protection to the newborn, and FcRn expressed on endothelial

cells and phagocytes plays a special role in protecting

IgG from intracellular catabolism, thereby prolonging

its half-life in the blood (see Chapter 8).

Principal

effector

functions

Fc receptordependent

phagocyte

responses;

complement

activation;

neonatal immunity

(placental transfer)

Complement

activation

B cell

Immunity

against

helminths

Mast cell

degranulation

(immediate

hypersensitivity)

Mucosal

immunity

(transport of

IgA through

epithelia)

IgG subclasses

(IgG1, IgG3) IgE IgA

Isotype

switching

IgM

Helper T cells: CD40L, cytokines

Various IL-4

Cytokines produced

in mucosal tissues,

e.g., TGF-ß, BAFF,

others

Fig. 7.12 Immunoglobulin (Ig) heavy-chain isotype (class) switching. Antigen-stimulated B lymphocytes

may differentiate into IgM antibody-secreting cells, or, under the influence of CD40 ligand (CD40L) and cytokines, some of the B cells may differentiate into cells that produce different Ig heavy-chain isotypes. The principal effector functions of some of these isotypes are listed; all isotypes may function to neutralize microbes

and toxins. B cell–activating factor belonging to the TNF family (BAFF) is a cytokine that may be involved in

switching to IgA, especially in T-independent responses. Switching to IgG subclasses is stimulated by the

cytokine interferon (IFN)-? in mice, but in humans it is thought to be stimulated by other cytokines. IL-4, interleukin-4; TGF-ß, transforming growth factor ß.

CHAPTER 7 Humoral Immune Responses 151

syndrome is caused by mutations in the CD40L gene,

which is located on the X chromosome, leading to production of nonfunctional forms of CD40L in males who

inherit the mutation. In this disease, much of the serum

antibody is IgM, because of defective heavy-chain isotype

switching. Patients with this disease also have defective

cell-mediated immunity against intracellular microbes,

because CD40L is important for T cell–mediated activation of macrophages and for the amplification of T cell

responses by dendritic cells (see Chapter 6).

The molecular mechanism of isotype switching,

called switch recombination, takes the previously

formed VDJ exon encoding the V domain of an Ig µ

heavy chain and moves it adjacent to a downstream

C region (Fig. 7.13). IgM-producing B cells, which have

not undergone switching, contain in their Ig heavychain locus a rearranged VDJ exon adjacent to the first

constant region cluster, which is Cµ. The heavy-chain

mRNA is produced by splicing a VDJ exon to Cµ exons

in the initially transcribed RNA, and this mRNA is translated to produce a µ heavy chain, which combines with

a light chain to give rise to an IgM antibody. Thus, the

first antibody produced by B cells is IgM. In the intron

5' of each constant region is a guanine-cytosine (GC)-

rich sequence called the switch region. Signals from

CD40 and cytokine receptors stimulate transcription

through one of the constant regions that is downstream

of Cµ. During switch recombination, the switch region

upstream of Cµ recombines with the switch region adjacent to the transcriptionally active downstream constant region, and the intervening DNA is deleted. An

VDJ Sµ Cµ S? C?

Sµ S? C?

C?

C?

VDJ

VDJ

VDJ

Cµ

IgG

AID

Signals from

helper T cells

(CD40 ligand,

cytokines)

Rearranged DNA in

IgM-producing cells

AAA Transcription;

RNA splicing

Translation

V DJ C?

