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CHAPTER 75 molecules, the binding of antibody to antigen initiates a limited series of

FUNCTIONS OF biologically important effector functions, such as complement activation
and/or adherence of the immune complex to receptors on leukocytes. The
B LYMPHOCYTES AND eventual outcome is the clearance and degradation of the foreign substance.
This chapter describes the structure of immunoglobulins and outlines the
PLASMA CELLS IN mechanisms by which B cells produce molecules of such tremendous diver-
sity with defined effector functions.
IMMUNOGLOBULIN IMMUNOGLOBULIN STRUCTURE AND

PRODUCTION FUNCTION

BASIC STRUCTURE
Thomas J. Kipps All naturally occurring immunoglobulin molecules are composed of
one or several basic units consisting of two identical heavy (H) chains
and two identical light (L) chains (Fig. 75–1). The four polypeptides
1
SUMMARY are held in a symmetrical, Y-shaped structure by disulfide bonds and
noncovalent interactions. The internal disulfide bonds of the heavy and
2–4
light chains cause the polypeptides to fold into compact globe-shaped
Much of our immune defense against invading organisms is predicated regions called domains, each containing approximately 110 to 120 amino
upon the tremendous diversity of immunoglobulin molecules. Immuno- acid residues. Each domain is composed of β-pleated sheets that are
globulins are glycoproteins produced by B lymphocytes and plasma cells. stabilized by a conserved disulfide bond (Fig. 75–1). The light chains
These molecules can be considered receptors because the primary function have two domains; the heavy chains have four or five domains. The
of the immunoglobulin molecule is to bind antigen. A single person can syn- aminoterminal domains of the heavy and light chains are desig-
thesize 10 to 100 million different immunoglobulin molecules, each having nated the variable (V) regions because their primary structure varies
a distinct antigen-binding specificity. The great diversity in this so-called markedly among different immunoglobulin molecules. The carboxy-
humoral immune system allows us to generate antibodies specific for a terminal domains are referred to as constant (C) regions because
variety of substances, including synthetic molecules not naturally present their primary structure is the same among immunoglobulins of the
in our environment. Despite the diversity in the specificities of antibody same class or subclass. The amino acids in the light- and heavy-chain
variable regions interact to form an antigen-binding site. Each four-
chain immunoglobulin basic unit has two identical binding sites. The
constant-region domains of the heavy and light chains provide
stability for the immunoglobulin molecule. The heavy-chain constant
regions also mediate the specific effector functions of the different
Acronyms and Abbreviations: ADCC, antibody-dependent cellular cytotoxicity; immunoglobulin classes (Table 75–1).
AID, activation-induced deaminase; BACH2, basic leucine zipper transcription factor 2; LIGHT CHAINS
BCL-6, B-cell chronic lymphocytic leukemia/lymphoma 6; BiP, immunoglobu-
lin-binding protein; Blimp-1, B-lymphocyte-induced maturation protein-1; BLNK, Immunoglobulin light chains have an approximate Mr of 23,000. They
B-cell linker protein; BTK, Bruton tyrosine kinase; C, constant; CDR, complementarity are divided into two types, κ and λ, based upon multiple amino acid
5
determining region; CRI, cross-reactive idiotype; CSR, class switch recombination; sequence differences in the single constant-region domain. The λ chains
D, diversity; DLBCL, diffuse large B-cell lymphoma; DNA-PK, DNA protein kinase; are divided further into subclasses. The proportion of κ-to-λ chains in
E2F1, E2F transcription factor 1; EBF1, early B-cell factor 1; ERGIC, ER-Golgi-in- adult human plasma is approximately 2:1. The immunoglobulin light-
termediate compartment; FR, framework region; H, heavy; HMG, high-mobility chain constant region has no known effector function. Its main purpose
group protein; Ig, immunoglobulin; IL, interleukin; IRF4, interferon regulatory fac- may be to allow for proper assembly and release of an intact immuno-
tor 4; ITAM, immunoreceptor tyrosine-based activation motif; κ, immunoglobulin globulin molecule. Soon after synthesis, the antibody light-chain con-
kappa light chain; Kde, kappa-deleting element; λ, immunoglobulin lambda light stant region associates with the nascent immunoglobulin heavy chain
chain; L, light; MITF, microphthalmia-associated transcription factor; MYBL1 and (see Fig. 75–1), releasing the latter from the immunoglobulin-binding
2, v-myb myeloblastosis viral oncogene homologues 1 and 2; NHEJ, nonhomologous protein (BiP). BiP is a heat shock protein that, in the absence of anti-
DNA end-joining; PAX5, paired box gene 5; PDI, protein disulphide isomerase; PLC, body light chain, binds the first constant-region domain of the newly
phospholipase C; POU2AF1, Pou domain, class 2, associating factor 1; POU2F2, Pou synthesized heavy chain, thereby retaining the heavy-chain polypeptide
domain, class 2, factor 2; PRDM1, positive regulatory domain 1-binding factor-1; in the cell’s endoplasmic reticulum. 6
RAG, recombination- activating gene; RSS, recombination signal sequence; SCID,
severe combined immunodeficiency; SHP-1, Src homology 2 domain-containing HEAVY CHAINS
protein tyrosine phosphatase-1; SHIP-1, phosphatidylinositol-3,4,5-trisphosphate Immunoglobulin heavy chains have an Mr of 50,000 to 70,000, depend-
5-phosphatase 1; TCFE2A, transcription factor E2a; UNG, uracil-DNA glycosylase; ing upon the number and length of the constant-region domains. The
V, variable-region gene; V(D)J, exon created by a rearranged immunoglobulin heavy- five major isotypes of heavy chains—γ, α, μ, δ, and ε—determine the
chain variable-region gene, diversity gene segment, and joining gene segment; five corresponding classes of immunoglobulin (Ig): IgG, IgA, IgM, IgD,
XBP1, X-box binding protein-1. and IgE. The individual immunoglobulin molecules of each isotype may
contain either κ or λ light chains, but not both. Tables 75–1 and 75–2

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