Functional autoantibodies against G-protein coupled receptors in patients with persistent post-COVID-19 symptoms, 2021, Wallukat et al

Abstract

Impairment of health after overcoming the acute phase of COVID-19 is being observed more and more frequently. Here different symptoms of neurological and/or cardiological origin have been reported. With symptoms, which are very similar to the ones reported but are not caused by SARS-CoV-2, the occurrence of functionally active autoantibodies (fAABs) targeting G-protein coupled receptors (GPCR-fAABs) has been discussed to be involved.

We, therefore investigated, whether GPCR-fAABs are detectable in 31 patients suffering from different Long-COVID-19 symptoms after recovery from the acute phase of the disease.

The spectrum of symptoms was mostly of neurological origin (29/31 patients), including post-COVID-19 fatigue, alopecia, attention deficit, tremor and others. Combined neurological and cardiovascular disorders were reported in 17 of the 31 patients. Two recovered COVID-19 patients were free of follow-up symptoms. All 31 former COVID-19 patients had between 2 and 7 different GPCR-fAABs that acted as receptor agonists. Some of those GPCR-fAABs activate their target receptors which cause a positive chronotropic effect in neonatal rat cardiomyocytes, the read-out in the test system for their detection (bioassay for GPCR-fAAB detection). Other GPCR-fAABs, in opposite, cause a negative chronotropic effect on those cells. The positive chronotropic GPCR-fAABs identified in the blood of Long-COVID patients targeted the β2-adrenoceptor (β2-fAAB), the α1-adrenoceptor (α1-fAAB), the angiotensin II AT1-receptor (AT1-fAAB), and the nociceptin—like opioid receptor (NOC-fAAB). The negative chronotropic GPCR-fAABs identified targeted the muscarinic M2-receptor (M2-fAAB), the MAS-receptor (MAS-fAAB), and the ETA-receptor (ETA-fAAB). It was analysed which of the extracellular receptor loops was targeted by the autoantibodies.

Open access: https://www.sciencedirect.com/science/article/pii/S2589909021000204

 

This is fascinating research, thank you for posting @Wyva. I wonder what type these antibodies are.

 

Some of these GPCR autoantibodies have been found in a majority of POTS patients previously. There's been similar studies in broader CFS with weaker findings. The autoantibodies have been shown to be pathogenic in other diseases but their exact role in POTS isn't yet understood, there is a growing number of studies and interest in them. Its seems pretty striking to me that every single long COVID patient in the study had some combination of these autoantibodies - iirc they're only found in 5% of healthy population.

 

These antibodies are found in everyone, unfortunately. I have discussed them at length with Angela Vincent who is probably the world authority on autoantibodies in neurological disease. She regards them as an artefact of no real interest. A very specific subset of antibodies may be causally related to one or two rare syndromes but the vast bulk of data on them is poor quality and almost certainly irrelevant. Antibodies to nicotinic acetyl choline receptors of course are relevant to myasthenia graves but there the difference between patients and controls is clear cut.

 

Funding

Part of this work was funded by the Berlin Cures GmbH, Germany. The funder provided support in the form of salaries but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.​

This contradicts what is declared thereafter (6 of the 8 authors are employed by Berlin Cures):

Declaration of competing interest

G. Wallukat, K. Wenzel, S. Schulze-Rothe, A. Wallukat, A.S. Hönicke, and J. Müller are employed by the Berlin Cures GmbH. G. Wallukat and J. Müller are shareholders of the Berlin Cures Holding AG, the holding company of Berlin Cures. The authors declare no competing interests. All other authors have nothing to declare. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject or materials discussed in the manuscript apart from those which are disclosed.​

Authors contributions

All authors contributed to the study conception and design. Material preparation and data collection and analysis were performed by Gerd Wallukat, Bettina Hohberger, Katrin Wenzel, Julia Fürst, Sara Schulze-Rothe, Anne Wallukat, Anne-Sophie Hönicke, and Johannes Müller. The first draft of the manuscript was written by Annekathrin Haberland and all authors commented on previous versions of the manuscript. All authors read, revised, and approved the final manuscript.
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This collaboration resembles that between Dr Scheibenbogen's team at Charité Berlin and the Celltrend lab, who have also been looking into the potential role of autoantibodies to beta-adrenergic and muscarinic receptors in ME/CFS using Celltrend's commercial assay.

