30

CONTENTS
Introduction 30
B Lymphocytes and the Humoral Immune
Response 30
Immunoglobulin Structure and Gene
Rearrangement 34
Immunoglobulin Function 38
Immunoglobulins and Human Disease 41
Summary 43
3
Immunoglobulin Structure
and Function
DIANE F. JELINEK | JAMES T. LI
Introduction
The hallmark features of the acquired immune response are the
B and T lymphocytes and their ability to recognize specic
antigens. T cells express the T cell antigen receptor (TCR) only
as a transmembrane molecule; B cells initially express immu-
noglobulin as a transmembrane molecule and later as a secreted
molecule after differentiation into plasma cells. A monomeric
antibody molecule consists of two identical heavy chains (HCs)
and two identical light chains (LCs). The B cell antigen receptor
(BCR) complex includes a transmembrane antibody, which
confers antigenic specicity, and requisite accessory signaling
molecules.
The humoral immune response exhibits remarkable diver-
sity. Humans typically generate 10 million different antibodies
and have the potential to generate billions, each specic for a
particular target. The antibody is elegantly constructed in a
manner that allows it to serve two complementary functions.
One region of the molecule confers the capability to recognize
and bind an enormous variety of antigenic determinants, and
the other region is involved in mediating a variety of diverse,
isotype-dependent biologic effects of the immunoglobulin,
such as complement xation or antibody-dependent cellular
cytotoxicity (ADCC).
The means by which immunoglobulins recognize antigens is
signicantly different from TCR antigen recognition. Secreted
or transmembrane immunoglobulin recognizes antigens in
their native, properly folded form, whereas the TCR recognizes
only antigens that have been processed and presented in the
context of the major histocompatibility complex (MHC) by an
antigen-presenting cell. B and T cells specic for the same
antigen are most likely recognizing different epitopes on that
antigen. Knowledge of the structural features of antibody
molecules and the genetics underlying the expansive immuno-
globulin repertoire is essential to understanding antigen-
antibody interactions and immunoregulation. The study of
hypersensitivity rightfully includes a review of antibody struc-
tural diversity and function.
B Lymphocytes and the Humoral
Immune Response
B and T cells develop from bone marrow hematopoietic stem
cells. Throughout life, the human body produces millions of
new B cells every day. In specialized bone marrow microenvi-
ronments, precursor B cells proceed through an orderly process
of antigen-independent development and immunoglobulin
gene rearrangement. Expression of a functional BCR is essential
for B cell development, maturation, and release from the bone
marrow. The BCR also plays a critical role during antigen-
induced activation of mature B cells in secondary lymphoid
tissues.
1
After differentiation into antibody-secreting plasma
cells, immunoglobulin molecules are largely expressed as
secreted molecules, and the rate of antibody production signi-
cantly increases. Plasma cells are capable of secreting thousands
of specic antibody molecules per second.
Transmembrane and secreted forms of immunoglobulin
from the same B or plasma cell exhibit the same antigenic
specicity, but they are different at the carboxyl (C) terminus
due to alternative messenger RNA (mRNA) splicing that results
in the presence or absence of a hydrophobic transmembrane
region (tail). This tail anchors immunoglobulin to the mem-
brane, and its absence enables immunoglobulin secretion (Fig.
3-1). B cell differentiation into plasma cells is accompanied by
the preferential processing of mRNA transcripts that encode the
secreted form.
SUMMARY OF IMPORTANT CONCEPTS
Antibodies specic for antigen mediate a variety of biologic
effects, including neutralization, activation of complement, and
interaction with specic cell surface Fc receptors.
To construct functional light and heavy immunoglobulin chain
genes, the discontinuous DNA coding sequences must rst be
rearranged.
Isotype class switching is highly T cell dependent and is regulated
through CD40 and the actions of cytokines.
Monoclonal and polyclonal immunoglobulins are used
therapeutically.
3 Immunoglobulin Structure and Function 31
the LYN tyrosine kinase, which phosphorylates tyrosine resi-
dues in the Ig/Ig ITAM motifs and triggers recruitment of
spleen tyrosine kinase (SYK) and Bruton tyrosine kinase (BTK).
Activated SYK phosphorylates and recruits the B cell linker
(BLNK) protein, which provides binding sites for phospholi-
pase C2 (PLC2), BTK, and VAV proteins, which are guanine
nucleotide exchange factors. PLC2 generates the second mes-
sengers inositol triphosphate and diacylglycerol, which are nec-
essary for calcium release from intracellular stores and protein
kinase C activation. BCR signal transduction also leads to acti-
vation of the mitogen-activated protein (MAP) kinase pathway.
B cell activation is further aided by a coreceptor complex that
amplies signals delivered by the BCR. The members of this
complex include CD19, the complement receptor type 2 (CR2
or CD21), and CD81. The CR2 enables the complement pathway
to synergize with BCR signal transduction, which enhances B
cell activation. Collectively, these signaling events lead to the
activation of the transcription factors known as nuclear factor
of activated T cells (NFAT), nuclear factor-B (NF-B), and
activator protein 1 (AP-1) (see Fig. 3-3).
1,9
HUMORAL IMMUNE RESPONSE
Peripheral B Cell Maturation and
Homeostatic Regulation
Immature, BCR-expressing B cells newly released from the bone
marrow are called transitional B cells, and only some of them
B CELL RECEPTOR STRUCTURE AND SIGNALING
Although the transmembrane forms of all immunoglobulin HC
isotypes possess cytoplasmic tails, they lack signaling motifs due
to their short length (3 to 28 amino acids). This limitation is
overcome by the association of one transmembrane immuno-
globulin molecule with one disulde-linked heterodimer con-
sisting of two polypeptides, Ig (CD79a) and Ig (CD79b) (Fig.
3-2). Ig and Ig are transmembrane glycoproteins character-
ized by an extracellular and intracellular C-terminal cytoplas-
mic domain that is obligatory for BCR signaling.
2
The
cytoplasmic domain of each Ig and Ig molecule contains an
important immunoreceptor tyrosine-based activation motif
(ITAM) sequence that allows the BCR to transmit downstream
signals after antigen binding.
2,3
The Ig/Ig heterodimer is essential for normal transport
and B cell membrane expression of all nine immunoglobulin
(Ig) isotypes. The Ig/Ig heterodimer also has a requisite role
in early B cell development. After rearrangement of the IgM ()
HC gene, pre-B cells must transiently express the HC on the
cell surface in association with surrogate LC and the Ig-Ig
heterodimer. This complex comprises the pre-BCR,
4
and its
expression stimulates the pre-B cell to undergo several rounds
of proliferation and allelic exclusion, preventing further rear-
rangement of HC genes on a sister chromatid, and rearrange-
ment of conventional LC genes.
5,6
Maturation of the pre-B cell
to an immature and then a mature B cell involves production
of or LCs that complex with HCs and the Ig/Ig het-
erodimer to form the mature BCR.
Engagement of the BCR by antigen initiates receptor aggre-
gation at the cell surface that is followed by recruitment to lipid
rafts, which are specialized membrane microdomains that facil-
itate assembly and activation of downstream signaling mole-
cules (Fig. 3-3).
7,8
This step places the complex in proximity to
Figure 3-1 Production of membrane and secreted chains in B cells.
Alternative processing of a primary RNA transcript produces mRNA
for the membrane or secreted form of the heavy chain; similar RNA
processing yields membrane and secreted forms for all nine heavy-
chain classes and subclasses. The tailpiece (TP), transmembrane (TM),
and cytoplasmic (CY) segments are indicated on the transcript. C

1,
C

2, C

3, and C

4 are four exons of the C

gene segment. D, Diversity

segment; J, joining segment; L, leader segment; V, variable segment.
(From Abbas A, Lichtman A, Pillai S. Cellular and molecular immunol-
ogy. 7th ed. Philadelphia: Saunders/Elsevier; 2012. p. 263.)
3ecreled lgV
Verorare lgV
Verorare rRNA
8 ce||
d|llererl|al|or
Pr|rary
RNA
lrarscr|pl
L v0J C

