Cholinergic autoantibodies in sinus-node dysfunction

Ferrari, Inés; Levìn, Mariano J.; Elizari, Marcelo V.; Rosenbaum, Mauricio B.; Chiale, Pablo A.

doi:10.1016/s0140-6736(05)62226-x

Cited by 13 publications

(7 citation statements)

References 4 publications

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“…In addition, the β 1‐AR stimulatory effect of the anti‐R13 antibodies has been further confirmed by the generation of an anti‐R13 monoclonal antibody, mAb17·2, with an exclusive stimulatory activity on this receptor subtype [14]. In contradiction with these observations, we have detected cChHD patients with sick sinus syndrome and high anti‐R13 antibody levels whose total IgG fraction stimulated the M2‐ChR, decreasing the beating rate of cardiomyocytes [6,15].…”

Section: Introductionmentioning

confidence: 99%

Structural and functional complexity of the humoral response against theTrypanosoma cruziribosomal P2βprotein in patients with chronic Chagas’ heart disease

Mahler

Hoebeke

Levìn

2004

Clinical and Experimental Immunology

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Structural and functional complexity of the humoral response against the SUMMARYHigh levels of antibodies against the C-terminus of the Trypanosoma cruzi TcP2 b ribosomal protein, defined by the peptide EEEDDDMGFGLFD, named R13, have been measured in sera from patients with chronic Chagas' Heart Disease (cChHD). These antibodies also recognize an epitope on the second extracellular loop of the b 1-adrenergic receptor, inducing a functional response on cardiomyocytes. The aim of this study was to gain novel insights into the structural basis of this cross-reactivity as well as to evaluate the origin of anti-M2-cholinergic receptor antibodies, which are also commonly found in cChHD patients. To address these questions we immunopurified anti-R13 antibodies and studied the structural requirements of epitope recognition. Results showed that the immunopurified antibodies recognized a conformation of R13 in which the third Glu residue was essential for binding, explaining their low affinity for the mammalian homologue (peptide H13: EESDDDMGFGLFD). Alanine mutation scanning showed individual variations in epitope recognition in each of the studied patients. The importance of a negatively charged residue at position 3 for the recognition of anti-R13 antibodies was further confirmed by competition experiments using a Ser3-phosphorylated H13 analogue, which had 10 times more affinity for the anti-R13 antibody than the native H13 peptide. Moreover, anti-R13 antibodies stimulated either the b 1-adrenergic or the M2-cholinergic receptor, in strict agreement with the functional properties of the IgG fractions from which they derived, demonstrating that the same parasite antigen may generate antibody specificities with different functional properties. This may be a clue to explain the high variability of electrophysiological disturbances found in cChHD.

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Section: Introductionmentioning

confidence: 99%

Structural and functional complexity of the humoral response against theTrypanosoma cruziribosomal P2βprotein in patients with chronic Chagas’ heart disease

Mahler

Hoebeke

Levìn

2004

Clinical and Experimental Immunology

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“…In the chronic phase of the disease, patients present antibodies against the acidic rich C-terminal of Trypanosoma cruzi ribosomal P proteins [2]. It has been proposed that cChHD is an autoimmune disease produced by the existence of molecular mimicry between the C-terminal of ribosomal P proteins and the second extra cellular loop of the β1-adrenergic receptor ( H26R ) [3]. …”

Section: Introductionmentioning

confidence: 99%

Three-dimensional studies of pathogenic peptides from the c-terminal of Trypanosoma cruziribosomal P proteins and their interaction with a monoclonal antibody structural model

2009

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The acidic C-terminal peptides from Trypanosoma cruzi ribosomal P proteins are the major target of the antibody response in patients suffering Chagas chronic heart disease. It has been proposed that the disease is triggered by the cross-reaction of these antibodies with the second extra cellular loop of the 1-adrenoreceptor, brought about by the molecular mimicry between the acidic C-terminal peptides and the receptor's loop. To improve the understanding of the structural basis of the autoimmune response against heart receptors, the 3-dimensional structure of the C-terminal peptides of Trypanosoma cruzi ribosomal proteins P0 (EDDDDDFGMGALF) and P2 (EEEDDDMGFGLFD) were solved using the Electrostaticaly Driven MonteCarlo method. Their structures were compared with the second extra-cellular loop of our homology model of human rhodopsin and the existing experimental NMR structures of the C-terminal peptides from human P0 (EESDDDMGFGLFD) and from Leishmania braziliensis P0 (EEADDDMGFGLFD). Docking of Trypanosoma cruzi peptides P0, P2 and human rhodopsin loop into our anti-P2 monoclonal antibody homology model allowed to explore their interactions.The solution structure of peptides P0 and P2 can be briefly described as a bend. Although the global conformations of the peptides are not identical they shared a common region of four residues (3 to 6) that have a similar structure. The structural alignment of the five peptides also showed a surprising conformational similarity for the same residues. The antibody model and docking studies revealed a most remarkable feature in the active site, a positively charged, narrow and deep cavity where the acidic residues 3 to 6 were accommodated. These results suggest that the most important

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“…Indeed, immune responses developed against self‐antigens via molecular mimicry‐dependent mechanisms have been shown to play a role in autoimmune phenomena associated with infectious disease [4–6]. Several T. cruzi antigens have been reported to present epitopes similar to mammalian antigens, including the family of trypomastigote‐specific FI‐160 antigens [7,8], the microtubule‐associated protein [9], the cardiac myosin antigen (B13) [10], and members of the ribosomal P protein family [11–13].…”

Section: Introductionmentioning

confidence: 99%

“…Patients with cChHD present a high titer of antibodies against the C‐terminal end of the ribosomal P protein of T. cruzi , which has high similarity to the C‐terminal region of human ribosomal P proteins and also to the second loop of the human β‐adrenergic [13] and M2 muscarinic receptors [14]. As the sera of these patients can elicit heart function disturbances, several researchers believe that the primary sequence similarity is related to the observed cross‐reactivity of antibodies from cChHD patients with the heart receptors [14].…”

Section: Introductionmentioning

confidence: 99%

Correlation between conformation and antibody binding: NMR structure of cross‐reactive peptides from T. cruzi, human and L. braziliensis

et al. 2004

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The structure of peptides corresponding to the C-terminal residues from Trypanosoma cruzi (R13), human (H13) and Leishmania braziliensis (A13) ribosomal proteins were determined using nuclear magnetic resonance. Although there is only one amino acid di¡erence between them, the peptides present distinct structures in solution: R13 adopts a random coil conformation while H13 and A13 form a bend. Interaction of these peptides with polyclonal antibodies from chronic Chagas' disease patients and a monoclonal antibody raised against T. cruzi ribosomal P2L L protein was probed by transferred NOE. The results show that the £exibility of R13 is fundamental for the binding to the antibody. ß 2004 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.

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Cholinergic autoantibodies in sinus-node dysfunction

Cited by 13 publications

References 4 publications

Structural and functional complexity of the humoral response against theTrypanosoma cruziribosomal P2βprotein in patients with chronic Chagas’ heart disease

Structural and functional complexity of the humoral response against theTrypanosoma cruziribosomal P2βprotein in patients with chronic Chagas’ heart disease

Three-dimensional studies of pathogenic peptides from the c-terminal of Trypanosoma cruziribosomal P proteins and their interaction with a monoclonal antibody structural model

Correlation between conformation and antibody binding: NMR structure of cross‐reactive peptides from T. cruzi, human and L. braziliensis

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