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1162 Part IX: Lymphocytes and Plasma Cells Chapter 75: Functions of B Lymphocytes and Plasma Cells in Immunoglobulin Production 1163

colony-stimulating factor, and IL-1, IL-3, IL-4, IL-5, and IL-6. These sub- clinical activity in the treatment of patients with various B-cell malig-
stances act on adjacent cells and may regulate the metabolism of the con- nancies, which appear dependent upon constitutive signaling via the
nective tissue extracellular matrix. These lipid mediators and biogenic immunoglobulin receptor. 27
amines may produce the rapid components of immediate hypersensi- To mitigate the problem of accidental initiation of signal trans-
tivity, such as vascular leakage, vasodilation, and bronchoconstriction. duction, the signaling cascade is subject to negative controls. The
The released cytokines, on the other hand, are responsible for the late quantity and quality of immunoglobulin receptor signaling are mod-
phase of the immediate hypersensitivity response. The physiologic func- ulated by several transmembrane proteins that are associated with the
tion of this response is not clear. Instead, the immediate hypersensitivity immunoglobulin–CD79a/CD79b receptor complex. These associ-
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response may represent a pathologic systemic exaggeration of a local ated proteins can be either costimulatory (e.g., CD19) or inhibitory
physiologic process that ordinarily contributes to the inflammatory (e.g., CD22, CD32 [FcγRII], CD72). In contrast to CD79a and CD79b,
response to invading organisms. CD22 and CD72 have cytoplasmic domains with immunoreceptor
tyrosine-based inhibitory motifs. When immunoreceptor tyrosine-
based inhibitory motifs are phosphorylated by activated Lyn kinase,
SURFACE IMMUNOGLOBULIN the domains recruit Src homology 2 (SH2) domain-containing pro-
Any one of the immunoglobulin isotypes may serve as a B-cell mem- tein tyrosine phosphatase 1 (SHP-1), otherwise known as protein
brane receptor for antigen. However, most B cells express surface tyrosine phosphatase 1c, 29,30 or phosphatidylinositol-3,4,5-triphos-
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IgM with or without IgD. Each immunoglobulin is expressed on the phate 5-phosphatase (SHIP-1). Bound SHP-1 or SHIP-1 can remove
surface membrane as a monomer complexed noncovalently with the phosphate group from the phosphorylated (and thereby activated)
disulfide-linked heterodimeric glycoproteins that, together with tyrosine kinases, returning these kinases to their inactive state so that
surface immunoglobulin, form the B-cell antigen–receptor complex they no longer trigger B-cell activation. The importance of SHP-1 in
(see Fig. 75–3). For surface IgM, each heterodimer is composed of limiting B cell activation is demonstrated by mutant mice that lack
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CD79a, an IgM α-chain of 33 kDa, complexed with CD79b, an Ig this phosphatase. The B lymphocytes of such animals are stimulated
β-chain of 37 kDa. CD79a interacts with the transmembrane domain by much lower concentrations of antigen than the B lymphocytes of
and C 4 domain of the immunoglobulin molecule, which mediates normal mice, causing excessive B-cell proliferation, autoimmune dis-
H
B-cell receptor clustering and signaling in response to antigen (see ease, and early mortality.
