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228 Part two Host Defense Mechanisms and Inflammation

KEY CoNCEPtS
Electron micrographs (above; x 350000) and interpretive Structure–Function Relationships of C H Domains
diagrams (below) of a mouse IgG3 mAb
• Immunoglobulin (Ig) function is influenced by differences in quaternary
HGAC 39 structure and segmental flexibility.
+ Anti- • The hinge region helps control segmental flexibility in IgG
molecules.
• The extended hinge region of IgA1 molecules allow their Fab arms
to range from the “Y” configuration of an IgG or IgA2 to a more open
Idl-2
“T” configuration.
• When interacting with multivalent antigens, IgM molecules can adopt
a dislocated configuration (staple configuration) in which the Fab arms
are bent out of the plane of the Fc regions.

Many features of C H domain structure exhibited by the Ig isotypes
can be understood in the context of this requirement for linkage
Cκ
between antigens and antigen-nonspecific effector molecules.
One property of prime significance for antibody function is
intramolecular mobility, often referred to as segmental flexibility.
Hydrodynamic methods, electron microscopy, X-ray crystal-
lography, and fluorescence polarization have all been used to
evaluate the degree of flexibility exhibited by IgG, IgM, IgA, and
γ3 IgE molecules. In the case of the best-studied isotype, IgG, it is
clear that the structural feature most associated with relative
motion of one subunit relative to another is the hinge, which
connects the C H 1 domain to the C H 2 domain and is encoded by
a separate exon. The human IgG3 subclass has an extended hinge
region that can impart increased flexibility. In the case of IgA,
FIG 15.4 Antigen–Antibody Interactions. Electron micrographs the IgA1 hinge is flexible such that the F(ab) arms can range
(above; × 350 000) and interpretive diagrams (below) of a mouse from the typical “Y” configuration to a “T” configuration whereas
immunoglobulin G3 (IgG3) monoclonal antibody (mAb) (HGAC IgA2 molecules are relatively constrained.
39, which is specific for a bacterial polysaccharide) in complex Ig flexibility has important functional consequences for the
with mAbs specific for an idiotope (IdI-2, top), a light chain antibody. First, inter-F(ab) movements can play an important
isotypic determinant (Cκ, middle), and a heavy chain isotypic role in permitting antibodies to bind in monogamous bivalent
determinant (γ3; bottom), respectively. The different antibodies (or multivalent) fashion to antigenic surfaces that display repetitive
are not intrinsically distinguishable in the electron micrographs, epitopes. Second, efficiency in precipitation of multivalent antigen
but the interpretations take into account information in addition molecules or agglutination of multivalent antigen particles can
to that provided directly by the electron microscopic images. In be correlated with inter-F(ab) flexibility. And, third, optimal
the top series of micrographs, the choice of which molecules interactions of effector molecules with IgG antibody Fc regions
to represent as solid or dotted figures is arbitrary. With permission has been postulated to depend on the ability of the Fc region
from Greenspan NS. Analyzing immunoglobulin functional anatomy to bend out of the plane of the F(ab) arms (dislocation) (but see
with monoclonal antiimmunoglobulin antibodies. BioTechniques discussion on complement activation below).
1989;7:1086.
FUNCTIONS MEDIATED BY ANTIBODY ALONE
(Chapter 4). The molecular events underlying these immuno- Although it is clear that in many in vivo situations antibodies
regulatory effects are being intensively studied, and they have mediate their effects with the aid of other molecules and, in
been exploited clinically for many years. For example, antibody to selected cases, cells (see next section), there are circumstances
the erythrocyte Rh antigens is used to prevent immunization of where the antibody can influence antigenic targets directly, at
an Rh-negative mother by an Rh-positive fetus, thereby avoiding least in vitro. The very name “antibody” implies the negation of
hemolytic disease of the newborn in a subsequent Rh-positive some activity, and antibodies were first defined as factors that
fetus. could inactivate or neutralize toxins. Subsequent studies have
shown inactivation of viruses, parasites, and enzymes, as well.
CORRELATIONS BETWEEN C H REGION STRUCTURE
AND ANTIBODY FUNCTION Virus Neutralization
A phenomenon of fundamental medical and biological impor-
14
Antibodies are heterodimeric proteins that can be functionally tance is the neutralization of viruses by antibodies. Although
divided into variable domains, which bind antigen, and constant neutralization is defined as the elimination or reduction of
domains, which define the effector function of the Ig (Chapter the virus’s ability to replicate, it does not imply a particular
4). This dual function allows an antibody to physically link a mechanism of interference with the process of replication.
specific antigen to a separate antigen-nonspecific effector molecule, Moreover, the measurement of neutralization can depend on
such as a component of complement or a cell-bound Fc receptor. the choice of host cell. Thus the neutralizing activity of a given