Molecular mimicry between the immunodominant ribosomal protein P0 of Trypanosoma cruzi and a functional epitope on the human beta 1-adrenergic receptor.
Sera from chagasic patients possess antibodies recognizing the carboxy-terminal part of the ribosomal P0 protein of Trypanosoma cruzi and the second extracellular loop of the human beta 1-adrenergic receptor. Comparison of both peptides showed that they contain a pentapeptide with very high homology (AESEE in P0 and AESDE in the human beta 1-adrenergic receptor). Using a competitive immunoenzyme assay, recognition of the peptide corresponding to the second extracellular loop (H26R) was inhibited by both P0-14i (AAAESEEEDDDDDF) and P0-beta (AESEE). Concomitantly, recognition of P0-beta was inhibited with the H26R peptide. Recognition of P0 in Western blots was inhibited by P0-14i, P0-beta, and H26R, but not by a peptide corresponding to the second extracellular loop of the human beta 2-adrenergic receptor or by an unrelated peptide. Autoantibodies affinity purified with the immobilized H26R peptide were shown to exert a positive chronotropic effect in vitro on cardiomyocytes from neonatal rats. This effect was blocked by both the specific beta 1 blocker bisoprolol and the peptide P0-beta. These results unambiguously prove that T. cruzi is able to induce a functional autoimmune response against the cardiovascular human beta 1-adrenergic receptor through a molecular mimicry mechanism.
Ferrari
I
I
Laboratorio de Biologia Molecular de la Enfermedad de Chagas, INGEBI (CONICET), Buenos Aires, Argentina.
Levin
M J
MJ
Wallukat
G
G
Elies
R
R
Lebesgue
D
D
Chiale
P
P
Elizari
M
M
Rosenbaum
M
M
Hoebeke
J
J
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D000913:Antibodies, Protozoan / Q000097:blood / Q000276:immunology; D000953:Antigens, Protozoan / Q000737:chemistry / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology*; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology*; D017298:Bisoprolol / Q000494:pharmacology; D002478:Cells, Cultured; D002598:Chagas Cardiomyopathy / Q000209:etiology / Q000276:immunology*; D014355:Chagas Disease / Q000097:blood / Q000150:complications / Q000276:immunology; D003429:Cross Reactions; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology*; D007893:Leishmania donovani / Q000276:immunology; D007896:Leishmaniasis / Q000276:immunology; D007898:Leishmaniasis, Visceral / Q000276:immunology; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology; D010750:Phosphoproteins / Q000737:chemistry / Q000276:immunology*; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D012269:Ribosomal Proteins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014349:Trypanosoma cruzi / Q000276:immunology*
D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D001323:Autoantibodies; D001324:Autoantigens; D016056:Immunodominant Epitopes; D010750:Phosphoproteins; D018342:Receptors, Adrenergic, beta-1; D011994:Recombinant Proteins; D012269:Ribosomal Proteins; C054675:ribosomal protein P0; D017298:Bisoprolol