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1168 Part IX: Lymphocytes and Plasma Cells Chapter 75: Functions of B Lymphocytes and Plasma Cells in Immunoglobulin Production 1169

non–template-encoded (N) nucleotides (see Fig. 75–6). Finally, addi- between the λ and the first C 1 domain of the μH chain allow VpreB
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H
tional junctional diversity comes from the nucleolytic activities that and λ μ heavy chains to form a primitive immunoglobulin receptor
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remove potential coding end nucleotides prior to the final ligation of that, with CD79a and CD79b, may be expressed on the surface mem-
the DNA breaks into one intact recombination joint. Such processes brane of the developing pre-B cell. Monoclonal antibodies that rec-
contribute to immunoglobulin diversity and are the principal mecha- ognize λ or VpreB specifically bind to pre-B cells and can react with
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nism responsible for somatic diversification of the T-cell repertoire (see B-lineage acute lymphocytic leukemia. 69
Chap. 76). The pre-B cell receptor complex is expressed only transiently,
V(D)J recombination during lymphocyte development is regu- as production of λ ceases as soon as it is formed. Nevertheless, this
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lated via transcription and through epigenetic changes that modulate protein plays an important role in normal B-cell development. When
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the accessibility of particular loci or regions of loci to RAG. Precursor immunoglobulin μ chains form a complex with the “surrogate” λ light
B cells have high-levels of V germline transcripts immediately prior chains, the complementarity determining region 3 (CDR3) of the
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to V-to-DJ recombination. Numerous epigenetic accessibility mark- “surrogate” λ light chain covers the CDR3 of the heavy chain in the
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ers, such as the histone H3 lysine 4 trimethylation, are enriched around pre-B-cell receptor, allowing the pre-B cell to avoid antigen-specific
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IGHJ in early pro-B cells in association with germline transcription. In selection. 70
addition, ubiquitination events can regulate recombination of immuno- In normal mice, the appearance of the pre-B cell receptor coincides
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globulin gene segments. The zinc finger region A of Rag-1 includes an with inactivation of the Rag-2 protein by phosphorylation and degra-
N-terminal RING domain that acts as an E3-ubiquitin ligase, which can dation of Rag-1 and Rag-2 mRNA, suggesting that this receptor plays a
ubiquitinate a panel of targets for various downstream events. 37,63–66 This role in suppressing further immunoglobulin gene rearrangement. How-
region of Rag-1 also can interact with other E2 enzymes to ubiquin- ever, expression of the pre–B-cell receptor on the surface membrane is
ate substrates involved in V(D)J recombination, such as histone 3. 63,64 associated with cell activation and proliferation, leading to generation of
Ubiquitination of Rag-2 allows for rapid degradation of the protein small, resting pre-B daughter cells that again express Rag-1 and Rag-2.
upon entering S phase, thereby halting any potential off-target activities This situation leads to subsequent light-chain gene rearrangement. As
of Rag and limiting its capacity to induce V(D)J recombination dur- such, expression of the pre–B-cell receptor appears to signal that a com-
ing inappropriate phases of the cell cycle. Indeed, DNA breaks during plete μ heavy-chain gene has been formed, that further rearrangements
S-phase are potentially harmful for cells, as such breaks can lead to dele- at this locus should be suppressed, and that development to the next
terious translocations when misrepaired by homologous recombination stage can proceed. Therefore, the surrogate light chains play a critical
(HR). It is therefore crucial to limit V(D)J recombination activity to role in normal B-cell development. This observation is underscored by
cells within G phase; this restriction appears to be controlled by Rag-2 studies on transgenic mice that lack functional λ genes. In these mice,
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degradation. 67 B-cell development in the marrow is blocked at the pre–B-cell stage,
Under normal conditions, a B-lymphocyte or plasma cell syn- thereby markedly reducing the numbers of functional mature B lym-
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thesizes only one species of light chain and heavy chain, even though phocytes in the blood and lymphoid tissues. Similarly, humans who
the cell has two different sets of immunoglobulin gene complexes that have inactivating mutations in the λ genes on both alleles of chromo-
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initially undergo seemingly independent immunoglobulin gene rear- some 22 have agammaglobulinemia and markedly reduced numbers of
rangements. The specificity of the humoral immune response depends B cells. 72
upon antigenic selection of unique clones of B cells, each clone express-
ing a homogeneous set of immunoglobulin receptors. Such restriction HEAVY-CHAIN CLASS SWITCHING
is achieved by limiting a given B cell to functional rearrangement and
expression of only a single heavy-chain allele and a single light-chain During differentiation, a single B lymphocyte can synthesize heavy
allele. This phenomenon is called allelic exclusion. Although occasional chains with different constant regions coupled to the same variable
neoplastic B-cell populations lack allelic exclusion and express both region through process called class switch recombination, which shares
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immunoglobulin alleles, allelic exclusion generally is observed with features of V(D)J recombination. As pre-B cells develop into mature
most B-cell tumors. 68 B cells, intact IgM monomers are inserted into the plasma membrane,
followed by IgD molecules with the same antigen-binding specificity.
The IgM and IgD constant-region genes are closely linked in embry-
SURROGATE λ LIGHT CHAINS onic DNA (see Fig. 75–4) and may be transcribed together. The differ-
Precursor B cells that only have rearranged D and J elements are ential splicing of the transcript allows simultaneous synthesis of the two
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referred to as progenitor B cells or “pro-B cells.” The term pre-B cells immunoglobulin heavy chains from a single species of mRNA. As such,
is reserved for precursor B cells that have completed immunoglobulin the expression of IgD that occurs during B cell maturation only rarely
heavy-chain gene rearrangement and have a functional V(D)J complex. involves deletion of Cμ.
Both pro-B cells and pre-B cells have immunoglobulin light-chain loci The switch from IgM to IgG, IgA, or IgE requires active transcrip-
in germline configuration. tion of the downstream constant-region exons encoding the future
Pre-B cells express some immunoglobulin μ chains in associa- immunoglobulin isotype. This process requires prior interaction of B
tion with “surrogate” λ light chains. One of these proteins, called λ , lymphocytes with antigen or mitogen and ligation of CD40 via the
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has similarity with known Cλ light-chain domains. Another protein is ligand for CD40 (CD154) expressed by activated T cells. Patients
called VpreB because it resembles a V domain but bears an extra N-ter- with inherited defects in CD40 or CD154 have an immune deficiency
minal protein sequence. Both proteins are encoded by genes located (hyper-IgM syndrome type I) characterized by normal to high serum
on chromosome 22. The λ gene is situated within a λ-like locus that levels of IgM with extremely low serum levels of other immunoglob-
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is telomeric to the true λ light-chain locus. The gene encoding VpreB ulin isotypes (Chap. 80). Interleukins provided by antigen-reactive
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(VPREB1) is located within the cluster of immunoglobulin Vλ genes T lymphocytes strongly influence (1) which B cells differentiate into
(see Fig. 75–5), defined by breakpoints of chromosomal translocations IgM-secreting plasma cells and (2) which B cells switch to synthesiz-
found in a few leukemias and lymphomas. Together, VpreB and λ pair ing the heavy chain of another immunoglobulin isotype, such as IgG
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with the μ heavy chains. Subsequent covalent linkages via an S-S bond and IgA. Isotype switching to IgA occurs most efficiently in mucosal

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