1 C

2 C

3 C

1 TP TV --- CY
Cylop|asr|c
AAA
3ecreled rRNA
Ta|| p|ece
AAA
Trarsrerorare
Po|yadery|al|or s|les
Resl|rg
8 ce||
Figure 3-2 B cell antigen receptor complex. Membrane immuno-
globulin M (IgM), along with all other types of transmembrane immu-
noglobulin, on the surface of mature B cells is associated with the
invariant Ig and Ig molecules, which contain immunoreceptor
tyrosine-based activation motifs in their cytoplasmic tails that mediate
signaling functions. One Ig/Ig heterodimer pairs with one trans-
membrane monomeric antibody molecule. Heavy-chain proteins are
shown in purple, and light chain proteins are shown in yellow. (From
Abbas A, Lichtman A, Pillai S. Cellular and molecular immunology. 7th
ed. Philadelphia: Saunders/Elsevier; 2012. p. 159.)
IgM
Ig Ig
Extracellular
space
Plasma
membrane
Cytoplasm
Immunoreceptor
tyrosine-based
activation motif (ITAM)
32 SECTION A Basic Sciences Underlying Allergy and Immunology
and low afnity, respectively. Unlike BAFF, APRIL binds only to
TACI and BCMA. APRIL effectively creates a higher-order
ligand by binding heparan sulfate proteoglycans such as synde-
cans, including CD138, on the surface of cells, allowing the
accumulation of APRIL trimers at high concentration in the
immediate vicinity of their target receptors. BAFFR is the rst
BBR expressed in B lineage cells, and expression is lost on
plasma cells. In contrast, TACI and BCMA expression appear
later, with BCMA serving as the primary plasma cell BBR.
Appropriate function of all three receptors is needed to regulate
B cell survival at several points in development. Whereas BAFFR
is necessary for mature B cell survival, BCMA and its high-
afnity ligand (APRIL) are required for survival of long-lived
plasma cells. TACI is important for class switch recombination
and for regulation of B cell proliferation (see Fig. 3-4, B).
10
T CellIndependent versus T CellDependent
B Cell Responses
Activation of the BCR on nave and memory B cells results in
their activation and migration to the draining lymph node or
other lymphatic tissue. B cells can respond to three types of
will develop into mature B cells. Factors regulating the number
of immature B cells navigating this transition include BCR
signals, limited space in the peripheral compartment due to
homeostatic regulation, and specic cytokines. A crucial cyto-
kine is the B cell activating factor belonging to the tumor necro-
sis factor superfamily (BAFF, also designated tumor necrosis
factor superfamily member 13B [TNFRSF13B]). On binding to
its specic receptor, the BAFF receptor (BAFFR), important
survival signals are delivered to maturing B cells. Maturation of
follicular B cells particularly depends on BAFF-BAFFR signal-
ing, and absence of BAFF or BAFFR in animal models results
in severe reductions of long-lived peripheral B cells or signi-
cant increases in the numbers of B cells on overexpression of
BAFF. High BAFF levels have been linked to several clinical
conditions in humans, including autoimmune and allergic dis-
eases, infections, and B cell lineage malignancies.
Transmembrane activator and calcium-modulating
cyclophilin ligand interactor (TACI) and B cell maturation
antigen (BCMA) (Fig. 3-4) are two additional BAFF-binding
receptors (BBRs), and another is called a proliferation-inducing
ligand (APRIL). TACI and BCMA bind BAFF with intermediate
Figure 3-3 Signal transduction by the B cell receptor (BCR) and its coreceptor complex. A, Antigen-induced cross-linking of the BCR leads to
clustering and localization in membrane lipid rafts. This relocation facilitates activation of SRC family tyrosine kinases and tyrosine phosphoryla-
tion of the immunoreceptor tyrosine-based activation motifs in the cytoplasmic domains of the Ig/Ig heterodimer. Activation leads to docking
of SYK and subsequent tyrosine phosphorylation events. B, The BCR coreceptor complex consists of the CR2 complement receptor, CD19, and
CD81. Microbial antigens that have bound the complement fragment C3d can simultaneously bind to the CR2 molecule and the BCR. Binding
triggers dual signaling cascades, which result in enhanced downstream signal transduction and B cell activation. Ig, Immunoglobulin; P, phos-
phate; PI3, phosphatidylinositol 3; PLC, phospholipase C. (Modied from Abbas A, Lichtman A, Pillai S. Cellular and molecular immunology. 7th
ed. Philadelphia: Saunders/Elsevier; 2012. p. 270-1.)
P
P P
LYN
P
P
P
P
P
Ig Ig Ig Ig
PLC
activation
Activated SRC
family kinases
(e.g., LYN, FYN, BLK)
GTP/GDP exchange
on RAS, RAC
Microbe
Bound
C3d
CR2
CD19
CD81
Pl3-kinase
SYK
P
P
P
IgM
SRC family
kinases
(e.g., LYN,
FYN, BLK)
Enhanced BCR signal transduction
and B cell activation
Increased
cytosolic Ca
2+
RASGTP
RACGTP
Complement
activation
Recognition
by B cells
Signals from
lg and CR2
complex
Cross-linking
of membrane
Ig by antigen
A
B
Tyrosine
phosphorylation
events
Biochemical
intermediates
Active
enzymes
Transcription
factors
Diacylglycerol (DAG)
PKC
NFAT AP-1 NF-B
PLC
ERK, JNK
SLP-65
GRB2
SYK
SOS
BTK
Ca
2+
-dependent enzymes
P
P
3 Immunoglobulin Structure and Function 33
of antigens are thymus dependent (TD), and they require T cell
help for full B cell activation.
11
There usually are few B and
T cells specic for the same antigen, and these cells must
make contact with each other. Lymphocyte recirculation to the
draining secondary lymph nodes or other lymphatic tissue
near the site of infection increases the chances of this critical
interaction.
As with TI antigens, TD antigens deliver signal 1 through the
BCR. The requisite second signal results from three B and T cell
receptor-ligand interactions that occur near each other. Because
B cells also function as antigen-presenting cells, the BCR inter-
nalizes antigen, processes it, and then displays antigenic pep-
tides on B cell MHC class II molecules that are recognized by
the TCR of antigen-specic T cells (Fig. 3-5). The next key
interaction occurs between B7-1 (CD80) and B7-2 (CD86)
expressed on B cells and the CD28 molecule expressed on T
cells. This interaction induces expression of CD40 ligand
(CD154) on T cells and subsequent activation of the CD40
molecule on B cells. These three sequential signals trigger T cell
cytokine secretion, which drives the immunoglobulin class
switch from IgM to other classes of antibodies as well as B cell
proliferation and differentiation into memory B cells, short-
lived plasma cells that die within the lymph nodes, and long-
lived plasma cells that migrate to the bone marrow. Various
T cellderived cytokines drive class switch recombination by
enhancing transcription through specic antibody switch
regions. For example, T cellderived interleukin-4 (IL-4) stimu-
lates transcription through the germline IgE class switch region,
a process that is necessary for IgE class switching.
Secreted antibodies produced in response to TD antigens
follow a typical pattern (Fig. 3-6). IgM production is character-
istic of an early primary immune response, and the class switch
to IgG (or IgA or IgE) occurs soon thereafter. At the end of the
primary immune response, the levels of IgM and IgG decrease.
However, on subsequent challenge with the same antigen, a
secondary response is observed that is characterized by much
faster and greater production of antigen-specic IgG with
higher afnity than was observed in the primary response due
antigens, and the type of antigenic exposure dictates the quality
of the ensuing response. There are two types of T cell
independent (TI) antigens. Type 1 TI antigens deliver the rst
signal through the BCR and the second signal through Toll-like
receptors. Type 2 TI antigens display repeating epitopes, allow-
ing the BCR to become extensively cross-linked and to activate
B cells in the absence of a second signal. Both types of TI anti-
gens result in low-afnity IgM responses and generation of
poor or no memory B cells. The third and most prevalent type
Figure 3-4 The BAFF/APRIL cytokine network. A, The cytokine
network consists of two main ligands: B cell activating factor belong-
ing to the tumor necrosis factor superfamily (BAFF) and a proliferation-
inducing ligand (APRIL). They are produced primarily by dendritic
cells, macrophages, osteoclasts, and stromal cells. BAFF occurs in the
immune milieu as a soluble trimer (sBAFF), a membrane-bound trimer
(mBAFF), and a 60-mer viruslike particle. APRIL occurs only in soluble
form or bound to heparan sulfate proteoglycans. Heteromers of the
ligands and BAFF and APRIL variants are not shown. B, The BAFF
receptor (BAFFR) is expressed on the surface of all B cells from the
rst expression of a complete B cell receptor (BCR) until differentia-
tion into plasma cells. The transmembrane activator and calcium-
modulating cyclophilin ligand interactor (TACI) is induced in later
stages of development beginning at activation, and the B cell matura-
tion antigen (BCMA) identies plasma cells almost exclusively. The
ligands of the system have various afnities for each receptor. BAFFR
binds only BAFF, TACI binds APRIL and BAFF with comparable afn-
ity, and BCMA has a distinctly higher afnity for APRIL than for BAFF.
CRD, Cysteine-rich domain; THD, tumor necrosis factor homology
domain.
THD
Furin cleavage
site
Proteoglycan-
binding domain
CRD
Partial CRD
APRIL
TACI
TACI
CD138
Pre-BCR
BCR
CD138
B lineage cell
Supportive cell
BCMA
BCMA
Memory B
Mature B
Plasma cell
Immature B Pre-B
BAFFR
BAFFR
BAFF 60-mer
mBAFF
sBAFF
A
B
Figure 3-5 Activation of B cells by T celldependent antigens. Spe-
cic B cells capture antigen through their B cell receptor (BCR), trig-
gering its internalization and subsequent processing and re-expression
on the surface on major histocompatibility complex (MHC) class II
molecules. Recognition of this complex by the T cell receptor (TCR)
of the antigen-specic T cells results in costimulatory signals delivered
through T cell CD28 and B cell B7 interactions, followed by T cell
CD40L and B cell CD40 interactions. The two forms of B7 are B7-1
(CD80) and B7-2 (CD86). T cells provide further help through secretion
of specic cytokines. (From Delves PJ, Martin SJ, Burton DR, Roitt IM.
Roitts essential immunology. 12th ed. Oxford: Wiley-Blackwell; 2011.
p. 219.)
T cell
Cytokines
CD4OL
TCR
CD28 B7
MHC
CD40
B cell
34 SECTION A Basic Sciences Underlying Allergy and Immunology
actively compete and dislodge existing plasma cells to gain
access to the survival advantages provided by the bone marrow
microenvironment.
13,14
Immunoglobulin Structure and
Gene Rearrangement
IMMUNOGLOBULIN PROTEIN STRUCTURE
Immunoglobulins are composed of two identical HCs and two
identical LCs (Fig. 3-7, A). LCs lack transmembrane domains
and are anchored to HCs by disulde bonds. The two HCs are
linked to each other by a distinct set of disulde bonds. Each
HC or LC has two major domains referred to as the constant
region (C) and the variable region (V), with each domain
responsible for a specialized function. They are denoted as C
L

