Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome.

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.