Recombination

of Sµ with S?;

deletion of

intervening

C genes

Induction of

AID

? protein

? RNA

Fig. 7.13 Mechanism of immunoglobulin heavy-chain isotype switching. In an immunoglobulin (Ig)M-producing B cell,

the rearranged VDJ encoding the V region is adjacent to the µ

constant region genes (Cµ). Signals from helper T cells (CD40

ligand and cytokines) may induce recombination of switch (S)

regions such that the rearranged VDJ DNA is moved close to a

C gene downstream of Cµ, which are C? genes in the example

shown. The enzyme activation-induced deaminase (AID), which

is induced in the B cells by signals from Tfh cells, alters nucleotides in the switch regions so that they can be cleaved by other

enzymes and joined to downstream switch regions. Subsequently, when the heavy-chain gene is transcribed, the VDJ exon

is spliced onto the exons of the downstream C gene, producing

a heavy chain with a new constant region and thus a new class

of Ig. Note that although the C region changes, the VDJ region,

and thus the specificity of the antibody, is preserved. (Each C

region gene consists of multiple exons, but only one is shown

for simplicity.)

Heavy-chain isotype switching is induced by a

combination of CD40L-mediated signals and cytokines. These signals act on antigen-stimulated B cells

and induce switching in some of the progeny of these

cells. In the absence of CD40 or CD40L, B cells secrete

only IgM and fail to switch to other isotypes, indicating

the essential role of this ligand-receptor pair in isotype

switching. A disease called the X-linked hyper-IgM

152 CHAPTER 7 Humoral Immune Responses

enzyme called activation-induced deaminase (AID),

which is induced by CD40 signals, plays a key role in

this process. AID converts cytosines in the transcribed

switch region DNA to uracil (U). The sequential action

of other enzymes results in the removal of the U’s and

the creation of nicks in the DNA. Such a process on both

strands leads to double-stranded DNA breaks. When

double-stranded DNA breaks in two switch regions are

brought together and repaired, the intervening DNA is

removed, and the rearranged VDJ exon that was originally close to Cµ may now be brought immediately

upstream of the constant region of a different isotype

(e.g., IgG, IgA, IgE). The result is that the B cell begins

to produce a new heavy-chain isotype (determined by

the C region of the antibody) with the same specificity

as that of the original B cell, because specificity is determined by the sequence of the VDJ exon, which is not

altered.

Cytokines produced by follicular helper T cells

determine which heavy-chain isotype is produced

(see Fig. 7.12). The production of opsonizing IgG

antibodies, which bind to phagocyte Fc receptors, is

stimulated by IL-10 and other cytokines in humans

and mainly by IFN-? in mice. In antibody responses,

these cytokines are produced by Tfh cells. The IgG

antibodies that are produced opsonize microbes and

promote their phagocytosis and intracellular killing.

By contrast, switching to the IgE class is stimulated

by IL-4 produced by Tfh cells. IgE functions to eliminate helminths, acting in concert with eosinophils,

which are activated by another Th2 cytokine, IL-5.

Predictably, helminths induce strong Th2 and related

Tfh cell responses. Thus, the nature of the helper T

cell response to a microbe guides the subsequent antibody response, making it optimal for combatting that

microbe. These are excellent examples of how different components of the immune system are regulated

coordinately and function together in defense against

different types of microbes and how helper T cells

may function as the master controllers of immune

responses.

The antibody isotype produced is also influenced by

the site of immune responses. For example, IgA antibody

is the major isotype produced in mucosal lymphoid

tissues, probably because cytokines such as transforming growth factor (TGF)–ß that promote switching to

IgA are abundant in these tissues. IgA is the principal

antibody isotype that can be actively secreted through

mucosal epithelia (see Chapter 8). B-1 cells also appear

to be important sources of IgA antibody in mucosal tissues, especially against nonprotein antigens.

Affinity Maturation

Affinity maturation is the process by which the affinity of antibodies produced in response to a protein

antigen increases with prolonged or repeated exposure to that antigen (Fig. 7.14). Because of affinity maturation, the ability of antibodies to bind to a microbe or

microbial antigen increases if the infection is persistent

or recurrent. This increase in affinity is caused by point

mutations in the V regions, and particularly in the antigen-binding hypervariable regions, of the genes encoding the antibodies produced. Affinity maturation is seen

only in responses to helper T cell–dependent protein

antigens, indicating that helper cells are critical in the

process. These findings raise two intriguing questions:

how are mutations in Ig genes induced in B cells, and

how are the highest affinity (i.e., most useful) B cells

selected to become progressively more numerous?

