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]

Has Professor Avindra Nath nailed the cause of ME/CFS?

An article in Scientific American details Prof Avindra Nath's latest NIH study on ME/CFS.

This study finds that in ME/CFS patients, the T-cells of the immune system have become exhausted, so cannot properly clear viral infections:

• In the blood, the study found killer T-cells which destroy virally infected cells had reduced CD226, which is a protein that normally boosts the proliferation and activity of these T-cells.

• And in the cerebrospinal fluid, they found killer T-cells had high levels of programmed cell death protein 1 (PD-1). This protein is considered an exhaustion marker, and its presence can indicate an overstimulated T-cell that has shut down.

Note that killer T-cells are also called: CD8 cells, CD8 T-cells, and cytotoxic T-cells.



Cause of T-Cell Exhaustion

Why does this immune exhaustion occur? Prof Nath speculates that if remnants of a viral infection persist in the body for a long time, and continue to stimulate immune cells, it may lead to such exhaustion. But he says further evidence is needed to confirm this.

So this seems like it could be a Catch-22 situation: in ME/CFS you cannot fully clear the last remnants of your viral infection because of T-cell exhaustion; and you cannot overcome T-cell exhaustion because the widespread viral remnants may be the cause of this exhaustion!

So the last remnants of the viral infection cannot be cleared, and these remnants may be responsible for causing all the ME/CFS symptoms.

And this Catch-22 situation could explain why weak immunity (eg from mould exposure, chronic stress or prescription corticosteroids) during the time of the acute viral infection often seems to lead ME/CFS: if immunity is weak during the acute infection, it may allow the virus to spread widely in the body, and so seeds itself in multiple organs and tissues. This then leaves a lot of viral remnants lying around, which in turn trigger T-cell exhaustion, which means these remnants cannot be cleared up.

This finding of T-cell exhaustion makes a sense to me, as I've always felt that there is something preventing the immune system from clearing the last remnants of a viral infection in the body tissues, and that it is these persistent remnants which cause the symptoms of ME/CFS.

This is not the only study finding T-cell exhaustion in ME/CFS; a 2016 study also found this.


Katharine Seton, an immunologist researching ME/CFS at the Quadram Institute, and who was not involved with this study, hypothesises that a leaky gut could be another trigger of exhaustion: if microbes that live in the gut leak into the bloodstream, they might perpetually stimulate immune cells, leading to exhaustion.





T-Cell Exhaustion Treatment

I wonder whether inhibitors of programmed cell death protein 1 (PD-1) might re-ignite the killer T-cells in the cerebrospinal fluid?

There is a PD-1 inhibitor called nivolumab which is FDA approved to treat certain cancers. As this post details, nivolumab has been shown to substantially decrease HIV reservoirs in the body. Unfortunately nivolumab is not without side effects: it can sometimes precipitate diabetes. Pembrolizumab is another approved PD-1 inhibitor.



T-Cell Exhaustion Overview

This paper gives an overview of T-cell exhaustion:

Highlights

• Persistent viral infections can result in the exhaustion of anti-viral T-cells.
• Excessive and sustained levels of viral antigen drive T-cell exhaustion.
• Exhausted T-cells are distinct from typical effector and memory subsets.
• Exhausted T-cells are functionally ineffective and compromise viral clearance.
• Blocking inhibitory receptors and modifying cytokine levels can alleviate exhaustion.

This paper says high antigen levels are the cause of T-cell exhaustion during chronic viral infection. This ties in with Prof Nath's idea that the remnants of a viral infection persisting in the body are causing T-cell exhaustion; if there are widespread viral remnants throughout the body, then you will get a lot of viral antigen, leading to T-cell exhaustion.

 

[Dude]

The paper receives considerable criticism online, but it provides the most comprehensive explanation I've encountered so far. I appreciate your insight Hip. Does this potentially elucidate why antivirals occasionally show efficacy? Additionally, I came across a suggestion to explore checkpoint inhibitors, are there any ongoing or planned studies investigating this possibility?

 

[Treeman]

So this seems like it could be a Catch-22 situation: in ME/CFS you cannot fully clear the last remnants of your viral infection because of T-cell exhaustion; and you cannot overcome T-cell exhaustion because the widespread viral remnants may be the cause of this exhaustion!

I'm pleased to see this, but I have to consider there is still more going on to explain the "catch 22" situation.

