Antibodies to ß adrenergic and muscarinic cholinergic receptors in patients with CFS

[Lolinda]

I had a very good response to one treatment of IVIG

Sounds wonderful!

My case is extremely autoimmune

I didnt know it helps against autoimmune issues. I only knew it helps if people have too little immunity, so they need the immunoglobulins to make up for their own:
https://en.wikipedia.org/wiki/Immunoglobulin_therapy

If you have more on that, I would be glad to learn!

 

[Gingergrrl]

Certainly. Sorry, I made a mistake, I wrote "basic question", but I did not mean it that basic. What I meant was: CFS people have
- fatigue
- post exertional malaise
- brain fog
- some are wired but tired
- some cant sleep

@Lolinda I apologize I have not yet re-read this thread in case my question is repetitive! It sounds like from your post, you are asking how the treatments in the study would help the above symptoms but that you did understand how they would help the symptoms below (of POTS and OH or OI?) based on having certain auto-antibodies? Is this correct?

What I mean I can illustrate by an example:
Here is my guess how it comes from antibodies to A1, A2, B1, B2, M1-5 receptors to POTS or to OH:

I do not know the answer but I feel your question pertains to me b/c I rarely have fatigue, I never have PEM, brain fog or bad sleep issues BUT I do have POTS and I have severe hypotension (80's/50's prior to IVIG or without Midodrine) and I can only stand for about 30-60 seconds without wheelchair. Dysautonomia, neuromuscular, and autoimmune issues are my main problem.

So does that match with your theory or question (if I am understanding what you wrote correctly?) It makes it seem more likely that I probably do have the additional auto-antibodies and would have been a good candidate for these treatments (if I lived in Germany or something like this were offered as a study here vs. me piecing it together on my own.) Hope my question makes sense.

 

[Lolinda]

Hi @Gingergrrl that is exactly what I mean. Your symptoms are what make sense for me: that is what should happen if you have elevated autoantibodies against A1-2, B1-2 and M1-5. These receptors sit to my knowledge everywhere in the vascular system, so it wont work if the receptors are all blocked by the antibodies. If anyone knows more about this / has papers, please prove me wrong and add in the papers!

(And as a question to everyone who is more into CFS/ME:
- why are exactly the 4 autoantibodies relevant for CFS/ME
- how on earth do they contribute to the typical CFS/ME symtpoms

 

[Hip]

CFS people have
- fatigue
- post exertional malaise
- brain fog
- some are wired but tired
- some cant sleep

so, how do we come from antagonizing these receptors to any of these symptoms?

As you point out, it easy to understand how adrenergic and muscarinic receptor autoantibodies might be responsible for the symptoms of POTS and orthostatic hypotension, but less clear if they can cause the other classic symptoms of ME/CFS.

First of all, note that in Michael VanElzakker's vagus nerve infection sickness behavior hypothesis of ME/CFS, VanElzakker points out that many of the symptoms of ME/CFS resemble sickness behavior symptoms (sickness behavior is the built-in automatic response the brain has during infectious episodes such as the flu).

The vagus nerve plays a fundamental role in triggering the sickness behavior response when this nerve detects infection in the body, so VanElzakker hypothesizes that a chronic infection of the vagus nerve itself might permenantly cause sickness behavior, and thus the symptoms of ME/CFS.

Along the lines of VanElzakker's theory, I wonder whether an autoantibody that activates the vagus nerve might also chronically trigger sickness behavior (but I am unclear on whether this is possible).


Adrenergic and muscarinic receptors also exist in the brain, so autoantibodies to these receptors may affect the brain directly, if the B-cells that make them cross into the brain (in multiple sclerosis, autoimmune B-cells do enter the brain; I am not sure if this happens in ME/CFS).


Remember though that autoimmunity may be a part of ME/CFS pathophysiology, but not the whole of the picture. There may be other facets of ME/CFS pathophysiology that produce symptoms, such as viral infection in the brain, which might cause symptoms by triggering brain inflammation.

 

[Lolinda]

chronic infection of the vagus nerve itself

wow! cool theory. infection by what?

wonder whether an autoantibody that activates the vagus nerve might also chronically trigger sickness behavior

if a comment is welcome: these autoantibodies do not activate (or deactivate) the vagus nerve. they just block the receptor that receives the signal from the vagus nerve. so this doesnt do anything with the nerve as such.
But I believe that these are only kinda " linguistic" comments, and I think I do understand what you mean: that before the information enters the vagus nerve, there is already acetylcholine signalling ön the brain(-stem) and this will be impaired if these receptors are blocked. And then not much information will enter and go down the vagus. Or?

