Perspectives on antigenicity and idiotypy.
The recent crystal determination of a lysozyme-antilysozyme complex provides a three-dimensional prototype of the manner in which contacts in idiotype-anti-idiotype interactions may be realized. Such interactions can be approximated by two complementary "flat" surfaces. Each IDR (autoantigenic locus) location might provide a particular recognition feature between two interacting partners. The combinatorial manner in which IDR domains are recognized by anti-idiotypic antibodies describe the repertoire of private and public (crossreactive) idiotopes of an antibody. Several interesting features emerge from consideration of the Ab contact residues in the crystal structure. First, framework residues are implicated in contacting the antigen: Thr 30 (FR1) of the heavy chain and Tyr 49 (FR2) of the kappa light chain. Both of these residues lie within predicted IDRs. Framework regions have recently been suggested to be involved in several anti-idiotypic systems, although such regions have, in the past, been disregarded based solely upon sequence analysis. The surface variability analysis, which identifies the repertoire of complementary interacting surfaces, depicts the immunoglobulin as having more variability than generally thought. This variability may also extend to T cell receptors since T cell chains express an extensive surface variable repertoire similar to that of the immunoglobulin light chains (Kieber-Emmons and Köhler, unpublished). Second, the D region plays a critical role in the generation of the antilysozyme combining sites. Similarly, the D segment makes up the largest component of an IDR. Third, while the CDR3 of the heavy chain contributes most to the antibody-lysozyme complex it is not the most surface-exposed (see Novotny, this issue). Nevertheless, surface variability analysis indicates that this region is generally immunodominant which is also observed experimentally. Together, these results indicate that perhaps certain IDR regions are intrinsically more antigenic. Idiotypic structures must be accessible for antibody recognition and binding. From a structural viewpoint, a single antibody molecule has a continuum or several different combining sites. Subsequently, a single residue can be contained in several overlapping idiotypic determinants. Surface variability analysis suggests that the hypervariable regions of Igs provide a diverse idiotope repertoire that can be utilized for binding. Monoclonal antibodies have been shown to have multiple specificities and this capacity for multiple binding is also intrinsic to the definitions that have emerged for anti-idiotypic antibodies.(ABSTRACT TRUNCATED AT 400 WORDS)
Kieber-Emmons
T
T
Department of Molecular Immunology, Roswell Park Memorial Institute, Buffalo, NY 14263.
Getzoff
E
E
Köhler
H
H
D000595:Amino Acid Sequence; D000941:Antigens / Q000276:immunology*; D007130:Immunoglobulin Idiotypes / Q000737:chemistry / Q000276:immunology*; D007135:Immunoglobulin Variable Region / Q000737:chemistry; D008969:Molecular Sequence Data; D011487:Protein Conformation; D012689:Sequence Homology, Nucleic Acid
D000941:Antigens; D007130:Immunoglobulin Idiotypes; D007135:Immunoglobulin Variable Region