We know that immune systems aim is to stop the infection/infections, and this causes inflammation, many researchers have stated this and described ME/CFS as a "cytokine storm". here

Research has also shown that inflammation leads to clotting in ME/CFS here

Research has also shown that clotting leads to reduce oxygen in the body. Here.

Accordingly, this clotting leads to less oxygen (vital in aerobic animals) in the tissues and cells so promoting "symptoms including fatigue, exercise intolerance, and cognitive impairment." here

In addition to the above oxygen is needed to create a good immune response here.

I consider that a multi approach is needed to deal with each stage of the diseases process, deal with low immunity, low oxygen in the cells, deal with persistent inflammation, deal with persistent infections.

With rest I consider some sufferers are able to allow the body to naturally do this, some stating it can take years, but during that time it's required to stay within the "energy envelope" and not stress the body by running out of oxygen causing the cascade effect. I consider that even catching a new infection like a respiratory infection can stress the body into worse health.

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.

 

[Wishful]

The theory runs counter to my experiences. My viral infections tend to last just a couple of days, and seem to clear fully. I've always felt that my immune system was more effective than average, and that didn't change with ME.

Would symptoms due to "exhausted t-cells" be able to switch 100% off over the space of minutes, then switch 100% back on some hours later, also over the space of minutes?

My guess is that this is a case of experts in one field looking for an explanation that is in their field, whether it's the right explanation or not (especially if it leads to more funding for their field). Since it's a fairly simple mechanism with possibly simple treatments, it will get positive press. A theory that is hard to explain and lacks a simple solution will get less attention.

 

[Hip]

Does this potentially elucidate why antivirals occasionally show efficacy?

Certainly for enterovirus ME/CFS, the antiviral interferon is very effective for many patients. Dr Chia has seen how after a few months of interferon therapy, severe bedbound ME/CFS patients are able to return to work.

Unfortunately nearly all patients treated with interferon relapse after around 4 to 12 months, often following a heavy prolonged bout of exercise. And with the relapse comes a rise in viral titres back to the original illness baseline.

So it would seem that interferon cannot fully clear the virus from the body, and the infection later regrows, and ME/CFS returns. If it were not for this relapse, interferon therapy would be an excellent treatment for enterovirus ME/CFS.


I think this interferon therapy relapse phenomenon may fit in with the T-cell exhaustion situation: if the T-cells remain exhausted even with the infection cut back after interferon, then the immune weakness is still present, and so may facilitate the regrowth of the infection.

Although you would think that after the enterovirus infection has been trimmed down by interferon, this would fix the T-cell exhaustion, going by Prof Nath's idea that it is the persisting remnants of the viral infection which overstimulate immune cells and cause T-cell exhaustion.

But maybe the T-cell exhaustion is not so easily rectified: maybe it persists for some time even after a good percentage of the viral infection has been eliminated by interferon. This article seems to confirm that:

Our findings suggest that once T cells become exhausted, they remain fundamentally ‘wired’ to be exhausted — thus it may be hard to get them to become effective virus and cancer fighters again

Or maybe the percentage of the viral infection which remains after interferon therapy is enough to maintain T-cells in an exhausted state.

Alternatively, maybe the source of the T-cell exhaustion is not the persisting viral remnants, but as Katharine Seton suggests, arises from a leaky gut which allows microbes and the toxins to leak into the bloodstream, continually overstimulating immune cells. Or it could be a combination of a leaky gut and the viral remnants which overstimulate immune cells to cause exhaustion.

 

[RYO]

I think we need studies to show effects of exercise on blood brain barrier of pwMECFS.

https://pubmed.ncbi.nlm.nih.gov/30678702/

 

[Hip]

It's worth bringing up vaccine-triggered ME/CFS here, because T-cell exhaustion might help explain this.

If you chat to patients with vaccine-triggered ME/CFS, and you find that these patients also have high titres to the standard ME/CFS viruses (coxsackievirus B, echovirus, EBV, cytomegalovirus, HHV-6, etc) — the same sort of high viral titres that you find in infection-induced ME/CFS.

This suggests that although it was the vaccine which triggered the ME/CFS, the ME/CFS illness may be still caused by an ongoing viral infection.

So this raises the question: did the vaccination cause existing dormant viruses in these patients to reactivate, thereby causing ME/CFS? If so, that suggests the vaccine has somehow weakened some aspect of immunity, allowing existing dormant infections to come back to life.

Could it be that the immune stimulation from a vaccine causes T-cell exhaustion, and this then allows dormant viruses to reactivate? Once they are reactivated, these infections themselves will cause immune overstimulation, and may thereby maintain the T-cells in an exhausted state.