and V
L
for the LCs and as C
H
and V
H
for the HCs.
Early studies subjecting intact immunoglobulin molecules to
limited enzymatic proteolysis in vitro were key in mapping
antibody functional domains. Papain cleaves the IgG hinge
region at the amino (N)-terminal side of the HC disulde
bonds to produce three fragments (see Fig. 3-7, A). Two frag-
ments are identical and are formed by intact LCs bound to the
V
H
and C
H
1 regions of the HCs. These fragments, referred to as
Fab fragments were able to bind antigen, enabling the discovery
that the variable domains of LCs and HCs combine to form the
antigen-binding site of the antibody. Fab fragments are mon-
ovalent and lack immunoglobulin effector functions. The third
fragment is composed of the C-terminal portion of the HCs
bound to each other. The ability of this Fc fragment to bind to
complement or Fc receptors (FcRs) but not to antigen allowed
mapping of antibody effector function to this region. The class
of antibody with its effector function is determined solely by
the structure of its HC. Use of the protease pepsin allowed
identication of the F(ab)
2
fragment based on cleavage of IgG
at the C-terminal side of the HC disulde bonds. Maintenance
of the disulde bond linking the two HCs results in a fragment
that consists of both Fab regions, rendering it bivalent and
capable of precipitating and cross-linking antigen. The identical
antigen specicity of the two Fab regions permits antigen-
mediated cross-linking and is of fundamental importance to
BCR-mediated activation of B cells and the effector activity of
secreted antibodies.
Immunoglobulin LCs contain about 220 amino acid residues
and have an approximate molecular weight of 23 kD. Amino
acid sequence analysis of several LCs revealed that they are
composed of two similar segments, each with about 110 amino
acids. One region has a variable sequence between individual
LCs, and the other is constant, depending on the precise LC
isotype. In a similar manner, HCs have a variable domain, but
instead of one constant domain, as in LCs, they have three or
four constant-region domains (i.e., C
H
1, C
H
2, C
H
3, and C
H
4),
depending on the immunoglobulin HC isotype (see Fig. 3-7,
B). Sequence analysis of the V
L
and V
H
regions from multiple
antibodies revealed three regions that have hypervariable
sequences. These regions are also called complementarity-
determining regions (CDRs). X-ray crystallographic studies of
human myeloma proteins indicated that the three HC and three
LC CDRs come together in the antibodys three-dimensional
structure to form the unique antigen-binding pocket. The HC
CDR3 region plays a particularly prominent role in determin-
ing antibody specicity.
to activation of memory B cells generated during the primary
response.
Antibodies to previously seen antigens are commonly
detected in serum decades after the last known exposure.
Long-lived plasma cells occupying unique niches in the bone
marrow are thought to be responsible for this remarkable
feature of humoral immunity.
12
Longevity of humoral immu-
nity, however, may not always be desirable. Food-specic IgE-
secreting plasma cells provide an example of this point. Although
it is clear that long-lived plasma cells can survive for some time
in the bone marrow, a key unanswered question is whether
an individual plasma cell survives for the life of the host
or continuously replicates at a slow rate. It has been proposed
that there is a limited long-lived plasma cell survival niche in
humans determined by the frequency of VCAM-1
+
/CXCL12
+

broblast-like reticular stromal cells. Study results suggest that
other cell types, such as megakaryocytes, basophils, and eosino-
phils, may also participate in forming plasma cell niches. Given
the limited space and apparent nite threshold of long-lived
plasma cells in each person, newly formed plasma cells must
Figure 3-6 Typical primary and secondary humoral response of
serum IgM and IgG levels after the rst and subsequent exposures to
a given antigen. Low-afnity IgM antibodies are the rst class of anti-
body typically secreted in an immune response. IgG (and isotypes
such as IgA and IgE) levels rise later in the primary response, but they
become prominent on antigen reexposure. Afnity maturation result-
ing from the somatic hypermutation process is largely seen in IgG
antibodies and to a lesser extent in IgA and IgE antibodies. Ig, Immu-
noglobulin. (From Abbas A, Lichtman A, Pillai S. Cellular and molecular
immunology. 7th ed. Philadelphia: Saunders/Elsevier; 2012. p. 451.)
10,000
1,000
100
10
1
0.1
0.01
IgM
IgM
IgG
IgG
C
o
n
c
e
n
t
r
a
t
i
o
n

(

g

m
L

1
)
A
f
f
i
n
i
t
y

(
M

1
)
10
10
Immunization
Time after immunization (wk)
Antibody Affinity
Antibody Level
10
9
10
8
10
7
10
6
10
5
10
4
1 0
1 2 3
2 3 4 5 6 7 8
3 Immunoglobulin Structure and Function 35
HUMAN LIGHT- AND HEAVY-CHAIN
IMMUNOGLOBULIN GENE LOCI
In humans, the immunoglobulin HC locus is on chromosome
14, and the and LC loci are located on chromosomes 2
and 22, respectively (Fig. 3-8). One level of antibody diversity
derives from multiple HC and LC variable (V) gene segments.
In each case, this cluster of functional V genes, (about 30 to 40
different V

, V

, or V
H
genes) is located at the 5 end of the locus.
Invariant amino acid residues in the HC and LC sequences
located at contact points between LC and HC domains allow
the LCs and HCs to pair in many combinations. Immunoglobu-
lins are glycoproteins, and there is evidence that glycosylation
affects the biologic function and structure of human immuno-
globulins.
15
Monoclonal antibodies produced in vitro without
carbohydrates exhibit impaired complement and FcR binding
and have enhanced ADCC activity.
Figure 3-7 Basic structure of immunoglobulin molecules. A, In the monomeric structure of immunoglobulin molecules, disulde bridges link
the two heavy chains and the light chains with heavy chains. Enzymatic digestion with papain cleaves the immunoglobulin molecule into three
fragments: two Fab fragments, each of which can bind a single antigen epitope, and the Fc fragment, which can bind to Fc receptors. Alterna-
tively, pepsin digestion of immunoglobulins results in a single F(ab)
2
fragment, which remains capable of cross-linking and precipitating multi-
valent antigen. The Fc portion usually is digested into several smaller peptides by pepsin (pFc). B, Schematic structures of the ve classes of
antibodies. IgG1 and IgA1 are shown as examples of the basic structure of the IgG and IgA classes of antibodies. The other IgG subclasses
differ primarily in the nature and length of the hinge, and the IgA2 hinge region is very short compared with IgA1. Although membrane IgM
and IgA exist as monomers, secreted IgA can exist as dimers, and secreted IgM as pentamers, when linked by an extra polypeptide called the
J chain. Both multimeric forms of antibodies can be transported across mucosal surfaces by binding to the polymeric immunoglobulin receptor.
Dimeric IgA coupled to the J chain and secretory component, a part of the polymeric immunoglobulin (Ig) receptor remaining after transport
through epithelial cells, is shown as an example of secretory Ig. (From Delves PJ, Martin SJ, Burton DR, Roitt IM. Roitts essential immunology.
12th ed. Oxford: Wiley-Blackwell; 2011. p. 56, 62.)
COOH COOH
Fc fragment
Fab fragment
F(ab)
2
fragment
pFc
Fab
Fc
V
H
V
L
C
L
Hinge
C

