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1170 Part IX: Lymphocytes and Plasma Cells Chapter 75: Functions of B Lymphocytes and Plasma Cells in Immunoglobulin Production 1171

defined based on their reactivity with the Oz, Kern, Mcg, and Mcp anti- with IgM secretion. Similarly, IgA molecules form dimers and polymers
sera raised against λ Bence Jones proteins and that reflect minor non- linked by the J chain just prior to secretion from the plasma cell.
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allelic amino acid differences in the λ light-chain constant regions. A
–
+
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fifth type of λ light-chain, termed Mcg Ke Oz is highly homologous to
Mcg Ke Oz and actually results from a polymorphic gene amplification REGULATION OF IMMUNOGLOBULIN
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in a functional polymorphic Cλ2 segment. 102
SYNTHESIS
IMMUNOGLOBULIN SYNTHESIS GENERATION OF PLASMA CELLS
AND SECRETION A normal adult has some preexisting B lymphocytes that can pro-
duce immunoglobulin that can bind almost any foreign antigen. Such
B cells can be recruited to the immune response against the antigen. In
IMMUNOGLOBULIN SYNTHESIS the presence of accessory T-follicular helper cells (T ; Chap. 76), an
FH
The total IgG content of the adult human body is approximately 75 g, of antigen-binding clone of B lymphocytes may transform into anti-
which 2.2 g is synthesized each day. Most immunoglobulin is produced body-secreting plasma cells. 111
by mature plasma cells, which have abundant rough endoplasmic retic- Transcription factors regulate this differentiation of B cells into
ulum, a well-developed Golgi apparatus, and high-level transcription of antibody-secreting plasma cells. An important factor in plasma cell dif-
the immunoglobulin genes. The final mRNAs for immunoglobulin light ferentiation is the B-lymphocyte-induced maturation protein-1 (Blimp-1),
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and heavy chains are derived by the processing of large nuclear RNA which also is called the positive regulatory domain 1-binding factor-1
transcripts. In plasma cells, the rearranged and spliced mRNA mole- (PRDM1) because it initially was identified by its ability to bind to the
cules for the heavy-chain and light-chain polypeptides are translated on positive regulatory domain I of the human interferon-β promoter.
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separate ribosomal complexes. Blimp-1 is a zinc finger-containing transcription factor encoded by
The folding and assembly of intact immunoglobulin molecules PRDM1 on human chromosome 6q21 that represses expression of
occur in the endoplasmic reticulum (ER), which contains a large set of genes encoding transcription factors that inhibit plasma-cell differen-
redox catalysts and chaperones that guide the folding of nascent pro- tiation (e.g., MYC, B-cell chronic lymphocytic leukemia/lymphoma 6
teins. First, an aminoterminal leader peptide approximately 18 to [BCL-6], paired box gene 5 [PAX5], microphthalmia-associated tran-
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30 residues long is cleaved prior to the release of the completed light scription factor [MITF], and basic leucine zipper transcription factor 2
and heavy chains in the cisternae of the ER. The ER harbors a single [BACH2]). On the other hand, Blimp-1 directly or indirectly induces
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prominent and highly conserved HSP70 family member, BiP, along expression of other transcription factors that control genes encoding
with over 20 protein-disulphide-isomerase (PDI) oxidoreductases with other transcription factors or proteins responsible for plasma-cell dif-
CXXC active site motifs. 104,105 The heavy-chain immunoglobulin poly- ferentiation and/or immunoglobulin secretion (e.g., X-box binding
peptides interact via their C 1 domains with BiP that allows for proper protein-1 [XBP1], E2F transcription factor 1 [E2F1], v-myb myeloblas-
H
folding of the heavy-chain polypeptide and prevents its transport into tosis viral oncogene homologues 1 and 2 [MYBL1/MYBL2], early B-cell
the Golgi. The nascent immunoglobulin polypeptides also bind the factor 1 [EBF1], Pou domain, class 2, factor 2, or associating factor 1
various ER or ER-Golgi-intermediate compartment (ERGIC) proteins [POU2F2/POU2AF1], and transcription factor E2a [TCFE2A]). This
transiently, some shorter and some for longer periods, either simultane- capacity of Blimp-1 to repress and to activate expression of a variety of
ously or in sequence, to allow for the proper folding and assembly of the different transcription factors accounts for its capacity to orchestrate the
IgM chains. For example, early in the process, GRP94 binds the nascent dramatic changes in B-cell morphology and function associated with
heavy chain after BiP to promote folding of H chains and assembly with plasma-cell differentiation and high-level secretion of immunoglobulin
L chains to HL “hemimers,” whereas much later, ERGIC53 acts after protein. Mice with a conditional deletion of PRDM1 encoding Blimp-1
ERp44, when they assist assembly of H L monomers into multimers. in the B lineage demonstrate the critical requirement of Blimp-1 in
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2 2
The nascent immunoglobulin light chains can displace BiP and then plasma cell development. Although such mice have normal numbers
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spontaneously combine with the heavy chain to form immunoglobu- of B cells and develop germinal centers in response to T-dependent anti-
lin half molecules that are stabilized by disulfide bonds. The process gens, they fail to generate plasma cells or to secrete normal levels of
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also requires the reduction-oxidation (redox) conditions generated by immunoglobulin in response to either T-independent or T-dependent
redox catalysts within ER, a requirement that has handicapped efforts to antigens. Furthermore, other studies found that expression of Blimp-1
produce immunoglobulin in prokaryotic cell-free expression systems. is required for the maintenance of long-lived plasma cells in the mar-
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The joining of two identical half molecules by disulfide bonds yields a row and the long-term expression of antigen-specific immunoglobulin
basic four-chain immunoglobulin unit, which then is allowed to trans- in the plasma. 115
port to the Golgi for glycosylation. Some diffuse large B-cell lymphomas (DLBCLs) have deletions or
Glycosyltransferase enzymes add a defined sequence of sugars to inactivating mutations in PRDM1, suggesting that this gene also might
the assembled immunoglobulin unit to form branched-chain oligosac- act as a tumor suppressor. However, PRDM1 mutations are not found
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charides composed of N-acetyl-glucosamine, mannose, galactose, fruc- in other lymphoid or myeloid leukemias, and myeloma cells and some
tose, and sialic acid. The oligosaccharides are attached covalently to the DLBCLs express abundant levels of Blimp-1, making it appear unlikely
immunoglobulin heavy chain at several sites. The carbohydrate facil- that Blimp-1 suppresses tumor development per se. Moreover, the
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itates the transport of the antibody molecule across the plasma mem- DLBCL cases that expressed Blimp-1 lacked detectable plasmacytic fea-
brane and into the extracellular space and increases the solubility of the tures and actually displayed more aggressive behavior. As such, B-cell
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secreted protein. Specific types of glycosylation also may improve the expression of Blimp-1 appears necessary but not sufficient for plasma-
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clinical activity of therapeutic monoclonal antibodies. 7,110 cell differentiation.
Five monomeric units of IgM combine to form a pentameric mac- The expression of Blimp-1 in B cells is regulated primarily at the
roglobulin linked by disulfide bonds and a single J-chain polypeptide. level of PRDM1 transcription, which requires activation by the tran-
Usually polymerization immediately precedes or occurs simultaneously scription factor interferon regulatory factor 4 (IRF4). Transgenic mice
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