Peptide analogs to pathogenic epitopes of the human acetylcholine receptor alpha 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 alpha 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.
Zisman
E
E
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Katz-Levy
Y
Y
Dayan
M
M
Kirshner
S L
SL
Paas-Rozner
M
M
Karni
A
A
Abramsky
O
O
Brautbar
C
C
Fridkin
M
M
Sela
M
M
Mozes
E
E
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000938:Antigen-Presenting Cells / Q000276:immunology; D001665:Binding Sites; D000939:Epitopes / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D046911:Macromolecular Substances; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000276:immunology / Q000628:therapy*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000276:immunology*; D013329:Structure-Activity Relationship
D000939:Epitopes; D007376:Interleukin-2; D046911:Macromolecular Substances; D010455:Peptides; D011950:Receptors, Cholinergic