Research on how adrenergic & muscarinic receptor antibodies cause symptoms in POTS, OH and CFS

[Lolinda]

Research on POTS, OH and CFS shows that many have elevated adrenergic or cholinergic (muscarinic or nicotinic) receptor antibodies. This thread is to discuss research on:

• How do these antibodies relate to POTS subtypes and pathomechanisms?
• Equally, how do these contribute to symptoms OH and CFS?

This is a research-oriented thread. There are separate threads for:

• All questions regarding: labs, tests, sample sending, etc.
  
• Doctors & treatment chances
• People who already got tested post their results and their symptoms so we can compare (yet to be created. PM me if you have already received your results and would be interested to share)

If you need a plain explanation what these antibodies are about, start with the section "Simple introduction" here.

Wonder why I create separate threads for these? I just hate it to browse through threads of 30 pages talking about everything on earth often not related to the thread title. Takes hours. So this is my little initiative to have small threads that answer exactly one specific question. You need some information and you get exactly that. I also support a lot @Hip 's idea for a clever search that finds the most relevant posts.

 

[halcyon]

Mayo has also found α3-AChR antibodies in a percentage of POTS patients.

How does this relate to POTS subtypes and pathomechanisms?

There are a lot of different links in the chain that can break, and they can break in different ways, and still cause the exact same outcome. Anywhere from the baroreceptors, to the brainstem, to the spinal cord, to the sympathetic ganglia, to the nerves on the smooth muscles in vessels themselves.

 

[Lolinda]

@halcyon sound very interesting! Would you mind posting your sources? Here are a few studies on the roles of adrenergic and muscarinic receptor antibodies in POTS, OH and CFS.


ROLES OF ADRENERGIC AND MUSCARINIC RECEPTOR ANTIBODIES IN POTS, OH AND CFS

A1, A2, B1, B2, M1, M2, M3, M4, M5
These are short names, where A1 stands for "Alpha 1 adrenergic receptor autoantibodies", B1 for "Beta 1 adrenergic receptor autoantibodies", M1 for "muscarinic cholinergic 1 receptor autoantibodies". See "Simple introduction" here.


POTS (postural ortostatic tachycardia syndrome)

Here A1, B1 and B2 are elevated. A1 blocks receptors for vasoconstriction. This is a bad thing because when standing up, you need a lot of vasoconstriction otherwise all blood flows into the lower half of the body. This is what happens when you see all in black after standing up. If it takes longer, you faint. To avoid this, your sympathetic nervous system (SNS) will try to constrict the blood vessels. This won't work if you have A1 receptor antibodies, which block vasoconstriction. Hence, the SNS activates more and more, and will try stronger and stronger. Essentially, standing up becomes so stressful as when a healthy person stands in front of a lion. This will make the heart beat more. Here come in the B1 and B2 antibodies, which will make the heart even more prone to tachycardia. The trick is: Receptor antibodies can be agonistic or dysfunctional. So they activate the receptor or switch it off. in POTS, the A1 antibody is dysfunctional, the B1 and B2 antibodies are agonistic:
http://www.ncbi.nlm.nih.gov/pubmed/24572257
Thanks a lot to @Hip for pointing me to this study!

http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2012.CE.2.OR48-1
There is a preliminary report on elevated levels of M1 and M2 antibodies in POTS patients, however no mechanism is presented as to how these antibodies contribute to the disease:
http://forums.phoenixrising.me/inde...-with-pots-potential-disease-biomarker.44890/


OH (ortostatic hypotension)

There are reports on elevated levels of agonistic B1, B2, M2 and M3. Circulating in the blood stream, these antibodies act as vasodilators. When laying, then excessive amounts of vasodilators do not make so much of a problem. But when standing up, they will cause the body to have a hard time preventing blood from pooling in the lower half or the body.
B2 and M3:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3275920/
http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2012.CE.2.OR48-1
B1, B2, M2, M3:
Details from the text body of the paper:
Agonistic M3 receptor antibodies increase the production of nitric oxide ("activation of endothelial nitric oxide synthase (eNOS) activity"). And M2 receptor antibodies inhibit the increase in heart rate seen in POTS ("M2R inhibition of pulse rate and cardiac responsiveness to upright posture")
http://www.sciencedirect.com/science/article/pii/S1933171111002452


CFS

The following are often elevated in CFS:
B1, B2, M3, M4
These are elevated in 20-30% of CFS patients.
http://www.sciencedirect.com/science/article/pii/S0889159115300209
I do not understand the pathomechanism how antibodies to adrenergic or muscarinic antibodies could contribute to illness. Prof Scheibenbogen, CFS researcher at the Charite in Berlin, is obviously convinced that these antibodies are causative or at least contributive to CFS. Otherwise she would not do this treatment study.
M1:
http://www.ncbi.nlm.nih.gov/pubmed/12851722


Various disclaimers...

