Anti-ligand antibodies as potential autoantigens: in vitro and in vivo characteristics of anti-bungarotoxin antibodies in the idiotype network.

Some antibodies to ligands of a receptor will have combining sites that structurally resemble the receptor's binding site for that ligand. The network hypothesis predicts that anti-idiotypic antibodies to these anti-ligand antibodies will also bind to the receptor. We pursued these hypotheses in the well-defined ligand-receptor system, alpha-bungarotoxin(BTX)-acetylcholine receptor (AChR). Monoclonal antibodies (mAbs) to BTX were generated; native BTX was used as the immunogen to optimize the probability of obtaining mAbs to the AChR binding site. These mAbs were then characterized for their ability to "mimic" AChR in the following in vitro assays: neutralization of BTX binding to native AChR on the surface of the cell line TE671, formation of a ternary complex with 125BTX-AChR, and ability of cholinergic ligands to interfere with binding to BTX. Three aBTX mAbs which had in vitro attributes of the AChR on the basis of these assays, were injected into C3H mice and serial sera tested for antibodies to Torpedo and murine AChR. Anti-AChR antibodies directed primarily to the gamma and delta subunits of the Torpedo AChR were detected, as well as low amounts of anti-mouse AChR antibody. The generation of anti-AChR antibodies by immunization with aBTX antibodies supports the network hypothesis and provides a theoretical basis for initiation of autoimmunity to cell receptors.