1
V
H
V
L
C
L
C

1
V
H
V
L
C
L
C

1
C

2
C

2
C

3
C

2
C

3
C

3
C

4
N termini
IgG1 IgA1 IgM
IgE
C termini
Tailpieces
Tailpieces
V
H
V
L
C
L
C

1
V
H
V
L
C
L
C

1
V
H
V
L
C
L
C

1
C

2
C

2
C

3
C

2
C

3
C

4
IgD Secretory IgA
S
-
S
S
-
S
S
-
S
S
-
S
S
-
S
S
-
S
S
-
S
S
-
S
S-S
S-S
S-S
Heavy chain
Pepsin cleavage
CHO CHO
Papain cleavage
Variable
region
Constant region
S
-
S S
-
S
S
-
S S
-
S
S-S
Ch2
Ch1
Ch3
Light chain
Vh
Vl
Cl
Hinge
A
B
C

3
C

2
Hinge
+
+

Secretory
component
Tailpieces
J chain
C

1
C

2
C

4
C

3
V
H
J
chain
36 SECTION A Basic Sciences Underlying Allergy and Immunology
GENERATION OF IMMUNOGLOBULIN
DIVERSITY AND CLASS SWITCH
V(D)J Light- and Heavy-Chain Gene Rearrangement
Except for B cells, all cell types in the body display a germline
organization of the immunoglobulin genes (see Fig. 3-8).
Organization of the genes encoding TCRs is strikingly similar
to that for immunoglobulin loci, and these genes also undergo
rearrangement. The transcription of immunoglobulins or
TCRs dees many conventions of traditional molecular biol-
ogy and involves directed DNA breakage, rearrangement, and
repair.
16
To provide protection from any potential pathogen, the
average human has 10 million unique antibodies. If each of
these antibodies were encoded by a unique gene, immuno-
globulin genes alone would take up the entire human genome.
The great diversity observed in the immunoglobulin repertoire
results from many mechanisms rather than depending on
genomic DNA sequences alone. Immunoglobulin diversity has
four sources: multiple V(D)J genes in the germline, random
assortment of HCs and LCs, junctional nucleotide variability
introduced during pre-B cell immunoglobulin gene rearrange-
ment, and somatic hypermutation of immunoglobulin variable
regions after encounters with TD antigens.
To generate functional LC and HC genes, the discontinuous
V(D)J coding sequences must rst be rearranged at the DNA
level. This is a process unique to B cells and T cells. The immu-
noglobulin HC rearranges rst during B cell development and
results in the random use of one V, one D, and one J gene, which
are rearranged into one exon that encodes the complete HC
variable region. Rearrangement results in permanent loss of
variable amounts of intervening genomic DNA that may contain
unused V-, D-, and J-region genes. If the rearranged V(D)J
exon encodes an open reading frame, pre-B cells make HC
protein, which is necessary to trigger LC gene rearrangement.
After a successful rearrangement has occurred, the respective
allele on the other chromosome is silenced by allelic exclusion
to ensure that only one immunoglobulin of one specicity is
expressed on any given B cell. However, if the rst rearrange-
ment does not result in a functional LC protein (i.e., a nonpro-
ductive rearrangement), the second allele will then rearrange.
If the latter event is also nonproductive, the developing B cell
will die.
Rearrangement requires two recombination signal sequences
(RSS-12 and RSS-23) that ank each of the germline V, D,
and J genes in a specic manner. Recombination occurs only
between dissimilar RSS signals (i.e., the 12/23 rule). For example,
each HC V
H
gene has the RSS-23 at its 3 terminus, each D
H

gene has the RSS-12 on both ends, and each J
H
gene has the
RSS-23 at its 5 terminus (preventing direct V
H
-J
H
recombina-
tion). The RSS are critical for double-strand breaks mediated
by the lymphoid-specic genes, called recombination-activating
gene 1 (RAG1) and RAG2. Expression of RAG1 and RAG2 pro-
teins is tightly regulated during B cell and T cell development,
and deciencies in the RAG genes lead to severe combined
immunodeciency (SCID) syndrome caused by the inability
of B cells and T cells to generate antigen receptors. Although
T and B cells express RAG1 and RAG2 during their develop-
ment, each rearranges only its unique antigen-recognition mol-
ecules. RAG-mediated DNA cleavage is followed by a DNA
recombination event that is similarly complex and error prone
and involves several enzymes that are present only in developing
The HC and LC V genes are organized into families with
approximately 80% sequence homology within each family.
There are 7 V

and V
H
families and 11 V

families. Each V gene

includes a 5 leader sequence, which encodes a signal peptide
necessary for guiding newly translated polypeptides into the
endoplasmic reticulum. Mature immunoglobulin molecules
lack this sequence because it is rapidly cleaved during the trans-
port process. Each V gene also has a 5 promoter that increases
transcription after rearrangement, placing the promoter closer
to the powerful immunoglobulin enhancer elements 5 of
constant-region genes.
HC variable regions are encoded by one V gene, which
encodes most V-region amino acids, as well as 1 of 23 diversity
(D) and 1 of 6 joining (J) gene segments that are located 3
of the V gene cluster. In contrast, LC variable regions are
encoded by only two types of genes: V genes and J genes.
Whereas the J

genes are organized in a cluster 3 to the V

gene
cluster, J

genes are interspersed with constant-region genes

(see Fig. 3-8).
In the HC and LC constant regions, the LCs are simplest
because there is only one constant-region gene. There are four
constant-region genes. In both LCs, a single exon encodes
approximately 100 to 110 constant-region amino acids. The
immunoglobulin HC locus encodes nine constant-region genes.
Because of the larger size of HCs, three or four exons encode
the bulk of the constant region, and two additional exons are
variably processed at the mRNA level, resulting in transmem-
brane or secreted antibodies (see Fig. 3-1).
Figure 3-8 Germline organization of human immunoglobulin gene
loci. The human heavy-chain (H) locus resides on chromosome 14, and
human - and -chain loci reside on chromosomes 2 and 22, respec-
tively. Pseudogenes are excluded from this diagram. Each H-chain
constant region (C
H
) gene is shown as a single box, but it is composed
of several exons (see Fig. 3-1). Gene segments are designated as
follows: leader (L) (i.e., signal sequence), variable (V), diversity (D),
joining (J), constant (C), and enhancer (enh). (Modied from Abbas A,
Lichtman A, Pillai S. Cellular and molecular immunology. 7th ed.
Philadelphia: Saunders/Elsevier; 2012. p. 179.)
H chain locus (1250 kb; chromosome 14)
chain locus (1820 kb; chromosome 2)
chain locus (1050 kb; chromosome 22)
C

enh
enh
enh enh
3
3
5
5
J
H D
H
(n = 23)
(n = ~40)
(n = ~35)
(n = ~30)
L V
H
1
L V

1
J

1 J

2 C

1 C

2 J

3 C

3 J

7 C

7
L V

n
enh
3 5
L V

1 L V

n
L V
H
n
C

2 C

4 C

2
C

3 C

1 C

1
3 Immunoglobulin Structure and Function 37
The process of afnity maturation results in selective clonal
expansion of B cells expressing high-afnity BCRs. This is
achieved through the preferential introduction of mutations in
all three immunoglobulin HC and LC CDRs. Somatic hyper-
mutation and class switch recombination (described later)
require expression of activation-induced cytidine deaminase
(AID), a highly mutagenic enzyme. AID expression is induced
primarily by CD40 signals delivered by CD40L-expressing acti-
vated T cells. AID has a mutation rate that is approximately one
million times greater than the spontaneous DNA mutation rate.
Because AID-mediated mutations are random, some mutations
may disrupt the open reading frame or reduce antibody afnity.
Mutations that increase the afnity of the BCR for antigen
afford the activated B cell a competitive advantage, leading to
its preferential clonal expansion. This is the basis for observa-
tions that higher-afnity antibodies are prevalent in the second-
ary and later immune responses.
Immunoglobulin Class Switch Recombination
As shown in Figure 3-8, the nine human constant-region genes
are located 3 to the V
H
, D
H
, and J
H
gene clusters and arranged
in the following order: , , 3, 1, 1, 2, 4, , and 2. The
exons encoding the constant region are located closest to the
J
H
cluster, and this proximity is the reason that IgM is the rst
antibody isotype expressed in developing B cells. The exons
encoding the constant-region gene are located just down-
stream of the constant-region genes, and most mature nave
B cells coexpress surface IgM and IgD. Transmembrane IgM and
IgD exhibit identical HC variable regions but differ in their
constant regions due to differential mRNA processing and splic-
ing in a manner analogous to the mechanism that permits
B cells to coexpress transmembrane and secreted immunoglob-
ulins (see Fig. 3-1).
Classic class switch recombination requires AID and involves
a switch from IgM expression to any of the downstream HC
constant-region genes other than .
22
Class switch recombina-
tion occurs at the DNA level and involves deletion of inter-
vening genomic DNA. IgM antibodies are produced rst,
followed by a switch to IgG (or IgA or IgE) antibodies. The
isotypes share the same recombined V region and therefore
share antigen-binding specicity. B cell class switching is
antigen dependent and occurs during activation in lymphoid
tissue germinal centers. The switch in immunoglobulin class
depends on nucleotide sequences called switch regions, which
are located at the 5 ends of each HC constant-region gene
except . As the immunoglobulins switch classes, the HC genes
between the recombined V(D)J segments and the current C
H

