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]

@Hip that might explain why you see a high incidence of meditation etc on sub reddits around long covid.

It also might explain why on rare occasions, some ME/CFS patients improve via psychological therapies that reduce stress levels. This does not mean that ME/CFS is "all in the mind", as some psychiatrists would have you believe, but that by reducing stress and sympathetic nervous system activation, you may increase the antiviral efficacy of your T-cells, and then reduce or clear the viral infections underlying your ME/CFS.

In my case, although I have a very low stressor level in my housebound daily life, I have a feeling that my sympathetic nervous system is permanently wired in the active state. This is because I am prone to sweating at the slightest physical exertion, and I believe this is a sign of an overactive sympathetic (see this thread).

Other symptoms of an overactive sympathetic nervous system are listed here.

So my guess is that somehow my sympathetic has become permanently switched on via some neurological cause in the central nervous system, rather than by any psychological cause. But just what sort of neurological dysfunction might cause an overactive sympathetic, I have not yet been able to figure out.

 

[godlovesatrier]

Leonardi suggests here that genes are being switched on not just in covid but other diseases via their epigentic signalling: https://threadreaderapp.com/thread/1702760549413470520.html but his tweets are hard to read unless you have a PHD in the given area

https://threadreaderapp.com/thread/1687597884701659138.html
""Basically, all people living after 2020 are subject to chronic activation, whether you have “long covid” or not."

I guess LC and ME are just the extreme manifestations of this.

I found papers for other RNA based viruses showing the rna virus never ever clears the body and remains there for life. So if covid is just better at escaping the immune system, it makes sense it would cause long term issues.

 

[godlovesatrier]

@Hip was also chatting with a friend who doesn't have ME but is hyper mobile. Her gastric intestine dumps food quite quickly, mine used to do this too when I first got ME but I also had adrenaline rushes at the smallest thing. However I think this shows two ends of a spectrum, one where a patient on one end dumps food, and on the oher where the food is not even digested.

As for meditation it's definitely helped but as I said to my GP on Friday it's not enough, like I need more. I took citalopram for 5 days post covid and all my long covid symptoms disappeared. I believe this was due to cortisol curve remeditation and serotonin modulation.

I wonder what other drugs might help with this sympathetic issue. Not saying SSRi's will work, there are all sorts of drugs to try but we do know now that lots of drugs have secondary actions like low dose abilify, low dose doxycycline, low dose naltrexone. Personally for me valtrex has been instrumental in getting control over adrenaline, I now have very specific triggers, instead of feeling wired all the time. Of course now I have covid to contend with too

 

[godlovesatrier]

RE my above post about t cell exhaustion

"ER stress is an important factor that regulates chromatin changes in the tumor (164), as well as in the regulation of transcriptome (165). Therefore, ER stress may play previously unexplored roles in regulating TOX-mediated CD8+ T-cell exhaustion."

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.03154/full

"Endoplasmic Reticulum Stress Contributes to Mitochondrial Exhaustion of CD8+ T cells"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397687/

So maybe tudca would help. Although I know it hasn't helped some people here who've tried it. Just thinking about @mariovitali learning models for CFS treatments.

 

[Rufous McKinney]

I have a feeling that my sympathetic nervous system is permanently wired in the active state. This is because I am prone to sweating at the slightest physical exertion

1) I can be both shivering from feeling cold (when it's not) AND sweating.

2) I now live with the one year old and four year old.

My nervous system is somehow jacked up, extremely reactive to simple things like the one year old falling over, or falling off the bed. Even if I know she wont fall off, my body just reacts.

Both kids have noticed this and tease Gramma.

Egad please, lets not tease Gramma like THAT.

3) the baby, months back, was actually falling off the sofa: into the hard coffee table; I reacted, lept from my chair and managed to grab her shirt. Just that little adrenaline rush was so TOXIC. Shockingly toxic.

 

[Marylib]

1) I can be both shivering from feeling cold (when it's not) AND sweating.

I wish I could loan you my inability to sweat...would be awful to sweat when you are cold. For those of us who can't, well, we live for winter...

 

[Rufous McKinney]

I wish I could loan you my inability to sweat

I think sweating for me is very patchy. Which females are know for anyway.

