Functional idiotypic mimicry of an adhesion- and differentiation-promoting site on acetylcholinesterase.

Acetylcholinesterase mediates cell adhesion and neurite outgrowth through a site associated with the peripheral anionic site (PAS). Monoclonal antibodies raised to this site block cell adhesion. We have raised anti-idiotypic antibodies to one of these antibodies. The anti-idiotypic antibodies recognized the immunogenic antibody and non-specific mouse IgG, but not acetylcholinesterase. Five antibodies (out of 143 clones, an incidence of 3.5%) were able to promote neurite outgrowth in human neuroblastoma cells in vitro in a similar manner to acetylcholinesterase itself, suggesting that these antibodies carry an internal image of the neuritogenic site. Two of the antibodies were significantly more effective (P < 0.01) than acetylcholinesterase in this regard. The antibodies also bound specifically to mouse laminin-1 and human collagen IV, as does acetylcholinesterase. This binding was displaced by unlabelled antibody, as well as by acetylcholinesterase itself, indicating competition with acetylcholinesterase. We have also investigated the development of anti-anti-idiotypic antibodies in mice in vivo, and have observed that four of these (out of 318 clones, an incidence of 1.26%) mimic the idiotypic antibody and abrogate adhesion in neuroblastoma cells. We have thus demonstrated functional mimicry of the neuritogenic site on acetylcholinesterase in anti-idiotypic antibodies, enhancement of this activity in one antibody, and mimicry of the idiotypic antibody site in anti-anti-idiotypic antibodies. Implications of these findings for differentiation-promoting cancer therapy are discussed. Copyright 2004 Wiley-Liss, Inc.