Autoimmunity in complex regional pain syndrome
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Complex regional pain syndrome (CRPS) is a painful condition affecting one ormore extremities of the body, marked by a wide variety of symptoms and sings thatare often difficult to manage since pathophysiology is incompletely understood.Thus, diverse treatments might be ineffective. A recent report revealed thepresence of autoantibodies against nervous system structures 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.Sera of CRPS patients, neuropathy patients and healthy volunteers were tested forsurface-binding autoantibodies to primary cultures of autonomic neurons and manydifferentiated neuroblastoma cell lines using flow cytometry. Further, functionalproperties of affinity-purified IgG of controls or CRPS patients were assessed usinga cardiomyocyte bioassay. Putative receptors and target antigens were identifiedusing antagonistic drugs and synthesized peptides sequences corresponding tosegments of these receptors. Peptides were also used to establish an enzymeimmunoassay. Antibodies were tested in stable transfected CHO cells with putativereceptors to ensure observed binding. Further, changes in the intracellular Ca2+concentration induced by agonistic IgG were measured using the Ca2+-sensitivefluorescent dye fura-2 assay. Potential cytotoxicity of binding antibodies weretested using LDH and WST-1 assay.13/30 CRPS patients, but none of 30 healthy controls and only one out of 20neuropathy sera had specific surface-binding to autonomic neurons. The majorityof the sera reacted with both sympathetic and myenteric plexus neurons. Thedifferentiation of SH-SY5Y into a cholinergic phenotype induced a surface-antigen,which is recognized by 60% of CRPS sera (18/30), but not by controls. Moreover,ELISA and an established cardiomyocyte assay demonstrated the presence ofautoantibodies in most CRPS patients with agonistic-like properties on the ß2ARand M2R. We identified these autoantibodies as immunoglobulin G directedagainst peptide sequences from the second extracellular loop of these receptors.Though antibodies acted on receptors and increase in intracellular Ca2+concentration in transfected cells, they were not able to induce receptordownregulation, desensitization or cytotoxicity.The recent detection of functionally active autoantibodies in serum samples fromCRPS patients against cell-surface determinants of sympathetic, myenteric anddifferentiated autonomic nervous system neurons, and the identification of thesedeterminants as part of ß2AR or M2R expressed in these cells suggested anautoimmune mechanisms as one important pathogenic factor in thepathophysiology of CRPS. Thus, our findings contribute to the understanding ofthis disease, could help in the diagnosis in future, and encourage new treatmentstrategies focusing on the immune system.Verknüpfung zu Publikationen oder weiteren Datensätzen
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Giessen : VVB Laufersweiler