Postural Orthostatic Tachycardia Syndrome Is Associated With Elevated G‐Protein Coupled Receptor Autoantibodies. Gunning et al 2019

John Mac · Sep 9, 2019

Background
The etiology of postural orthostatic tachycardia syndrome (POTS) is yet to be established. The disorder is often misdiagnosed as chronic anxiety or a panic disorder because the autonomic failure in these patients is not severe. A growing body of evidence suggests that POTS may be an autoimmune disorder. Antinuclear antibodies and elevations of ganglionic, adrenergic, and muscarinic acetylcholine receptor antibodies have all been reported.

Methods and Results
We collected detailed clinical symptoms of 55 patients diagnosed with POTS. We also evaluated serum levels of autoantibodies against 4 subtypes of G‐protein coupled adrenergic receptors and 5 subtypes of G‐protein coupled muscarinic acetylcholine receptors by ELISA. Our patients had a multitude of comorbidities, were predominantly young females, and reported viral‐like symptoms preceding episodes of syncope. We detected a significant number of patients with elevated levels of autoantibodies against the adrenergic alpha 1 receptor (89%) and against the muscarinic acetylcholine M4 receptor (53%). Surprisingly, elevations of muscarinic receptor autoantibodies appeared to be dependent upon elevation of autoantibodies against the A1 adrenergic receptor! Four patients had elevations of G‐protein coupled autoantibodies against all 9 receptor subtypes measured in our study. Five POTS patients had no elevation of any autoantibody; similarly, controls were also negative for autoantibody elevations. There was a weak correlation of clinical symptom severity with G‐protein coupled autoantibodies.

Conclusions
Our observations provide further evidence that, in most cases, POTS patients have at least 1 elevated G‐protein coupled adrenergic autoantibody and, in some instances, both adrenergic and muscarinic autoantibodies, supporting the hypothesis that POTS may be an autoimmune disorder.

ELISA Kits for Detection of G‐Protein Coupled Receptor Antibodies
ELISA kits were purchased from CellTrend GmbH (Luckenwalde, Germany) to detect antibodies against 9 different G‐protein coupled receptor antibodies, including 4 anti–human AdrR epitopes and 5 anti–human mAChR epitopes. These kits have been validated by the manufacturer and used successfully in a recent report identifying autoantibodies to beta adrenergic and muscarinic cholinergic receptors in chronic fatigue syndrome, of which many symptoms overlap with POTS
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https://www.ahajournals.org/doi/10.1161/JAHA.119.013602

ahimsa · Sep 9, 2019

Thanks for posting. I'm hoping this discovery (and future studies) will eventually be helpful for the subset of ME/cfs patients who have POTS, NMH or some other sort of Orthostatic Intolerance.

ahimsa · Sep 9, 2019

Article about this study by Science Daily - https://www.sciencedaily.com/releases/2019/09/190909081756.htm

Gunning and Grubb say much more research is needed. However, this study adds significantly to the evidence that POTS is an autoimmune disorder -- and it shows it may be possible to give physicians unfamiliar with the condition an easy way to test for it.

"What this does is prove the concept," Grubb said. "Other studies had used very expensive research tests. What we used are the same kind of testing methods that would be used by regular hospitals. We wanted to do something that would potentially be a test applicable to the general population, not just a research test."
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Edited to add a quote from the article

OverTheHills · Sep 19, 2019

I look to smarter people than me for guidance on the importance of this.

As a pwME with POTS, to me this looks like it could be very useful indeed. I know that talk of subgrouping gives rise to worries about throwing the rest/others under the bus, but it might get a large group of patients a medical speciality 'home' and change attitudes from some medical professionals. POTS and ME are both poorly understood at the moment and have large symptom overlap. I dont really care at the moment which labels doctors attach, as long as they provide sensible advice/ symptom relief/treatment one day.

Is this a robust study or flaky?

Jonathan Edwards · Sep 19, 2019

It does not look like a rigorous scientific study to me. Almost nothing is said about controls.

In general these antibodies tend to turn up I almost any situation people look for them in. Anti-muscarinic receptor antibodies have become a bit of a joke in neuro-immunology.

From my perspective if researchers are not prepared to describe work in a way that allows others to assess it meaningfully then they cannot expect it to be taken seriously.

wigglethemouse · Sep 19, 2019

Dysautonomia International have been funding studies in this area, but the researchers in Oaklahoma carrying out the work with their funding had doubts about the test and spent a long time figuring out that norepinephrine in serum samples can artificially elevate a1AR and ß1AR activity. It's not clear that the Cell Trend ELISA tests used in the paper of this thread account for that fact.

This study has controls @Jonathan Edwards (37 patients, 61 controls)

Paper : A functional cell-based bioassay for assessing adrenergic autoantibody activity in postural tachycardia syndrome (20 June 2019)
https://www.sciencedirect.com/scien...7hAiZv6YmgsbJhRPIEqKV-6fey-R3b7zdGFAHFVEPuxkY

Abstract

Background
Activating autoantibodies (AAb) to adrenergic receptors (AR) have previously been reported in patients with postural tachycardia syndrome (POTS). These AAb may contribute to a final common pathway for overlapping disease processes, reflecting a possible autoimmune contribution to POTS pathophysiology. In prior studies, measurement of AAb activity was inferred from costly, low-throughput, and laborious physiological assays. In the present study, we developed and validated an alternative cell-based bioassay for measuring AAb activity in serum by means of pre-treatment with monoamine oxidase (MAO).