• To say it clearly, POTS, OH AND ME/CFS have a myriad of other possible causes. So for example, if you are interested, this is how I got out of ME. And that thread discusses a wonderful new study on CFS causes, which was probably mine. My POTS however stayed and I do have these antibodies discussed above.
• Also, one antibody affects several body systems. So for example, B2 receptor antibodies are involved in POTS, OH and CFS. That is no wonder if one looks at the manifold functions of the B2 receptor. Also, you will have noticed that not all the A1, A2, B1, B2, M1-5 were mentioned above. Guess what, not everything is known yet...

 

[halcyon]

@halcyon sound very interesting! Would you mind posting your sources? Here are a few studies on the roles of adrenergic and muscarinic receptor antibodies in POTS, OH and CFS.

I put this together the other day, looks like you listed most or all of the papers I found on the other types:

http://www.ncbi.nlm.nih.gov/pubmed/17352367
http://www.ncbi.nlm.nih.gov/pubmed/14732619
http://www.smartscitech.com/index.php/rci/article/view/516

 

[Gingergrrl]

You guys are amazing and I wish I could contribute something helpful to this thread except to say thank you!

 

[kangaSue]

@halcyon sound very interesting! Would you mind posting your sources?

α3-(nicotonic) AChR antibodies are found in 50% of cases of Autoimmune Autonomic Ganglionapathy. Unpublished date from Mayo suggests 25% of those with POTS has α3-AChR antibodies
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671239/
https://www.hindawi.com/journals/ad/2013/549465/

 

[Dr.Patient]

α3-(nicotonic) AChR antibodies are found in 50% of cases of Autoimmune Autonomic Ganglionapathy. Unpublished date from Mayo suggests 25% of those with POTS has α3-AChR antibodies
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671239/
https://www.hindawi.com/journals/ad/2013/549465/

Is there a commercial lab test to detect these antibodies?

 

[kangaSue]

Is there a commercial lab test to detect these antibodies?

Yes, Mayo does several different panels which includes a test for this antibody as it crops up in paraneoplastic syndromes too. Autoimmune Gastrointestinal Dysmotitility Evaluation, Serum is one panel;
http://www.mayomedicallaboratories.com/test-catalog/Overview/37429

Athena diagnostics (a division of Quest labs) and the research lab of Dr Vernino at UT Southwestern in Dallas also do the test, not sure if they will do the α3-(nicotonic) AChR Ab test alone. I had it done as a single test through Oxford University Hospital in the U.K.

A restricted form of AAG, Autoimmune Gastrointestinal Dysmotility can cause just GI dysfunction alone
http://www.mayoclinic.org/medical-p...ces/autoimmune-gi-dysmotility-a-new-direction

 

[TimothyKeltron]

I have POTS with positive N-type calcium channel antibodies. I don’t have the P/Q antibody so no doctor will diagnosis me with LEMS even though I suffer from extreme weakness and POTS. I found this article interesting. Seems M1 Antibody is found in a large percentage of LEMS patients….. and seronegative (P/Q) suspected LEMS patients
Autoantibodies against M1 muscarinic acetylcholine receptor in myasthenic disorders
https://www.ncbi.nlm.nih.gov/pubmed/17764462
Immunoblotting against solubilized human M1 mAChR, we detected autoantibodies in: (a) 14 of 20 (70%) anti-VGCC-positive LEMS patients; (b) all five anti-VGCC-negative LEMS patients, one of whose serum had previously passively transferred LEMS-type electrophysiological defects to mice; (c) all five LEMS patients with autonomic symptoms; (d) seven of 25 (28%) myasthenia gravis (MG) patients in whom increased ACh release partially compensates for post-synaptic defects; (e) none of 10 SCLC patients without LEMS. Although not proving primary pathogenicity of anti-M1 mAChR antibodies, the present results highlight their potential to affect synaptic compensatory mechanisms, more in LEMS than MG.

 

[TimothyKeltron]

so great that halcyon made that picture

 

[Gingergrrl]

@TimothyKeltron it is so strange to see you posting here vs. in the CA+ group (strange in a good way of course)!

I am having my second day of IVIG as we speak so it's hard to bend my arm to post but had to say hi. (Please don't use my real name here and just call me Gingergrrl or Ginger)!

