Conformational modification enhances myasthenogenicity in synthetic peptide of acetylcholine receptor α-subunit
Department of Neurology, Kanazawa University School of Medicine, Japan.Journal of the Neurological Sciences (Impact Factor: 2.47). 12/1990; 99(2-3):219-27. DOI: 10.1016/0022-510X(90)90157-I
The induction of myasthenia gravis depends on linked recognition of antigenic sites of acetylcholine receptor (AChR) by B-cells and T-cells. The former is conformationally restrained, and the latter is under the MHC class II restriction. We synthesized an artificially formed peptide (model peptide) by coupling the alpha 190-195 selected as B-cell site and cholinergic binding site and the alpha-107-116 selected as T-cell site and agretope with the intervening chain segment aligned as Asn-Pro-Gly-Gly (NPGG) to adopt beta-turn conformation. This model peptide, alpha 107-116-NPGG-alpha 190-195, was potently immunogenic in Lewis rats to provoke anti-peptide antibody reactive with native AChR and to induce the animal model of immunopharmacologic blockade of acetylcholine (ACh)-binding site. Low immunogenicity compared with this was found when using natural peptides predicted as sequences of B-cell site or T-cell site and the peptide synthesized by linking both without intervention of NPGG. The alpha 190-195 had no function of cholinergic binding either as a single segment or as part of the conformation-modified peptides; results suggest that the conformation modified for high immunogenicity does not assume the bioactive conformation for ACh-binding.
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ABSTRACT: Myasthenogenic regions in the acetylcholine receptor (AChR) alpha-subunit were studied in view of the conformation-dependent B-cell epitope expected at beta-turn and the MHC class II-restricted T-cell epitope expected at alpha-helix. Torpedo AChR alpha 67-76 and alpha 107-116 were synthesized as the main immunogenic region and the site specific for T-cell epitope in Lewis rat, respectively. Model peptides, synthesized by combining these natural sequence segments or by intervening the segment aligned as Asn-Pro-Gly-Gly (NPGG) in natural sequence segments, were tested in terms of antigenic conformation. The model peptide, alpha 107-116.alpha 67-76.alpha 107-116, was immunogenic in the induction of the animal model of myasthenia, accompanied by the anti-peptide antibody cross-reactive with the native AChR. High antigenicity in antibody assays for various peptide- and native AChR-immunized rats was found when the model peptides, alpha 107-116.alpha 67-76 and/or alpha 107-116.NPGG.alpha 67-76 were used for measurement as antigens. Antigenic conformation for the induction of the disease may thus be different from that for the reactivity to antibody.Journal of the Neurological Sciences 07/1992; 109(2):182-7. DOI:10.1016/0022-510X(92)90166-I · 2.47 Impact Factor
- Annals of the New York Academy of Sciences 07/1993; 681:168-71. · 4.38 Impact Factor
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ABSTRACT: We investigated the effect of the IgG from patients with myasthenia gravis (MG) on the degradation of normal rat junctional acetylcholine receptor (AChR) labeled with 125I-alpha-bungarotoxin (BuTx) and calculated the degradation rate (DR). The DR for the IgG from these patients was significantly higher than that from healthy volunteers and patients with other autoimmune diseases. For MG, DR was significantly correlated with the severity of the disease but not with anti-AChR antibody titer. DR was accelerated by IgG from patients with generalized MG whose antibody titers were in the normal range and by IgG from patients with ocular MG. These results indicate that measurement of the DR of junctional AChR in normal rats is more closely correlated with the severity of the disease than is measurement of anti-AChR antibody and that the former is a sensitive and confirmatory method for evaluating MG.Muscle & Nerve 08/1993; 16(8):840-8. DOI:10.1002/mus.880160807 · 2.28 Impact Factor
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