T-cell exhaustion might be a vicious circle: one you get T-cell exhaustion, this immune weakness may allow infections to reactivate and spread widely in body tissues; and once the infections are widespread, they may continually overstimulate the immune system, maintaining the T-cell exhaustion.

 

[Hip]

My viral infections tend to last just a couple of days, and seem to clear fully. I've always felt that my immune system was more effective than average, and that didn't change with ME.

Dr Rich Van Konynenburg offered a very interesting explanation for why many ME/CFS patients appear to have a super-charged immune system that often prevents them catching colds, or allows them to overcome colds easily. And Rich's explanation for this seem to fit in nicely with the discovery of exhausted T-cells in ME/CFS.

Rich suggested that some parts of the immune system are weak in ME/CFS, and this results in other areas of immunity getting super-charged, in order to compensate.

Rich believed the first line in immune defence, namely the type 1 interferon response, was constantly ramped up in ME/CFS patients, in order to compensate for weaknesses in other areas of the immune system, namely weaknesses in NK cell and killer T-cell functioning.

If interferon, the first line in immune defence, is constantly ramped up, this means any cold virus that lands on the mucous membranes of your respiratory tract will tend to get eradicated immediately by the interferon response, before the virus has a chance to take hold in the body.

So Rich's idea may explain why most ME/CFS patients rarely catch colds. (Although there is a small subset of ME/CFS patients who experience the opposite: they are much more prone to colds, and often have lingering colds which take months to clear).

With this finding of T-cell exhaustion in ME/CFS, we now have a theory of why NK cell functioning and killer T-cell functioning is below par in ME/CFS.

 

[andyguitar]

Why does this immune exhaustion occur? Prof Nath speculates that if remnants of a viral infection persist in the body for a long time, and continue to stimulate immune cells, it may lead to such exhaustion.

Yep this can happen.

But he says further evidence is needed to confirm this.

And to rule out other potential causes of T-cell exhaustion. I'm interested in the possibility that it is induced by low oxygen levels. Just thought I'd put that thought down for those of us who have doubts about viral persistance being the driver of symptoms. I wonder what is meant by "remnants of a viral infection"?

 

[Hip]

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

other potential causes of T-cell exhaustion. I'm interested in the possibility that it is induced by low oxygen levels

Googling on hypoxia and T-cell exhaustion, I came across one in vitro study which found:

T cells maintained functionality in the presence of hypoxia or continuous stimulation alone, but combination of both stressors produced an exhausted-like state

So this finding suggests it takes both hypoxia as well as antigen overstimulation to trigger T-cell exhaustion.

This article on T-cell exhaustion and cancer states that in the hypoxic conditions normally found in tumours contributes to T cell exhaustion.

I wonder what is meant by "remnants of a viral infection"?

Presumably viral remnants refers to any persistent viral presence or infection in the body tissues after the acute viral infection is over. This might mean non-cytolytic infections, abortive infections, and partially reactivated latent infections; these are all active but low-level infections that would stimulate the immune system.

 

[andyguitar]

So this finding suggests it takes both hypoxia as well as antigen overstimulation to trigger T-cell exhaustion. However, there does not appear to be much research on the effects of hypoxia on T-cell exhaustion, and I could not find much that corroborates this in vitro finding.

I've been looking at research like this-not a very strong connection but might be of interest...... The last 4 lines of this....

 

[heapsreal]

Sounds alot like Dr Martin Lerner when he mentioned persistent abortive lytic infections found in cfsme.

 

[Hip]

Looks like the University of Pennsylvania is a centre for T-cell exhaustion research. If you search their website, there are dozens of press release articles on their work.

Some highlights:

This article outlines how T-cells respond to acute versus chronic infections. With chronic infections, the immune system and the pathogen initially reach stalemate. But over time, the battle-weary T-cells become exhausted, giving the pathogen the edge.

This article talks about the persistence of T-cell exhaustion. It says that once T-cells become exhausted, they remain fundamentally "wired" to be exhausted. Which means that it is hard to coax such T-cells back into the state where they fight infections and cancers.

One question the researchers wanted to answer is what happens to exhausted T-cells once they no longer have exposure to the virus or cancer that exhausted them. Do they then become un-exhausted? Well they found that once the exposure was removed, most of the T-cells died. But the ones that survived still remained exhausted, as they are epigenetically programmed to be in the exhausted state.

