Endothelin, Multiple Sclerosis, Systemic Sclerosis, Anti-ETAR AAb, Exosomes and CFS/ME

[pattismith]

These data demonstrate that reduced Cerebral Blood Flow in MS is mediated by Endothelin 1, which is likely released in the cerebral circulation from reactive astrocytes in plaques.

According to this 2019 study, Sulfisoxazole inhibits the secretion of small extracellular vesicles (exosomes) by targeting the endothelin receptor A. (Sulfisoxazole is a non selective antagonist for endothelin receptors)

This other recent study indicates a possible role of exosomes in Systemic Sclerosis (an autoimmune disease) pathogenesis.

And Systemic Sclerosis was found to be associated with high anti Endothelin A receptor auto-antibodies. (These antibodies are in the Cell Trend panel for POTS).

These Ab are activator to these receptors...

So my question would be : could ETA inhibitors have a beneficial effect on CFS/ME (either by improving cerebral blood flow or by decreasing exosomes)?

I have high anti ETAR Ab, so I wish to try them, but I don't have access … Anyone ever try one?

 

[pattismith]

Interestingly, macrolides anti-inflammatory effect could be mediated by Endothelin lowering effect:

"Erythromycin and clarithromycin uniquely suppressed mRNA levels as well as the release of ET-1 at therapeutic and non-cytotoxic concentrations(percentage in hibition of ET-1 protein release: 26.4±5.22% and 31.2±7.45%, respectively, at 10−6 M). Furthermore, erythromycin and clarithromycin inhibited ET1 expression in broncho-epithelial cells from patients with chronic, stable asthma"

 

[SlamDancin]

@necessary8

I have alpha1>2 positive and also M2/3.
My doc didn’t order the other ones Patti did though but I’m wondering if you might find this research on Endothelin to be interesting re: a triggering mechanism of the NOX containing exosomes in your hypothesis?

 

[SlamDancin]

@pattismith Any evidence of the macrolides lowering ET-1 outside of the lungs as well?

 

[pattismith]

@pattismith Any evidence of the macrolides lowering ET-1 outside of the lungs as well?

I don't find any, but Macrolides have spinal anti-inflammatory properties and also shown ability to lower IL8 and proinflammatory M1 macrophages.
As IL8 production was shown to be induced by ETAR activation (by endothelin), macrolides probably have this effect in spine and brain as well as lungs.
Macrolides saved me several times, when I had spinal pain and each time I have bronchopneumonia (which happens on a regular basis).

Again they help me these days with a combo of Carnitine + Lipoic acid to fight resistant headache!

 

[necessary8]

This is an interesting idea. I've looked at endothelin a bit before but not super in depth.

I’m wondering if you might find this research on Endothelin to be interesting re: a triggering mechanism of the NOX containing exosomes in your hypothesis?

The answer to this is, suprisingly to myself, yes. I think it could. Maybe. Source

There is only one big problem. Endothelin-1 levels have been tested in CFS and appear to be normal.
One way around that might be that perhaps in the case of CFS there is some other molecule that resembles endothelin and mimicks its action. But this is pure conjecture at this point. I haven't seen any data that would suggest this. If you guys find any, feel free to tag me.

 

[pattismith]

This is an interesting idea. I've looked at endothelin a bit before but not super in depth.


The answer to this is, suprisingly to myself, yes. I think it could. Maybe. Source

There is only one big problem. Endothelin-1 levels have been tested in CFS and appear to be normal.
One way around that might be that perhaps in the case of CFS there is some other molecule that resembles endothelin and mimicks its action. But this is pure conjecture at this point. I haven't seen any data that would suggest this. If you guys find any, feel free to tag me.

Yes Anti ETAR antibodies from the Celltrend POTS panel are believed to have endothelin like activity. They are not typical for ME/CFS but might be present in a subgroup?

(These antibodies are also found in Sjogren and Systemic Sclerosis)

 

[SlamDancin]

This is an interesting idea. I've looked at endothelin a bit before but not super in depth.


The answer to this is, suprisingly to myself, yes. I think it could. Maybe. Source

There is only one big problem. Endothelin-1 levels have been tested in CFS and appear to be normal.
One way around that might be that perhaps in the case of CFS there is some other molecule that resembles endothelin and mimicks its action. But this is pure conjecture at this point. I haven't seen any data that would suggest this. If you guys find any, feel free to tag me.

