DESENSITIZATION AND SEQUESTRATION OF HUMAN M2 MUSCARINIC ACETYLCHOLINE-RECEPTORS BY AUTOANTIBODIES FROM PATIENTS WITH CHAGAS-DISEASE

Chronic Chagas' disease is associated with pathologic changes of the c ardiovascular, digestive, and autonomic nervous system, culminating in autonomic denervation and congestive heart failure. Previously, circu lating autoantibodies that activate signaling by cardiac muscarinic ac etylcholine receptors (mAChRs) have been described, However, it remain s unclear whether the chagasic IgGs directly interact with the m2 mACh Rs (predominant cardiac subtype), and, if so, whether chronic exposure of the mAChRs to such activating IgGs would result in receptor desens itization. Here we performed studies with purified and reconstituted h m2 mAChRs and demonstrate that IgGs from chagasic serum immunoprecipit ated the mAChRs in a manner similar to an anti-m2 mAChR monoclonal ant ibody tested in parallel, The chagasic antibodies did not directly int eract with the ligand binding site, because the binding of radiolabele d antagonist was unchanged by the addition of the chagasic IgG, In int act cells stably expressing the hm2 mAChR, the chagasic IgGs, but not normal IgGs, mimicked the ability of the agonist acetylcholine to indu ce two effects associated with agonist-induced receptor desensitizatio n: a decrease in affinity for agonist binding to m2 mAChR and sequestr ation of the hm2 mAChRs from the cell surface. The results demonstrate that the chagasic IgGs can directly interact with and desensitize m2 mAChRs and provide support for the hypothesis of autoimmune mechanisms having a role in the pathogenesis of Chagas' cardioneuromyopathy.