Affinity maturation occurs in the germinal centers of lymphoid follicles and is the result of somatic

hypermutation of Ig genes in dividing B cells, followed by the selection of high-affinity B cells by

V C

V C

Mutations

Somatic mutations

in Ig V genes

Selection of

high-affinity B cells

Low-affinity

antibody

High-affinity

antibody

Fig. 7.14 Affinity maturation in antibody responses. Early

in the immune response, low-affinity antibodies are produced.

During the germinal center reaction, somatic mutation of

immunoglobulin (Ig) V genes and selection of mutated B cells

with high-affinity antigen receptors result in the production of

antibodies with high affinity for antigen.

CHAPTER 7 Humoral Immune Responses 153

antigen (Fig. 7.15). In the dark zones of germinal centers (where the proliferating B cells are concentrated),

numerous point mutations are introduced into the Ig

genes of the rapidly dividing B cells. The enzyme AID,

which is required for isotype switching, also plays a

critical role in somatic mutation. This enzyme, as stated

above, converts C into U. The uracils that are produced in Ig V-region DNA are frequently replaced by

B cells with somatically

mutated Ig V genes

and Igs with varying

affinities for antigen

B cells with highaffinity membrane Ig

bind antigen on

follicular dendritic cells

(FDCs) and present

antigen to helper T cells

B cells that recognize

antigen on FDCs or

interact with helper

T cells are selected

to survive;

other B cells die

B cell activation by

protein antigen

and helper T cells

High-affinity

B cell

Naive B cell

Antigen

FDC

Follicular

helper

T cell

(Tfh)

Migration into germinal center

Fig. 7.15 Selection of high-affinity B cells in germinal centers. Some activated B cells migrate into follicles

to form germinal centers, where they undergo rapid proliferation and accumulate mutations in their immunoglobulin (Ig) V genes. These B cells produce antibodies with different affinities for the antigen. Follicular

dendritic cells (FDCs) display the antigen, and B cells that recognize the antigen are selected to survive. FDCs

display antigens by utilizing Fc receptors to bind immune complexes or by using C3 receptors to bind immune

complexes with attached C3b and C3d complement proteins (not shown). B cells also bind the antigen, process it, and present it to follicular helper T (Tfh) cells in the germinal centers, and signals from the Tfh cells

promote survival of the B cells. As more antibody is produced, the amount of available antigen decreases, so

only the B cells that express receptors with higher affinities can bind the antigen and are selected to survive.

154 CHAPTER 7 Humoral Immune Responses

thymidines during DNA replication, creating C-to-T

mutations, or they are removed and repaired by errorprone mechanisms that often lead to introduction of

nucleotides other than the original mutated cytosine.

The frequency of Ig gene mutations is estimated to be

one in 103 base pairs per cell division, which is much

greater than the mutation rate in most other genes. For

this reason, Ig mutation in germinal center B cells is

called somatic hypermutation. This extensive mutation

results in the generation of different B cell clones whose

Ig molecules may bind with widely varying affinities to

the antigen that initiated the response. The next step in

the process is the selection of B cells with the most useful antigen receptors.

Germinal center B cells undergo apoptosis unless

rescued by antigen recognition and T cell help. While

somatic hypermutation of Ig genes is taking place in

germinal centers, the antibody secreted earlier during

the immune response binds residual antigen. The antigen-antibody complexes that are formed may activate

complement. These complexes are displayed by follicular dendritic cells (FDCs), which reside in the light

zone of the germinal center and express receptors for

the Fc portions of antibodies and for complement products, both of which help to display the antigen-antibody

complexes. B cells that have undergone somatic hypermutation are given a chance to bind antigen either on

FDCs or free in the germinal center. These B cells can

internalize the antigen, process it, and present peptides

to germinal center Tfh cells, which then provide critical

survival signals. High-affinity B cells more effectively

compete for the antigen and thus are more likely to survive than B cells with Igs that have lower affinities for

the antigen, akin to a process of Darwinian survival of

the fittest. As the immune response to a protein antigen develops, and also with repeated antigen exposure,

the amount of antibody produced increases. As a result,

the amount of antigen available in the germinal center

decreases. The B cells that are selected to survive must

be able to bind antigen at lower and lower concentrations, and therefore these are cells whose antigen receptors are of higher and higher affinity.

