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Immunoglobulin Function

Neil S. Greenspan, Lisa A. Cavacini

Antibody-mediated immunity generally requires noncovalent usually confer a high degree of specificity. For example, any two
contact between an antibody and the antigen (Chapters 4 and atoms can interact through van der Waals forces. It is only through
6). The ability of an antigen to bind noncovalently to an antibody, the simultaneous action of many such bonds that molecular
termed antigenicity, is a physical–chemical property that is specificity arises. Hence, the importance of a close fit, often
evaluated with respect to a given antibody population. In contrast, referred to as complementarity, between the epitope and the
immunogenicity, the ability to induce the biosynthesis and secre- paratope.
tion of soluble antibody molecules, is a biological property. Thus Complementarity can be maximized by matching the physical–
its measurement requires in vivo studies. Although antigenicity chemical properties of the epitope and the paratope. For example,
is necessary for immunogenicity (as defined by the production binding can be facilitated when one molecule is concave and
of antibodies), it is not sufficient. Moreover, the immunogenicity the other is convex, when one molecule is positively charged
of a given molecule or molecular complex is influenced by host and the other is negatively charged, or when one molecule is a
genetic variation. When an antibody binds to a macromolecular hydrogen bond donor whereas the other offers a hydrogen bond
antigen, it directly contacts only a portion of the molecular surface acceptor. It is expected that the greater the complementarity
of that antigen. Similarly, only a portion of the antibody molecule between receptor and ligand, the stronger is the interaction
makes direct contact with the antigen. By convention, the portion (greater affinity) between the two molecules. Specificity (see
2
of an antibody or T-cell receptor (TCR) that makes physical below) is also expected to be influenced by complementarity. In
contact with an antigen is referred to as the paratope or combining rationalizing the strength of interactions between antibodies and
site. Conversely, the region of the antigen in physical contact antigens, it is important to remember that the antibody competes
with the paratope, the antigenic determinant, is termed the epitope. with solvent for binding to antigen. The thermodynamics of the
Most of the amino acids in an antibody variable domain that interaction between these two structures reflects the influence of
contact a given antigen are located in the hypervariable regions the interaction on the solvent and other solutes. Moreover, bound
(also termed complementarity determining regions [CDRs]). water molecules may make important, even crucial, contributions
However, X-ray crystallographic analyses of antibody–protein to an interaction between two biomolecules.
antigen complexes have shown that contact residues can reside Antibody recognition of antigen serves as a paradigm for
1
in the framework regions as well. understanding molecular recognition in the immune system and
Although an epitope (paratope, etc.) is usually defined in biology in general. As will be discussed below, this fact, coupled
in terms of intermolecular contact, the region of a molecule with the inducibility of antibodies, permits them to be used as
involved in physical contact with another molecule may not surrogate ligands for almost any receptor (and vice versa).
correspond exactly to the structural correlates for energetics and Affinity is the concept used to convey how strongly two
specificity. 2 molecules bind to each other. Antibody–antigen interactions
can be categorized with respect to the numbers of different kinds
ANTIGEN BINDING AND MOLECULAR IDENTITY of paratope–epitope bonds and the absolute number of such
bonds of each kind (Table 15.1). Reflecting the different types
Physical Aspects of Binding of antibody–antigen interaction, two categories of affinity merit
Antibody–antigen interactions are, with rare exceptions, non- consideration: intrinsic affinity and functional affinity. It should
covalent. This fact is significant in that these interactions are, in be noted that some immunologists use the term “avidity” in
principle, spontaneously reversible under the conditions of place of “functional affinity.”
temperature, pressure, pH, and ionic strength that generally Intrinsic affinity is a measure of the strength of the monovalent
prevail in living organisms. interaction between a particular paratope and a particular epitope
Several types of noncovalent bonds have been shown to under defined conditions of temperature, pressure, ionic strength,
contribute to antibody–antigen binding. These include van der and pH (Fig. 15.1). By convention, the intrinsic affinity is taken
Waals forces, hydrogen bonds, ionic bonds, and hydrophobic to be the equilibrium association constant characterizing the
interactions. Individually the strength of these bonds is in the paratope–epitope pair. It is the reciprocal of the concentration
range of one to a few kilocalories per mole (kcal/mole), versus of monovalent antigen at which half of the paratopes will be
50–100 kcal/mole for covalent bonds. Since the potential to engage occupied. It is not an intrinsic property of either the paratope
in these types of bonds is shared by many of the components or the epitope, but rather intrinsic affinity characterizes the
of biological macromolecules, individual weak bonds do not relationship between two molecules under defined conditions.

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