[A joint undertaking by molecular biology and immunology in search for the pathogenesis of neuromuscular synaptic disorders].
Immunogenic sites in the molecular structure of acetylcholine receptor (AChR) in relation to myasthenia gravis and voltage-gated calcium channel in relation to Lambert-Eaton myasthenic syndrome (LEMS) were studied by the use of peptides synthesized corresponding to their amino acid sequences. In general, synthetic peptides do not effectively assume an antigenic conformation recognized by autoantibodies raised against native proteins. To solve this problem, structural models for the recognition of AChR synthetic peptides by B-cell expected at beta-turn (alpha 183-200 and alpha 67-76) were designed to seek a conformation that could approach the myasthenogenic architecture. To approach potential epitopes of LEMS antibodies, the peptide loops, S5-S6 linker regions in each of 4 domains constructing the alpha 1A subunit of voltage-gated calcium channel, were designed including calcium conduction pore and ligand-binding sites. Informations based on knowledges from the molecular biology served as clues that helped to find antigenic sites reactive with pathogenic antibodies in two proteins concerned. T-cell epitopes essential for the induction of the diseases were constrained by the MHC class II-restriction dependent on species of mammals as well as cofactors that control immune responses.
Takamori
M
M
Department of Neurology, Kanazawa University School of Medicine.
D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D006801:Humans; D015624:Lambert-Eaton Myasthenic Syndrome / Q000209:etiology*; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000209:etiology*; D009469:Neuromuscular Junction; D011487:Protein Conformation; D011950:Receptors, Cholinergic
D001323:Autoantibodies; D011950:Receptors, Cholinergic