Idiotypic study of a bispecific thyroglobulin and thyroperoxidase monoclonal antibody

We have previously established that thyroperoxidase (TPO), a major thyroid antigen involved in autoimmune thyroid diseases, interacts with an idiotype present on human and mouse antibodies directed to thryoglobulin (TG), another thyroid autoantigen. In order to characterize the TPO-reactive idiotype, we selected a TG monoclonal antibody (mAb J7 B49.15) which bound to TPO and cross-reacted with human bispecific TG and TPO autoantibodies (TGPO aAb) for both TG and TPO binding. The TPO-reactive structure of the mAb J7 B49.15 was present on the F(ab')2, located next to the TG binding site and dependent on the association of the heavy and light chains. We found that mAb J7 B49.15 shared a TPO-reactive idiotypic structure with TG mAb from the same cluster of TG reactivity. All the mAb from this cluster were directed to an immunodominant region of TG, recognized by TG aAb. Natural anti-idiotypes from pooled normal human IgG used as a therapeutic intravenous preparation inhibited the TPO binding to mAb J7 B49.15. By homologous immunization in BALB/c mice, mAb J7 B49.15 induced an antiserum with both TG and TPO reactivities. Whereas TG reactivity decreased as early as day 14 post-immunization, TPO reactivity remained at a plateau value from day 21 to day 42. The TG and TPO reactive antisera were shown to inhibit the binding of mAb J7 B49.15 to TG and TPO, respectively. We concluded that mAb J7 B49.15 reacted with TPO through an interspecies idiotype which appeared conformational and related to the epitopic specificity of the mAb. Interestingly, this idiotype would carry the internal image of a TG structure able to induce, in homologous system, a TG antibody response followed by a TPO response without the need of any immunizing antigen.