Thyroglobulin monoclonal antibody cross-reacting with thyroperoxidase induces in syngeneic mice anti-idiotypic monoclonal antibodies with dual autoantigen binding properties. The intertope hypothesis

Autoimmune thyroid diseases are characterized by antibodies (Ab) directed t o thyroglobulin (Tg) and thyroperoxidase (TPO). Some of them, TGPO Ab, are Tg Ab with an interspecies idiotype (Id) reacting with TPO. Taking advantag e of a carefully studied TGPO monoclonal antibody (mAb), we examined the ba sis of the hypothesis that TPO Ab would ultimately derive from TGPO Ab thro ugh idiotypic induction. We repeatedly immunized naive, syngeneic mice with the TGPO mAb and we derived three novel mAb directed to both Tg and TPO. T he most reactive of them, mAb 4F8, was further purified, radiolabeled and i ts binding properties studied by radioimmunoassay. mAb 4F8 bound to Tg, TPO , the immunogen Ab(1) and even to itself, being thus considered as a self-b inding Ab(2). Competitive binding inhibition experiments demonstrated that Tg, TPO, Ab(1) and Ab(2) cross-reacted for Ptb, binding to Tg, TPO and Ab(2 ). Fine specificity mapping using panels of specific mAb revealed that Ab(1 ) and Ab(2) were similar because they were directed against the same immuno dominant regions on Tg and TPO. We propose that unique Id of TGPO Ab resemb le dominant epitopes of Tg as well as paratopes of Ab directed against domi nant TPO epitopes. This category of Id that we called intertopes may induce TPO-monospecific Ab from TGPO Ab by idiotypically driven somatic mutations .