Crystal structure of secreted IgG
78 CHAPTER 4 Antigen Recognition in the Adaptive Immune System
The C-terminal end of the heavy chain may be anchored
the antibody is produced as a secreted protein. Light chains
in Ig molecules are not directly attached to cell membranes.
There are five types of Ig heavy chains, called µ, d, ?, e,
and a, which differ in their C regions; in humans, there
are four subtypes of ? chain, called ?1, ?2, ?3, ?4, and two
of the a chain, called a1 and a2. Antibodies that contain
(IgM, IgD, IgG, IgE, and IgA). Each isotype has distinct
physical and biologic properties and effector functions
(Fig. 4.3). The IgG subtypes also differ from one another
in functional properties, but the IgA subtypes do not.
The antigen receptors of naive B lymphocytes, which are
mature B cells that have not encountered antigen, are
that secrete antibodies. Some of the progeny of IgM and
heavy-chain classes. This change in Ig isotype production
is called heavy-chain class (or isotype) switching; its
mechanism and importance are discussed in Chapter 7.
The two types of light chains, called ? and ?, differ in
their C regions. Each antibody has only ? or ? light chains,
but not both, and all the antibodies made by any B cell
have the same type of light chain. Each type of light chain
fixed throughout the life of each B cell clone, regardless of
whether or not heavy-chain class switching has occurred.
The function of light chains is to form the antigen-binding
surface of antibodies, along with the heavy chains; light
chains do not participate in effector functions, except
binding and neutralizing microbes and toxins.
Binding of Antigens to Antibodies
Antibodies are capable of binding a wide variety
of antigens, including macromolecules and small
chemicals. The reason for this is that the antigenbinding CDR loops of antibody molecules can either
come together to form clefts capable of accommodating small molecules or form more extended surfaces
capable of accommodating larger molecules (Fig. 4.4).
Antibodies bind to antigens by reversible, noncovalent
interactions, including hydrogen bonds, hydrophobic
interactions, and charge-based interactions. The parts
of antigens that are recognized by antibodies are called
epitopes, or determinants. Some epitopes of protein
antigens may be a contiguous stretch of amino acids
in the primary structure of the protein; these are called
linear epitopes. Sometimes, amino acids that are not
next to one another in the primary structure may be
such determinants are called conformational epitopes.
The strength with which one antigen-binding site of
an antibody binds to one epitope of an antigen is called
the affinity of the interaction. Affinity often is expressed
as the dissociation constant (Kd), which is the molar
concentration of an antigen required to occupy half the
available antibody molecules in a solution; the lower the
Kd, the higher the affinity. Most antibodies produced in
a primary immune response have a Kd in the range of
10-6 to 10-9 M, but with repeated stimulation (e.g., in a
secondary immune response), the affinity increases to a
Kd of 10-8 to 10-11 M. This increase in antigen-binding
strength is called affinity maturation (see Chapter 7).
Each IgG, IgD, and IgE antibody molecule has two
antigen-binding sites. Secreted IgA is a dimer of two
on two or more neighboring antigens. The total strength
of binding is much greater than the affinity of a single
antigen-antibody bond and is called the avidity of the
interaction. Antibodies produced against one antigen
In B lymphocytes, membrane-bound Ig molecules
are noncovalently associated with two other proteins,
called Iga and Igß; these latter proteins combine with
the membrane Ig to make up the BCR complex. When
of B cell activation. These and other signals in humoral
immune responses are discussed in Chapter 7.
CHAPTER 4 Antigen Recognition in the Adaptive Immune System 79
activation, antibodydependent cellmediated cytotoxicity,
80 CHAPTER 4 Antigen Recognition in the Adaptive Immune System
technical advances in immunology, with far-reaching
cells (tumors of plasma cells), which can be propagated
indefinitely in tissue culture (Fig. 4.5). The myeloma cell
line lacks a specific enzyme, as a result of which these
cells cannot grow in the presence of a certain toxic drug;
fused cells, containing both myeloma and normal B cell
nuclei, however, do grow in the presence of this drug
because the normal B cells provide the missing enzyme.
Thus, by fusing the two cell populations and culturing
them with the drug, it is possible to grow out fused cells
that are hybrids of the B cells and the myeloma, and
are called hybridomas. These hybridoma cells produce
antibodies, like normal B cells, but grow continuously,
having acquired the immortal property of the myeloma
tumor. From a population of hybridomas, one can select
and expand individual cells that secrete the antibody of
on any antigen can be produced using this technology.
Most monoclonal antibodies to molecules of interest
are made by fusing cells from mice immunized with that
antigen with mouse myelomas. Such mouse monoclonal
Ig as foreign and mounts an immune response against
the injected antibodies. This problem has been partially
overcome by genetic engineering approaches that retain
the antigen-binding V regions of the mouse monoclonal
antibody and replace the rest of the antibody with human
Ig; such humanized antibodies are less immunogenic and
more suitable for administration to people. More recently,
monoclonal antibodies have been generated by using
recombinant DNA technology to clone the DNA encoding
human antibodies of desired specificity. Another approach
is to replace the Ig genes of mice with human antibody
genes and then immunize these mice with an antigen to
diagnostic reagents for many diseases in humans (Fig. 4.6).
chain, each chain containing one variable (V) region
and one constant (C) region (Fig. 4.7). The V and C
regions are homologous to immunoglobulin V and C
regions. In the V region of each TCR chain, there are
three hypervariable, or complementarity-determining,
regions, each corresponding to a loop in the V domain.
As in antibodies, CDR3 is the most variable among different TCRs.
Antigen Recognition by the T Cell Receptor
Both the a chain and the ß chain of the TCR participate in specific recognition of MHC molecules and
bound peptides (Fig. 4.8). One of the features of T cell
complexes is that each TCR interacts with as few as one
to three amino acid residues of the MHC-associated
peptide, and also interacts with the MHC molecule presenting the peptide.
The TCR recognizes antigen, but as with membrane
Ig on B cells, it is incapable of transmitting signals to
the T cell on its own. Associated with the TCR is a
group of proteins, called the CD3 and ? proteins, which
together with the TCR make up the TCR complex (see
In addition, T cell activation requires engagement of
the coreceptor molecule CD4 or CD8, which recognize
Fig. 4.4 Binding of an antigen by an antibody. This model
of a protein antigen bound to an antibody molecule shows how
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