Modification of cholinergic-mediated cellular transmembrane signals by the interaction of human chagasic IgG with cardiac muscarinic receptors.
The possible role of altered humoral immunity in cardiac Chagas' disease was examined by analyzing the interaction of IgG and the corresponding F(ab')2 from Trypanosoma cruzi-infected patients with cardiac muscarinic cholinergic receptors (mAchR). Human chagasic IgG and its F(ab')2 simulated the agonist actions triggering the biological effects associated with cholinergic-mediated cellular transmembrane signals, i.e. stimulation of cGMP, inhibition of cAMP and a decrease in atrial contractility. Atropine blunted all of these effects while pertussis toxin prevented the inhibition of cAMP and contractility confirming the G-regulatory-protein-mediated response in the interaction of chagasic antibodies with cardiac mAchR. In addition, chagasic IgG and its F(ab')2 behaved as partial agonists activating the specific receptor and inhibiting in a noncompetitive manner the activity of an exogenous agonist (pilocarpine). Moreover, chagasic IgG immunoprecipitated the mAchR solubilized from cardiac membrane in a concentration-dependent fashion. By means of SDS-PAGE and immunoblotting analysis, chagasic serum was shown to recognize a band of approximately 75 kD. The electrophoretic studies of prelabeled immunoprecipitated proteins revealed a peak of [3H] propylbenzilylcholine mustard with an apparent molecular weight similar to that of mAchR, which disappeared in the presence of atropine. The presence of these antibodies in the serum of chagasic patients could explain the progressive receptor blockade in the parasympathetic branch of the cardiac autonomic nervous system associated with the cardioneuromyopathy described in the course of Chagas' disease.
Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
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Goin
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Perez Leiros
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Borda
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Sterin-Borda
D000906:Antibodies / Q000276:immunology; D014355:Chagas Disease / Q000276:immunology*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology* / Q000378:metabolism; D010862:Pilocarpine / Q000494:pharmacology; D011233:Precipitin Tests; D011976:Receptors, Muscarinic / Q000276:immunology*; D015398:Signal Transduction; D013997:Time Factors
D000906:Antibodies; D007074:Immunoglobulin G; D011976:Receptors, Muscarinic; D010862:Pilocarpine; D000242:Cyclic AMP; D006152:Cyclic GMP