Generation of Plasma Cells and

Memory B Cells

Activated B cells in germinal centers may differentiate

into long-lived plasma cells or memory cells. The antibody-secreting cells enter the circulation and are called

plasmablasts. From the blood, they tend to migrate to

the bone marrow or mucosal tissues, where they may

survive for years as plasma cells and continue to produce

high-affinity antibodies, even after the antigen is eliminated. It is estimated that more than half of the antibodies in the blood of a normal adult are produced by

these long-lived plasma cells; thus, circulating antibodies reflect each individual’s history of antigen exposure.

These antibodies provide a level of immediate protection if the antigen (microbe or toxin) reenters the body.

A fraction of the activated B cells, which often are the

progeny of isotype-switched high-affinity B cells, do not

differentiate into active antibody secretors but instead

become memory cells. Memory B cells do not secrete

antibodies, but they circulate in the blood and reside

in mucosal and other tissues. They survive for months

or years in the absence of additional antigen exposure,

undergo slow cycling, and are ready to respond rapidly

if the antigen is reintroduced. Therefore, memory from

a T-dependent antibody response can last for a lifetime.

The requirements for activation of functionally quiescent memory B cells to differentiate into plasma cells,

and especially the role of T cell help in this reaction, are

not well defined.

ANTIBODY RESPONSES TO

T-INDEPENDENT ANTIGENS

Polysaccharides, lipids, and other nonprotein antigens

elicit antibody responses without the participation of

helper T cells. Recall that these nonprotein antigens cannot bind to MHC molecules, so they cannot be seen by

T cells (see Chapter 3). Many bacteria contain polysaccharide-rich capsules, and defense against such bacteria

is mediated primarily by antibodies that bind to capsular polysaccharides and target the bacteria for phagocytosis. Antibody responses to T-independent antigens

differ from responses to proteins, and most of these differences are attributable to the roles of helper T cells in

antibody responses to proteins (Fig. 7.16; see also Fig.

7.2). Extensive cross-linking of BCRs by multivalent

antigens may activate the B cells strongly enough to

stimulate their proliferation and differentiation without

a requirement for T cell help. Polysaccharides also activate the complement system, and many T-independent

antigens engage TLRs, thus providing activating signals to the B cells that enhance B cell activation in the

absence of T cell help (see Fig. 7.5).

CHAPTER 7 Humoral Immune Responses 155

REGULATION OF HUMORAL IMMUNE

RESPONSES: ANTIBODY FEEDBACK

After B lymphocytes differentiate into antibody-secreting

cells and memory cells, a fraction of these cells survive

for long periods, but most of the activated B cells probably die by apoptosis. This gradual loss of the activated

B cells contributes to the physiologic decline of the

humoral immune response. B cells also use a special

mechanism for shutting off antibody production. As

IgG antibody is produced and circulates throughout the

body, the antibody binds to antigen that is still available

in the blood and tissues, forming immune complexes. B

cells specific for the antigen may bind the antigen part of

the immune complex by their Ig receptors. At the same

time, the Fc tail of the attached IgG antibody may be

recognized by a special type of Fc receptor expressed on

B cells (as well as on many myeloid cells) called Fc?RIIB

(Fig. 7.17). This Fc receptor delivers inhibitory signals

that shut off antigen receptor–induced signals, thereby

terminating B cell responses. This process, in which

antibody bound to antigen inhibits further antibody

Chemical

nature

Thymus-dependent

antigen

Thymus-independent

antigen

Features of

anitbody

response

Isotype

switching

Affinity

maturation

Plasma

cells

Yes

Long-lived

Yes

Polymeric antigens,

especially polysaccharides;

also glycolipids,

nucleic acids

Low-level switching to IgG

Short-lived

Secondary

response

(memory

B cells)

