title: Autoimmunity against the β2 adrenergic receptor and muscarinic-2 receptor in complex regional pain syndrome.
abstract: Complex regional pain syndrome (CRPS) is a painful condition affecting one or more extremities of the body, marked by a wide variety of symptoms and signs that are often difficult to manage because the pathophysiology is incompletely understood. Thus, diverse treatments might be ineffective. A recent report revealed the presence of autoantibodies against differentiated autonomic neurons in CRPS patients. However, it remained unclear how the antibodies act in the development of CRPS. We therefore aimed to characterize these antibodies and identify target antigens. Functional properties of affinity-purified immunoglobulin G of control subjects or CRPS patients were assessed using a cardiomyocyte bioassay. Putative corresponding receptors were identified using antagonistic drugs, and synthesized peptide sequences corresponding to segments of these receptors were used to identify the target epitopes. Chinese hamster ovary cells were transfected with putative receptors to ensure observed binding. Further, changes in the intracellular Ca(2+) concentration induced by agonistic immunoglobulin G were measured using the Ca(2+)-sensitive fluorescent dye fura-2 assay. Herein, we demonstrate the presence of autoantibodies in a subset of CRPS patients with agonistic-like properties on the β(2) adrenergic receptor and/or the muscarinic-2 receptor. We identified these autoantibodies as immunoglobulin G directed against peptide sequences from the second extracellular loop of these receptors. The identification of functionally active autoantibodies in serum samples from CRPS patients supports an autoimmune pathogenesis of CRPS. Thus, our findings contribute to the further understanding of this disease, could help in the diagnosis in future, and encourage new treatment strategies focusing on the immune system.
authors.affiliation: Department of Neurology, Justus-Liebig-University, Giessen, Germany Department of Veterinary Physiology, Justus-Liebig-University, Giessen, Germany Department of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany Department of Neurology, University Medical Centre, Mainz, Germany Wheatherall Institute of Molecular Medicine, Oxford University, Oxford, UK Department of Translational Medicine, University of Liverpool, Liverpool, UK Max-Delbrück-Center, Berlin, Germany.
authors.forename: Danielle
authors.initials: D
authors.lastname: Kohr
authors.forename: Pratibha
authors.initials: P
authors.lastname: Singh
authors.forename: Marlene
authors.initials: M
authors.lastname: Tschernatsch
authors.forename: Manfred
authors.initials: M
authors.lastname: Kaps
authors.forename: Ervice
authors.initials: E
authors.lastname: Pouokam
authors.forename: Martin
authors.initials: M
authors.lastname: Diener
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kummer
authors.forename: Frank
authors.initials: F
authors.lastname: Birklein
authors.forename: Angela
authors.initials: A
authors.lastname: Vincent
authors.forename: Andreas
authors.initials: A
authors.lastname: Goebel
authors.forename: Gerd
authors.initials: G
authors.lastname: Wallukat
authors.forename: Franz
authors.initials: F
authors.lastname: Blaes
mesh_terms: D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D001323:Autoantibodies / Q000096:biosynthesis / Q000502:physiology*; D020274:Autoimmune Diseases of the Nervous System / Q000276:immunology* / Q000378:metabolism*; D016466:CHO Cells; D020918:Complex Regional Pain Syndromes / Q000276:immunology* / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000502:physiology; D008297:Male; D008875:Middle Aged; D061251:Primary Cell Culture; D051381:Rats; D017208:Rats, Wistar; D043585:Receptor, Muscarinic M2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D043585:Receptor, Muscarinic M2; D018343:Receptors, Adrenergic, beta-2