Peptide Analogs to Pathogenic Epitopes of the Human Acetylcholine Receptor α Subunit as Potential Modulators of Myasthenia Gravis

Myasthenia gravis is an autoimmune disease in which T cells specific to epitopes of the autoantigen, the human acetylcholine receptor, play a role. We identified two peptides, p195-212 and p259-271, from the α subunit of the receptor, which bound to major histocompatibility complex (MHC) class II mo...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1996-04, Vol.93 (9), p.4492-4497
Main Authors: Zisman, Einat, Katz-Levy, Yael, Dayan, Molly, Kirshner, Susan L., Paas-Rozner, Miri, Karni, Arnon, Abramsky, Oded, Brautbar, Chaim, Fridkin, Mati, Sela, Michael, Mozes, Edna
Format: Article
Language:English
Subjects:
Adult
Aged
Amino Acid Sequence
Amino acids
Antigen-Presenting Cells - immunology
Autoimmune diseases
B lymphocytes
Binding Sites
Cholinergic receptors
Disease
Epitopes
Epitopes - chemistry
Epitopes - therapeutic use
Female
Humans
Immunity (Disease)
Interleukin-2 - biosynthesis
Lymphocyte Activation
Lymphocytes
Macromolecular Substances
Male
Medical research
Middle Aged
Molecular Sequence Data
Myasthenia gravis
Myasthenia Gravis - immunology
Myasthenia Gravis - therapy
Peptides
Peptides - chemical synthesis
Peptides - chemistry
Peptides - therapeutic use
Receptors, Cholinergic - chemistry
Receptors, Cholinergic - immunology
Structure-Activity Relationship
T cell antigen receptors
T lymphocytes
Transponders
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Myasthenia gravis is an autoimmune disease in which T cells specific to epitopes of the autoantigen, the human acetylcholine receptor, play a role. We identified two peptides, p195-212 and p259-271, from the α subunit of the receptor, which bound to major histocompatibility complex (MHC) class II molecules on antigen-presenting cells (APCs) from peripheral blood lymphocytes of myasthenia gravis patients and stimulated lymphocytes of >80% of the patients. We have prepared analogs of these myasthenogenic peptides and tested their ability to bind to MHC class II determinants and to interfere specifically with T-cell stimulation. We first determined relative binding efficiency of the myasthenogenic peptides and their analogs to APCs of patients. We found that single substituted analogs of p195-212 (Ala-207) and p259-271 (Lys-262) could bind to human MHC molecules on APCs as efficiently as the original peptides. Moreover, dual analogs containing the two single substituted analogs in one stretch (either sequentially, Ala-207/Lys-262, or reciprocally, Lys-262/Ala-207) could also bind to APCs of patients, including those that failed to bind one of the single substituted analogs. The single substituted analogs significantly inhibited T-cell stimulation induced by their respective myasthenogenic peptides in >95% of the patients. The dual analogs were capable of inhibiting stimulation induced by either of the peptides: They inhibited the response to p195-212 and p259-271 in >95% and >90% of the patients, respectively. Thus, the dual analogs are good candidates for inhibition of T-cell responses of myasthenia gravis patients and might have therapeutic potential.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.93.9.4492