Its going to get hot here for a couple of months at least and I'll be checking out how that goes (recently moved to a new biome)

That sounds hard, dealing with a total inability/ thermoregulating is tough enough!

 

[Marylib]

That sounds hard, dealing with a total inability/ thermoregulating is tough enough!

Thanks. Yeah, it makes life ... umm... well, you kind of wish you lived somewhere where the temps stayed under 60 degrees (F). In my case, I can ALWAYS get warm. All I have to do is move my body slightly or wear layers. But I know that always being cold is difficult too. I have known people who cannot get warm no matter what. Hope you do well in your new biome...

 

[MaximilianKohler]

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.

I don't think that's an accurate view. You need to think of the gut microbiome as a whole ecosystem. Antibiotics do long-term damage that accumulates over generations.

This ecosystem impacts and regulates the entire body, and once it's damaged it has a wide variety of detrimental impacts:

Moderator note: Link removed due to self-advertising

Once you have "gut dysbiosis" an antibiotic can be helpful, but it's not a solution. There is no known way to "reset" the gut microbiome.

 

[godlovesatrier]

Yep Max is right, Martin Blasers book missing microbes explains the research really well.

Doxy for example is meant to kill oxalabacter formigenes, mine was already very low, just waiting to see if it's gone extinct.

Akkermansia went extinct this year without taking antibiotics though I will say that. I assume the intestinal viral load got too much for it.

Obviously with a chronic infection antibiotics are the only way to get better, there are a few remission stories around this.

 

[Hip]

Methylene blue (MB) appears a good PD-1 inhibitor, according to this study. The study found that vivo in mice, MB at a dose of 20 mg/kg daily is effective for fighting cancer tumours.

In vitro experiments found that MB is stronger than standard checkpoint inhibitor drugs:

100 nM of MB elicited stronger proliferation of CD8+ T cells than 25 μg/ml of pembrolizumab or 20 μg/ml nivolumab

Apparently non-antibody based PD-1 inhibition (as you get from methylene blue) is much safer than standard monoclonal antibody checkpoint inhibitor drugs like nivolumab, which can cause fatal side effects:

Unfortunately, PD‐1 inhibitors currently used in clinic show severe, sometimes fatal, side effects

it is antibodies, rather than PD‐1 inhibition per se, that cause the side effects currently seen in clinic

Small molecular PD‐1 inhibitors are, therefore, expected to achieve therapeutic effect comparable to antibody drugs while eliminating the toxicity issues.

The mouse 20 mg/kg daily dose would equate to a human dose of 1.6 mg/kg, which is a daily oral dose of 130 mg daily for an 80 kg human.

MB is safe for humans at doses of less than 2 mg/kg, according to this article:

Methylene blue is a safe drug at a therapeutic dose of less than 2 mg/kg; however, when levels are greater than 7 mg/kg, many of the adverse effects it exhibits will occur.

Serotonin syndrome has been found to occur when combining serotonergic agents with methylene blue at a dose of 5 mg/kg. Methylene blue use also requires caution in patients with renal failure due to its ability to reduce renal blood flow. Also, as noted in adverse effects, patients taking any drug with serotonergic activity, such as SSRIs, should avoid the administration of methylene blue due to the risk of serotonin syndrome.

A Health Rising article about various benefits of MB for ME/CFS, suggesting doses of up to 34 mg daily for a 68 kg person.

 

[godlovesatrier]

That stuff scares me but I did bookmark a brand of it to try. I'm currently retrying higher doses of lactoferrin for long covid symptoms. Heart rate is far too high against my five year average.

Thanks Hip. If anyone tries MB be good to know if they get improvement.

 

[Wishful]

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.

I was thinking further about it, and the abrupt change in symptom severity is more likely the neurological response to immune activity. "Flu symptoms" are mainly from the brain's responses to cytokines, so blocking those signals or altering the neural response could cause the rapid change in symptom severity.

When I had the type IV sensitivity, a food trigger would be followed by a 48 hr delay, then an abrupt flare up of the symptoms, followed by IIRC (it's harder to notice and judge reductions in severity) a slightly slower return to baseline. The rate of change from that was similar to that of my temporary remissions.

I agree that the abrupt changes are unlikely to involve t-cell function directly.