Yes Only seen with some

polysaccharide antigens

Little or no

IgA

IgE

IgM

IgG IgG

Proteins

IgM

Fig. 7.16 Features of Antibody responses to T-dependent and T-independent antigens. T-dependent

antigens (proteins) and T-independent antigens (nonproteins) induce antibody responses with different characteristics, largely reflecting the influence of helper T cells in T-dependent responses to protein antigens and

the absence of T cell help in T-independent responses. Ig, Immunoglobulin.

156 CHAPTER 7 Humoral Immune Responses

production, is called antibody feedback. It serves to

terminate humoral immune responses once sufficient

quantities of IgG antibodies have been produced. Inhibition by the Fc?RIIB also functions to limit antibody

responses against self antigens, and polymorphisms in

the gene encoding this receptor are associated with the

autoimmune disease systemic lupus erythematosus (see

Chapter 9).

SUMMARY

• Humoral immunity is mediated by antibodies that

bind to extracellular microbes and their toxins,

which are neutralized or targeted for destruction by

phagocytes and the complement system.

• Humoral immune responses to nonprotein antigens

are initiated by recognition of the antigens by specific membrane Ig antigen receptors of naive B cells.

The binding of multivalent antigen cross-links B cell

Secreted antibody

forms complex

with antigen

Inhibition of

B cell

response

Block in B cell

receptor signaling

Ig Iga Igß

Fc

receptor

ITIM

ITAM

Antigen-antibody

complex binds

to B cell Ig

and Fc receptor

Fig. 7.17 Mechanism of antibody feedback. Secreted immunoglobulin (Ig)G antibodies form immune complexes (antigen-antibody complexes) with residual antigen (shown here as a virus but more commonly is a

soluble antigen). The complexes interact with B cells specific for the antigen, with the membrane Ig antigen

receptors recognizing epitopes of the antigen and a certain type of Fc receptor (Fc?RIIB) recognizing the

bound antibody. The Fc receptors block activating signals from the antigen receptor, terminating B cell activation. The cytoplasmic domain of B cell Fc?RIIB contains an ITIM that binds enzymes that inhibit antigen

receptor–mediated B cell activation. ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibition motif.

CHAPTER 7 Humoral Immune Responses 157

antigen receptors of specific B cells, and biochemical

signals are delivered to the inside of the B cells by

Ig-associated signaling proteins. These signals induce

B cell clonal expansion and IgM secretion.

• Humoral immune responses to a protein antigen,

called T-dependent responses, are initiated by binding of the protein to specific Ig receptors of naive B

cells in lymphoid follicles. This results in the generation of signals that prepare the B cell for interaction

with activated helper T cells that express CD40L and

secrete cytokines. The B cells internalize and process

that antigen and present class II MHC–displayed

peptides to activated helper T cells specific for the

displayed peptide-MHC complex. These helper T

cells contribute to early B cell activation at extrafollicular sites.

• The early T-dependent humoral response occurs in

extrafollicular foci and generates low levels of antibodies, with little isotype switching, that are produced by short-lived plasma cells.

• Activated B cells induce the further activation of T

cells and their differentiation into Tfh cells. The B

cells, together with the Tfh cells, migrate into follicles

and form germinal centers.

• The full T-dependent humoral response develops

in germinal centers and leads to extensive isotype

switching and affinity maturation; generation of

long-lived plasma cells that secrete antibodies for

many years; and development of long-lived memory

B cells, which rapidly respond to reencounter with

antigen by proliferation and secretion of high-affinity

antibodies.

