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

MBoC6 m25.37/24.31
B CELLS AND IMMUNOGLOBULINS
1321
5′
germ-line DNA
V1
V2
V3
regions of DNA to be joined
V~35
J1 J2
J3 J4
5′ 3′
B cell DNA
V1
V2 V3 C
J3 J4 J5
J5
5′ 3′
RNA transcript
V3 C
J3 J4 J5
5′ 3′
mRNA
V3 J3 C
C
TRANSCRIPTION
RNA SPLICING
3′
DNA REARRANGEMENT
DURING B CELL
DEVELOPMENT
Figure 24–28 The V–J joining process
involved in making a human
κ light chain. In the “germ-line” DNA
(where the Ig gene segments are not
rearranged and are therefore not being
expressed), the cluster of five J gene
segments is separated from the C‐region
coding sequence by a short intron and from
the 35 or so functional V gene segments
by thousands of nucleotide pairs. During
the development of a B cell, a randomly
chosen V gene segment (V3 in this case)
is moved to lie precisely next to one of the
J gene segments (J3 in this case). The
“extra” J gene segments (J4 and J5) and
the intron sequence are transcribed (along
with the joined V3 and J3 gene segments
and the C‐region coding sequence) and
then removed by RNA splicing to generate
mRNA molecules with contiguous V3,
J3, and C sequences, as shown. These
mRNAs are then translated into κ light
chains. A J gene segment encodes the
15 or so C‐terminal amino acids of the
V region, and a short sequence containing
the V–J segment junction encodes the third
hypervariable region, which is the most
variable part of the light-chain V region.
TRANSLATION
NH 2
COOH
light chain
V3 J3 C
chosen nucleotides are also inserted. This random loss and gain of nucleotides
at joining sites is called junctional diversification, and it enormously increases
the diversity of V‐region coding sequences created by V(D)J recombination (up
to about 10 8 ‐fold), specifically in the third hypervariable region. This increased
diversification comes at a price, however. In many cases, it shifts the reading frame
to produce a nonfunctional gene, in which case the developing B cell fails to make
a functional Ig molecule and consequently MBoC6 m25.36/24.30
dies in the bone marrow. Once a B cell
makes a functional heavy chain and light chain that form an antigen-binding site, it
turns off the V(D)J recombination process, thereby ensuring that the cell makes Ig of
only one antigen-binding specificity.
B cells making BCRs that bind strongly to self antigens in the bone marrow
would be dangerous. Such B cells maintain expression of an active V(D)J recombinase
and are activated by such self-binding to undergo a second round of
V(D)J recombination in a light-chain locus, thereby changing the specificity of its
BCR—the process of receptor editing discussed earlier; self-reactive B cells that
fail to change their specificity die by apoptosis, in the process of clonal deletion
(see Figure 24–21).
Antigen-Driven Somatic Hypermutation Fine-Tunes Antibody
Responses
As mentioned earlier, with the passage of time following an infection or vaccination,
there is usually a progressive increase in the affinity of the antibodies produced
against the pathogen. This phenomenon of affinity maturation is due to
5′
V1 V2 V40 D1 D2 D~23 J1 J6 Cµ Cδ Cγ Cε Cα
germ-line DNA
3′
Figure 24–29 The human heavy-chain
locus. There are 40 V segments, about 23
D segments, 6 J segments, and an ordered
cluster of C‐region coding sequences,
each cluster encoding a different class
of heavy chain. The D segment (and part
of the J segment) encodes amino acids
in the third hypervariable region, which
is the most variable part of the heavychain
V region. The genetic mechanisms
involved in producing a heavy chain
are the same as those shown in Figure
24–28 for light chains, except that two
DNA rearrangement steps are required
instead of one: first a D segment joins
to a J segment, and then a V segment
joins to the rearranged DJ segment. The
rearrangements lead to the production of
a VDJC mRNA that encodes a complete
Ig heavy chain. The figure is not drawn to
scale: the total length of the heavy-chain
locus is over two megabases. Moreover, a
number of details are omitted: for example,
the exons encoding each C-region Ig
domain and the hinge region (see Figure
24–27) and the different subclasses of
C γ ‐coding segments are not shown.