MOLECULAR-BASIS OF ANTIGEN MIMICRY BY AN ANTI-IDIOTOPE

IDIOTOPES are antigenic determinants, unique to an antibody or group o f antibodies, defined by the reaction of anti-idiotopic antibodies wit h the antibodies bearing the idiotopes. The ensemble of idiotopes of a n antibody constitutes its idiotype. Idiotypes are useful as markers t o follow specific antibodies and clones of cells in immune responses a nd the inheritance of immunoglobulin genes. As external antigens and a nti-idiotypic antibodies can competitively bind the combining site of specific antibodies, some antiidiotypic antibodies may resemble the ex ternal antigen, thus mimicking its structure. It has been proposed(1-5 ) that an anti-idiotypic antibody, anti-anti-X, may resemble the exter nal antigen X and thus carry its 'internal image', but this idea is no t unequivocally supported by the three-dimensional structures of anti- idiotopic antibodies(6-9), either because the structures of the extern al antigen(8) or of the anti-idiotopic antibody(7) were unknown, or be cause the anti-idiotopic antibodies showed no resemblance to the exter nal antigens(6,9) (reviewed in ref. 10). Functional mimicry of ligands of biological receptors by anti-idiotypic antibodies has been describ ed in several systems (reviewed in ref. 11). But how closely can antib odies mimic antigens at the molecular level? Here we present the cryst al structure of an idiotope-anti-idiotope complex between the Fv fragm ents of the anti-lysozyme antibody D1.3 and the anti-D1.3 antibody E5. 2. D1.3 contacts the antigen, lysozyme and the anti-idiotopic E5.2 thr ough essentially the same combining-site residues, In addition, E5.2 i nteracts with D1.3, making contacts similar to those between lysozyme and D1.3. Thus, the anti-idiotopic antibody E5.2 mimics lysozyme in it s binding interactions with D1.3. Validating these observations, E5.2, used as an immunogen, induces an anti-lysozyme response.