 

[Sidereal]

I have POTS with positive N-type calcium channel antibodies. I don’t have the P/Q antibody so no doctor will diagnosis me with LEMS even though I suffer from extreme weakness and POTS. I found this article interesting. Seems M1 Antibody is found in a large percentage of LEMS patients….. and seronegative (P/Q) suspected LEMS patients
Autoantibodies against M1 muscarinic acetylcholine receptor in myasthenic disorders
https://www.ncbi.nlm.nih.gov/pubmed/17764462
Immunoblotting against solubilized human M1 mAChR, we detected autoantibodies in: (a) 14 of 20 (70%) anti-VGCC-positive LEMS patients; (b) all five anti-VGCC-negative LEMS patients, one of whose serum had previously passively transferred LEMS-type electrophysiological defects to mice; (c) all five LEMS patients with autonomic symptoms; (d) seven of 25 (28%) myasthenia gravis (MG) patients in whom increased ACh release partially compensates for post-synaptic defects; (e) none of 10 SCLC patients without LEMS. Although not proving primary pathogenicity of anti-M1 mAChR antibodies, the present results highlight their potential to affect synaptic compensatory mechanisms, more in LEMS than MG.

Great info. Just to add that an older Japanese study linked above found M1 antibodies in some patients diagnosed with CFS. Those who had the antibody had higher levels of self-reported weakness than those diagnosed with CFS who didn't have the antibody. It's been a while since I read that paper so don't quote me on this. I wonder if those were actually seronegative LEMS patients, not CFS. I've noticed that neurologists totally lose interest in your symptoms if your labs/tests don't tick the right diagnostic boxes and they are extremely prone to dismissing problems as psychiatric when a patient has a problem they don't understand.

 

[kangaSue]

I have POTS with positive N-type calcium channel antibodies. I don’t have the P/Q antibody so no doctor will diagnosis me with LEMS even though I suffer from extreme weakness and POTS.

I'll see if I can track down the papers but I'm sure I read that LEMS sometimes occurs with just N-type calcium channel antibody. Either way, 15% of LEMS cases don't have a P/Q-type calcium channel antibody finding so there is always exceptions to the rule.

I've also come across several cases of people with both Sjogren's Syndrome and Autoimmune Ganglionopathy where they have POTS, N-type calcium channel antibody and α3-(nicotonic) AChR antibody which come with extreme fatigue too.

 

[futuritycarpaccio]

Cool, I've just reached acetylcholinergic receptors as a potentially valid root cause of my issues,and now I see you are also searching this as of recently.

In my case specifically alpha 7 nicotinic acetylcholine receptors.

What got me into these receptors is my noise sensitivity which I just recently found to be part of an auditory gating issue, either P50, N1, or mismatch negativity events.

I'll write more soon and I'm following this thread.

 

[kangaSue]

In my case specifically alpha 7 nicotinic acetylcholine receptors.

This particular antibody doesn't have a commercially available test for it unfortunately so it's only tested for in a research setting as far as I am aware. It has been detected along with a3-nAChR Ab's from research into Autoimmune Autonomic Ganglionopathy though so no doubt it could turn up in other conditions.

 

[kms1990]

This is all very interesting. I was wondering if someone could have a look at my mayo labs and see if this test was run on me? Thanks!

 

[Gingergrrl]

@kms1990 Your testing is similar to the PAVAL panel that I had on blood sent to Mayo except that I test positive on the N-type CA+ Channel Ab and the GAD65 Ab and it looks like you are negative on everything (which is good)!

 

[kms1990]

@kms1990 Your testing is similar to the PAVAL panel that I had on blood sent to Mayo except that I test positive on the N-type CA+ Channel Ab and the GAD65 Ab and it looks like you are negative on everything (which is good)!

@Gingergrrl

Thanks for your reply Gingergrrl! Does this mean the α3-(nicotonic) AChR antibodies are not covered by this test? I am not sure if these are super important and if I should specifically be tested for them.

 

[kangaSue]

@Gingergrrl

Thanks for your reply Gingergrrl! Does this mean the α3-(nicotonic) AChR antibodies are not covered by this test? I am not sure if these are super important and if I should specifically be tested for them.

The AChR Ganglionic Neuronal Ab test listed in your above panel is the test for α3-(nicotonic) AChR antibodies so yes, you have had it done.
The proviso that all the labs use when they say a negative test doesn't rule an autoimmune cause makes the results less certain though when 50% of cases of the likes of Autoimmune Autonomic Ganglionopathy have a negative result too but as you have no indication of other antibodies at any level, it's probably safe to assume this is not the issue for you.

 

[Gingergrrl]

Thanks for your reply Gingergrrl! Does this mean the α3-(nicotonic) AChR antibodies are not covered by this test? I am not sure if these are super important and if I should specifically be tested for them.

@kms1990 I am so glad that @kangaSue replied b/c I was not sure of the answer and didn't want to guess and tell you something incorrect! It does not appear that autoantibodies are the issue for you but my understanding, like KangaSue's is that you can be seronegative on some of them.

@kangaSue I asked this in another thread (now am not certain which one?!) but are "anti-neuronal" and "paraneoplastic" antibodies just two terms for the same thing or do they actually mean two totally different things? Have been trying to understand this from posts on PR and Google search but still unclear! I think different countries may also use the terms differently adding to my confusion?