ANTIGEN MIMICRY IN AUTOIMMUNE-DISEASE SHARING OF AMINO-ACID-RESIDUES CRITICAL FOR PATHOGENIC T-CELL ACTIVATION

A nonamer peptide from murine nicotinic acetylcholine receptor delta c hain (ACRdelta), which shared four amino acid residues with a nonamer peptide of murine ovarian zona pellucida glycoprotein ZP3, induced mur ine autoimmune oophoritis and IgG autoantibody to the zona pellucida. Crossreaction between the ACRdelta and ZP3 peptides was established by the response of a ZP3 peptide-specific, oophoritogenic T cell clone t o both peptides in association with IA(alpha(k)beta(b)). By substituti ng the ZP3 peptides with a single alanine, four amino acids within the ZP3 peptide were found to be important for ovarian autoimmune disease , autoantibody response, and stimulation of the ZP3-specific T cell cl one. Substitution with conservative amino acids of three residues also ablated activity, whereas the fourth, a phenylalanine, was replaceabl e by tyrosine without loss of activity. Of the four critical amino aci ds, three were shared between the ZP3 peptide and the ACRdelta peptide . Moreover, polyalanine peptides with the four critical ZP3 amino acid s or the four amino acids common to the ZP3 and ACRdelta peptides indu ced immune response to ZP3 and elicited severe ovarian autoimmune dise ase. Thus, organ-specific autoimmune disease can occur through immune response against unrelated self (or foreign) peptides that share with a self-peptide sufficient common amino acid residues critical for acti vation of pathogenic, autoreactive T cells.