Page 124 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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B-Cell Development and Differentiation

Harry W. Schroeder, Jr., Andreas Radbruch, Claudia Berek

B lymphocytes arise from multipotent hematopoietic stem cells other secondary lymphoid tissues and organs, where selection
that successively populate the embryonic paraaortic splanchno- for specificity continues (Chapter 2).
pleure, the fetal liver, and then bone marrow. Stem-cell daughter B-cell differentiation (Fig. 7.1) is commonly presented as a
cells give rise to lymphoid-primed multipotent progenitors linear process defined by the regulated expression of specific
(LMPPs), which, in turn, can give rise to either myeloid or sets of transcription factors, immunoglobulin (Ig), and cell-surface
1,2
lymphoid cells. LMPPs then produce common lymphoid molecules. Given the central role of the BCR (Chapter 4), initial
progenitors (CLPs), which can generate T cells, B cells, natural developmental steps are classically defined by the status of the
killer (NK) cells, and dendritic cells (DCs). Final B-cell differentia- rearranging Ig loci. With the development of monoclonal antibody
tion requires the exposure of CLP daughter cells to specialized (mAb) technology, analysis of cell-surface markers, such as CD10,
microenvironments, such as those found in the fetal liver and CD19, CD20, CD21, CD24, CD34, and CD38 (Fig. 7.2), has
bone marrow. These two tissues are the primary B-lymphoid facilitated definition of both early and late stages of development,
organs. In humans, the shift from fetal liver to bone marrow especially in those cases where Ig cannot be used to distinguish
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begins in the middle of fetal life and ends just prior to birth. B between cell types. Of these, CD19, a signal transduction molecule
cells continue to be produced in bone marrow throughout the expressed throughout B-cell development up to, but not including,
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life of the individual, although the rate of production decreases the mature plasma cell stage warrants special mention as the
with age. single best clinical marker for B-cell identity.
In practice, B-cell development is a more complex process
KEY CONCEPTS than the simple, linear pathways depicted in Figs. 7.1 and 7.2.
B-Cell Development in the Primary For example, proB cells typically derive from a CLP, but they
can also develop from a bipotent B/macrophage precursor. Thus
Lymphoid Organs B-lineage subsets identified by one fractionation scheme may
• Commitment to the B-cell lineage reflects differential activation of consist of mixtures of subsets identified by others. The practitioner
transcription factors that progressively lock the cell into the B-cell would therefore be wise to clarify the fractionation scheme used
pathway. by the reference laboratory when comparing patient findings to
• B-cell development is typically viewed as a linear, stepwise process the literature.
that is focused on the assembly and testing of immunoglobulin function, Initial commitment to the B-cell lineage requires activation
first in the fetal liver and bone marrow and then in the periphery: of a series of transcriptional and signal transduction pathways.
• Failure to assemble a functional receptor leads to cell death. At the nuclear level, the transcription factors PU.1, Ikaros, ID-1,
• Expression of a functional receptor subjects the B cell to antigen
selection. E2A, EBF, and PAX5 play major roles in committing progenitor
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• B cells with inappropriate specificities tend to be eliminated. cells to the B-cell lineage. After lineage commitment has been
• B cells responding appropriately to external antigen can develop established, however, it is generally accepted that the composition
either into immunoglobulin-secreting plasma cells or into memory of the BCR controls further development.
cells. Each B-cell progenitor has the potential to produce a large
• At the clinical level, B-cell development can be monitored by examining number of offspring. Some will develop into mature B cells, and
the pattern of expression of characteristic surface proteins.
even less into long-lived memory B cells or plasma cells. Others,
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indeed the majority, will perish. Most of the defined steps in
An intact and functional B-cell receptor (BCR) complex, which this process of development represent population bottlenecks:
consists of membrane-bound immunoglobulin (mIg), the Igα developmental checkpoints wherein the developing B cell is tested
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and Igβ coreceptors, and ancillary signal transduction compo- to make sure that its BCR will be beneficial. In the periphery,
nents, must be present for the developing B cell to survive exposure to antigen is associated with class switching and
(Chapter 4). The composition of the BCR is subject to intense hypermutation of the variable domains of the antigen receptor.
selection. In the primary organs, hazardous self-reactive BCRs, A few select survivors earn long lives as part of a cadre of memory
as well as nonfunctional ones, can be culled by changing the B cells. These veterans are charged with the responsibility to
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light (L) chain (receptor editing), by cell anergy, or by apoptosis rapidly engage antigen to which they have been previously
of the host cell. Survivors of this initial selection process are exposed, providing experienced protection against repeated
released into blood and thence to the spleen, lymph nodes, and assault.

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