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Structural Basis of Antibody Specificity

AbstractAntibodies carry out two major functions in the immune response: 1) they bind to a great variety of sterically different antigen molecules (antigen-binding function or ABF); and 2) they mediate essential immune reactions within the organism, such as complement fixation (effector functions or EF). The ABF is selective, i.e. the information for synthesizing antibodies to a large range of chemically different antigens already exists in the organism before exposure to these antigens. Particular antigens serve only to stimulate (and thereby select) those antibody-forming cells that synthesize antibodies having appropriately complementary antigen-binding sites. This process requires that the number of sites must greatly exceed the number of different antigens. Furthermore, there must be an exceedingly efficient system for amplifying the production of specific antibodies after stimulation by injection of a particular antigen. This appears to be achieved by maturation and cell division of stimulated cells, each of which synthesizes only one kind of antibody. Division and maturation are followed by an increased synthesis of that particular antibody by the clonal progeny of the stimulated cell.Studies of the molecular structure of antibodies or immunoglobulins have been useful in an analysis of some of the mechanisms of the selective immune response. The covalent structure of an entire γG immunoglobulin (molecular weight 150,000) has been determined and compared with portions of other immunoglobulin molecules analyzed by other workers. The light and heavy polypeptide chains of the molecule each consists of a variable, or V, region for antigen binding and a constant, or C, region for effector functions. The amino-acid sequences of V regions differ from molecule to molecule, whereas the sequence of C regions is relatively invariant. The mechanism by which diversification of amino- acid sequence is achieved in antibody V regions has not been established, but several theories on the origin of diversity have been proposed and will be reviewed.The amino-acid sequence of γG immunoglobulin shows a linear periodic arrangement which suggests the evolutionary origin of the molecule by gene duplication. It is proposed that the molecule is arranged in successive compact domains organized about axes of symmetry and pseudosymmetry. According to this proposal, domains of V regions mediate antigen binding, and successive domains of the C regions mediate different effector functions. This is in accord with the hypothesis that the antibody molecule evolved from two genes, V and C, each of which underwent successive duplication.The analysis of antibody structure suggests the possibility that a number of unusual genetic mechanisms may be required to account for the evolution of selective recognition systems. Evidence from several laboratories has led to the conclusion that each polypeptide chain is specified by a V gene and a C gene. It is suggested that the V gene may be translocated in the lymphoid cell to form a single VC gene. Translocation could account for the clonal nature of the selective response, for, although each cell may have information for many V sequences, genetic analysis indicates that it has at most only two C genes for each chain. Translocation would commit the cell to the expression of the smallest possible number of antibody chains and help to maintain the specificity and efficiency of the selective immune response.