 

[Gingergrrl]

I didnt know it helps against autoimmune issues. I only knew it helps if people have too little immunity, so they need the immunoglobulins to make up for their own:
https://en.wikipedia.org/wiki/Immunoglobulin_therapy If you have more on that, I would be glad to learn!

@Lolinda IVIG is also used frequently to treat autoimmune diseases or to reduce auto-antibodies (and is not just for immune deficiency although this is what it is more commonly used for). IVIG is used in higher doses for autoimmunity although in my case, we purposely started with a lower dose to make sure I was not allergic and can tolerate it and will slowly attempt to build up to a true autoimmune dose. I wish that I could explain the mechanism of how it works in autoimmunity but I don't think that anyone truly knows. I think the theory is that the normal or good antibodies from the pooled donors will someone knock out the pathogenic ones?

Hi @Gingergrrl that is exactly what I mean. Your symptoms are what make sense for me: that is what should happen if you have elevated autoantibodies against A1-2, B1-2 and M1-5. These receptors sit to my knowledge everywhere in the vascular system, so it wont work if the receptors are all blocked by the antibodies. If anyone knows more about this / has papers, please prove me wrong and add in the papers!

Cool, and am glad I actually understood what you meant! Just to clarify, I do not yet know if I actually have the beta adrenergic or anti muscarinic auto-abs tested for in Dr. Scheibenbogen's study and am only assuming that I do. What I do know for a fact though is that I have the N-type calcium channel ab, other random auto-abs like Anti GAD65, the two Hashi's Abs, a positive ANA titer 1:160 speckled pattern, POTS, OI, MCAS and neuromuscular weakness on spirometry and EMG tests. (I have things that match with ME/CFS like viral titers, low NK cell functioning, etc) but other things that do not match.

(And as a question to everyone who is more into CFS/ME:
- why are exactly the 4 autoantibodies relevant for CFS/ME
- how on earth do they contribute to the typical CFS/ME symtpoms

I wish I knew! I think the test that I am trying to obtain is for three auto-antibodies, and you just mentioned four, so am not certain if it is the same test?

Remember though that autoimmunity may be a part of ME/CFS pathophysiology, but not the whole of the picture.

I suspect it is for one sub-group and either I am the prototype of that sub-group or it will turn out that I have a different yet very similar and overlapping illness.

 

[Hip]

these autoantibodies do not activate (or deactivate) the vagus nerve. they just block the receptor that receives the signal from the vagus nerve.

My understanding is that autoantibodies can act as receptor agonists or antagonists. If you look at the POTS study, you see that they discovered both agonist and antagonist autoantibodies in POTS (an α1AR agonist, a β1AR antagonist, and a β2AR antagonist).

 

[Hip]

it will turn out that I have a different yet very similar and overlapping illness.

Is your exertional dyspnea the main issue that results in needing to use a wheelchair?

 

[Gingergrrl]

Is your exertional dyspnea the main issue that results in needing to use a wheelchair?

Yes and I often call it "Orthostatic dyspnea" vs. exertional dyspnea although both terms are very accurate for me. If I stand for more than about 30-60 seconds (at present) I get completely winded as if I had run up a flight of stairs. If I push it, then I get chest pain and it can take hours to recover. Having a motorized wheelchair at home, I do not have as many situations where I have to push it and I can literally go for weeks without getting chest pain. But this is only b/c I am not standing. I can stand up to transfer from wheelchair to table, bed, couch, shower chair, car, etc, but that is about it. (I do not drive but I have no problems being a passenger in the car).

I do not feel "sick" or "fatigued" but if I cross the line and try to walk, I can only go a few steps and then literally have to sit down on floor no matter where I am (inside or outside). My theory (which could be totally wrong!) is that all of these auto-antibodies (the ones I have proof of and the ones I will be testing in the future) are causing neuromuscular weakness in my lungs, arms, etc, and if I can reduce the auto-antibodies, all of this might improve. I show weakness on EMG (even though I do not have LEMS) and I show huge pulmonary restriction on spirometry, plus POTS confirmed by two TTT's in 2014 and 2016.

Part of my problem is autonomic b/c of my low BP and POTS but part is autoimmune/neuromuscular. All my research points to these auto-antibodies, plus the calcium auto-antibodies, messing with my muscle strength and now I have a positive ANA titer for the first time when it was negative for years. Somehow the viral stuff shifted into autoimmunity and I think this is the hypothesis they are working with in Germany? I was IgM positive for EBV since I had mono in 2012 and for the first time, I am no longer IgM positive but am positive for all of these weird autoimmune things.

