the bureaucrats have come up with. It would probably be best to ask an expert in this field (collecting samples) what the various hurdles are and what would be needed to minimize cost and inconvenience.

 

[unto]

It would be very worthwhile to be able to donate our bodies to a ME/CFS research. For autopsy research studies or biopsy/tissue samples for biobanks. Unfortunately, this isn't discussed more or has much support because it may encourage suicides. Of course, lack of funding is also a huge prohibitive reason. At the very least, we should be able to send any independent biopsies we do/have to a biobank for ME/CFS research. For instance, I could have forwarded a small intestinal biopsy (for celiacs) & skin punch biopsy (for SFN). Other examples could be commonly donated are muscle biopsy, CSF, etc. A significant portion of the cost is in the collection & procedure to acquire the biopsy, which would already be done/paid for.

It'd be great if any CFS patient had a bone marrow biopsy done for some reason could save it in a biobank. I'm interesting in seeing if there's a persistent antigen there since some research's pointing to something there being dysfunctional possibly creating the "something in the blood."

Hi, I didn't mean to talk about deceased people, nor to instigate suicide, but I was referring to those surgeries that some of us may be forced to do for various reasons (especially those who, like me, have been ill for decades);I think this research direction is fundamental.
To collect biopsies, of course, the ME patient and research associations must be activated; a researcher ME Dr. Michael VanElzakker, PhD, of the Division of Neurotherapy at Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, commenting on the study Dr. Avindra Nath said: The profiling conducted in the study is noteworthy and deserves further study. “For me, the obvious next step would be techniques like tissue testing and T-cell sequencing to try to understand what exactly those antigens are and what their source might be.
Another researcher (Dr. Prusty? or Dr. Ron Davis?) had also obtained significant results by contaminating the blood or plasma of a healthy individual with that of an ME patient, resulting in the healthy person's blood becoming ill.
Good night

 

[Dakota15]

3/25/24: 'A Discussion with Dr. Avindra Nath: Ted Burns Humanism Award Winner’ (around 12:20 minute-mark)

Dr. Nath: “What is really challenging my mind at the moment, and I think what it is is in broad terms, it is the post infection syndromes. I say that because with the current pandemic, it's long COVID, prior to that it was chronic fatigue syndrome, and there's significant overlap. I think that’s another segment of society that has not been taken seriously. So often times, they come to the physician, and they get all the testing done and nobody finds anything wrong with them and they are labeled as being psychological, but really they have a biological basis. So, we spend a huge amount of effort trying to understand these diseases, understanding the overlap between them. We just recently published a paper showing that there are specific immune abnormalities that drive these two syndromes. There is a possibility that there is a residual antigen that is still present from the past infection that precipitated the event. There are similar syndromes: post Lyme disease, Gulf War Syndrome, sick building syndrome. They all, I think are one of the same. They just have different names. I think if you can solve one, you can solve them all. That is what I am very passionate about at the moment because I think it's a huge segment of society that's been impacted by this and we need to do something to fix this."

 

[Rufous McKinney]

I just HAD a biopsy done, and I'd like to know whether THAT becomes part of some repository for future studies or not.

 

[cfs since 1998]

We just recently published a paper showing that there are specific immune abnormalities that drive these two syndromes. There is a possibility that there is a residual antigen that is still present from the past infection that precipitated the event.

Scientists have been reporting immune abnormalities in CFS since the 80s. It's nothing new to us, but it's new to other scientists, since it keeps getting swept under the rug.

"One thing is certain at this juncture: there are no immune disorders in CFS patients on the scale traditionally associated with disease." Centers for Disease Control, 2009

Anyway, of course glad to have Dr. Nath on board.