Role of Neurotransmitter Autoantibodies in the Pathogenesis of Chagasic Peripheral Dysautonomia

Abstract

A BSTRACT : 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 ␤ -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 ␤ 1 adrenoceptor and M 2 cholinoceptor. Also, the corresponding affinity-purified antipeptide antibodies displayed an agonist-like activity associated with specific receptor activation. A strong association between circulating antipeptide M 2 mAChR autoantibodies and the presence of patients' low heart rate variablity 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.

Trypanosoma cruzi infection induces up-regulation of cardiac muscarinic acetylcholine receptors in vivo and in vitro

“…The possible agonistic activity of some anti-muscarinic and/or anti-nicotinic cholinergic receptor antibodies (11,12,17) could induce receptor functional subsensitivity and down-regulation of the post-synaptic cardiac muscle mAChR, due to an agonist-induced receptor desensitization phenomenon (20); however, this event in cardiac tissues of chagasic animals has not been observed or reported. In the scenario in which both phenomena (vagal denervation and muscarinic receptor modulation by autoantibodies) are supposed to occur simultaneously, each phenomenon could neutralize the other with no overall changes in mAChR expression.…”

“…The participation of the muscarinic cholinergic system in the development of chagasic cardiomyopathy is supported by both the neurogenic (6) and the autoimmune theories (11). During the acute phase of Chagas disease, the post-ganglionic vagal neurons of the intra-cardiac plexus are selectively destroyed by either T. cruzi cell invasion or by auto-antibodies directed to membrane structures (5,6).…”

“…Immunologic insults can modulate cardiac function by causing direct muscle remodeling associated with modulation of the β-adrenergic receptor-associated adenylylcyclase activity (7)(8)(9)(10). Similarities between T. cruzi epitopes and human cardiomyocyte receptor epitopes such as β-adrenergic receptors, M 2 -subclass muscarinic acetylcholine receptor (mAChR), nicotinic cholinergic receptors, and certain voltage-dependent channels have been described (11)(12)(13)(14)(15).…”

Muscarinic antibodies and heart rate responses to dynamic exercise and to the Valsalva maneuver in chronic chagasic patients

“…The findings of these clinical investigations have been conflicting and controversial. Nonetheless, parasympathetic effects on heart rate are currently considered, by most investigators, as being impaired by cardiac muscarinic auto-antibodies 14,[21][22][23]42,43 . We have postulated, on the contrary, that parasympathetic activity is enhanced by the allosteric effects of the muscarinic cardiac auto-antibodies 11,12 .…”

“…The second extracellular (o2) and the third intracellular loops (i3), of these receptors, are considered as autoimmune epitopes in patients with chronic Chagas' disease 22,40. The autoimmune response occurs early on the natural history of the disease and it is considered to be responsible for the abnormalities of parasympathetic control of heart rate 14,21,23,[41][42][43][44] . These investigations have demonstrated that, the chronotropic responses to cardiac autonomic tests are apparently impaired in the indeterminate form of the disease.…”