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CHaPTEr 7 B-Cell Development and Differentiation 109

Specialized microenvironments also play a role in peripheral the Cδ exons downstream of Cµ. Alternative splicing permits
+
+
B-cell development (Chapter 2), each of which enables the B coproduction of IgM and IgD. These now newly mature IgM IgD
cell to properly engage different types of antigens or venues of B cells enter blood and migrate to the periphery, where they
attack. In the marginal zone (MZ), mature splenic MZ B cells form the majority of the B-cell pool in the spleen and the other
await bacterial pathogens. In the lymphoid follicles, B cells reactive secondary lymphoid organs. The IgM and IgD on each of these
with a given antigen collaborate with follicular T helper (Tfh) cells share the same variable domains.
cells and DCs to maximize the immune response (Chapter 6).
In the germinal centers (GCs), B cells use class switching and Tyrosine Kinases Play Key Roles in B-Cell Development
somatic mutation to modify and optimize the function and Signaling through the BCR is required for continued development.
affinity of their Igs. And, underneath mucosal surfaces, B cells Bruton tyrosine kinase is an important component of the
are primed to express IgA (Chapter 20). phospholipase Cγ (PCLγ) pathway, which is used in BCR signaling.
Deficiency of BTK function results in the arrest of human B-cell
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development at the preB cell stage and is the genetic basis of
B-CELL DEVELOPMENT BEGINS IN THE PRIMARY X-linked agammaglobulinemia (XLA) (Chapter 34).
LYMPHOID ORGANS BLNK is a SRC homology 2 (SH2) domain–containing signal
Generation of a Functioning Antigen Receptor Is Key to transduction adaptor. When phosphorylated by SYK, BLNK
serves as a scaffold for the assembly of cell activation targets
the Viability of a B Cell that include GRB2, VAV, NCK, and phospholipase C-[γ] (PLCγ).
Ig rearrangement is hierarchical. In proB cells, heavy (H) chain LOF mutations in BLNK can result in the loss of preB and mature
D H →J H joining precedes V H →DJ H rearrangement (Chapter 4), B cells and thus agammaglobulinemia.
followed by light (L) V L →→J L joining in late-stage preB cells. FLT3 (FLK2) is a receptor tyrosine kinase belonging to the
Production of a properly functioning B-cell receptor (BCR) same family as c-FMS, the receptor for colony stimulating factor-1
is essential for development beyond the preB cell stage. For (CSF-1). FLT3 ligand, which has homology to CSF-1, is a potent
example, loss-of-function (LOF) mutations in RAG-1/2 and costimulator of early proB cells. In mice, targeted disruption of
DNA-dependent protein kinase (DNA-PKcs, Ku 70/80) preclude flt3 leads to a selective deficiency of primitive B-cell progenitors.
B-cell as well T-cell development (Chapter 35). Each proB cell
faces the probability that only one of three possible splices will Cell Surface Antigens Associated With
place the V H and J H in the same reading frame. The opportunity B-Cell Development
to try rearrangement on the second chromosome gives failing B-cell development is associated with the expression of a cascade
proB cells a second opportunity. Together, this provides the cell of surface proteins, each of which plays a key role in the fate of
1
2
1
with five chances out of nine for initial survival ( 3 + [ 3 × 3] the cell (see Fig. 7.1; Table 7.1). The timing of the appearance
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= 9). This calculation reflects the fact that after failure of the of each of these proteins can be used to further analyze the
2
first rearrangement for 3 of the cells, these remaining cells will process of B-cell development.
each have a 1 in 3 chance of a functional rearrangement of the CD34 is a highly glycosylated type I transmembrane glyco-
second chromosome. In-frame, functional VDJ H rearrangement protein that binds to CD62L (L-selectin) and CD62E (E-selectin)
allows the proB cell to produce µ H chains, most of which are and thus likely aids in cell trafficking (Chapter 11). It is expressed
retained in the endoplasmic reticulum (ER). The appearance of on a small population (1–4%) of bone marrow cells that includes
cytoplasmic µ H chains marks initiation of the preB cell stage. hematopoietic stem cells (HSCs). Minimal hematopoietic defects
These early preB cells tend to be large in size. have been documented in mice deficient in CD34. However,
VpreB and λ14.1 [λ5], which together form the surrogate such observations must be viewed with caution when extrapolated
light chain (ψLC), and Igα and Igβ (Chapter 4) are constitu- to humans because CD34 is not expressed on HSCs in mice.
tively expressed by proB cells. The first H chain quality control CD10, also known as neprilysin, neutroendopeptidase, and the
checkpoint tests for the ability of the µ H chain to associate with common acute lymphocytic leukemia antigen (CALLA), is a type
surrogate light chain to form a preB-cell receptor. In addition to II membrane glycoprotein metalloprotease. CD10 has a short
checking to see if the scaffolding (frameworks) of the L chain N-terminal cytoplasmic tail, a signal peptide transmembrane
can associate correctly with the scaffolding of the H chain, VpreB domain, and an extracellular C-terminal domain that includes
encodes a sensing site that can test the H chain antigen-binding six N-linked glycosylation sites. The extracellular domain contains
site. Thus the surrogate light chain functions as the first, and 12 cysteines whose disulfide bonds help stabilize its zinc-binding
invariant, antigen to screen for antigen-binding characteristics. pentapeptide motif, which is involved in its zinc-dependent
Successful formation of a stable preBCR is followed by the metalloprotease catalytic activity. By virtue of its protease activity,
termination of further H chain rearrangement (allelic exclusion), it is thought to downregulate cellular responses to peptide
which is followed by four to six cycles of cell division, a process hormones and cytokines. Inhibition of CD10 activity on bone
associated with a progressive decrease in cell size. Late preB marrow stromal cells enhances B-cell maturation. CD10 (CALLA)
daughter cells reactivate recombinase activating gene 1 (RAG1) is used as a marker for preB acute lymphocytic leukemias (ALLs)
and RAG2 and begin to undergo V l →J l rearrangement. Successful and for certain lymphomas.
production of a complete κ or λ light chain permits expression CD19 is a cell-surface glycoprotein of the immunoglobulin
of conventional IgM on the cell surface (sIgM), which identifies superfamily (IgSF) that is exclusively expressed throughout
the immature B cell. Immature B cells expressing self-reactive B-cell development from the proB-cell stage up to the plasma
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IgM antibodies may undergo repeated rounds of light chain cell stage (see Fig. 7.1). CD19 exists in a complex with CD21
rearrangement to lessen the self specificity of the antibody, a (complement receptor 2: CDR2), CD81 (TAPA-1), and Leu 13.
process termed receptor editing. With the help of CD21, CD19 can bind the complement C3
Immature B cells that have successfully produced an acceptable cleavage product C3d. The simultaneous binding of sIgM and
IgM BCR extend transcription of the H chain locus to include CD19 to a C3d-antigen complex enables CD19 and the BCR to