Role of neurotransmitter autoantibodies in the pathogenesis of chagasic peripheral dysautonomia.
Chagas' disease is caused by a parasite, Trypanosoma cruzi, which is widely distributed in South and Central America. Dysautonomias, derangements of sympathetic and parasympathetic nervous system function, are seen fairly often during the chronic course of Chagas' disease. Many infected subjects developed, in the course of the disease, neurogenic cardiomyopathy or digestive damage. Our investigations show the existence of circulating antibodies in Chagas' disease that bind to beta-adrenergic and muscarinic cholinergic receptor (mAChR). The neurotransmitter receptor-autoantibody interaction triggers in the cells intracellular signal transductions that alter the physiological behavior of the target organs, leading to tissue damage. Moreover, the deposit of autoantibodies behaving as agonists induces desensitization and/or down regulation of the receptors. This in turn can lead to a progressive blockade of them with sympathetic and parasympathetic denervation. Using synthetic peptides for immunoblotting and enzyme immunoassay, we demonstrated that these autoantibodies reacted against the second extracellular loop of the human heart beta 1 adrenoceptor and M2 cholinoceptor. Also, the corresponding affinity-purified antipeptide antibodies displayed an agonist-like activity associated with specific receptor activation. A strong association between circulating antipeptide M2 mAChR autoantibodies and the presence of patients' low heart rate variability index, bradycardia and cardiac or esophageal autonomic dysfunction in chronic chagasic patients was verified. This fact make these antipeptide antibodies a proper marker of cardiac neuromyopathy and achalasia.
Centro de Estudios Farmacológios y Botánicos (CEFYBO), Pharmacology Department, School of Medicine and Dentistry, Buenos Aires University, Buenos Aires, Argentina.
L
L
Sterin-Borda
E
E
Borda
D001323:Autoantibodies / Q000276:immunology*; D014355:Chagas Disease / Q000209:etiology / Q000276:immunology*; D006801:Humans; D018377:Neurotransmitter Agents / Q000276:immunology*
D001323:Autoantibodies; D018377:Neurotransmitter Agents