Well @pattismith has high levels of agonistic antibodies towards the ET-A receptor, which may make normal levels of ET-1 non-reflective of overexpressed ETA signaling cascade, which apparently includes exosome release.

@necessary8 tagging you since you asked

 

[SlamDancin]

I’ve read a paper separate to any of these specific antibodies, that paraphrasing from, said that it’s normal for the immune system to use antibodies and autoantibodies to effect deemed imperative
Functions. So the positive antibodies towards alpha adrenergic 1/2 and m2/3 muscarinic make total sense to me relative to my own case when I’ve learned their fuction. Unfortunately, my doc at the time didn’t think apparently that the ETAR test was necessary so I didn’t get it done. AT1R neither but they are all offered by Celltrend labs and their positive results in some of these antibodies are being seen and written about mostly in German research. It was B2 adrenergic and M2 muscarinic levels apparently that were the most predictive in ME/CFS.

 

[SlamDancin]

What’s weird is I while believe that the adrenergic and muscarinic antibodies are a positive adaptation for me, I can’t see how ETAR activation would be beneficial. Especially, if they are releasing these damaging exosomes. Unless those exosomes are somehow more useful than they are harmful. That’s hard to tell so I’m not taking any pharmacological action with it at this point.

 

[pattismith]

This is an interesting idea. I've looked at endothelin a bit before but not super in depth.


The answer to this is, suprisingly to myself, yes. I think it could. Maybe. Source

There is only one big problem. Endothelin-1 levels have been tested in CFS and appear to be normal.
One way around that might be that perhaps in the case of CFS there is some other molecule that resembles endothelin and mimicks its action. But this is pure conjecture at this point. I haven't seen any data that would suggest this. If you guys find any, feel free to tag me.

I found another study about high endothelin in ME/CFS so things are not clear.
Also IL8 is high in ME/CFS and I found a correlation with endothelin and anti-ETAR Ab:

This study about auto antibodies against G Protein Coupled Receptors says:

"Considering the central role of interleukin-8 (IL-8) as an important chemokine that regulates neutrophil migration29, we were able to show that HealthyDonors-IgG triggered IL-8 production by peripheral blood mononuclear cells (PBMCs) (Fig. 8d), which also express EDNRA32.
The spontaneous IL-8 synthesis by PBMCs strongly correlated with EDNRA expression (Fig. 8e).
These findings suggest that HD-IgG controls the trafficking of neutrophils directly via chemotactic mechanisms and indirectly by triggering IL-8 production."

They showed that Ab anti-EDNRA (endothelin receptor type A) are activator of neutrophil migration via IL8 production (this is the result of agonist effect of these auto-antibodies against EDNRA also called ETA-R in other studies and in the celltrend panel)

These auto antibodies are natural part of the immune regulation, but the equilibrium can be disrupted in some auto-immune diseases, with too much or too little of these Ab.

In ME/CFS we have too much IL8, so we may have too much of these ETA auto-antibodies.

 

[knackers323]

Clarithromycin makes me feel much better within a day of taking it.

All effects are gone with a day of stopping taking it

Is there anything else that might have similar effects?

 

[pattismith]

@necessary8
I can't find the study saying Endothelin 1 could be high in CFS/ME, only the studies saying endothelin 1 is high in FM blood.
That said, maybe endothelin could be locally elevated in the brain only?

Also this study about "Influence of Circulating Endothelin-1 and Asymmetric Dimethylarginine on Whole Brain Circulation Time in Multiple Sclerosis " says:
"It is supposed that high ET1 and ADMA levels stem from a protective response to early insults, aimed at opposing nitric oxide overproduction, whereas persistent pathological ET1 and ADMA levels translate into detrimental long-term effects, due to increased brain micro-vessel resistance."
so I wonder if ADMA alone can be involved?

Clarithromycin makes me feel much better within a day of taking it.

All effects are gone with a day of stopping taking it

Is there anything else that might have similar effects?

How long did you take Clarithromycin? What symptoms did you had before taking it that disappeared?

Maybe endothelin receptor inhibitors could do the job too. They have shown some interest in Systemic Sclerosis, an auto-immune disease with endothelin involvement.

 

[necessary8]

Yes Anti ETAR antibodies from the Celltrend POTS panel are believed to have endothelin like activity.

