Interaction of human chagasic IgG with the second 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 extracellular loop of the human heart muscarinic acetylcholine receptors (mAChR) in patients with Chagas' disease by using a synthetic 24-mer peptide in immunoblotting and enzyme immunoassay. Affinity-purified antipeptide IgG from chagasic patients, similar to monoclonal antihuman M2 mAChR, recognized bands with a molecular weight corresponding to the cardiac mAChR. The binding was inhibited by the peptide, assessing the specificity of the interaction. The antipeptide autoantibody also displayed an "agonist-like" activity modifying the intracellular events associated with mAChR activation, i.e., decreased contractility, increased cGMP, and decreased cAMP production. All of these effects on rat atria by chagasic antipeptide autoantibodies resemble the effects of the authentic agonist and those of the total polyclonal chagasic IgG, being selectively blunted by atropine and neutralized by the synthetic peptide corresponding in aminoacid sequence to the second extracellular loop of the human M2 mAChR. A clinical relevance of these findings is demonstrated by a strong association between the existence of circulating antipeptide autoantibodies in chagasic patients and the presence of dysautonomic symptoms, making these autoantibodies a proper early marker of heart autonomic dysfunction.
Goin
J C
JC
Centro de Estudios Farmacólogicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas de la Repüblica Argentina (CONICET), Buenos Aires.
Leiros
C P
CP
Borda
E
E
Sterin-Borda
L
L
D000109:Acetylcholine / Q000276:immunology*; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology*; D000953:Antigens, Protozoan / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology / Q000302:isolation & purification; D001342:Autonomic Nervous System Diseases / Q000276:immunology / Q000473:pathology; D015415:Biomarkers; D002598:Chagas Cardiomyopathy / Q000276:immunology* / Q000473:pathology; D003429:Cross Reactions / Q000276:immunology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006325:Heart Atria / Q000294:innervation / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007074:Immunoglobulin G / Q000276:immunology* / Q000302:isolation & purification; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009200:Myocardial Contraction / Q000502:physiology*; D051381:Rats; D011976:Receptors, Muscarinic / Q000737:chemistry / Q000276:immunology*; D014349:Trypanosoma cruzi / Q000276:immunology*
D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D001323:Autoantibodies; D015415:Biomarkers; D007074:Immunoglobulin G; D011976:Receptors, Muscarinic; D000242:Cyclic AMP; D006152:Cyclic GMP; D000109:Acetylcholine