Sorry for the long answer and am always hoping that it helps someone down the line.

 

[Jenny TipsforME]

@Gingergrrl I get out of breath like that too with belt around the chest sensation and immediate fatigue. POTS drugs help. I use wheelchair out of the house because my legs go like concrete +/ give way randomly (not because breathing issue).
I do also get the more classic delayed PEM though

Trying to understand this thread with mild PEM.
I checked my DNA against the SNPs from recent research and have some relevant ones eg AchR muscarinic ones. How do the SNPs relate to auto antibodies? Would some people have relevant mutations and other people autoantibody issues? Or could mutations in AchR cause autoantibodies?

 

[Hip]

@Gingergrrl Have you looked at all the causes of exertional dyspnea / orthostatic dyspnea; there seems to be several conditions that can cause it. Anemia is one of them; I take it that you have been tested for anemia.

 

[Gingergrrl]

@Gingergrrl Have you looked at all the causes of exertional dyspnea / orthostatic dyspnea; there seems to be several conditions that can cause it. Anemia is one of them; I take it that you have been tested for anemia.

Yes, have looked at everything and it's truly "orthostatic dyspnea" as the closest fitting term vs. exertional dyspnea though both apply. I do not have anemia or anything simple that would explain it! We are pretty sure it is related to the autoimmune antibodies causing the pulmonary restriction on tests and muscle weakness on EMG. I wish every day it was something simple (or even something complex) that a doctor could fix.

 

[Gingergrrl]

@Gingergrrl I get out of breath like that too with belt around the chest sensation and immediate fatigue. POTS drugs help. I use wheelchair out of the house because my legs go like concrete +/ give way randomly (not because breathing issue).

My legs do not ever get like concrete (or like jelly as some others describe) and I had felt my legs were strong until I read another post in which there was a leg lifting exercise that I was completely incapable of doing. So I suspect I have more profuse muscle weakness including my legs. But the reason I cannot stand/walk is not b/c of my legs but b/c of my breathing. It is exactly what you describe in that if I push it (meaning walk more than 60 seconds max), I get a tight belt around my chest/spasm and can no longer inhale a full breath past the "belt" area. But sitting or lying flat, I can breathe perfectly.

I do also get the more classic delayed PEM though

I do not get the classic delayed PEM and have really tracked this. I was "active" (with wheelchair) all weekend planning a party for my niece, executed the party the next day, and at no point did I develop anything even remotely like PEM and now it is almost a week later. I just lack the ability to breathe if I stand/walk. But seated, I can do what is needed as long as it does not require much arm strength. My arms are very weak and I cannot lift a regular weight cup, open a bottle, etc, (with the exception of right after my IVIG but that has now faded).

I checked my DNA against the SNPs from recent research and have some relevant ones eg AchR muscarinic ones. How do the SNPs relate to auto antibodies? Would some people have relevant mutations and other people autoantibody issues? Or could mutations in AchR cause autoantibodies?

I have no idea and wish I knew!

 

[Hip]

Yes, have looked at everything and it's truly "orthostatic dyspnea" as the closest fitting term vs. exertional dyspnea though both apply.

I am not querying that you have orthostatic and exertional dyspnea; I appreciate that you have both; rather, I am saying that exertional dyspnea is a symptom of several other diseases. So logically, you may have one of those other diseases driving your exertional dyspnea, and it may be worth looking into the diseases that can cause exertional dyspnea, to see if any of them resonate with you (ie, see if their symptoms match yours).

As for the orthostatic dyspnea, that appears to be a symptom that can occur in orthostatic hypotension. Have you tried any of the standard drug treatments for orthostatic hypotension, by the way, to see if they help?

Were your officially diagnosed with orthostatic hypotension and POTS?

Your MCAS may be unrelated to the dyspnea, or it might play a role; it is common for people to have several comorbid diseases that are distinct from each other (in other words, you cannot necessarily look at all your symptoms and assume that they are part of just one disease; you may have two or more comorbid diseases that are responsible for your "portfolio" of symptoms).

 

[Gingergrrl]

I am not querying that you have orthostatic and exertional dyspnea; I appreciate that you have both; rather, I am saying that exertional dyspnea is a symptom of several other diseases. So logically, you may have one of those other diseases driving your exertional dyspnea, and it may be worth looking into the diseases that can cause exertional dyspnea, to see if any of them resonate with you (ie, see if their symptoms match yours).

