Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with CFS, 2016, Loebel et al

Hutan

Hutan

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https://www.sciencedirect.com/science/article/pii/S0889159115300209?via=ihub
Open Access
Madlen Loebel 1, Patricia Grabowski 2, Harald Heidecke 3, Sandra Bauer 2, Leif G Hanitsch 2, Kirsten Wittke 2, Christian Meisel 4, Petra Reinke 5, Hans-Dieter Volk 6, Øystein Fluge 7, Olav Mella 8, Carmen Scheibenbogen 6


2016 paper but has been referred to a lot by other ME/CFS researchers

Abstract
Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in CFS point to an autoimmune disease directed against neurotransmitter receptors. Autoantibodies against G-protein coupled receptors were shown to play a pathogenic role in several autoimmune diseases. Here, serum samples from a patient cohort from Berlin (n=268) and from Bergen with pre- and post-treatment samples from 25 patients treated within the KTS-2 rituximab trial were analysed for IgG against human α and β adrenergic, muscarinic (M) 1-5 acetylcholine, dopamine, serotonin, angiotensin, and endothelin receptors by ELISA and compared to a healthy control cohort (n=108).

Antibodies against β2, M3 and M4 receptors were significantly elevated in CFS patients compared to controls. In contrast, levels of antibodies against α adrenergic, dopamine, serotonin, angiotensin, and endothelin receptors were not different between patients and controls. A high correlation was found between levels of autoantibodies and elevated IgG1-3 subclasses, but not with IgG4. Further patients with high β2 antibodies had significantly more frequently activated HLA-DR+ T cells and more frequently thyreoperoxidase and anti-nuclear antibodies. In patients receiving rituximab maintenance treatment achieving prolonged B-cell depletion, elevated β2 and M4 receptor autoantibodies significantly declined in clinical responder, but not in non-responder.

We provide evidence that 29.5% of patients with CFS had elevated antibodies against one or more M acetylcholine and β adrenergic receptors which are potential biomarkers for response to B-cell depleting therapy. The association of autoantibodies with immune markers suggests that they activate B and T cells expressing β adrenergic and M acetylcholine receptors. Dysregulation of acetylcholine and adrenergic signalling could also explain various clinical symptoms of CFS.
 
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From the paper:
2.2. Quantification of autoantibodies by ELISA
Serum IgG against GPCRs were determined by ELISA by CellTrend GmbH, Luckenwalde, Germany. Recombinant GPCR proteins were expressed in CHO cells. Pre- and post-treatment samples from the rituximab trial were analysed in the same assay plate, and these samples were analysed blinded to group allocation (CFS patients versus controls, responder versus non-responder, pre- versus post-treatment).
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Well, each dot is the level of the specific autoantibody for a person. So, yes, we can compare the mean, as shown by the red lines, which show little difference. And we can compare the range visually - and there is quite a lot of overlap. There are the p values, which suggest that there are differences, but they don't tell the whole story.

Knowing what we know about the unreliability of the Celltrend test, it does make the findings of the paper very questionable. I would be interested to know what the authors now say about this paper - maybe someone has said something?
 
Hutan said:
Well, each dot is the level of the specific autoantibody for a person. So, yes, we can compare the mean, as shown by the red lines, which show little difference. And we can compare the range visually - and there is quite a lot of overlap. There are the p values, which suggest that there are differences, but they don't tell the whole story.

Knowing what we know about the unreliability of the Celltrend test, it does make the findings of the paper very questionable. I would be interested to know what the authors now say about this paper - maybe someone has said something?
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I would argue that even if the findings do hold, the mean differences between ME/CFS patients and healthy control seem so marginal that they would rather suggest this ELISA assay does not provide evidence for a putative role of GPCR autoantibodies in ME/CFS.
 
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Celltrend continues to offer these tests as diagnostic e.g.
https://www.celltrend.de/en/pots-cfs-me-sfn/important-publications/
CFS-diagnostics
Together with Prof. Dr. Carmen Scheibenbogen, University Hospital Charite Berlin, CellTrend developed a straightforward Immuno-Assay for the diagnostic of the Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). The results have been published in Brain, Behavior, and Immunity. A first clinical trial for treatment has been successfully completed and is published in PLoS ONE(Scheibenbogen C. et al 2018).

