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

Brain Behav Immun. 2016 Feb;52:32-39. doi: 10.1016/j.bbi.2015.09.013. Epub 2015 Sep 21.

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.

Keywords: Autoantibodies; Chronic Fatigue Syndrome; GPCR; Rituximab.

MeSH terms

  • Adrenergic Agents
  • Adult
  • Autoantibodies / blood*
  • B-Lymphocytes / immunology
  • Case-Control Studies
  • Cholinergic Agents
  • Cohort Studies
  • Fatigue Syndrome, Chronic / blood
  • Fatigue Syndrome, Chronic / drug therapy
  • Fatigue Syndrome, Chronic / immunology*
  • Female
  • Humans
  • Immunoglobulin G / blood
  • Immunoglobulin G / immunology
  • Male
  • Norepinephrine / metabolism
  • Receptors, Adrenergic, beta / immunology*
  • Receptors, Muscarinic / immunology*
  • Rituximab / therapeutic use

Substances

  • Adrenergic Agents
  • Autoantibodies
  • Cholinergic Agents
  • Immunoglobulin G
  • Receptors, Adrenergic, beta
  • Receptors, Muscarinic
  • Rituximab
  • Norepinephrine