gene are permanently deleted and can never be used again by
that B cell. However, sequential isotype switching can occur,
meaning that any constant-region gene downstream of the
gene currently being used remains available for use by that
B cell (Fig. 3-9).
Cytokines play a major role in class switch recombination.
Cytokine-specic response elements reside in the promoter
region of each constant-region gene S region, and transcription
through the region is required for the process of class switch
recombination. For example, the helper T cell type 2 cytokines
IL-4 and IL-13 can direct class switching to IgG4 and IgE,
whereas interferon- can inhibit class switching to these two
isotypes. Similarly, transforming growth factor- induces a class
switch to IgA. Isotype switching is highly T cell dependent,
although there is evidence that BCR signaling in concert with
lymphocytes and other ubiquitously expressed DNA double-
strand breakrepair enzymes.
After HC signaling in concert with surrogate LCs and
Ig and Ig, one of the LC alleles is triggered to rearrange
one V gene next to one J gene in a manner analogous to HC
V regions. If this rearrangement is not productive, the develop-
ing B cell next attempts rearrangement of the second allele
and each of the two LC alleles if necessary. The V(D)J rear-
ranged segments remain in this conguration throughout the
lifetime of the individual B cell or plasma cell, and intronic
sequences segregate the V(D)J exon from constant-region
genes. The nal coding sequence for the full HC or LC requires
RNA processing to yield functional mRNA coding for the
mature HC or LC.
Signicant additional diversity is introduced during the
joining process and is referred to as junctional diversity. The
exact site of recombination between the V, D, and J segments
typically varies by a few nucleotides, resulting in further diver-
sity of this region. CDR3 overlaps with this region. However,
the sloppy joining of the V(D)J genes means that by chance, one
in three rearrangements will not be nonproductive.
17
Random,
nontemplated nucleotides may be added at V-D-J junctions by
terminal deoxynucleotidyl transferase. This form of junctional
diversity is termed nucleotide (N) diversity. A third form of
junctional diversity results from the insertion of palindromic
(P) nucleotides, which are short inverted-repeat sequences
identied at V(D)J junctions. Because each of these mecha-
nisms specically affects the CDR3 region, if the nucleotide
changes result in amino acid changes, they can have a dramatic
effect on the antigenic specicity of the nal immunoglobulin
molecule.
Because immunoglobulin gene rearrangement occurs in an
antigen-independent manner, it is possible that some newly
generated BCRs may be autoreactive. However, if the immature
autoreactive B cell encounters specic self-antigens in the bone
marrow in a molecular form that causes extensive BCR cross-
linking, the B cell dies. If B cells expressing autoreactive BCRs
escape this negative selection and leave the bone marrow as
mature B cells, a second level of regulation must still be over-
come. Most B cells require T cell help to develop into memory
B cells and plasma cells. For the autoreactive B cell to become
activated to produce autoantibodies, it needs to interact with
similarly autoreactive T cells. In contrast to B cells, T cells
undergo a very extensive process in the thymus to eliminate
autoreactive T cells or render them nonfunctional. In the
absence of T cells recognizing the same autoantigen, autoreac-
tive B cells should not be activated. The autoreactive B cells also
can edit their BCRs through a process referred to as receptor
editing.
18
This process requires RAG1 and RAG2 expression and
results in replacement of the autoreactive V region with a new
one, thereby modifying the antigenic specicity of the B cell.
Receptor editing can occur during B cell development or in the
periphery, and it can take place at both HC and LC loci.
19-21
Immunoglobulin Somatic Hypermutation
Because the HC and LC CDRs comprise the antigen-binding
pocket, amino acid variability in these regions diversies antigen
recognition. Although signicant diversity is introduced into
the CDR3 during antigen-independent B cell development, all
three CDRs can acquire additional diversity during antigen-
dependent activation in secondary lymphoid organs through
the process of immunoglobulin somatic hypermutation.
38 SECTION A Basic Sciences Underlying Allergy and Immunology
the IgG subclasses are closely related isotypes that exhibit a
similar overall structure. The two subclasses of IgA are similarly
related to each other. There are two types of LCs: and . There
are four subtypes but only one form of .
Specialized Effector Functions of
Immunoglobulin Molecules
The nine class and subclasses of antibody molecules have sig-
nicantly different expression levels, anatomic locations, and
effector functions (Table 3-1). The ve antibody classes also
display characteristic structural features (see Fig. 3-7, B). For
example, the number of constant domains varies among the
classes, there are notable differences in the hinge region between
classes, and IgM and IgA can exist in monomeric as well as
multimeric congurations.
Immunoglobulin M. Transmembrane, monomeric IgM is the
earliest immunoglobulin expressed by developing B cells.
Antigen binding results in B cell activation and differentiation,
leading to IgM secretion. An increase in antigen-specic IgM
levels indicates a primary immune response. IgM is secreted as
a pentamer of ve IgM monomers linked together by disulde
bonds with the J chain, a 15-kD glycoprotein rich in cysteine
residues. Because of its size, pentameric IgM is largely found in
serum. IgM is extremely effective at xing complement and
neutralizing antigens, and it can bind to effector cells expressing
the Fc receptor, Fc/R.
24,25
Because pentameric IgM includes
the J chain, it can bind to the poly-Ig receptor on the basolateral
surface of mucosal epithelial cells. The poly-Ig receptor facili-
tates immunoglobulin transport through the epithelial barrier,
and it is ultimately cleaved and remains bound to mucosal
immunoglobulins as the secretory component (Fig. 3-10, A).
26
Immunoglobulin D. Because of alternative mRNA splicing,
IgD is typically coexpressed with IgM on the surface of mature
B cells before antigenic stimulation. IgM and IgD may deliver
qualitatively different signals, perhaps as a result of their ability
to associate with different BCR-associated proteins. There is
evidence that IgD signaling may protect B cells from being
tolerized. IgD is also present in serum, albeit at very low con-
centrations. A small subset of B cells in humans expresses IgD
in the absence of IgM due to a noncanonical form of class
switch recombination that occurs in upper respiratory mucosa.
IgM

IgD
+
human B cells use only LCs. Secreted IgD binds to
basophils and other innate immune cells through unknown
receptors, which on cross-linking promotes antimicrobial
activities.
27,28
Immunoglobulin G. IgG is secreted as a monomer and is the
major class of antibody in serum and nonmucosal tissues.
Among the four subtypes of IgG, IgG1 is by far the most preva-
lent, followed in decreasing order by IgG2, IgG3, and IgG4.
Although the IgG subtypes are 90% to 95% homologous,
they have different functional properties (see Table 3-1).
29

One key difference is that IgG1, IgG2, and IgG3 (but not IgG4)
can activate the complement cascade. A unique role of IgG
is providing passive immunity to infants, because this is the
only immunoglobulin isotype that can cross the placenta by
means of the neonatal Fc receptor (FcRn). Because IgG2 is rela-
tively inefcient at crossing the placenta, the other three sub-
classes constitute most of the passively transferred maternal
antibody.
Toll-like receptor signaling may induce class switch recombina-
tion in the absence of T cell help in response to microbial
pathogens.
23
T cellderived cytokines regulate switching, and
direct T and B cell collaboration is necessary for induction
of AID expression and normal class switch recombination
through CD40.
Immunoglobulin Function
SPECIALIZED IMMUNOGLOBULIN CLASS
FUNCTIONS AND EXPRESSION LEVELS
Structural Differences in Immunoglobulin Molecules
The ve classes of antibody molecules are designated IgM, IgD,
IgG, IgA, and IgE. The IgG and IgA classes have more than one
member. There are four IgG () subclasses, designated as IgG1,
IgG2, IgG3, and IgG4, and their constant regions exhibit 90%
homology with each other. However, because each IgG subclass
constant region is encoded by a separate constant-region gene,
Figure 3-9 Diagram of human immunoglobulin (Ig) class switch
recombination from IgM or IgD expression to IgE. A, The and
heavy-chain proteins are coexpressed on B cells as a result of alterna-
tive RNA transcription and processing. On receipt of signals delivered
by T cells, activation-induced cytidine deaminase (AID) expression is
induced. AID introduces DNA double-strand breaks in the transcrip-
tionally active switch (S) regions that lie upstream of each constant-
region gene except C

