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

[Hip]

That would explain why anything that is not "fixing gut dysbiosis" is only addressing symptoms, and thus is usually only temporary.

I think fixing dysbiosis, or fixing a leaky gut in the way Prof Micheal Maes has done in his ME/CFS studies, might help reduce the immune stimulation that leads to exhausted T-cells; but if there is still a widespread viral infection in the body, that itself will continue to produce immune stimulation, and so may maintain the T-cell exhaustion, and the virus will thus not be cleared.

From what I have read, T-cell exhaustion is quite persistent, and hard to reverse. Once T-cells become exhausted, they are epigenetically programmed to remain exhausted. It's only when the source of the immune stimulation is removed, do these exhausted T-cells die off.

 

[Hip]

Good find, @Dude!

Great news that the University of California, San Francisco are hoping to perform a clinical trial of checkpoint inhibitors on ME/CFS patients. Checkpoint inhibitors function to reverse T-cell exhaustion.

Checkpoint inhibitor drugs are monoclonal antibodies which bind to receptors such as PD-1, CTLA-4, and some bind to PD-L1 or PD-L2, which are receptors on antigen-presenting cells that PD-1 binds to.

Checkpoint inhibitor drugs:

• Nivolumab and pembrolizumab bind to PD-1 (aka CD279)
• Durvalumab, atezolizumab and avelumab bind to PD-L1
• Ipilimumab and tremelimumab bind to CTLA-4

Source: here

 

[Marylib]

I wonder if this takes us back to the rituximab days?

 

[Hip]

I wonder if this takes us back to the rituximab days?

In the sense that there is hope on the horizon perhaps; but the assumed mechanism is different: rituximab clinical trials for ME/CFS assumed that this illness was autoimmune, whereas I believe a checkpoint inhibitor clinical trial assumes that ME/CFS is caused by a chronic underlying viral infection, which the immune system cannot clear due to T-cell exhaustion.

 

[junkcrap50]

@Hip, how do sudden/instant remissions (either spontaneous or from a supplement/treatment) that seem like a switch was flipped or temporarily very short remissions, where the ME/CFS states flips back and forth within a short time frame, fit with your theory here? Seems inconsistent with exhausted t-cells.

 

[Hip]

how do sudden/instant remissions (either spontaneous or from a supplement/treatment) that seem like a switch was flipped or temporarily very short remissions, where the ME/CFS states flips back and forth within a short time frame, fit with your theory here? Seems inconsistent with exhausted t-cells.

I wouldn't have thought that short remissions or improvements would be related to T-cell exhaustion, since this exhaustion is hard to reverse. My guess is that such remissions might involve a temporary lull in immune activation/inflammation, which leads to improved symptoms.

 

[BrightCandle]

I wouldn't have thought that short remissions or improvements would be related to T-cell exhaustion, since this exhaustion is hard to reverse. My guess is that such remissions might involve a temporary lull in immune activation/inflammation, which leads to improved symptoms.

The remission biome was all based on Doxycycline. If a lot of people have undiagnosed Lyme or a bacteria in their gut that was continuing the challenge to the immune system then a few weeks of intervention with an antibiotic would at the very least disturb the status quo and might give time for the system to reset.

 

[Forummember9922]

Just to get a philosophical question out of the way
Assuming CFS patients have T cell exhaustion why do we not have the same trajectory as AIDS patients IE getting gravely ill from a common cold? Or a huge trend in cancer in CFS patients?
And moreso imaginative and probably wrong, but could there be a shred of rationale in thinking in CFS the body switched to using viruses as a defense system?

 

[Hip]

Assuming CFS patients have T cell exhaustion why do we not have the same trajectory as AIDS patients IE getting gravely ill from a common cold?

I am still learning about this subject, but I think the answer might be that the T-cell exhaustion is antigen-specific.

So for example if you have a widespread chronic viral infection in your body, which presents certain antigens to the immune system, it is only T-cells which target those antigens which will eventually get programmed to become exhausted. You then end up with a stalemate between the immune system and the pathogen.

But T-cells which target some fresh and new infection would work as normal, as far as I am aware.

 

[Forummember9922]

Interesting, so that would be the body saying "Alright we can't win this mini battle, proceed with all the other ones" Sounds like they need a motivational speaker

 

[Forummember9922]

To the ever shrinking school of thought that CFS would be psychosomatic, T cell exhaustion strikes me as the most validating thing proving how real, non psychological and messed up of a condition it is. If that were the whole issue, and treatments actually worked, it really warrants a name change for the illness.
(Neither of those issues being the biggest of our problems)

Myself I actually live near SF and have no hope I could get into it because after 1.5 years I still have not had my very first appointment at the stanford cfs clinic

 

[Hip]

Interesting, so that would be the body saying "Alright we can't win this mini battle, proceed with all the other ones" Sounds like they need a motivational speaker

Yes, according to Penn Medicine at the University of Pennsylvania:

T cell exhaustion happens during a prolonged response to a virus or other infection that is challenging to get rid of entirely. It arises during chronic stimulation of the immune system when the body recognizes that it might be better to live with the virus than kill yourself trying to get rid of it.

In T cell exhaustion, the immune system switches from destroying everything to eliminate the pathogen, to learning how to manage it. T cells sit in this under-responsive state. They’re not inert. They’re partially responsive. It’s as though the body’s defense goal has changed to keep the virus in check without causing too much damage along the way.

The body appears to be clever enough to know when to go for the kill and fully clear the pathogen, versus when to abandon trying to eliminate the pathogen, and instead just try to control it and learn to live with it. The decision to follow the latter course is presumably to prevent too much collateral damage to body cells whilst trying to root out the pathogen.