Can you link me this one? I can't find it.
If it's true then that's a really good argument.

 

[pattismith]

Can you link me this one? I can't find it.
If it's true then that's a really good argument.

Yes, as I have quoted earlier in this thread :

This study about auto antibodies against G Protein Coupled Receptors says:

"Considering the central role of interleukin-8 (IL-8) as an important chemokine that regulates neutrophil migration29, we were able to show that HealthyDonors-IgG triggered IL-8 production by peripheral blood mononuclear cells (PBMCs) (Fig. 8d), which also express EDNRA32.
The spontaneous IL-8 synthesis by PBMCs strongly correlated with EDNRA expression (Fig. 8e).
These findings suggest that HD-IgG controls the trafficking of neutrophils directly via chemotactic mechanisms and indirectly by triggering IL-8 production."

They showed that Ab anti-EDNRA (endothelin receptor type A) are activator of neutrophil migration via IL8 production (this is the result of agonist effect of these auto-antibodies against EDNRA also called ETA-R in other studies).

In this study the celltrend elisa kit were used for antibodies testing.

 

[necessary8]

They showed that Ab anti-EDNRA (endothelin receptor type A) are activator of neutrophil migration via IL8 production (this is the result of agonist effect of these auto-antibodies against EDNRA also called ETA-R in other studies).

Okay but this is not a study on POTS. You said that there are anti-ENDR antibodies present in POTS. Show me the source for that.

 

[pattismith]

Okay but this is not a study on POTS. You said that there are anti-ENDR antibodies present in POTS. Show me the source for that.

There must be some reason why celltrend added it to their pots panel. For now i have only found the japanese study about auto antibodies post HPV vaccine (patients had either POTS or CRPS)
In the present study, compared with those in controls, the serum
levels of autoantibodies against adrenergic receptors α1, α2, β1, β2; muscarinic acetylcholine receptor 1, 2, 3, 4, and 5; and ETAR were signi cantly elevated in patients with HPV vaccination. In contrast, there was no signi cant di erence of serum levels of autoantibody againstAT1R between both groups of individuals examined.

I have a problem for copying the link to the japanese study on my tablet but it can be found in celltrend site or in the cited references in this article:
https://forums.phoenixrising.me/bookmarks/confirm?content_type=post&content_id=2240858

 

[knackers323]

@pattismith ive taken clarithromycin multiple times for a couple of weeks each time
Each time the effect was the same

I didn’t want to stay in them too long an have them destroy my stomach bacteria

 

[necessary8]

In the present study, compared with those in controls, the serum
levels of autoantibodies against adrenergic receptors α1, α2, β1, β2; muscarinic acetylcholine receptor 1, 2, 3, 4, and 5; and ETAR were signi cantly elevated in patients with HPV vaccination. In contrast, there was no signi cant di erence of serum levels of autoantibody againstAT1R between both groups of individuals examined.

This text is from this study: http://www.remedypublications.com/a...ology/articles/pdfs_folder/aacr-v2-id1014.pdf
which also does not show the presence of anti ETAR antibodies in POTS.
I'm sorry but "this one lab added that test to their POTS panel" is not evidence of a presence of those antibodies.

It's still not a bad idea overall, but from what I see we definitely do not have evidence of such antbodies being present in CFS or POTS.

 

[SlamDancin]

@necessary8 I know this isn’t exactly what we’re looking for but it’s the first thing I found.

https://www.ncbi.nlm.nih.gov/m/pubmed/30031661/?i=1&from=orthostatic hypotension endothelin

Role of the Autonomic Nervous System and Vascular Endothelial Factors in the Development of Primary Arterial Hypotension in Paediatric Patients.

The change of position from horizontal into vertical was accompanied by a rise only in sympathetic activity (p<0.001). However, there was a decline in the sympathetic nervous system (p<0.001) compared to the indices of the initial (resting) position registered in the tenth minute of the vertical position. The parasympathetic division of the ANS based on heart rate variability showed high activity in all positions of the clino-orthostatic test in the patients with PAH compared with healthy children. The activity of the parasympathetic nervous system was associated with increased synthesis of endothelial factors (nitric oxide and endothelins) in blood.

Similarly we’ve been seeing heart rate variability studies in CFS starter to publish abnormalities similiar to these children with pulmonary hypotension and orthoststic intolerance (I have OI but just miss the mark for clinical POTS).