Change in specificity of antibodies to a random synthetic branched polypeptide in mice tolerant to its ordered analogs.

The crossreactivity between the random synthetic polypeptide antigen, (Tyr,Glu)-poly(DLAla)- -poly(Lys), and its ordered sequence analogs, (Tyr-Tyr-Glu-Glu)-poly(DLAla)- -poly(Lys) and (Tyr-Glu-Tyr-Glu)-poly(DLAla)- -poly(Lys), has been studied on the level of tolerance induction. Induction of tolerance to the random (Tyr,Glu)-poly(DLAla)- -poly(Lys) affected the response of the tolerant mice to the homologous antigen as well as to (Tyr-Tyr-Glu-Glu)-poly(DLAla)- -poly(Lys), which was shown previously to represent the major determinant of (Tyr,Glu)-poly(DLAla)- -poly(Lys). In contrast, these mice responded with high antibody titers to the hardly crossreacting (Tyr-Glu-Tyr-Glu)-poly(DLAla)- -poly(Lys). Mice tolerant to the ordered peptide antigen (Tyr-Glu-Tyr-Glu)-poly(DLAla)- -poly(Lys) did not respond to the homologous polypeptide; however, their immune response to either (Tyr-Glu)-poly(DLAla)- -poly(Lys) or (Tyr-Tyr-Glu-Glu)-poly(DLAla)- -poly(Lys) was not affected. Mice that were tolerant to (Tyr-Tyr-Glu-Glu)-poly(DLAla)- -poly(Lys) responded well to (Tyr-Glu-Tyr-Glu)-poly(DLAla)- -poly(Lys). Furthermore, these mice produced high antibody titers after immunization with the random (Tyr,Glu)-poly(DLAla)- -poly(Lys). However, the antibodies produced were not specific to the major determinant of (Tyr,Glu)-poly(DLAla)- -poly(Lys), namely, Tyr-Tyr-Glu-Glu, but were directed to minor determinants of the random polypeptide, including Tyr-Glu-Tyr-Glu, which are not immunopotent when nontolerant mice are immunized with (Tyr,Glu)-poly(DLAla)- -poly(Lys). Thus, whereas antigenic specificity reflects itself also at the level of tolerance induction, the animals that had been made tolerant are capable of responding to previously silent antigenic determinants.