 

[Rufous McKinney]

and the abrupt change in symptom severity is more likely the neurological response to immune activity.

if I consume some chemical or herb which directly reduces inflammation and pain, within about twenty minutes, my body starts to be able to move around far more readily. And I can start to focus my eyes, which are swollen and blurred and aching and awful otherwise. I can think more clearly, as the swollen awful eye thing is also felt in the brain and in the tinnitus reaction.

So once there is far less of this "swollen up" state, and less actual inflammatory pain, I might start to clean the bathroom. This activity response usually does not seem to crash me very much.

 

[joshualevy]

My personal view of this study is that no scientific progress will come from it. It will get quoted (it is $8 million government research project, after all), but none of its findings will lead anywhere. The checkpoint drug trials will be unsuccessful, and if more than one checkpoint drugs are tested, most will fail, and even any that succeed will then fail in later testing. The fMRI and EEfRT results will lead nowhere.

This is what I think happened:
1. The researched designed an experiment which needed about 35 people for good data, and therefore tried to recruit 40 people so they would have a safety margin.
2. Because of bad design and COVID they were actually able to recruit less than 20 people, which means the study is statistically under powered for almost everything they planned to do.
3. At this point, they should have canceled the clinical trial, or basically just published all the data but without any conclusions, because the under powering would not lead to meaningful conclusions, anyway.
4. But obviously, there were huge non-scientific pressures put on them, and they published stuff anyway. However, they did not have anything real to publish (because of the under power), so all the conclusions are weak and tentative. Each author got to say what they wanted to say, because the vague and weak data could support anything.
5. Because it is a relatively large, government funded, long awaited, research project, all of the various quotes (many implying contradictory things) will be reused in arguments for years to come, but the actual science is not going to lead anywhere, because it is all under powered and therefore vague and weak. (In an ironic turn of events, my guess is you will see both biosocial and biomedical supporters quoting different parts of this paper. (A clear sign that the paper was written by a committee with different opinions, and the data is not strong enough to support some of these opinions over others.)
6. The researchers had this data available years ago. None of them used it to start follow on research projects or funding to do new research, and that is very strong evidence that there is nothing there to follow up on. (Except maybe the check point drugs, see above.)

 

[Rufous McKinney]

statistically under powered

that HUGELY limits the value of these data

 

[Hip]

@datadragon your attempts to relate every single discussion on any subject whatsoever on PR back to zinc are pseudoscientific. Sorry, but zinc is not cure for ME/CFS.

 

[SlamDancin]

Guys I just want to warn you, UCSF picking this up with trials concerns me. I have had some very lacking treatment from various doctors there over the years and it has always been so cookie cutter, ignorant of me/cfs nearly completely, expensive af and pretty unhelpful.

Anyone have a link with more info on the checkpoint trials?

 

[kangaSue]

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.

Nerve blocks from injecting various local anaesthetics into different nerve bundles or plexuses in the body work in part via the suppression of SNS hyperactivity.

This is an interesting article about a long covid patient suggesting his recovery in large part was due to doing nerve blocks at several different points so maybe that could at least help with moderating some of the symptoms of ME/CFS for some people too.

Local anesthetics as a therapeutic tool for post COVID-19 patients: A case report (2022)
https://journals.lww.com/md-journal...hetics_as_a_therapeutic_tool_for_post.33.aspx

 

[Hip]

Nerve blocks from injecting various local anaesthetics into different nerve bundles or plexuses in the body work in part via the suppression of SNS hyperactivity.

Yes, I've heard of people getting a stellate ganglion block as an experimental treatment for ME/CFS and long COVID (the stellate ganglion is located in the neck). This block can calm the sympathetic nerves in the neck, head, upper chest and upper arm.

SGB is also used to treat Raynaud’s disease, a condition involving cold hands and feet.

One theory is that the cold hands and feet found in many ME/CFS patients are caused by sympathetic nervous system overactivation.


I wonder what causes this sympathetic nervous system hyperactivity in the first place. Ever since I caught the Coxsackie B4 virus which triggered my ME/CFS, I developed constantly cold hands and feet, as well as sweating on the slightest of activity, which I believe are both signs of SNS overactivation.

I'd like to find some effective ways of calming my SNS.