. B, Cytokine signals determine the isotype to

which B cells will switch to by inducing specic transcription from
distinct promoters located upstream of each S region. C, Intervening
constant-region genes are eliminated through a process of intrachro-
mosomal deletion. D, Diversity segment; J, joining segment; V, vari-
able segment. (Modied from Stavnezer J, Guikema JE, Schrader CE.
Mechanism and regulation of class switch recombination. Annu Rev
Immunol 2008;26:263.)
A
B
C
S S S S S S S
S
C

3
C

3
C

1 VDJ
Switch recombination
(requires DSBs)
Heavy chain genes
in IgE-expressing cells
VDJ
Heavy chain genes in IgM-expressing cells
AID
AID
AID
AID
C

4
C

4
C

mRNA
mRNA
mRNA
Germline
transcript
C

2
C

2
S VDJ C

2
C

2
C

2
C

1
C

1
C

1
3 Immunoglobulin Structure and Function 39
for an antigenic determinant is determined by the sum of the
noncovalent forces between the antigen-binding site of the
immunoglobulin and the antigen itself. Because the strength of
these noncovalent forces is greatly increased at short distances,
the strongest binding site and determinant interactions occur
when complementarity exists between the two structures. The
interaction of oscillating dipoles of adjacent atoms generates van
der Waals forces, which result in the atoms mutual attraction.
Because the attractive force is greatest at distances of only 0.18
to 0.20 nm, the strongest binding occurs when complementarity
is greatest. The COO

or NH
4
+
side groups on polar amino acids
lining the antibody-binding site can interact with oppositely
charged moieties on antigenic determinants to form electrostatic
bonds. Hydrogen bonds may also be involved, and effects are
maximal at distances of 0.2 to 0.3 nm. Both steric t of antigen
to the combining site and juxtaposition of attracting chemical
groups are essential for efcient antibody-ligand binding.
30
The term avidity is used in a semiquantitative way to describe
the overall binding of antibodies to antigen, which is highly
dependent on immunoglobulin valence. Antibody avidity is an
average measure of the afnity of the antibodies for a particular
antigen, and increases in avidity during an immune response
are largely a result of somatic hypermutation and subsequent
selection of high-afnity B cells.
31
When antigen has multiple
identical sites, the valence of the antibody contributes signi-
cantly to the stability of the antigen-antibody complex, such as
the binding of pentameric IgM to a multideterminant antigen.
IMMUNOGLOBULIN-MEDIATED CLEARANCE
OF ANTIGENS
Antibodies have three major effector functions after binding
antigen. First, neutralization of the antigen or toxin by forma-
tion of soluble complexes prevents further binding of that
antigen to other cells. Second, antibodies can promote phago-
cytosis of antigens through complement cascade activation or
interactions with FcRs. Third, the cross-linking of antibodies
bound to FcRs on effector immune cells, such as natural killer
(NK) cells or macrophages, leads to ADCC.
Immunoglobulin A. Humans produce more IgA than any
other class of antibody, and the major role of IgA is mucosal
immunity.
27
The two subclasses of IgA, IgA1 and IgA2, can exist
as monomers or dimers tethered together by a J chain. Although
most monomeric serum IgA is IgA1, secreted IgA is split evenly
between the two subtypes. IgA dimers contain a single J chain
joined to two IgA monomeric subunits. Like IgM, polymeric
IgA can bind to the poly-Ig receptor and be transported across
mucosal epithelium, and it is the primary antibody found in
mucosal tissue secretions (see Fig. 3-10, A). The shorter hinge
region of IgA2 renders this subclass of IgA more resistant to
bacterial proteases than IgA1, providing a distinct advantage in
the mucosal environment.
Immunoglobulin E. IgE is secreted as a monomer and plays a
key role in responses to parasitic infections. Most IgE is bound
to high-afnity IgE Fc receptors (FcRI) on mast cells or baso-
phils. Binding of antigen to the FcRI-bound IgE antibodies
triggers the central event in type I hypersensitivity. Although
IgE is typically not seen at high circulating levels in Western
societies, it is often elevated in atopic persons (see Chapters 23
and 69).
ANTIGENIC EPITOPES AND
ANTIBODY-ANTIGEN INTERACTIONS
Binding of antigenic determinants to the antibody-combining
site is similar to other forms of ligand-receptor interactions.
However, antibody binding is unique in that a vast number of
related molecules have different binding specicities. In their
natural environment, antibodies usually bind to complex mac-
romolecules such as proteins, polysaccharides, phospholipids,
and nucleic acids. The ability of an antiserum to bind with
complex, multideterminant macromolecules depends on the
number of binding sites in addition to intrinsic equilibrium
constants, and immunoglobulins can be described in terms of
their afnity and their avidity for a particular antigen.
The term afnity reects antibody binding with a single
epitope or binding site. The afnity of an antibody-binding site
Selected Biologic Properties of Human Immunoglobulin Isotypes
Characteristics IgG1 IgG2 IgG3 IgG4 IgM IgA1 IgA2 IgD IgE
PHYSICAL PROPERTIES
Molecular weight (kD) 146 146 165 146 970* 160 160 170 190
Serum half-life (days) 29 27 7 16 5 6 6 2
ANATOMIC DISTRIBUTION
Mean serum level (mg/mL) 5-12 2-6 0.5-1.0 0.2-1.0 0.5-1.5 0.5-2.0 0-0.2 0-0.4 0-0.002
Transport across placenta +++ + ++
Transport across epithelium + +++

+++

Extravascular diffusion +++ +++ +++ +++ ++

++

+ +
FUNCTIONAL ACTIVITY
Antigen neutralization ++ ++ ++ ++ ++ ++ ++
Complement xation ++ + ++ +++ + +
ADCC + + + +
Immediate hypersensitivity +++
ADCC, Antibody-dependent cellular cytotoxicity; , no effect; , no effect or negligible degree; +, small degree; ++, moderate degree; +++, large
degree.
*Pentameric IgM plus J chain.

Dimer.

Monomer.
TABLE
3-1
40 SECTION A Basic Sciences Underlying Allergy and Immunology
immunoglobulin superfamily, are widely distributed, and have
different afnities for immunoglobulin (Fig. 3-11).
Fc Receptors. There are four types of Fc receptors for IgG:
FcRI, FcRII, FcRIII,
32-34
and a fourth type called FcRn, which
is expressed in neonates, where it is responsible for binding
maternal IgG for transport across the placenta. FcRn is also
expressed on the surface of several adult cell types, including
endothelial cells.
35
When IgG binds to the FcRn, it is internal-
ized into endosomes for some time before being released back
into the circulation; this explains the longer serum half-lives of
IgG antibodies, particularly IgG1, IgG2, and IgG4 (see Fig. 3-10,
B). FcRI (CD64) is expressed on macrophages, monocytes,
neutrophils, and dendritic cells, and it functions as the major
phagocytic FcR. It is also the only FcR that binds monomeric
IgG1 and IgG3 with high afnity.
The three forms of FcRII (CD32) are FcRIIA, FcRIIB2,
and FcRIIB1. Each FcRII form recognizes the same ligands
through use of the same extracellular domain. FcRIIA is an
activating receptor, but FcRIIB1 and FcRIIB2 are inhibitory
receptors because of the presence of an immunoreceptor
tyrosine-based inhibitor motif (ITIM) in their cytoplasmic
domains. All three forms of FcRII bind monomeric IgG poorly
but do bind immune complexes containing IgG1 and IgG3 with
higher afnity.
FcRIII (CD16) is a 50- to 80-kD glycoprotein that can be
attached to the membrane by a transmembrane tail or linked
by glycosylphosphatidylinisotol (GPI). FcRIII binds IgG1,
IgG3, and lectins and is highly expressed on neutrophils. FcRIII
has low afnity for monomeric IgG and exists in two forms,
referred to as FcRIIIA and FcRIIIB. FcRIIIA is primarily
expressed on macrophages and NK cells, whereas the FcRIIIB
is expressed on neutrophils and eosinophils. Because the B
isoform is anchored in the membrane by GPI linkage, it lacks a
signaling motif. Its function remains poorly understood.
36
Fc Receptors. There are at least three distinct IgA receptors.
FcRI (CD89), a 55- to 75-kD glycoprotein that binds IgA1 and
IgA2, is expressed on macrophages, neutrophils, and eosino-
phils.
37
FcR expression on eosinophils is upregulated in atopic
individuals and likely plays a key role in eosinophil activation.
Mice lack this receptor. Although several cells express FcRI,
neutrophils account for most CD89
+
cells. IgA can also bind to
Fc/R, an Fc receptor that also binds to IgM.
24
This receptor
has higher afnity for IgM than IgA. It may mediate phagocy-
tosis of IgM- and IgA-coated bacteria and is expressed on a
variety of cell types.
25
The transferrin receptor (CD71) can also
bind IgA. It selectively binds monomeric IgA1, and its role in
immunity is not well dened.
38
Fc Receptors. There are two IgE receptors: FcRI is the high-
afnity IgE receptor that is expressed by mast cells and baso-
phils and by dendritic cells and Langerhans cells in the skin.
39

