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

1322 Chapter 24: The Innate and Adaptive Immune Systems
the accumulation of point mutations in both heavy-chain and light-chain V‐region
coding sequences. The mutations occur long after the coding regions have
been assembled. After B cells have been stimulated by antigen and helper T cells
in a peripheral lymphoid organ, some of the activated B cells proliferate rapidly
in the lymphoid follicles and form germinal centers (see Figure 24–20). Here, the
B cells mutate at the rate of about one mutation per V‐region coding sequence
per cell generation. Because this is about a million times greater than the spontaneous
mutation rate in other genes and occurs in somatic cells rather than germ
cells, the process is called somatic hypermutation.
Very few of the altered Igs generated by hypermutation will have an increased
affinity for the antigen. But, because the same Ig genes produce both BCRs and
secreted antibodies, the antigen will stimulate preferentially those few B cells that
do make BCRs with increased affinity for the antigen. Clones of these altered B
cells will preferentially survive and proliferate, especially as the amount of antigen
decreases to very low levels late in the response. Most other B cells in the germinal
center will die by apoptosis. Thus, as a result of repeated cycles of somatic hypermutation
followed by antigen-driven proliferation of selected clones of effector
and memory B cells, antibodies of increasingly higher affinity become abundant
during an adaptive immune response, providing progressively better protection
against the pathogen (Movie 24.6).
A breakthrough in understanding the molecular mechanism of somatic hypermutation
came with the identification of an enzyme that is required for the process.
It is called activation-induced deaminase (AID) because it is expressed specifically
in activated B cells and deaminates cytosine (C) to uracil (U) during transcription
of V‐region coding DNA. The deamination produces U:G mismatches in
the DNA double helix, and the repair of these mismatches produces various types
of mutations, depending on the repair pathway used. Somatic hypermutation
affects only actively transcribed DNA, because AID works only on single-stranded
DNA (which is transiently exposed during transcription) and because proteins
involved in the transcription of V‐region coding sequences are required to recruit
the AID enzyme. AID is also required for activated B cells to switch from IgM and
IgD production to the production of the other classes of Ig, as we now discuss.
B Cells Can Switch the Class of Ig They Make
After a developing B cell leaves the bone marrow, before it interacts with antigen, it
expresses both IgM and IgD BCRs on its surface, both with the same antigen-binding
sites (see Figure 24–24). Stimulation by antigen and helper T cells activates
many of these mature naïve B cells to become IgM‐secreting effector cells, so that
IgM antibodies dominate the primary antibody response. Later in the immune
response, however, when activated B cells are undergoing somatic hypermutation,
the combination of antigen and helper-T‐cell-derived cytokines (discussed
later) stimulates many of the B cells to switch from making membrane-bound
IgM and IgD to making IgG, IgE, or IgA, in the process of class switching. Some
of these cells become memory cells that express the corresponding class of Ig
as BCRs on their surface, while others become effector cells that secrete the Ig
molecules as antibodies. The IgG, IgE, and IgA molecules retain their original
antigen-binding site and are collectively referred to as secondary classes of Igs,
because they are produced only after antigen stimulation, dominate secondary
antibody responses, and make up the secondary Ig repertoire.
As discussed earlier, the constant region of an Ig heavy chain determines
the class of the Ig. Thus, the ability of B cells to switch the class of antibody they
make without changing the antigen-binding site implies that the same assembled
V H ‐region coding sequence (which specifies the antigen-binding part of the
heavy chain) can sequentially associate with different C H ‐coding sequences. This
has important functional implications. It means that, in an individual animal, a
particular antigen-binding site that has been selected by environmental antigens
can be distributed among the various classes of antibodies, thereby acquiring the
different biological properties of each class.