Methods
A total of 37 POTS patients and 61 sex-matched healthy control participants were included. Serum was pre-treated with MAO to remove endogenous catecholamines that could falsely inflate AR activation by AAb. A receptor-transfected cell-based bioassay was used to detect presence of a1AR-AAb and ß1AR-AAb in serum.

Results
MAO effectively degraded catecholamines as demonstrated by suppression of norepinephrine-induced a1AR activation in POTS (6.4 ?± ?0.7 vs. 5.5 ?± ?0.9; P ?= ?0.044) and in controls (4.1 ?± ?0.5 vs. 3.9 ?± ?0.6; P ?= ?0.001). Mean activity values were greater in the POTS vs. Controls for a1AR-AAb (6.2 ?± ?1.2 vs. 5.3 ?± ?1.0; P ?< ?0.001) and ß1AR-AAb (5.7 ?± ?1.8 vs. 4.1 ?± ?0.9; P ?< ?0.001). Compared to controls, more POTS patients were positive for a1AR-AAb activity (22% vs 4%; P ?= ?0.007) and ß1AR-AAb activity (52% vs. 2%; P ?< ?0.001).

Conclusions
The co-presence of norepinephrine in serum samples can artifactually elevate a1AR and ß1AR activity, which can be avoided by serum pre-treatment with MAO. Using this novel bioassay, we show that POTS patients have increased a1AR-AAb and ß1AR-AAb activity compared to healthy controls in the largest POTS cohort reported to-date.
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This was the commentry on the paper and work posted by Dysautonomia International in June

BIG NEWS! Results from the 2014 Dysautonomia International Conference POTS Antibody Study, our very first conference study, have finally published! And what the researchers found is super important to advancing our understanding of autoimmunity in POTS.

It's a very technical journal article, but to summarize the key points...

1. People with POTS tend to have higher than normal levels of norepineprhine (NE) in their blood, which is a catecholamine that activates the sympathetic nervous system. We already knew this from prior research, but what we didn't have clear evidence of until this study is that NE can cause false positives on adrenergic receptor antibody tests. This makes sense, because NE binds to adrenergic receptors, similar to the way an antibody binds to the receptor.

2. Researchers have always assumed that NE degrades quickly if you don't carefully preserve the blood sample. Since the researchers in this study weren't trying to preserve the NE, they initially assumed it would have degraded before they ran their antibody tests. But it didn't degrade and it messed up their first round of antibody tests (which is why it took long to finish this study, because they had to figure out what was messing up the antibody assays, and how to fix the problem). Finding that NE doesn't degrade as quickly in blood samples as previously thought is really important for POTS research, but is also an important finding that will impact research on other diseases too, because NE and its effect on adrenergic receptors is studied in a lot of other diseases: other forms of dysautonomia, heart rhythm disorders, asthma and allergic disorders, anxiety, PTSD, Parkinson's, etc.

3. After the researchers figured out the NE was messing up the antibody results, they had to develop a way to remove NE from the blood/serum samples before running the antibody test without removing antibodies that may be present. They did this by "washing out" the NE with monoamine oxidase, and enzyme that breaks down NE.

4. After they washed out the NE from the blood/serum samples, they found that a majority of POTS patients had antibodies to one or both of the adrenergic receptors they explored in this study (alpha1 and beta1 adrenergic receptors). This is the largest cohort of POTS patients to date that have been tested for these antibodies (37 patients). Prior smaller cohort studies have found these antibodies in a majority of POTS patients too. And if you have been following our page, you know that other antibodies have also been found in a majority of POTS patients, like angiotensin receptor antibodies.

5. Most people with POTS (and people with related disorders like OI, AAG, NCS, etc.) want to know if they have these antibodies, but to date we haven't had a reliable way to test for these antibodies on a large scale, because the testing done in prior research studies was very expensive, time consuming, and labor intensive. For a test to be widely available on a commercial scale, it has to be accurate, economical and not very labor intensive. The new testing approach developed by the University of Oklahoma lays the groundwork for eventually commercializing this antibody assay and making it available to patients around the world. There will be more research required before that happens, but we are on the right path and making good progress in our quest to identify biomarkers in POTS!

You can find the full journal article here: http://bit.ly/2KFBT9u.

Tremendous thanks to all of the donors and study volunteers who made this possible, and the researchers who worked tirelessly on this project for the past five years! You can help Dysautonomia International advance POTS research even further by making a contribution at CurePOTS.org.
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s4me thread on this paper
https://www.s4me.info/threads/a-fun...al-tachycardia-syndrome-2019-raj-et-al.10162/

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Postural Orthostatic Tachycardia Syndrome Is Associated With Elevated G‐Protein Coupled Receptor Autoantibodies. Gunning et al 2019

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