The body might think: "OK, this pathogen is widespread, it has infected millions of cells, but actually it's a very slow infection which is not life threatening, so maybe it's better to just live with it, and gently try to control it".

If you look at the infections associated with ME/CFS, they are very slow and smouldering, like these smouldering non-cytolytic enterovirus infections which have been found in the tissues of ME/CFS patients. So perhaps ME/CFS arises when the body makes a decision to live with these slow smouldering infections.


In this T-cell exhaustion model, getting ME/CFS may just be an unfortunate accident that happens during the acute infection:

If during the initial acute viral infection the immune response is weakened (by some external factor), then the virus may spread widely in body organs and tissues, so that by the time the acute stage of the infection is brought under control by the immune response, the virus has already seeded itself very widely in millions of body cells. This may set the stage for ME/CFS.

After the acute infection is over, and the chronic phase begins, because the chronic infection is widespread but replicates very slowly, the body may decide the best strategy is to live with this infection, otherwise too many cells might die in any attempt to eliminate it.


This could be why ME/CFS is linked to immunosuppressive factors during the onset of this disease, as these immunosuppressive factors may allow the acute infection to seed a widespread chronic infection in millions of cells in the body.

Immunosuppressive factors such as mould exposure, major chronic stress (which is known to weaken antiviral immunity), and corticosteroids inadvertently given during an acute viral infection are all linked to the triggering of ME/CFS.

Had there not been an immunosuppressive factor present during the acute viral infection, the virus may not have been able to seed itself widely, and then the immune system might have simply chosen a kill and eliminate strategy during the acute phase.

 

[Marylib]

After the acute infection is over, and the chronic phase begins, because the chronic infection is widespread but replicates very slowly, the body may decide the best strategy is to live with this infection, otherwise too many cells might die in any attempt to eliminate it.

You explain things well, @Hip. Subjectively, it has felt like the body has found a way to stay alive by staying sick.

 

[MonkeyMan]

It would be so exciting if checkpoint inhibitors are effective treatment for ME/CFS. Since these drugs are available NOW, we patients would not have to wait for clinical trials, which take years and years.

 

[Hip]

It would be so exciting if checkpoint inhibitors are effective treatment for ME/CFS. Since these drugs are available NOW, we patients would not have to wait for clinical trials, which take years and years.

Yes, there are quite a few different checkpoint inhibitor drugs that are already being used to treat cancer.

Though from what I have read, there can be immune-related adverse events when checkpoint inhibitors are used, and when these events happen, you need a team of physicians to promptly handle them.

Sometimes checkpoint inhibitors can cause dormant viral infections to reactivate, and they are then treated with antiviral drugs. Confusingly for doctors, you can also get adverse events which look like viral reactivations, but are not, and require a different approach to handle.

The incidence of fatal adverse events in checkpoint inhibitor therapy is estimated to be between 0.3% and 1.3%, according to this paper. That's in cancer treatment; whether the fatality rate would be lower when using checkpoint inhibitors to treat viral infections, I am not sure.

So from I have seen, unfortunately it does not look like these are drugs which could be casually tried by ME/CFS patients; I am guessing they would have to be administered in a hospital setting, with physicians on standby if adverse events occurred.



From the ME/CFS patient personal experimentation perspective, perhaps a focus on fixing things like leaky gut might be worthwhile. As mentioned in the first post, one scientist speculated that the immune stimulation from bacteria and their toxins leaking into the bloodstream might be a factor in causing T-cell exhaustion.

 

[Wishful]

My guess is that such remissions might involve a temporary lull in immune activation/inflammation, which leads to improved symptoms.

Do t-cells respond that quickly though (switching over a period of minutes)? If t-cells were fighting viruses in the body, would a signal in the bloodstream for "temporary lull" suddenly turn off all the neurological signals associated with immune activation? I think hormones and some toxins work that rapidly, but I don't know how fast immune signals work.

 

[Hip]

Do t-cells respond that quickly though (switching over a period of minutes)?

The temporary remissions that ME/CFS patients sometimes get could be due to anything, I don't think anyone really knows why these occur. I doubt if it has anything to do with T-cell exhaustion.

 

[Hip]

Just found something interesting: activation of the sympathetic nervous system promotes T-cell exhaustion:

Sympathetic nerves in tissues and tumours drive T-cell exhaustion through the action of the neurotransmitter noradrenaline on the β1-adrenergic receptors (ADRB1) of T cells

These data identify the adrenergic receptor ADRB1 as a new immune checkpoint with increased expression on exhausted T cells paving the way for new therapeutic approaches by which blocking β-adrenergic signalling in CD8+ T cells rejuvenates anti-tumour functions.

See also this article: Reducing Stress on T Cells Makes Them Better Cancer Fighters.

Salk researchers find that stress hormones released by nerves exhaust immune cells in humans and mice, but beta-blockers can help revive them

So for ME/CFS patients with a chronically over-active sympathetic nervous system, finding some way to calm sympathetic activity could reduce T-cell exhaustion, and thereby boost the antiviral potency of your T-cells.

 

[godlovesatrier]

AJ was the first person to raise the T Cell Exhaustion flag in long covid, so might be worth reading his tweets: https://threadreaderapp.com/user/fitterhappierAJ

 

[godlovesatrier]

@Hip that might explain why you see a high incidence of meditation etc on sub reddits around long covid. Also anti inflammatroy foods and low histamine diets are high up there too, which could be contributing to taking stress off the system. I also wonder if ER stress is even part of the disease process - it maybe fits into it somewhere.

So would tudca help by lowering ER stress is my point.