INTERACTION OF HUMAN CHAGASIC IGG WITH THE 2ND EXTRACELLULAR LOOP OF THE HUMAN HEART MUSCARINIC ACETYLCHOLINE-RECEPTOR - FUNCTIONAL AND PATHOLOGICAL IMPLICATIONS

Circulating antibodies from human and murine chagasic sera are able to interact with myocardium-activating neurotransmitter receptors, Here we reported the presence of autoantibodies against the second extracel lular loop of the human heart muscarinic acetylcholine receptors (nACh R) in patients with Chagas' disease by using a synthetic 24-mer peptid e in immunoblotting and enzyme immunoassay, Affinity-purified antipept ide IgG from chagasic patients, similar to monoclonal antihuman M(2) m AChR, recognized bands with a molecular weight corresponding to the ca rdiac mAChR. The binding was inhibited by the peptide, assessing the s pecificity of the interaction, The antipeptide autoantibody also displ ayed an ''agonist-like'' activity modifying the intracellular events a ssociated with mAChR activation, i.e., decreased contractility, increa sed cGMP, and decreased cAMP production, All of these effects on rat a tria by chagasic antipeptide autoantibodies resemble the effects of th e authentic agonist and those of the total polyclonal chagasic IgG, be ing selectively blunted by atropine and neutralized by the synthetic p eptide corresponding in aminoacid sequence to the second extracellular loop of the human Mp mAChR. A clinical relevance of these findings is demonstrated by a strong association between the existence of circula ting antipeptide antoantibodies in chagasic patients and the presence of dysautonomic symptoms, making these antoantibodies a proper early m arker of heart autonomic dysfunction.