MOLECULAR MIMICRY BETWEEN AN IMMUNODOMINANT AMINO-ACID MOTIF ON THE 47-KDA LIPOPROTEIN OF TREPONEMA-PALLIDUM (TPP47) AND MULTIPLE REPEATS OF ANALOGOUS SEQUENCES IN FIBRONECTIN

Molecular mimicry, resulting from structural similarities between self -determinants on host Ags and an organism's antigenic determinants (ep itopes), can incite autoimmune events in certain bacterial and viral d iseases. In the course of comprehensively mapping the 47-kDa lipoprote in (Tpp47) of Treponema pallidum subsp. pallidum using an overlapping synthetic peptide strategy, we identified a major immunoreactive epito pe (411PGTEYT416) that exhibited considerable motif identity with mult iple repeats of analogous linear sequences found in mammalian fibronec tins. To further explore the importance of this motif as a probable in stigator in the induction of polyspecific cross-reactive Abs, mimetic variants were synthesized for immunologic studies. Mimetics with ala ( A) replacements in each amino acid position were used to determine whi ch residues were critical for Ab binding. Animals immunized with two m imetics (PGTEYT or PGSEYT) coupled to tetanus toroid exhibited: 1) mod ified responses when challenged with viable T. pallidum; and 2) classi cal Arthus reactions when challenged intradermally with either motif l inked to a different carrier. The cross-reactive nature of the Ab resp onses to both mimetics was confirmed in a variety of ELISAs using mime tics, fibronectins, and collagens. Inhibition-ELISA studies with both fibronectin and an unrelated mimetic of the RGD motif suggest that int ra- and intermolecular epitope spreading occurs following mimetic immu nization and involves additional self-epitopes. These observations sug gest that although molecular mimicry plays a pivotal role in initially triggering the anti-fibronectin and anti-collagen responses associate d with disseminated syphilis, expansion of those autoimmune responses may be due to other self-epitopes once tolerance is abrogated.