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

doi:10.1016/j.bbih.2020.100047

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

Brain Behav Immun Health. 2020 Feb 5:3:100047. doi: 10.1016/j.bbih.2020.100047. eCollection 2020 Mar.

Authors

Affiliations

¹ Institute for Medical Immunology, Charité University Medicine Berlin, Berlin, Germany.
² CellTrend GmbH, Luckenwalde, Brandenburg, Germany.
³ Department of Rheumatology Department of Rheumatology and Clinical Immunology, University of Lübeck, Lübeck, Germany.
⁴ Department of Nephrology, Charité University Medicine Berlin, Berlin, Germany.
⁵ Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Germany.

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 AAB_high) and 5 with normal levels (CFS AAB_norm) 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 AAB_high 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 AAB_high patients had no significant effect on both cytokine production and T cell proliferation, while IgGs from CFS AAB_norm 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.

Keywords: Autoantibodies; Chronic fatigue syndrome; IgG; Myalgic encephalomyelitis; β2 adrenergic receptor.