To investigate the molecular basis of antigenic mimicry by peptides, we studied a panel of closely related mAbs directed against the cell-wall polysaccharide of group A Streptococcus. These antibodies have restricted V-gene usage, indicating a shared mechanism of binding to a single epitope. Epitope mapping studies using synthetic fragments of the cell-wall polysaccharide supported this conclusion. All of the mAbs isolated crossreactive peptides from a panel of phagedisplayed libraries, and competition studies indicated that many of the peptides bind at or near the carbohydrate binding site. Surprisingly, the peptides isolated by each mAb fell into distinct consensus-sequence groups that discriminated between the mAbs, and in general, the peptides bound only to the mAbs used for their isolation. Similar results were obtained with polyclonal antibodies directed against synthetic oligosaccharide fragments of the streptococcal cell-wall polysaccharide. Thus, the peptides appear to be specific for their isolating antibodies and are not recognized by the same mechanism as their carbohydrate counterparts.Carbohydrates (CHOs) have proven to be valuable tools in demonstrating immunologic mimicry. Anti-idiotypic antibodies (Abs) directed against the V domains of anti-CHO Abs can, in some instances, elicit CHO-binding Ab responses when used themselves as immunogens (e.g., refs. 1-4). This has been attributed to chemical similarity (known as the ''internal image'') between an anti-idiotypic Ab and the corresponding CHO antigen (1). Likewise, crossreactive peptides have been identified for several anti-CHO mAbs (4-7). In one case, the peptide was shown to elicit Abs having the same idiotype as the cognate, anti-CHO mAb (5), and in another to elicit a CHObinding response (4).The work described here addresses the molecular basis of crossreactivity between CHO and protein antigens with Abs. Our goal was to determine if the crossreactive peptides recognized by anti-CHO Abs would bind by the same mechanism as the corresponding epitope on the CHO target; if so, the basis of crossreactivity would be structural mimicry. We assembled a panel of five closely related mAbs against the cell-wall polysaccharide (CWPS) of group A Streptococcus (GAS) and showed by oligosaccharide mapping studies that they indeed bind a similar, if not identical, epitope. Each of four anti-GAS CWPS mAbs and three polyclonal Abs (PCAbs) against synthetic oligosaccharide fragments of the GAS CWPS isolated peptides bearing unique, chemically distinct consensus sequences. Moreover, representative peptides from each consensus group were functionally specific, because they usually bound only to their isolating Ab. Thus, these Abs were more restricted in their peptide reactivity than in their CHO recognition. We conclude that the predominating basis of peptide recognition by anti-CHO Abs differs between Abs, with true CHO mimics being relatively rare. We propose that the antigenic mimicry observed for CHO-crossreactive peptides is determined mainly by the ...

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