IgG stimulated β2 adrenergic receptor activation is attenuated in patients with ME/CFS, 2020, Hartwig et al

Andy

Andy

Retired committee member
Highlights
• IgG physiologically stimulates β2 AdR signaling
• β2 AdR activation by IgG is attenuated in ME/CFS patients
• first evidence that IgG from ME/CFS patients differentially modulates β2 AdR ligand signaling
Abstract
Background
There is emerging evidence of a network of natural autoantibodies against GPCR which is dysregulated in various diseases. β2 adrenergic and M3 and M4 cholinergic receptor (β2 AdR and M3/4 mAChR) antibodies were found to be elevated in a subset of ME/CFS patients.

Methods
We comparatively analyzed the effects of polyclonal IgG on β2 AdR signaling and immune cell function in vitro. 16 IgG fractions were isolated from serum of 5 ME/CFS patients with elevated (CFS AABhigh) and 5 with normal levels (CFS AABnorm) of β2 AdR autoantibodies, and from 6 healthy controls (HC). The effect of each IgG on β-arrestin recruitment and cAMP production in β2 AdR and M3/4R reporter cell lines was studied. Further effect of each IgG on human monocyte cytokine production and on T cell proliferation in vitro was analyzed. In addition, studies on cytokine production in β2 AdR wild type and knockout mice splenocytes incubated with IgG fractions were performed.

Results
We found that IgGs from HC could stimulate β-arrestin recruitment and cAMP production in β2 AdR reporter cell lines whereas IgGs from CFS AABhigh had no effect. The IgG-mediated activation of β2 AdR was confirmed in β2 AdR wt and ko mice. In accordance with previous studies IgG fractions from HC inhibited LPS-induced TNFα and stimulated LPS-induced IL-10 production of monocytes. Further IgG fractions from HC enhanced proliferation of T-cells stimulated with anti-CD3/CD28. IgG fractions from CFS AABhigh patients had no significant effect on both cytokine production and T cell proliferation, while IgGs from CFS AABnorm had an intermediate effect. We could also observe that IgG can modulate the signaling of β2 AdR ligands isoprenline and propranolol.

Conclusions
We provide evidence that IgG can activate β2 AdR. The β2 AdR activation by IgG is attenuated in ME/CFS patients. A dysregulation of β2 AdR function could explain many symptoms of ME/CFS.
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Open access, https://www.sciencedirect.com/science/article/pii/S2666354620300120
 
With N = 5 patients, I can't see how this is anything but PR/advertisement for CellTrend. The study relies on CellTrend's assay for ME/CFS [1, 2]. Harald Heidecke is the CEO of CellTrend and Carmen Scheibenbogen is a co-author of the paper.

In 2016, they published a similar study in the same journal: "Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome" [3].

The results are interesting but not statistically significant. To my knowledge Charité Berlin is the biggest ME/CFS hub in Germany so it shouldn't be difficult to recruit patients like they did for the 2016 study (N = 268). Until then, these preliminary results are not telling much.

[1] https://www.celltrend.de/en/pots-cfs-me-crps.html
[2] https://me-pedia.org/wiki/CellTrend_diagnostic_test
[3] https://www.sciencedirect.com/science/article/pii/S0889159115300209
 
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5 ME/CFS patients with elevated level of antibodies against β2 AdR (>90% percentile of HC, CFS AABhigh) and autonomic dysfunction defined by a high COMPASS-31 score and higher heart rate, 5 patients with normal β2 AdR antibody level (< 90% percentile of HC, CFS AABnorm), and 6 HC were selected.
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Could this be a problem? Are they studying dysautonomia rather than ME? Do people with higher AABs have more dysautonomia? Would it have been better to have the AABs being the only difference between the 2 ME groups, rather than one group additionally having dysautonomia? Or is it a good way of trying to identify subgroups? So many questions...
We found that IgGs from HC could stimulate β-arrestin recruitment and cAMP production in β2 AdR reporter cell lines whereas IgGs from CFS AABhigh had no effect. The IgG-mediated activation of β2 AdR was confirmed in β2 AdR wt and ko mice. In accordance with previous studies IgG fractions from HC inhibited LPS-induced TNFα and stimulated LPS-induced IL-10 production of monocytes. Further IgG fractions from HC enhanced proliferation of T-cells stimulated with anti-CD3/CD28. IgG fractions from CFS AABhigh patients had no significant effect on both cytokine production and T cell proliferation, while IgGs from CFS AABnorm had an intermediate effect. We could also observe that IgG can modulate the signaling of β2 AdR ligands isoprenline and propranolol.
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Dumbed down this seems to mean that IgG isolated from healthy blood does positive things to cells in vitro, but IgG isolated from high AAB patients fails do do those positive things. That seems to be something worth looking at in a larger cohort.
 
The results of this study are strange, and my first instinct was to blame the results on false positives on the Cell Trend test for CFSAABhigh, but then we find:

The costimulatory effect we observed in mice splenocytes was opposite to the inhibitory effect on human monocytes and may be either related to the fact that the ß2R in mice is not fully homologous or that the spleen contains mostly differentiated macrophages.
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Suggesting they are reactive, but in a different way. It is not explained in this study why some IgG become agonists and others antagonists.

Also, β-arrestin recruitment inhibits the functioning of the GPCR and targets receptors for internalization. β-arrestin activity is basically a cellular response to aberrant kinetics of receptor activation.

We and others observed capillary endothelial dysfunction in ME/CFS patients ((Newton et al., 2007) and own manuscript submitted). There is evidence from experimental studies indicating a role of β2 AdR autoantibodies in the development of endothelial dysfunction (Liu et al., 2013). We found a normalization of endothelial function in patients with elevated levels of β2 AdR antibodies who underwent immunoadsorption to remove β2 AdR antibodies (own manuscript submitted).
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Interesting.

Norepinephrine and epinephrine levels were higher in ME/CFS than controls in two studies (Kavelaars et al., 2000; Wyller et al., 2016).
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This is not true, Kavelaars et al stated "Plasma noradrenaline levels in CFS patients did not differ from levels in healthy subjects (CFS, 1.47 ± 0.1 nmol/L, n = 14; control, 1.46 ± 0.2 nmol/L, n = 14; P = 0.98)."
Wyller have several studies that find elevated basal catecholamines, however the participants of their studies were adolescents and there can be social factors (e.g. anxiety about the blood draw) leading to artefactual results.

Suspiciously they didn't mention the other studies found that found normal catecholamines levels at rest.

They also did not mention the several studies by Light and colleagues that found increased β2 Adrenergic receptor expression in leukocytes post-exercise challenge, despite normal or slightly low receptor expression before the exercise challenge.

https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22210239/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757484/
 
I have not looked in detail but it seem as if they previously found a (very slight) increase in antibody levels to receptors in ME/CFS patients but now they find that these antibodies do nothing to the receptors, whereas ordinary people's antibodies do do something. That seems pretty confusing.
 
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