Page 244 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 15 Immunoglobulin Function 225

Ag Ag Ag

Ag
Ab
Ab Ab

A Monovalent B Monogamous Cross-linking
binding bivalent binding C (bivalent) binding
FIG 15.2 Interaction of a Bivalent Antibody, Such as Immunoglobulin G (IgG), With Multivalent
Antigens Can Result in Monogamous Bivalent Binding (B) or Cross-Linking (C). The complexes
in (B) are referred to as cyclic antibody–antigen complexes. With permission from Eisen HN.
General immunology. J. B. Lippincott Company; 1990.

virus; however, conformational changes following antibody and evaluated relative to a specified set of ligands. Thus one
binding may expose these epitopes for neutralization by other should be cautious about extrapolating claims that one antibody
antibodies. is more or less specific than another antibody without any refer-
ence to the relevant universe of ligands. However, there are
practical cases where it is justifiable to speak globally of more-or
KEY CoNCEPtS less-specific antibodies. Polyspecific antibodies have been
5
Binding of Antibody to Antigen described in the neonatal primary repertoire. These antibodies
appear to be globally less discriminating than antibodies typical
• Paratopes interact with epitopes through multiple noncovalent (weak) of the immune repertoire (secondary or later response) when
bonds, each of which is reversible at room temperature. tested on large panels of antigens.
• For the clinician, immunological specificity needs to be viewed in its Nevertheless, it is important to note that even antibodies
biological rather than physical context. derived from secondary (or later) responses are not, and cannot
6
• Intrinsic affinity and functional affinity both refer to the strength of be, absolutely specific. The impossibility of perfect recognition
2
antigen–antibody interactions but often play separate roles in the
biology of that interaction. or discrimination can be understood in both thermodynamic
• Intrinsic affinity measures the strength of the interaction between a and structural terms. First, perfect fit and absolute discrimination
monovalent epitope and the paratope on the antibody. This can be would imply infinite intrinsic affinity (negative free energy change
2
determined by the equilibrium association constant. Intrinsic affinity of complex formation), which is not physically plausible. Second,
is influenced both by the degree of complementarity between the the convexity of atoms prevents perfect shape complementarity
epitope and the paratope and by ambient conditions, including the between antibody (receptor) and antigen (ligand). Recent results
2
temperature, pressure, ionic strength, and pH.
• Functional affinity is a measure of the average strength of the interaction also indicate that at least some antibodies can adopt two or more
between a multivalent antigen and an intact antibody. It is influenced different unbound conformations, each of which exhibits a
by the spatial relationships characterizing the epitopes that are being different ligand-binding profile. Such paratopes may undergo
recognized as well as the physical properties of both the underlying further structural adjustment in the process of binding to an
substrate and the antibody. epitope. This property can be advantageous to the function of
7
an antibody. Antibodies that react with multiple conformations
of a viral surface antigen may be much more likely to interfere
IMMUNOLOGICAL SPECIFICITY with viral infection because they can bind more rapidly to the
virus than the virus can bind to its receptor, as demonstrated
The concept of specificity is fundamental to an understanding for HIV. 8
of the nature and consequences of interactions between immu- Whereas the first two aspects of specificity focused on the
nological receptors and antigens. However, in the immunological epitope, a third relates to the ability of an antibody to discriminate
context, the term specificity encompasses multiple different among antigens that display multiple copies of one or more
aspects. 2 distinct epitopes. An antigen expressing many copies of one
One aspect of specificity focuses on the goodness of fit between epitope is termed multivalent, and an antigen that expresses
the paratope and the epitope. Intrinsic affinity is regarded as a two or more structurally distinguishable epitopes is referred to
reasonable measure of this goodness of fit. However, substantial as multideterminant (see Table 15.1). Because two different cells,
conformational adjustments of either the paratope or the epitope bacteria, viruses, and so on may both express multiple copies of
4
may be necessary for formation of the complex. Such confor- the same or nearly the same epitope, an antibody that is highly
mational changes will generally incur energetic costs. Conse- specific (in the first aspect above) for such a shared epitope may
2
quently, intrinsic affinity and final complementarity may not be be a poor discriminator between such multivalent particles. Yet,
perfectly correlated. an antibody with a relatively poor degree of complementarity
A second aspect of specificity focuses on the ability of a and intrinsic affinity for an epitope found on only one of two or
paratope to distinguish among different epitopes. Such specificity more multivalent targets may be superior at discriminating among
is most readily studied when the epitope is in monovalent form these antigens. Furthermore, antibodies (or other molecules)