Modulatory effects on myocardial physiology induced by an anti-Trypanosoma cruzi monoclonal antibody involve recognition of major antigenic epitopes from beta1-adrenergic and M2-muscarinic cholinergic receptors without requiring receptor cross-linking.
It has been proposed that anti-myocardial antibodies (Ab) against neurotransmitter (NT) receptors are involved in the immunopathology of chronic Chagas' heart disease. We demonstrated that an anti-Trypanosoma cruzi monoclonal Ab (mAb), CAK20.12, binds to murine cardiac beta-adrenergic and muscarinic acetyl choline (mACh) receptors eliciting abnormal physiological responses on normal heart. No cross-linking requirement for mAb actions was demonstrated using Fab fragment derived from CAK20.12. mAb binding to synthetic peptides from the second extracellular loop of both beta1-adrenergic and mACh receptors, demonstrated by ELISA, identified the region of NT receptors involved. Cross-reactivity between these peptides and T. cruzi antigen was confirmed by binding inhibition assays. These results support the existence of cross-reactivity due to molecular mimicry between a parasite antigen and the major antigenic epitopes present on both beta1-adrenergic and M2-ACh receptors. Its possible relationship with cardiac dysfunction during chronic stage of Chagas' disease is also discussed.
Cremaschi
Graciela
G
Centro de Estudios Farmacológicos y Botánicos (CEFYBO-CONICET), Serrano 669, 1414 Buenos Aires, Argentina.
Fernández
Marisa M
MM
Gorelik
Gabriela
G
Goin
Juan C
JC
Fossati
Carlos A
CA
Zwirner
Norberto W
NW
Malchiodi
Emilio L
EL
D000319:Adrenergic beta-Antagonists; D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000913:Antibodies, Protozoan / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D000939:Epitopes / Q000378:metabolism / Q000494:pharmacology; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D066298:In Vitro Techniques; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D010869:Pindolol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011813:Quinuclidinyl Benzilate / Q000493:pharmacokinetics; D011863:Radioimmunoassay / Q000379:methods; D011869:Radioligand Assay / Q000379:methods; D043585:Receptor, Muscarinic M2 / Q000737:chemistry / Q000276:immunology*; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry / Q000276:immunology*; D017186:Titrimetry / Q000379:methods; D014349:Trypanosoma cruzi / Q000737:chemistry / Q000276:immunology*
D000319:Adrenergic beta-Antagonists; D000911:Antibodies, Monoclonal; D000913:Antibodies, Protozoan; D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; D007456:Iodine Isotopes; D018727:Muscarinic Antagonists; D043585:Receptor, Muscarinic M2; D018342:Receptors, Adrenergic, beta-1; C047975:cyanopindolol; D011813:Quinuclidinyl Benzilate; D010869:Pindolol; D000242:Cyclic AMP; D006152:Cyclic GMP