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Chapter 20 B-Cell Development 219

FO B Cells and Germinal Centers deletions, and mutations are introduced into the genes encoding the
antibody-binding regions of the Ig receptor. A B-cell-specific gene
When mature, naive FO B cells are generated, they recirculate and that encodes activation-induced cytidine deaminase (AID), which
take up residence in various lymphoid tissues that include lymph is expressed in germinal center B cells, has been identified. AID is a
nodes, intestinal Peyer patches, and the spleen itself. Within these putative RNA-editing enzyme that acts as a cytidine deaminase and
tissues, mature naive cells localize in clusters of B lymphocytes, and has been shown to be indispensable for somatic hypermutation and
each such cluster is termed a primary follicle (see Fig. 20.5). Within class switch recombination. 27,28
these regions, the FO B cells are poised to respond to antigen and These events are dependent on signals delivered to the antigen-
undergo the germinal center reaction described later. Although some responsive B cells by antigen-specific T-follicular helper (Tfh) lym-
B cells in the MZ can respond to T-dependent antigens, most B cells phocytes that migrate into the germinal center from the PALS. Tfh
that do so are the mature, naive FO B cells located in these sites. cells mediate their effects on B cells through the secretion of cytokines
After their binding of a T-dependent antigen (as soluble antigen, as well as through direct intercellular contacts, and these stimuli result
indirectly via presentation by a local antigen-presenting cell, or as an in B-cell growth, differentiation, and Ig class switching. For example,
immune complex) mature, naive B cells in primary follicles undergo CD40 is a T-cell–surface glycoprotein encoded by a member of the
a blastogenic response. Some of these cells will immediately mature tumor necrosis gene family, and its ligand is expressed on B cells.
into plasma cells that secrete low-affinity IgM to provide a rapid CD40 ligand knock-out mice do not form germinal centers, and
initial response to infection. In response to T-cell help, however, humans who do not express CD40 ligand have X-linked hyper IgM
other B cells undergo further proliferation and differentiation. The immunodeficiency. Another key T-cell costimulatory signal includes
histologic appearance of the follicle changes as these events evolve. the cytokine IL-10, which is secreted by T cells in response to their
The nonresponsive B cells form an outer mantle zone surrounding activation via the “inducible costimulator” (ICOS). Humans lacking
the proliferating, antigen-responsive B cells in a central germinal expression of ICOS on T cells have adult-onset common variable
center. immune deficiency, leading to a severe deficit in generation of class-
Germinal center B cells are shielded from soluble antigens and switched and memory B cells.
are exposed only to a unique set of antigens presented by follicular There are two unintended consequences of affinity maturation.
dendritic cells. Two regions can be distinguished within the germinal One is that autoreactive clones may be inadvertently generated. The
center of the secondary follicle. At one pole, the cycling B-cell blasts other is the development of B-cell lymphoma. Lymphomagenesis
are referred to as centroblasts and form the dark zone. The other pole, results in part from the fact that vigorous B-cell proliferation, com-
referred to as the light zone, consists of nonproliferating cells referred bined with the changes at the DNA level that lead to molecular
28
to as centrocytes (Fig. 20.5). Some of these centrocytes go on to become alterations, may promote malignant transformation. Numerous
memory B cells, which constitute about 40% of all B cells and are studies have assigned B-cell lymphomas to each of the normal B-cell
responsible for the relatively rapid response observed on secondary counterparts described earlier. Events that limit differentiation of
exposure to the same antigen. Others mature into short- or long-lived immature or activated mature B cells can also promote malignant
plasma cells that secrete high-affinity Ig. Plasma cells migrate to the transformation. Importantly, many genetic lesions leading to B-cell
BM where they associate with stromal cells secreting the chemokine lymphoma directly affect the BCR signaling cascade, and improved
CXCL12 and APRIL, a TNF-receptor cytokine similar to BAFF, that understanding of these signaling events may lead to new therapies.
supports plasma cell survival (Fig. 20.4). These include application of Btk-specific small-molecule inhibitors
in a broad range of human lymphomas. 29
Immunoglobulin Class Switching and Affinity
Maturation EFFECTS OF AGING ON B-CELL DEVELOPMENT AND
FUNCTION
After the initial low-affinity IgM response that helps to keep a
developing infection in check, germinal center B cells can undergo Studies of both rodents and humans have demonstrated that the
three distinct modifications that can increase the affinity of the Ig quality of the immune response is diminished with age. Such declines
for antigen. are not incompatible with life, but they may become a factor when
Ig class switching involves deletions of germline DNA resulting the individual is required to mount an immune response to a novel
in religation of the VDJ complex to downstream heavy chain C pathogen, respond to vaccination, or when considering the use of
region genes, such as γ3, γ1 γ2b, γ2a, ε, and α. These DNA deletions BM derived from older donors. 30
are believed to occur at or near nucleotide sequences called switch The production of B cells from HSCs is severely attenuated with
regions that are located in the intron 5′ to each CH exon. These age, and the frequency and number of CLPs, pro-B cells, and pre-B
class-switching events are highly regulated, secondary-differentiation cells is significantly reduced in the BM of old mice. Similar age-
events that occur in spleen and lymph nodes and are potentiated related reductions in B lymphopoiesis also occur in humans. B-cell
by helper T cells and their secreted products. Note that Ig class progenitors from young and old mice have been compared, and this
switching is distinct from the previously discussed differential has revealed that expression of the Ink4a and Arf genes increases with
splicing events that allow the newly produced B cell to express the age and is a factor that contributes to the diminished proliferation
same VDJ complex associated with either the µ or δ heavy chain C and increased apoptosis of aging B-cell progenitors.
regions. 27 In addition to declines in primary B lymphopoiesis, which reduces
B cells may also undergo receptor editing. Receptor editing the number of newly generated naive B cells that are produced,
usually involves modifications of the existing light chain, in which an senescence also affects mature B cells resident in peripheral lymphoid
upstream V region segment joins to a downstream J region gene. As a tissues. For example, in addition to an accumulation of memory B
result, the genetic region encoding the originally expressed light chain cells in the spleen of old mice, the Igs they produce are less protective
is deleted. For this process to occur, RAG-1 and RAG-2 expression is because of low titer and affinity. Some of these defects may be
required. It has been proposed that B cells in germinal centers might intrinsic to the B cells but others may be secondary to age-related
reactivate Rag gene expression to mediate events such as receptor defects in T cells.
editing. However, that this occurs has been questioned. Instead, Although the molecular changes that underlie the aging of HSCs
receptor editing in splenic B cells may be limited to a small subset of and B lineage cells are being delineated, the events that trigger the
recent immature BM immigrants that enter germinal centers before aging process are incompletely defined. One possibility is that HSCs
their Rag expression has been extinguished. and lymphoid progenitors are genetically programmed to age. An
Somatic hypermutation provides a third means to increase alternative hypothesis is that these age-related events occur secondary
antibody affinity. During this process, single-nucleotide exchanges, to changes in the local and systemic environments.