Because of the very high afnity of FcRI for monomeric IgE,
it effectively functions as an antigen receptor on the surface of
FcRI-expressing cells. In contrast to B cells, which express only
a single type of immunoglobulin, FcRI-expressing cells can
bind a wide variety of IgE antibodies, each with a potentially
different specicity. This usually is the case in nonatopic indi-
viduals. In contrast, allergic individuals have increased levels of
specic IgE antibodies. As a result, the FcRIs are armed to a
greater extent with specic IgE, achieving a density that permits
Immunoglobulin Fc Receptors
Although immunoglobulins are responsible for recognizing
pathogens or toxins, in most cases, additional cells expressing
receptors for the Fc region of antibodies are needed to
effect immune clearance. FcRs are all members of the
Figure 3-10 Receptors mediating intracellular trafcking of antibody
molecules. A, Plasma cells located in the lamina propria of mucosal
tissue secrete J chaincontaining dimeric IgA and pentameric IgM.
Mucosal-epithelial cell poly-Ig receptors bind polymeric antibodies,
endocytose the IgA/IgM/poly-Ig receptor complexes, and transport
them through the cell to the lumen. Luminal release results after
proteolytic cleavage of the poly-Ig receptors. The extracellular domain
of the poly-Ig receptor remains bound to the secreted IgA and IgM
molecules, and it is referred to as the secretory component (SC). The
SC is thought to protect the IgA and IgM molecules from proteolysis.
B, Endothelial cells and monocytes express the neonatal Fc receptor
for IgG (FcRn) that internalizes serum IgG in an acidic endosomal
compartment. FcRn then recycles IgG molecules back into circulation,
effectively prolonging their half-life. Serum proteins without a recy-
cling receptor are internalized in lysosomes and degraded. Ig, Immu-
noglobulin. (A, Modied from Abbas A, Lichtman A, Pillai S. Cellular
and molecular immunology. 7th ed. Philadelphia: Saunders/Elsevier;
2012. p. 304; B, from Roopenian DC, Akilesh S. FcRn: the neonatal c
receptor comes of age. Nat Rev Immunol 2007;7:718.)
Lamina propria Mucosal epithelial cell
Poly-lg receptor
with bound
IgA/IgM
J chain
J chain
IgA-producing
plasma cell
IgM-producing
plasma cell
Dimeric IgA
Pentameric IgM
FcRn
IgG Serum
protein
Recycling
endosome
Endocytic
vesicle
Blood (physiologic pH)
Monocyte or
endothelial cell
Lysosome
Endocytosed
complex of
IgA/IgM and
poly-lg receptor
Proteolytic
cleavage
Secreted IgA
SC
Secreted IgM
Lumen
A
B
IgG dissociates
at physiologic pH
Sorting of
FcRn-IgG
complexes
FcRn binds
IgG in
acidified
endosome
Acidified
endosome
Nonreceptor bound proteins
are degraded in the lysosome
3 Immunoglobulin Structure and Function 41
In a manner analogous to FcR activation, complement
bound to immune complexes in circulation or antibodies
bound to certain antigenic determinants on cell surfaces
prompts cell activation and release of mediators that can
damage tissue and recruit and activate additional inammatory
cells. In some cases, the downstream results of complement-
and FcR- mediated activation can cause disease, a process
referred to as type II (antibody-mediated) or type III (immune
complexmediated) hypersensitivity. Type II hypersensitivity is
frequently observed in a number of autoimmune conditions.
Type III hypersensitivity typically results when excessive
amounts of immune complexes are formed, leading to their
frequent deposition in blood vessels.
Immunoglobulins and Human Disease
DYSREGULATED IMMUNOGLOBULIN
PRODUCTION
Human conditions of dysregulated immunoglobulin produc-
tion include antibody deciencies and overproduction of spe-
cic antibodies. The most serious of the three major categories
of antibody deciencies results in reduced B cell numbers and
a severe decrease in all isotypes of serum immunoglobulin, as
in agammaglobulinemia (Table 3-2) (see Chapters 71 and 72).
40

This type of immunodeciency underscores the importance of
tyrosine kinases in early B cell BCR signal transduction. The
second category includes selective deciencies of IgA or IgG2
production and various genetic mutations that result in hypo-
gammaglobulinemia, such as deciencies in TACI. The third
cross-linking of the FcRIs on exposure to allergen and results
in mast cell and basophil mediator release and mild to severe
allergic reactions. The low-afnity IgE receptor FcRII (CD23)
is expressed on monocytes, B cells, and dendritic cells. CD23 is
thought to play positive and negative regulatory roles. CD23
acts as a buffer against the accumulation of excessive levels of
IgE, and in its soluble form it can prevent binding of IgE to the
FcRI. CD23 also may play a role in regulating IgE synthesis,
but a consensus opinion about whether it enhances or sup-
presses IgE synthesis has not been reached.
39
Immunoglobulins and Complement Activation
Antibodies play a pivotal role in activation of the classic com-
plement pathway, which becomes activated by specic isotypes
of antibody bound to microbes and other antigens. In humans,
IgM, IgG1, and IgG3 efciently activate the complement cascade
(see Chapter 8). The rst step in this pathway is activation
of C1q, which depends on binding to the Fc region of at least
two immunoglobulin molecules. Because immunoglobulin Fc
regions possess a single C1q-binding site, the complement
pathway is activated only by antibodies in immune complexes
and not by circulating free antibody. IgM-mediated comple-
ment activation depends on bound antigen, which induces a
conformational change necessary for C1q binding. Because of
the pentameric structure of serum IgM, this class of antibody
is particularly effective at complement activation. Further acti-
vation of the complement cascade leads to deposition of addi-
tional complement components that are recognized by a variety
of complement receptors expressed by several cell types, includ-
ing macrophages, neutrophils, NK cells, and erythrocytes.
Figure 3-11 Fc receptor expression patterns on human cells and biologic activity. A variety of accessory cell types express Fc receptors. The
subunit structure and binding properties of these receptors and the cell types expressing them are shown. The Fc receptors vary greatly in their
specicity and afnity for antibodies, and they trigger a range of cellular activities. CD89 is also called FcRI. Ig, Immunoglobulin; ITIM, immu-
noreceptor tyrosine-based inhibitor motif; *, lack the beta chain;

, not plasmacytoid dendritic cells;

, 70-100 kDa. (Modied from Murphy K.