Fig. 75–3). The CD79a chain is a product of the human mb-1 gene
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(designated CD79a) located at 19q13.2, whereas CD79b is the product
of CD79b located on a different chromosome at 17q23. B cells that GENETICS OF IMMUNOGLOBULINS
lack expression of CD79a or CD79b cannot express surface immu-
noglobulin. CD79a/CD79b are necessary, not only for transport of IMMUNOGLOBULIN GENE COMPLEXES
the assembled immunoglobulin to the cell surface but also for sig- Immunoglobulin genes are inherited in three unlinked gene complexes:
nal transduction following surface immunoglobulin-receptor cross- one for the heavy-chain classes, one for κ light chains, and one for λ light
linking by antigen. Patients with inherited defects in CD79a have chains. The immunoglobulin heavy-chain gene complex is located at
an immune deficiency that is indistinguishable from that of classic band q32 of the long arm of chromosome 14. This complex is composed
X-linked agammaglobulinemia (Chap. 80). The cytoplasmic tails of 39 functional heavy-chain variable-region (V ) genes, more than
20
H
of CD79a and CD79b each contain immunoreceptor tyrosine-based 120 nonfunctional V pseudogenes, 25 functional diversity (D) seg-
H
activation motifs (ITAMs). Such motifs are found in the cytoplasmic ments, six functional J minigenes, and exons encoding the con-
H
domains of several immune system signaling molecules, including stant regions for each of the immunoglobulin heavy-chain isotypes
those of the T-cell receptor complex (Chap. 76). (Fig. 75–4). The κ light-chain gene complex is contained within band
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B cells can become activated following ligation of their surface p12 on the short arm of chromosome 2. This gene complex consists of
immunoglobulin receptors by antigen, which typically is presented approximately 40 functional κ light-chain variable-region genes (Vκ
on the surface of dendritic cells or macrophages. 21–24 This can cause genes), more than 30 nonfunctional Vκ pseudogenes, five Jκ segments,
microclustering of the immunoglobulin receptor complex into the one constant-region exon, and one kappa-deleting element (Kde)
immunologic synapse, which accumulates src family tyrosine kinases (Fig. 75–5). Many of the Vκ genes in the so-called p region most proxi-
(e.g., Lyn, Blk, and Fyn), which can phosphorylate tyrosine residues in mal to the Jκ segments are in the opposite orientation of the Jκ segments,
the ITAMs of CD79a and CD79b. In turn, the phosphorylated ITAM thus requiring that the Vκ exons in the proximal region to undergo
binds cytoplasmic signaling molecules, the most important of which inversion during immunoglobulin gene rearrangement (Fig. 75–5). The
is p72 , a 72-kDa tyrosine kinase. Following its recruitment to the λ light-chain gene complex is located at band q11.2 on the long arm
Syk
activated immunoglobulin receptor complex, p72 itself becomes of chromosome 22, 6 Mb from the centromere. This gene complex
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Syk
activated through phosphorylation, allowing it to phosphorylate the consists of approximately 41 functional λ light-chain variable-region
cytosolic adapter protein BLNK (B-cell linker protein, also known as genes (Vλ genes), more than 30 Vλ pseudogenes, four functional λ con-
SLP-65, BASH, or BCA). BLNK serves as a docking site for a number stant-region genes (Cλ1, Cλ2, Cλ3, Cλ7), and three λ constant-region
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of important signaling molecules, including Bruton tyrosine kinase pseudogenes (Cλ4, Cλ5, Cλ6), each associated with one Jλ segment
(BTK), Vav-1, Vav-2, and phospholipase C gamma (PLCγ). Dual (Fig. 75–5). The constant-region elements of the heavy-chain gene
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phosphorylation and activation of PLCγ by BTK and p72 allows complex are proximal to variable-region segments on chromosome 14,
syk
PLCγ to effect hydrolysis of the polyphosphoinositides into inosi- whereas the constant-region segments of the two light chains are in the
tol-1,4,5-trisphosphate and diacylglycerol, which, in turn, increase opposite orientation, telomeric to the variable-region genes.
intracellular Ca and activate protein kinase C and Ras, respectively. Each germline V gene, D element, and J segment is flanked by
2+
The importance of these activation events in B-cell signaling and recognition sequences that are necessary to direct site-specific recom-
development is underscored by patients with inherited defects in bination (Fig. 75–6). Such sequences consist of a highly conserved
BTK, who lack B-cell development and have X-linked agammaglob- palindromic heptamer (5′-CACAGTG-3′) a nonconserved spacer
ulinemia (Chap. 80). Furthermore, inhibitors of BTK demonstrate of 12 or 23 bp, and a conserved nonamer (5′ACAAAAACC-3′).
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Kaushansky_chapter 75_p1159-1174.indd 1163 9/21/15 12:11 PM