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

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.