IgG stimulated β2 adrenergic receptor activation is attenuated in patients with ME/CFS


Jelka Hartwig, Franziska Sotzny, Sandra Bauer, Harald Heidecke, Gabriela Riemekasten, Duska Dragun, Christian Meisel, Claudia Dames, Patricia Grabowski, Carmen Scheibenbogen


Institute for Medical Immunology, Charité University Medicine Berlin, Berlin, Germany

Comment by ME Research UK

The immune system continues to be a fertile area for research in ME/CFS, and a number of recent and ongoing studies funded by ME Research UK have been exploring various aspects of abnormal immune function in the illness.

This includes work carried out by Prof. Carmen Scheibenbogen and her team at the Institute for Medical Immunology in Berlin, and the first results from their programme of research were recently published in the journal, Brain, Behavior, & Immunity – Health.

Immunoglobulins (also known as antibodies) play a key role in the immune system. They are proteins produced by the white blood cells which recognise and attack harmful invaders such as bacteria and viruses.

Some immunoglobulins (autoantibodies) are directed against the body’s own proteins, cells or tissues. While these may have useful functions (such as destroying cancers or removing waste), they can lead to the development of a so-called autoimmune disease such as multiple sclerosis or lupus. Some recent research suggests that these immunoglobulins may also have a role in ME/CFS, at least in some patients.

In 2016, Prof. Scheibenbogen found that nearly a third of ME/CFS patients they studied had increased levels of autoantibodies directed against adrenergic receptors. These receptors are involved in the sympathetic nervous system, and are found in many cells of the body, including immune cells.

In their current study, the group wanted to look in detail at the effects of immunoglobulins on adrenergic receptors and on immune function in ME/CFS.

The researchers obtained blood samples from five ME/CFS patients known to have increased levels of autoantibodies against adrenergic receptors, from five ME/CFS patients with normal autoantibody levels, and from six healthy control subjects. Immunoglobulin was then isolated from these samples.

In the first part of the experiments, this immunoglobulin was added to cells containing adrenergic receptors in order to assess whether or not the receptors became activated as a result. In the second part, the immunoglobulin was added to immune cells (specifically, white blood cells called monocytes) to see if this altered their function.

Firstly, immunoglobulin from healthy control subjects was found to activate the adrenergic receptors (as demonstrated by the stimulation of β-arrestin recruitment and cAMP production), and there was a similar result with immunoglobulin from ME/CFS patients who had normal autoantibody levels. In contrast, there were no such effects when using immunoglobulin taken from ME/CFS patients with increased autoantibody levels.

Secondly, immunoglobulin from healthy controls also had an effect on immune cell function, by inhibiting the production of tumour necrosis factor-α and interleukin-10 (which are involved in regulating inflammation), and increasing the production of specific T-cells (involved in the immune response). Immunoglobulin from ME/CFS patients with increased autoantibody levels had no such effect, while there was a modest effect using immunoglobulin from patients with normal autoantibody levels.

How can we summarise these fairly complex results, and what do they mean for patients with ME/CFS?

The key finding of this study is that, in a subgroup of ME/CFS patients with increased autoantibody levels, the activation of adrenergic receptors by immunoglobulin is lower than normal. This suggests that many of the symptoms of the illness – such as immune activation and autonomic abnormalities – may be mediated or made worse by dysfunction of these receptors.

The authors suggest that targeting of the adrenergic system may therefore have potential as a treatment for ME/CFS. However, this goal could be a long way off. In the meantime, we look forward to the continuation of this research by Prof. Scheibenbogen and her team as they explore this area further.



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.


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.


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.


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.


This work was supported by grants from ME Research UK, from German Ministry of Economy (grant no. 16KN041848 to CS and HH) and the Weidenhammer-Zöbele Foundation.


Brain, Behavior, & Immunity – Health, 2020 March; 3:100047

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