Sorry I didn't think you were questioning me at all, was just trying to explain that my breathing problems are when I attempt to stand so I often use the term "orthostatic dyspnea" b/c it is the closest match. And I have literally been tested for everything. My doctors feel it is the auto-antibodies causing the muscle weakness and pulmonary restriction.

As for the orthostatic dyspnea, that appears to be a symptom that can occur in orthostatic hypotension. Have you tried any of the standard drug treatments for orthostatic hypotension, by the way, to see if they help?

yes have tried everything (beta blockers, florinef, midodrine, mestinon, compression stockings, drinking water and salt stick tablets, etc). Every single doctor for 3+ years has said that part of my breathing issue is autonomic but there is another part causing the muscle weakness/pulmonary restriction that they could not identify until we found this auto-antibody.

Were your officially diagnosed with orthostatic hypotension and POTS?

Yes

Your MCAS may be unrelated to the dyspnea, or it might play a role; it is common for people to have several comorbid diseases that are distinct from each other (in other words, you cannot necessarily look at all your symptoms and assume that they are part of just one disease; you may have two or more comorbid diseases that are responsible for your "portfolio" of symptoms).

I definitely have more than one co-morbid disease (POTS, MCAS, hashimotos, etc) but the auto-antibodies are where my doctors are focused now which is why this thread is of such great interest to me. If the autoantibodies are attacking my phrenic nerve and neuromuscular junctions, what if IVIG and RTX, etc, could improve this?!!! It would be a miracle. I would love for it to be a simple disease from a list, but it isn't, and I don't want to take this off topic from the auto-antibodies and Dr. Scheinbogen's tests b/c I feel it is the closest match to me by far.

 

[Gingergrrl]

I wanted to add this quote @Hip from one of the links you sited above but I did not get to read until now:

Ventilation perfusion mismatch, due to inadequate perfusion of ventilated lung apices may be the most likely underlying cause of orthostatic dyspnea in patients with OH.

It was debated back and forth by multiple doctors whether my VQ scan in Sept 2014 (when my breathing really started to decline and prior to this was still walking and driving) whether I had a ventilation/perfusion or V/Q mismatch.

The test was done in hospital and I was told it was "normal" b/c it did not have a blood clot. However, I later learned it was not normal and when I showed it to another doctor in March of this year, he felt it showed a V/Q mismatch and used the exact words that the apices of my lungs were not getting adequate perfusion.

However, once he referred me to the pulmonary clinic, they looked at the scan and said that it did not show a V/Q mismatch. Now my cardio and MCAS docs are not certain if it does or does not.

Unfortunately I cannot repeat this test b/c I am now allergic to contrast dye (b/c of MCAS) and am told that contrast dyes are about the most allergic trigger I could possibly have and not safe to do it.

The only recommendation to try to get more lung perfusion was to increase Midodrine. No doctor (and I've asked at least ten at this point since 2014) has had any other ideas.

But, I am curious, in your opinion, could a pathogenic auto-antibody cause this lack of perfusion to the lungs while standing? Because it does not happen seated (and I can do a six hour car ride with no issues) but I cannot stand for one minute. If it's not a V/Q mismatch (or even if it is) could this be caused by an auto-antibody?

Am curious @Hip and @Lolinda what you think? The doctors seem to feel that my breathing issues are BOTH autonomic and neuromuscular from the auto-antibodies but could these two things actually be tied together and if I can lower or knock out the antibodies, could this also improve blood perfusion or the V/Q mismatch (if there is one, which I am still unclear and no two doctors agree).

 

[Troyza]

As you point out, it easy to understand how adrenergic and muscarinic receptor autoantibodies might be responsible for the symptoms of POTS and orthostatic hypotension, but less clear if they can cause the other classic symptoms of ME/CFS.

First of all, note that in Michael VanElzakker's vagus nerve infection sickness behavior hypothesis of ME/CFS, VanElzakker points out that many of the symptoms of ME/CFS resemble sickness behavior symptoms (sickness behavior is the built-in automatic response the brain has during infectious episodes such as the flu).

The vagus nerve plays a fundamental role in triggering the sickness behavior response when this nerve detects infection in the body, so VanElzakker hypothesizes that a chronic infection of the vagus nerve itself might permenantly cause sickness behavior, and thus the symptoms of ME/CFS.

Along the lines of VanElzakker's theory, I wonder whether an autoantibody that activates the vagus nerve might also chronically trigger sickness behavior (but I am unclear on whether this is possible).