Auto-antibodies against the Beta-2 adrenergic receptor, auto-antibodies against the muscarinic cholinergic Receptor 3 (M3) and auto-antibodies against the muscarinic cholinergic Receptor 4 (M4) are elevated in a subset of 20-30% of all patients suffering from Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Tests are available in our lab, it is possible to send samples (IMPORTANT: Only send the seperated sera after centrifugation, not the entire unprocessed blood or plasma sample) for auto-antibody CFS-diagnostic to the CellTrend lab. The costs per biomarker are € 27,- ($ 33,-) and in total € 108,- ($ 132,-).

  • Beta-1 adrenergic receptor auto-antibodies
  • Beta-2 adrenergic receptor auto-antibodies
  • Muscarinic cholinergic (M3) receptor auto-antibodies
  • Muscarinic cholinergic (M4) receptor auto-antibodies
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Does anyone know if Professor Scheibenbogen or Charite Berlin benefits from the ongoing sale of these tests?


It's a bit interesting to look back on the Phoenix Rising threads discussing these findings. This is the main thread discussing the paper:
https://forums.phoenixrising.me/thr...ptors-in-patients-with-cfs.40109/#post-644031
At the time, there was excitement about rituximab as a possibly effective treatment, and so the parts of the paper that seemed to show a correlation between a reduction of antibody levels and response to rituximab probably helped with an initial burst of enthusiasm.
 
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Hutan said:
Does anyone know if Professor Scheibenbogen or Charite Berlin benefits from the ongoing sale of these tests?
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I don't know but doubt it. I'm sure Professor Scheibenbogen's efforts to find pathomechanisms and a treatment for ME are genuine. Her work seems also to be backed up by a broader international academic network.

See this symposium that will take place in September:

International RAB symposium on regulatory autoantibodies targeting G-protein-coupled receptors (GPCR)

But then I have no idea how good the evidence is on the role that autoantibodies against GPCR play in other diseases?

Also, I wonder if research into GPCR in general actually could give any clues to the pathophysiology of ME but not necessarily via autoantibodies?)

Wikipedia on GPCR: https://en.wikipedia.org/wiki/G_protein-coupled_receptor

(I was thinking these more general questions about the research into GPCR autoantibodies might deserve a thread on its own but currently too unwell to set up one. I am concerned though about the confidence with which researchers in this field claim evidence on the relevance to ME and post covid symptoms/ syndromes and also the confidence of German ME / Long Covid patient organizations into this kind of research.)
 
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It's unethical to continue to sell this test to patients considering the findings of the more recent study:

Autoantibody concentrations against all of the receptors tested were not significantly different between controls and patients with POTS. The majority of patients with POTS (98.3%) and all controls (100%) had α1 adrenergic receptor autoantibody concentrations above the seropositive threshold provided by the manufacturer (7 units/mL).
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Just to add to my post above (#10)-- and apologies if off topic -- but I really hope there will be some people on the mentioned RAB (Regulatory Autoantibody Research) symposium who will ask about the issues posted by forum members on this thread.

Scheibenbogen will speak there on "Role of GPCR abs in Post-COVID syndrome".

There are also three contributions under the headline "Fibromyalgia and ME/CSF as another challenge".

And not sure if there are more typos in the program:

"Aptamer BQ007, a novel therapeutic agent?"
B. Hohenberger

Maybe they actually mean BC007 and B. Hohberger?

(*) RAB = Regulatory Autoantibody Research

They also have a journal: https://journals.infinite-science.de/index.php/rab

@Jonathan Edwards : Would be interesting to hear what you and your Rheumatology colleagues think of this area of research (autoantibodies against GPCR ) as Rheumatologists are involved and it seems the main direction of research into ME/CFS that currently gets funding in Germany. The symposium is funded by the German Research Foundation.
 
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cassava7 said:
@Hutan Following this study, Profs Scheibenbogen & Bergquist conducted a validation study in two cohorts (Charité & Sweden) but failed to find an association between elevated autoantibodies and symptoms. https://www.s4me.info/threads/autoa...me-patients-bynke-bergquist-et-al-2020.16017/
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Yes, but that makes the ongoing sale of the test through Celltrend, particularly with the narrative that doesn't refer to the later work on the website, all the more strange.
 
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