 

This doctor has a response to that (these are public posts so other people who don’t have Twitter either should also be able to read - edit, I found this thread on the biology of covid 19 thread on S4ME):

https://twitter.com/user/status/1383747131328983041


https://twitter.com/user/status/1383893907524636677

 

Enthusiasts will always claim that the real antibodies show up on special tests.
The reality is that the levels of autoantibodies of this sort are hardly any different from normals in the studies that try to show a difference. Nobody should take them seriously in ME/CFS and I suspect to in 'dysautonomia' or Covid either.

The likelihood of LongCovid being autoimmune I would rate as zero. The idea that autoimmunity is triggered by infection is largely a myth.

 

Looks like the private lab peddling tests for these autoantibodies in ME/CFS and POTS is now looking to branch out into the new field of Long Covid. We discussed the huge overlap between normal controls and patients on these antibodies years ago on the other forum. There is nothing there. An honest examination of their own published data shows that the test can't satisfactorily separate between the groups.

 

I wasn’t around for that discussion, and can’t find it with a cursory search. Do you mind linking me if possible?

 

I’ll try. The threads in question aren’t popping up on a Google search.

 

I tested positive for 11 out of the 11 selected autoantibodies in the CellTrend test panel, which I believe is from the same people who wrote this article. I don't know what to make of it, but surely the likelihood of getting that result would be extremely low if we assume I represented the general population.

 

Probably not if the assays are designed to make money out of coming out positive on patients.

There is also an issue with having antibodies to more than one receptor. Autoimmunity of significance is usually directed at one or perhaps two specific targets only. The more targets showing positive the less likely I would think the result means anything. It is a bit like recognising everyone in an identity parade!

 

CellTrend and Berlin Cures are two different labs. Both are based in Germany and specialize in testing for autoantibodies against G-protein-coupled receptors.

https://berlincures.de/the-team/
https://www.celltrend.de/en/company-profile/management/

I'm not aware of published results from Berlin Cures on ME/CFS or POTS, but those from CellTrend have been discussed in this thread previously: Autoantibodies to Beta-Adrenergic and Muscarinic cholinergic receptor in ME patients - Bynke, Bergquist et al -2020

ETA: Berlin Cures are also developing a compound (BC007) to neutralize these autoantibodies which is now in a Phase II trial (i.e. they have a strong financial incentive).

 

A huge red flag.

 

[EDIT] Just to demonstrate that I haven't read the previous posts or indeed hadn't read the abstract this is about Long covid and I was ranting on about autoimmunity in ME/CFS - oops!

I seem to recall all of this re ME (same "diagnostic" test for autoimmune antibodies?) - which sort of reflects @Jonathan Edwards comment about a commercial aspect!
Can't sell your wares to people with ME/CFS well how lucky you are - there's a new market Long covid!

Autoimmunity seems to be an easy thing to claim is the cause of a difficult disease.

 

No worries, thanks for checking.

I think a practitioner that I will be seeing soon uses one of these labs, so I am just trying to do a bit of legwork in order to be more prepared.

I appreciate everyone filling in some of the backstory in this thread

 

I'm in no position to comment on the validity of the science but one of Fedorowski's more recent videos discusses how viewing these antibody tests in isolation is worthless, little to no difference with HC. Instead he suggests combination scoring shows the significant difference between POTS and HC.

From 28mins: Autoimmunity in POTS - 2020 Update - Artur Fedorowski, MD, PhD, FESC on Vimeo

 

Try harder - only 11 out of 11!

Yea and ME/CFS is more than likely not (B-cell/autoantibody) autoimmune - if it was then rituximab would have worked.