title: 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.
authors.affiliation: Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany. Electronic address: madlen.loebel@charite.de.
authors.forename: Madlen
authors.initials: M
authors.lastname: Loebel
authors.affiliation: Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Grabowski
authors.affiliation: CellTrend GmbH, Luckenwalde, Brandenburg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Heidecke
authors.affiliation: Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Bauer
authors.affiliation: Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
authors.forename: Leif G
authors.initials: LG
authors.lastname: Hanitsch
authors.affiliation: Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Wittke
authors.affiliation: Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany; Labor Berlin GmbH, Immunology Department, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Meisel
authors.affiliation: Department of Nephrology, Charité University Medicine Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Reinke
authors.affiliation: Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Germany.
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Fluge
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Olav
authors.initials: O
authors.lastname: Mella
authors.affiliation: Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Scheibenbogen
mesh_terms: D018663:Adrenergic Agents; D000328:Adult; D001323:Autoantibodies / Q000097:blood*; D001402:B-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D018678:Cholinergic Agents; D015331:Cohort Studies; D015673:Fatigue Syndrome, Chronic / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000276:immunology*; D011976:Receptors, Muscarinic / Q000276:immunology*; D000069283:Rituximab / Q000627:therapeutic use
chemical_list: D018663:Adrenergic Agents; D001323:Autoantibodies; D018678:Cholinergic Agents; D007074:Immunoglobulin G; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D000069283:Rituximab; D009638:Norepinephrine
keywords: Autoantibodies; Chronic Fatigue Syndrome; GPCR; Rituximab