The regulatory idiotope concept originated from an immunochemical analysis of four members of an idiotypic network pathway initiated by ABPC-48 (A48), a monoclonal protein with/32-6 fructosan binding activity. By studying polyclonal populations

We recently proposed that a special category of idiotopes called regulatory idiotopes play an important role in idiotype-driven events in an autologous system (1, 2). Regulatory idiotopes are defined by three criteria: the ability to function as autoimmunogens, the potential to become dominantly expressed because they are recognized by regulatory T cells, and their shared expression by antibodies with different antigenic specificities (3). The regulatory idiotope concept originated from an immunochemical analysis of four members of an idiotypic network pathway initiated by ABPC-48 (A48), a monoclonal protein with/32-6 fructosan binding activity. By studying polyclonal populations of syngeneic Ab2 (anti-Id), Ab3 [anti(anti-Id)], and Ab4 (anti[anti(antiId)]) antibodies, we found that Ab3 antibodies share A48 idiotopes because Ab2 and Ab4 bind to both A48 and Ab~ antibodies (1). To explain these results, we proposed that Abl antibodies bear a special set of idiotopes which are immunogenic in an autologous system and which elicit the production of Abe. Parenteral administration of these Ab2 antibodies would lead to the activation of Ab~ clones that express mainly these regulatory idiotopes. Hence, the immunization with Ab3 antibodies would lead primarily to the production of anti-regulatory idiotope antibodies. This concept suggests that, through such an "idiotype cascade immunization," clones with the predicted idiotopes are activated. A corollary is that those clones activated by anti-Id antibodies will display the same antigen specificity as the Abl which initiated the cascade. Furthermore, the idiotypes borne by such clones may be phenotypic markers of the same germline heavy chain variable region (VH) 1 gene from which is derived the VH genes encoding the specificity of these antibodies. This last characteristic represents an important trait that differen-