Similar antigenic surfaces, rather than sequence homology, dictate T-cell epitope molecular mimicry.

TLDR

Molecular mimicry, traditionally defined by primary‑sequence similarities between self and foreign antigens, has been considered a key element in the pathogenesis of autoimmunity. Molecular modeling of MHC class II–peptide complexes shows that the two recognized peptides generate similar antigenic surfaces despite differing amino acid sets, whereas a one‑residue shift produces a distinct surface. Our data reveal that two overlapping self‑peptides elicit the same T‑cell clone, that their anchor residues differ, and that antigenic surface similarity—not sequence identity—drives mimicry, underscoring the need to evaluate surface properties in mimicry studies.

Abstract

Molecular mimicry, normally defined by the level of primary-sequence similarities between self and foreign antigens, has been considered a key element in the pathogenesis of autoimmunity. Here we describe an example of molecular mimicry between two overlapping peptides within a single self-antigen, both of which are recognized by the same human self-reactive T-cell clone. Two intervening peptides did not stimulate the T-cell clone, even though they share nine amino acids with the stimulatory peptides. Molecular modeling of major histocompatibility complex class II-peptide complexes suggests that both of the recognized peptides generate similar antigenic surfaces, although these are composed of different sets of amino acids. The molecular modeling of a peptide shifted one residue from the stimulatory peptide, which was recognized in the context of the same HLA molecule by another T-cell clone, generated a completely different antigenic surface. Functional studies using truncated peptides confirmed that the anchor residues of the two "mimicking" epitopes in the HLA groove differ. Our results show, for two natural epitopes, how molecular mimicry can occur and suggest that studies of potential antigenic surfaces, rather than sequence similarity, are necessary for analyzing suspected peptide mimicry.