Janeways immunobiology. 8th ed. London: Garland Science [Taylor & Francis Group]; 2012. p. 418.)
Structure
Binding
Cell type
Effect of
ligation
IgG1
1) IgG1 = IgG3
2) IgG4
3) IgG2
Macrophages
Neutrophils
Dendritic cells
Monocytes
Phagocytosis
Cell activation
Phagocytosis
Inhibition of
cell activity
Phagocytosis
(inefficient)
Induction of
killing
Phagocytosis
Induction of
microbe
killling
Endocytosis
Induction of
microbe
killling
Inhibition of
cell activity
Phagocytosis
Degranulation
Degranulation Largely
unknown
function
Possible
adhesion
Mast cells
Basophils
Dendritic cells*
Langerhans
cells
Macrophages
Neutrophils
Eosinophils
Platelets
Monocytes
Macrophages
Eosinophils

Monocytes
Neutrophils
Macrophages
B cells
Macrophages
Neutrophils
Eosinophils
Basophils
NK cells
Macrophages
Neutrophils
B cells
Mast cells
Basophils
B cells
Monocytes
Dendritic cells

10
8
M
1
1) IgG1
2) IgG3 = IgG2*
3) IgG4
2 10
6
M
1
1) IgG1 = IgG3
2) IgG4
3) IgG2
2 10
6
M
1
1) IgG1 = IgG3
2) IgG4
3) IgG2
2 10
6
M
1
3 10
9
M
1
1) IgG1 = IgG3
IgA1, IgA2 IgE IgE IgG1 IgG1 IgG1 IgG1
5 10
5
M
1
10
10
M
1
27 10
7
M
1
(trimer)
27 10
5
M
1
(monomer)
10
7
M
1
IgA1 = IgA2
IgA, IgM
Order of
affinity
Receptor
Characteristics
FcRI
(CD64)
FcRII-A
(CD32)
FcRII-B2
(CD32)
FcRII-B1
(CD32)
FcRIII
(CD16)
or
or
FcRII
(CD23)
FcRI
(CD89)
72 kD 40 kD
ITIM
ITIM
N
50-70 kD 45 kD
70 kD
55-75 kD
33 kD
9 kD 9 kD
Fc/R FcRI
Lectin
domain
Trimer

-like
domain
1) IgM
2) IgA
42 SECTION A Basic Sciences Underlying Allergy and Immunology
replacement gamma globulin can be given intravenously (IVIG)
or subcutaneously. The polyclonal nature of the IgG is desirable
because it is used to provide passive immunity to patients with
certain immunodeciency diseases.
41
These infusions are also
used to treat antibody-mediated inammatory and hypersensi-
tivity diseases.
42,43
The precise mechanism by which this treat-
ment provides benet remains unclear, but its effectiveness may
result from the ability of the IgG to bind to Fc receptors, thereby
inhibiting the patients pathologic antibodies from binding.
IVIG may also compete with the patients own antibodies for
FcRn-mediated recycling of IgG (see Fig. 3-10, B), resulting in
an increased rate of pathologic antibody degradation. Evidence
suggests that IgG molecules with sialylated Fc regions have anti-
inammatory activity, suggesting another mechanism by which
gamma globulin has clinical efcacy.
42
In contrast to polyclonal antibodies, monoclonal antibodies
are generated by cloning individual B cells and expanding
one particular antibody-secreting plasma cell, resulting in a
monoclonal antibody preparation in which all antibodies are
identical.
44
Although monoclonal antibodies have long been
considered potential magic bullets, clinical use of these reagents
for immunotherapeutic purposes has only slowly come about,
45

primarily because of signicant initial obstacles. For example,
therapy with mouse monoclonal antibodies was severely limited
by the rapid production of anti-mouse antibodies by the patient
being treated, rendering future treatments with mouse mono-
clonal antibodies ineffective. This problem was drastically mini-
mized by using genetic engineering techniques to humanize
the monoclonal antibodies.
46
A humanized monoclonal anti-
body has only the CDRs from the original mouse monoclonal
category includes a number of mutations that give rise to hyper-
IgM syndromes, which result from the failure of B cells to
undergo class switch recombination. These disorders highlight
the critical role that CD40-CD40L interaction plays in class
switch recombination, as revealed by the lack of IgG, IgA, and
IgE antibodies in these patients.
Some diseases are categorized by overproduction of antibod-
ies. Polyclonal gammopathies are seen in conditions such as
chronic infections and autoimmune diseases. In several benign
and malignant conditions, overproduction of monoclonal anti-
bodies results from clonal expansion of a single plasma cell,
which produces large quantities of monoclonal immunoglobu-
lin. Multiple myeloma is an example of a malignant plasma cell
disorder resulting in an abnormally large number of malignant
plasma cells that cause considerable end-organ damage. Serum
from multiple myeloma patients contains large amounts of
relatively homogeneous antibody molecules. This material was
used in the initial studies that elucidated the structure of anti-
body molecules and their amino acid sequences.
THERAPEUTIC APPLICATIONS OF
IMMUNOGLOBULINS
Isolated immunoglobulins used for immunotherapy can be
polyclonal or monoclonal. One type of polyclonal antibody
preparation is specically generated by immunization. Poly-
clonal antibodies share antigen reactivity but typically vary in
the precise epitope recognized, afnity, or even isotype. A
second type of polyclonal antibody is pooled polyclonal immu-
noglobulins (primarily IgG) isolated from healthy donors. This
Antibody and B Cell Deciencies
Disease Functional Deciencies Mechanism of Defect
AGAMMAGLOBULINEMIA
X-linked Decrease in all serum Ig isotypes; reduced B cell
numbers
Pre-B receptor checkpoint defect; Btk
mutation
Autosomal recessive forms Decrease in all serum Ig isotypes; reduced B cell
numbers
Pre-B receptor checkpoint defect;
mutations in IgM heavy chain (),
surrogate light chains, Ig, BLNK
HYPOGAMMAGLOBULINEMIA, ISOTYPE DEFECTS
Selective IgA deciency Decreased IgA; may be associated with increased
susceptibility to bacterial infections and protozoa such
as Giardia lamblia
TACI mutations in some patients
Selective IgG2 deciency Increased susceptibility to bacterial infections Small subset have deletion in IgG2 locus
Common variable immunodeciency Hypogammaglobulinemia; normal or decreased B cell
numbers
ICOS and TACI mutations in some
patients
ICF syndrome Hypogammaglobulinemia; occasional mild T cell defects DNMT3B mutations
HYPER-IgM SYNDROMES
X-linked Defects in helper T cellmediated B cell, macrophage,
and dendritic cell activation; defects in somatic
mutation, class switching, and germinal center
formation; defective cell-mediated immunity
CD40L mutations
Autosomal recessive with cell-
mediated immune defects
Defects in helper T cellmediated B cell, macrophage,
and dendritic cell activation; defects in somatic
mutation, class switching, and germinal center
formation; defective cell-mediated immunity
CD40, NEMO mutations
Autosomal recessive with antibody
defect only
Defects in somatic mutation and isotype switching AID, UNG mutations
From Abbas A, Lichtman A, Pillai S. Cellular and molecular immunology. 7th ed. Philadelphia: Saunders/Elsevier; 2012. p. 453.
AID, Activation-induced cytidine deaminase; BLNK, B cell linker; DNMT3B, DNA methyltransferase 3B; ICF, immunodeciencies, centromeric
instability, and facial anomalies; Ig, immunoglobulin; ICOS, inducible costimulator; NEMO, NF-B essential modulator; TACI, transmembrane
activator and calcium modulator and cyclophilin ligand interactor; UNG, uracil N-glycosylase.
TABLE
3-2
3 Immunoglobulin Structure and Function 43
Summary
The dual functions of the antibody moleculeantigen binding
and biologic effector functionare reected in antibody struc-
ture and genetic organization. The B cell precursor contains
immunoglobulin genes inherited from both parents. However,
these inherited genes determine only to a limited extent the
BCR repertoire of the offspring. B cell development depends on
successful rearrangement of immunoglobulin genes and uses
membrane-bound immunoglobulins as a key component of the
BCR. Diversity of the variable regions of the immunoglobulins
is generated by a variety of genetic mechanisms, all of which
contribute to the phenomenal variety of antigenic specicities
expressed in the immunoglobulin repertoire.
Interaction of the IgM cell surface BCR with antigen activates
the B cell to produce secreted IgM. With appropriate T cell help,
immunoglobulin class switching may occur, resulting in secre-
tion of IgG, IgA, or IgE. Class switch recombination depends on
CD40 signaling and the action of cytokines. Somatic hypermu-
tation can increase the variability of the antibody and improve
afnity. Antibodies specic for antigen mediate a variety of
biologic effects, including neutralization, activation of comple-
ment, and interaction with specic cell surface Fc receptors.
antibody, ensuring that the antigen-binding sites are still func-
tional. The rest of the immunoglobulin, including the variable
region framework sequences and the constant regions, is derived
from human immunoglobulin sequences using recombinant
DNA technology.
47
Mice have been genetically engineered to express the whole
human unrearranged HC and LC loci, allowing production
of antibodies entirely human in origin. To improve tissue pen-
etration, recombinant antibody fragments (e.g., Fab fragments)
are being engineered as alternatives to intact antibodies.
48

Almost 30 monoclonal antibodies have been approved by the
U.S. Food and Drug Administration (FDA) for therapeutic use.
For example, several CD20 monoclonal antibodies are in use
for the treatment of various B cell malignancies, a humanized
antibody to IgE (omalizumab) is in use for asthma patients, and
several cytokine-specic monoclonal antibodies are in use for
patients with certain autoimmune diseases. Information about
the source of the antibody can be gleaned from the generic
names of the therapeutic monoclonal antibodies.
49
If the generic
name ends in -ximab or -zumab the monoclonal antibody is
chimeric or humanized, respectively.
50
An ending of -omab
indicates it is a mouse antibody, and -umab indicates a human
origin.
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