Characterization of anti-anti-idiotypic antibodies that bind antigen and an anti-idiotype

Abstract

Two mouse monoclonal anti-anti-idiotopic antibodies (anti-anti-Id, Ab3), AF14 and AF52, were prepared by immunizing BALB͞c mice with rabbit polyclonal antiidiotypic antibodies (anti-Id, Ab2) raised against antibody D1.3 (Ab1) specific for the antigen hen egg lysozyme. AF14 and AF52 react with an ''internal image'' monoclonal mouse anti-Id antibody E5.2 (Ab2), previously raised against D1.3, with affinity constants (1.0 ؋ 10 9 M ؊1 and 2.4 ؋ 10 7 M ؊1 , respectively) usually observed in secondary responses against protein antigens. They also react with the antigen but with lower affinity (1.8 ؋ 10 6 M ؊1 and 3.8 ؋ 10 6 M ؊1 ). This pattern of affinities for the anti-Id and for the antigen also was displayed by the sera of the immunized mice. The amino acid sequences of AF14 and AF52 are very close to that of D1.3. In particular, the amino acid side chains that contribute to contacts with both antigen and anti-Id are largely conserved in AF14 and AF52 compared with D1.3. Therapeutic immunizations against different pathogenic antigens using anti-Id antibodies have been proposed. Our experiments show that a response to an anti-Id immunogen elicits anti-anti-Id antibodies that are optimized for binding the anti-Id antibodies rather than the antigen.The complementarity determining regions (CDR) of Ab display great structural diversity and constitute a vast array of potential antigenic determinants. Under appropriate experimental conditions, these determinants give rise to immune responses and are called idiotypic (1, 2). Idiotypes of Ab are the sum of idiotopes (Id) or antigenic determinants characterized experimentally by the reaction of an anti-idiotopic (anti-Id) antibody (Ab2) with the Id (Ab1). In most cases, idiotypes have been shown to be associated, partially or entirely, with the CDR of Ab molecules (3).The observation that external antigens and anti-Id Ab can competitively bind to specific Ab has led to proposals that anti-Id Ab may carry an ''internal image'' (2) of the external antigen. Functional mimicry of ligands of biological receptors by anti-Id Ab has been described in several systems (4). The potential for mimicking external antigens has led to proposals (5, 6) to use anti-idiotypic Ab as surrogate antigens. Recent reviews (7-9) have discussed this topic from a structural viewpoint. Indeed, anti-Id Ab have been used in exploring therapeutic immunizations against different pathogenic antigens.A report from this laboratory compared the threedimensional structures of the complexes between an Ab1-antigen and an Ab1-anti-Id and provided a concrete example of how an anti-Id Ab can structurally mimic an external antigen (10, 11). In this system, the Ab1 was the mAb D1.3 specific for the antigen, hen egg lysozyme (HEL). The three-dimensional crystal structure of the complex between the Fv fragment of D1.3 with HEL has been determined at the resolution of 1.8 Å (12). Subsequently, the three-dimensional structure of a complex between the Fv from D1.3 and the anti-Id Fv from mAb E5.2 (the Ab2; BALB͞c I...

Homology of ab1 and ab3 Monoclonal Antibodies That Neutralize Semliki Forest Virus

“…In the GAT (Glu 60 Ala 30 Tyr 10 ) model similar observations are noticed: ab1 and idiotype/antigen positive ab3 antibodies also display restrictive variation, and moreover, are encoded by the same V H genes (4). Similar observations were made with ab1 and ab3 mAbs against the branched synthetic polypeptide antigen poly-L-(Tyr,Glu)-poly-D,L-(Ala)-poly-L-(lys), designated (T,G)-A-L and egg lysozyme (6,18). Their models, however, are presumably based on an internal image type of the anti-idiotypic antibody, whereas ab2 mAb A321 is unequivocally of a noninternal image character (11).…”

Perpetuation of immunological memory: a relay hypothesis

“…However, the idiopeptide of the antibody loaded onto the MHC class I, if similar to the antigen‐derived peptide, will generate T‐cell memory by keeping CD8 + cells at elevated frequencies with cycles of proliferation. Recently, it has been shown that CDR3 regions of anti antibody have a stretch of amino acids which are similar to the antigen 27,28 . It may be noted here that CD8 + T‐cell and B‐cell populations will exhibit an inverse relationship similar to a predator–prey relationship found in an ecosystem.…”

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

“…We have previously described idiotypic mimicry of MAb E8 in antianti-idiotypic Abs [Johnson and Moore, 2002]: it was interesting that, in the catalytic mimics, while there were obvious similarities in function (ester hydrolysis), there appeared to be significant differences in the active site structures, as deduced from their kinetic behavior and reaction with different substrates and inhibitors. The crystallographic structures of a number of antigen-anti-Id combinations have been solved; it is noteworthy that in no cases were the anti-idiotypic antibodies internal images replicas of the antigenic sites [e.g., Fields et al, 1995;Goldbaum et al, 1997]. Instead, considerable structural variation was found, in some cases with little or no sequence identity.…”