Adrenergic and muscarinic receptors also exist in the brain, so autoantibodies to these receptors may affect the brain directly, if the B-cells that make them cross into the brain (in multiple sclerosis, autoimmune B-cells do enter the brain; I am not sure if this happens in ME/CFS).


Remember though that autoimmunity may be a part of ME/CFS pathophysiology, but not the whole of the picture. There may be other facets of ME/CFS pathophysiology that produce symptoms, such as viral infection in the brain, which might cause symptoms by triggering brain inflammation.

Hip, in realation to your comment about VanElzakker theory, I think this video goes pretty close to visually displaying what goes on. Go to http://www.innovativemedconcepts.com/ and in the bottom right, click on 'See the science'. (or try this link, http://www.innovativemedconcepts.com/video/HSV-1-HD.mp4)

 

[Hip]

@Gingergrrl Has any doctor recommended pulmonary vasodilators as something to try? Some are listed here. The nitric oxide donors in that list would be easy to try (nitric oxide donors include arginine-based supplements, or nitrate sources such as beetroot juice).

Have you looked at the symptoms of pulmonary hypertension?

 

[Gingergrrl]

Thanks @Hip and pulmonary HTN has been ruled out. I have tried oxygen, Nitro and also a CCB and did not help. Am actually not supposed to take any CCB's b/c I already have an antibody blocking the calcium channel.

They think my breathing issue is neuromuscular vs. pulmonary and the only med that's helped even slightly from this general category is Midodrine which is a vasoconstrictor vs. dilator.

I was curious though in your opinion if the antibodies that Dr. Scheibenbogen is studying could cause neuromuscular weakness of the diaphragm and breathing muscles? An "extrapulmonary" cause of the pulmonary restriction is what they call it.

I was curious if these specific antibodies could cause both the autonomic and neuromuscular causes of muscle and breathing weakness in your opinion? (In general and not b/c of ME/CFS)?

No worries if you don't know!

 

[kangaSue]

Excessive vasodilatation means low blood pressure

It doesn't always work that way in practice though. I have low blood pressure and problems getting sufficient blood flow to the bowel so using nitrate vasodilators increase the bowel blood flow but paradoxically raises my blood pressure too.

First of all, note that in Michael VanElzakker's vagus nerve infection sickness behavior hypothesis of ME/CFS, VanElzakker points out that many of the symptoms of ME/CFS resemble sickness behavior symptoms (sickness behavior is the built-in automatic response the brain has during infectious episodes such as the flu).

It may not be the vagus nerve as such that is the issue, rather an issue of nicotonic acetylcholine receptors (vagus nerve is a nAChR) which have an influence on mood and behavior (including sickness behavior I believe) through the cholinergic anti-inflammatory pathway. Antibodies to a7- nAChR in this pathway have been reported in the literature but it's one of those ones that doesn't have an accepted commercial test for.

I don't know how to link to this pdf but the title is " a7 Nicotonic acetylcholine receptor-mediated anti-inflammatory actions modulate brain functions" which says;
[The interaction between the immune system and the central nervous system is largely unknown and under intense scrutiny by the biomedical community. Research results during the last decades have identified important two-way communication processes between these two systems, mediated by the cytokine network as well as by “classical” neurotransmitters. The dogma of a separate functioning of the two systems has been conclusively challenged with the discovery that not only neurotransmitters affect immune system function, but also inflammation affects neuronal cells through the same “cytokine network” that connects the different components of the immune system. The “classical” transmitter acetylcholine is an important modulator of both neuronal and immune function through both muscarinic and nicotinic receptors. Among the latter, a7 nicotinic acetylcholine receptors (nAChRs) possess the peculiar property of being expressed in immune cells as well as in neurons. While the modulation of neuronal activity by direct activation of a7 nAChRs is relatively well described, the hypothesis that a7 nAChRs may influence neuronal behavior indirectly, through inhibition of inflammation, is a relatively new concept. This review aims to summarize the evidence that activation of a7 nAChRs may influence brain function not only by direct action on certain neuronal pathways, but also by reducing inflammation (central and/or peripheral), decreasing the levels of circulating cytokines and consequently, their influence on neuronal activity.]

@Gingergrrl Has any doctor recommended pulmonary vasodilators as something to try? Some are listed here.

Thanks @Hip and pulmonary HTN has been ruled out. I have tried oxygen, Nitro and also a CCB and did not help. Am actually not supposed to take any CCB's b/c I already have an antibody blocking the calcium channel.

@Gingergrrl , You have also tried a phosphodiesterase (PDE) inhibitor off @Hip's list of pulmonary vasodilators, Pentoxifylline is in that family of PDE inhibitors.