This article says there are many types of exhausted T-cell, and they generally express inhibitory receptor proteins on their surface that stall key biochemical pathways in fighting cancer or infection. By targeting receptor proteins such as PD-1 or CTLA-4 with immunotherapies, it can have dramatic effects for patients with melanoma and other diseases.

This article says that T-cells have a pathway to exhaustion, and if you want to coax T-cells back into functioning again, you have to know at what point they are on along this pathway, so that you can take the right action.

There are four stages on the pathway to exhaustion: stem-cell like progenitor cells that remain dormant; progenitor cells that proliferate and circulate; "intermediate" cells that circulate and are slightly cytotoxic; and terminally exhausted cells.

This article focuses on specially engineered T-cells called CAR T-cells. These are T-cells that have been harvested from the blood of a patient and genetically reprogrammed. The reprogramming alters the patient’s T-cells so that they now recognise a marker (antigen) on cancer cells in that patient. Once created, these CAR T-cells are re-infused into the patient to attack the cancer.

This article talks about checkpoint pathways (which inhibit T-cell activation) and checkpoint inhibitor drugs (which block the checkpoint process, to re-invigorate the T-cell response). Such drugs include: nivolumab, pembrolizumab, ipilimumab and atezolizumab).

 

[Hip]

ME/CFS has been linked to extensive use of antibiotics during childhood, and this finding might be explained in terms of T-cell exhaustion:

The theory is that such heavy antibiotic use at a young age will create dysbiosis in the gut. Well perhaps such dysbiosis acts as a constant immune stimulant, thereby increasing the chances of T-cell exhaustion developing during a viral infection.

Once T-cell exhaustion develops, then the viral infection may become hard to clear, and ME/CFS manifests.

 

[Strawberry]

Hi all you brainiacs! Many of us here have almost zero NK cell function, would this be another cell disfunction on top of NK function? Or would it be an either or scenario?

I hope this leads to a treatment, as I’m over this disease. Coming up on my 30 year anniversary…

 

[Hip]

Many of us here have almost zero NK cell function, would this be another cell disfunction on top of NK function?

According to this paper, there is such a thing as natural killer cell exhaustion, but it is much less studied than T-cell exhaustion.

Not sure if the conditions that lead to T-cell exhaustion (such as high exposure to antigens from pathogens) can also lead to natural killer cell exhaustion.

I suspect not, since T-cells are part of the adaptive immune system, so they need to be trained on an antigen before they can attack. Whereas NK cells are part of the innate immune system, so can attack without needing to be trained on an antigen.

But I don't really know.

 

[MaximilianKohler]

The theory is that such heavy antibiotic use at a young age will create dysbiosis in the gut. Well perhaps such dysbiosis acts as a constant immune stimulant, thereby increasing the chances of T-cell exhaustion developing during a viral infection.

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

 

[heapsreal]

Hi all you brainiacs! Many of us here have almost zero NK cell function, would this be another cell disfunction on top of NK function? Or would it be an either or scenario?

I hope this leads to a treatment, as I’m over this disease. Coming up on my 30 year anniversary…

Griffith university in Australia have done alot of research on low nk function in cfsme pts. The nk function study I was involved in 2009, they also told us that there is a high percentage of cfsme pts with low cd8 t cell function.

I know they have published alot of papers on nk function but I can't recall if they have published anything on cd8 t cell function, just that they mentioned it to us pts in the trial.

 

[heapsreal]

Griffith university in Australia have done alot of research on low nk function in cfsme pts. The nk function study I was involved in 2009, they also told us that there is a high percentage of cfsme pts with low cd8 t cell function.

I know they have published alot of papers on nk function but I can't recall if they have published anything on cd8 t cell function, just that they mentioned it to us pts in the trial.

It didn't take long to find a study done by Griffith university on cd8 T cells. It seems to be a common finding in cfsme???

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736227/

In summary, these preliminary findings provide new insight into the possibility of hyper activated inflammatory CD8+ T cell profile in untreated MS patients while CFS/ME patients may display an exhausted profile which permits viral prevalence and persistence. The above data may suggest that the differential expressions of receptors and adhesion molecules in MS patients are in response to imbalances in neuroimmune homeostasis. In comparison to CFS/ME patients, MS patients may have more severe immune dysregulation. Nevertheless it is likely that impairments in CD8+ T cells in CFS/ME patients relate to abnormal levels of adhesion and migratory molecules and these abnormalities may contribute to the persistent immune dysregulation observed and warrant further validation in a larger sample size.

 

[Dude]