Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

B CELLS AND IMMUNOGLOBULINS
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VDJ Cµ Cδ Cγ Cε Cα
5′ 3′
DNA
switch sequence
Cδ
Cµ Cε
5′ 3′
DNA VDJ
Cα
AID
DNA DELETION BY CUTTING
AND REJOINING OF DNA
Cδ
IN SWITCH SEQUENCES
Cµ Cε
VDJ Cα
5′ 3′
DNA
Cγ
Cγ
deleted
DNA
VDJ
TRANSCRIPTION,
RNA SPLICING,
AND TRANSLATION
VDJ
Cµ
Cα
IgM
IgA
Figure 24–30 An example of the DNA
rearrangement that occurs in class
switch recombination. A B cell making
IgM molecules with a V region encoded
by a particular assembled VDJ DNA
sequence is stimulated to switch to
making IgA molecules with the same
V region. In the process, it deletes the
DNA between the VDJ sequence and
the C α ‐coding sequence. Specific DNA
sequences (switch sequences) located
upstream of each C H ‐coding sequence
(except C δ , as B cells don't switch from
C μ to C δ ) can recombine with one another,
with the deletion of the intervening DNA,
as shown here. As discussed in the text,
the recombination process depends on
AID, the same enzyme that is involved in
somatic hypermutation. When switching
from IgM to IgG or IgE, the C-region coding
sequences downstream of C γ or C δ , which
remain after the DNA deletion, are removed
during RNA splicing.
When a B cell switches from making IgM and IgD to one of the secondary classes
of Ig, an irreversible change occurs in the DNA—a process called class switch
recombination. It entails the deletion MBoC6 m25.41/24.32
of all the C H ‐coding sequences between
the assembled VDJ‐coding sequence and the particular C H ‐coding sequence
that the cell is destined to express. Class switch recombination differs from V(D)J
recombination in several ways. (1) It happens after antigen stimulation, mainly in
germinal centers, and depends on helper T cells. (2) It uses different recombination
signal sequences, called switch sequences, which flank the different C H ‐coding
segments. (3) It involves cutting and joining the switch sequences, which are
noncoding sequences, and leaves the assembled V H -region coding sequence
unchanged (Figure 24–30). (4) Most importantly, the molecular mechanism is
different. It depends on AID, which is also involved in somatic hypermutation,
rather than on the V(D)J recombinase. The cytokines that activate class switching
induce the production of transcription regulators that activate transcription from
the relevant switch sequences, allowing the recruitment of AID to these sites.
Once bound, AID initiates switch recombination by deaminating some cytosines
to uracil in the vicinity of these switch sequences. Excision of these uracils is
thought to lead to double-strand breaks in the participating switch regions, which
are then joined by a form of nonhomologous end joining (discussed in Chapter 5).
Thus, whereas the primary Ig repertoire in humans (and mice) is generated by
V(D)J joining mediated by V(D)J recombinase, the secondary antibody repertoire
is generated by somatic hypermutation and class switch recombination, both of
which are mediated by AID. Figure 24–31 lists the main mechanisms that we have
discussed in this chapter that diversify Igs.
Summary
Each B cell clone makes Ig molecules with a unique antigen-binding site. Initially,
the Ig molecules are inserted into the plasma membrane and serve as B cell receptors
(BCRs) for antigen. Antigen binding to the BCRs, together with co-stimulatory
signals from helper T cells, activates the B cells to proliferate and differentiate into
either memory cells or antibody-secreting effector cells. The effector cells secrete large
amounts of antibodies with the same antigen-binding site as the BCRs.
A typical Ig molecule is composed of four polypeptide chains—two identical
heavy chains and two identical light chains. Parts of both the heavy and light chains
form the two identical antigen-binding sites. There are multiple classes of Ig (IgA,
IgD, IgE, IgG, and IgM), each with a distinctive heavy chain, which determines the
combinatorial
joining of gene
segments
junctional diversification
during genesegment
joining
combinatorial
joining of L and H
chains
somatic hypermutation
+ class switch
recombination
Figure 24–31 The main mechanisms of
Ig diversification in mice and humans.
Those shaded in green occur during B cell
development in the bone marrow, whereas
the two mechanisms shaded in red occur
when B cells are stimulated by foreign
antigen and helper T cells in germinal
centers in peripheral lymphoid organs,
either late in a primary response or in a
MBoC6 m25.42/24.33
secondary response.