Page 259 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 20

B-CELL DEVELOPMENT

Kenneth Dorshkind and David J. Rawlings

B lymphocytes are the subset of white blood cells specialized to µ Heavy chain protein is detected in the cytoplasm of pre-B cells
synthesize and secrete immunoglobulin (Ig). Their name derives that no longer express CD34. Finally, when Ig light chain expression
from the finding that the avian bursa of Fabricius is a site of B-cell occurs, the cells become surface IgM-expressing B cells. Developing
production. However, B-cell production in mammals takes place in and mature B lineage cells also express additional cell surface deter-
the bone marrow (BM). Following their production in that organ, minants, which include CD20, CD21, CD22, CD24, CD38, and
newly generated B lymphocytes migrate into secondary lymphoid CD40, several of which are linked to critical intracellular signaling
organs such as the spleen where they undergo final maturation. At pathways. Antibodies against the CD20 determinant (rituximab)
this point, the mature B cells may remain in the spleen or relocate are in widespread clinical use for the treatment of lymphoma and,
via the circulation to additional tissues such as lymph nodes, where increasingly, autoimmune diseases.
they are poised to respond to antigenic challenge.
This chapter will focus on adult B-cell development and the regula-
tion of that process, although we briefly discuss fetal B lymphopoiesis B LINEAGE SPECIFICATION AND COMMITMENT
and its distinguishing features. We then outline B-cell maturation
in secondary lymphoid tissues. The information presented provides As differentiation of HSCs and other immature precursors into the
a basis for understanding abnormalities of B-cell development such B lineage occurs, genetic programs that promote B lymphopoiesis are
as leukemia, lymphoma, and immunodeficiency states, which are activated while those used by non-B lineage cells are silenced. This
discussed in other chapters. Studies in mice have contributed much results in gradual “specification” of progenitors towards the B-cell
to what is known about B-cell development and have served as a lineage. For example, cells at the CLP stage of development are
basis for understanding human B lymphopoiesis. Thus, although destined to generate B cells, but they retain limited T and myeloid
we emphasize the human literature as much as possible, frequent potential. Because of this, CLPs can be thought of as B lineage “speci-
reference to findings in mice are made. fied.” However, by the time the pro-B-cell stage has been reached,
the cells can only generate B lymphocytes and are “committed”
to the B-cell lineage. The processes of specification and commit-
STAGES OF B-CELL DEVELOPMENT ment are dependent on the regulated expression of a network of
transcription factors and other regulatory molecules in developing B
As a result of advances in the development of monoclonal antibodies lineage cells. 5
to leukocyte cell surface antigens and in flow cytometry, it is possible
to resolve various stages of murine and human B-cell development
from the hematopoietic stem cell (HSC) to newly produced, surface Transcriptional Regulation of B-Cell Development
IgM-expressing B cells (Fig. 20.1).
The generation of lymphoid cells from HSCs is critically dependent
on expression of the Ets family member PU.1. Mice in which Sfpi1,
Murine B-Cell Development the gene encoding PU.1, is not expressed produce erythroid and
megakaryocytic but not monocytic, granulocytic, and lymphoid cells.
As the progeny of murine HSCs differentiate, they generate lymphoid- As a result of this severe defect, PU.1 knock-out mice die during
primed multipotent progenitors (LMPPs). LMPPs, defined by their the fetal period or within a few days after birth. PU.1 regulates a
+
+
+
−
lineage negative (Lin ) CD117 (c-kit) Sca-1 Flt3 phenotype, lack number of early events as precursors become B lineage specified.
erythroid and megakaryocyte potential but can generate all other These include the expression of Flt3, which is expressed on LMPPs,
lymphoid and myeloid cells. A subset of LMPPs includes early lym- the CD45R(B220) cell surface determinant, and IL-7Rα. However,
phoid progenitors (ELPs), which express the Rag1 gene (discussed deletion of Sfpi1 at the CLP stage of development has no negative
−
+
low
low
later). ELPs are the precursors of Lin c-kit Sca-1 CD127 effect on B-cell development, indicating that PU.1 expression is not
(interleukin-7 receptor α) common lymphoid progenitors (CLPs). required once B-cell specification has occurred.
−
Lin indicates that the cells lack expression of determinants present Further specification toward the B-cell lineage is dependent on
on mature myeloid, erythroid, and lymphoid lineage cells. CLPs the expression of additional transcription factors that include early
then mature through pre-pro-B-, pro-B-, pre-B-, and B-cell stages B-cell factor (EBF) and the E2A-encoded splice variants E12 and
of development that can be phenotypically resolved based on their E47. Each of these DNA-binding proteins regulates the expression
expression of various cell surface and cytoplasmic determinants, as of a variety of B-lineage target genes. For example, Ebf1 regulates
shown in Fig. 20.1. 1 the expression of Igα, VpreB, λ5, and Pax5, and represses genes
associated with alternative lineage fates. That EBF and E2A expres-
sion play a critical role in B lymphopoiesis has been demonstrated by
Human B-Cell Development the fact that mice in which they are not expressed exhibit an almost
complete block in B-cell development at the pro-B-cell stage.
Various stages of human B-cell development can also be phenotypi- Ebf1- and E2A-expressing progenitors can still exhibit some
−
−
hi
2
cally identified. A population of human Lin CD10 CD62L cells non-B lineage potential, indicating that the expression of these DNA-
appears to be the human LMPP counterpart, whereas CLPs are binding proteins does not result in absolute commitment of cells to
+
+
+
+
CD34 CD45RA CD10 IL-7R . As in the mouse, CLPs sequen- the B lineage. Instead, this is dependent on expression of the Pax5
6
3,4
tially generate pro-B, pre-B, and B cells. Human pro-B cells can transcription factor. Phenotypically identifiable B-cell precursors are
be identified based on their expression of CD10, CD34, and CD19. present in Pax5 knock-out mice, and when placed under appropriate
210