• Heavy-chain isotype switching (or class switching) is the process by which the isotype, but not the

specificity, of the antibodies produced in response

to an antigen changes as the humoral response proceeds. Isotype switching is stimulated by the combination of CD40L and cytokines, both expressed by

helper T cells. Different cytokines induce switching

to different antibody isotypes, enabling the immune

system to respond in the most effective way to different types of microbes.

• Affinity maturation is the process by which the affinity of antibodies for protein antigens increases with

prolonged or repeated exposure to the antigens. The

process is initiated by signals from Tfh cells, resulting

in migration of the B cells into follicles and the formation of germinal centers. Here the B cells proliferate rapidly, and their Ig V genes undergo extensive

somatic mutation. The antigen may be displayed by

FDCs in the germinal centers. B cells that recognize

the antigen with high affinity are selected to survive,

giving rise to affinity maturation of the antibody

response.

• Polysaccharides, lipids, and other nonprotein antigens are called T-independent antigens because they

induce antibody responses without T cell help. Most

T-independent antigens contain multiple identical

epitopes that are able to cross-link many Ig receptors on a B cell, providing signals that stimulate B cell

responses even in the absence of helper T cell activation. Antibody responses to T-independent antigens

show less heavy-chain class switching and affinity

maturation than typical for responses to T-dependent

protein antigens.

• Secreted antibodies form immune complexes with

residual antigen and shut off B cell activation by

engaging an inhibitory Fc receptor on B cells.

REVIEW QUESTIONS

1. What are the signals that induce B cell responses to

protein antigens and polysaccharide antigens?

2. What are the major differences between primary and

secondary antibody responses to a protein antigen?

3. How do helper T cells specific for an antigen interact with B lymphocytes specific for the same antigen?

Where in a lymph node do these interactions mainly

occur?

4. What are the signals that induce heavy-chain isotype

switching, and what is the importance of this phenomenon for host defense against different microbes?

5. What is affinity maturation? How is it induced, and

how are high-affinity B cells selected to survive?

6. What are the characteristics of antibody responses to

polysaccharides and lipids? What types of bacteria

stimulate mostly these types of antibody responses?

Answers to and discussion of the Review Questions are

available at Student Consult.

158

Elimination of Extracellular

Microbes and Toxins

Humoral immunity is the type of host defense mediated by secreted antibodies that is necessary for protection against extracellular microbes and their toxins.

Antibodies prevent infections by blocking microbes

from binding to and entering host cells. Antibodies

also bind to microbial toxins and prevent them from

damaging host cells. In addition, antibodies function

to eliminate microbes, toxins, and infected cells from

the body. Although antibodies are a major mechanism

of adaptive immunity against extracellular microbes,

they cannot reach microbes that live inside cells.

However, humoral immunity is vital even for defense

against microbes that live inside cells, such as viruses,

because antibodies can bind to these microbes before

they enter host cells or during passage from infected to

uninfected cells, thus preventing spread of infection.

Defects in antibody production are associated with

increased susceptibility to infections by many bacteria, viruses, and parasites. All the vaccines that are

currently in use work by stimulating the production of

antibodies.

This chapter describes how antibodies provide defense

against infections, addressing the following questions:

• What are the mechanisms used by secreted antibodies to combat different types of infectious agents and

their toxins?

• What is the role of the complement system in defense

against microbes?

• How do antibodies combat microbes that enter

through the gastrointestinal and respiratory tracts?

• How do antibodies protect the fetus and newborn

from infections?

Before describing the mechanisms by which antibodies function in host defense, we summarize the features of

antibody molecules that are important for these functions.

PROPERTIES OF ANTIBODIES THAT

DETERMINE EFFECTOR FUNCTION

Several features of the production and structure of antibodies contribute in important ways to the functions of

these molecules in host defense.

Effector Mechanisms of

Humoral Immunity

CHAPTER OUTLINE

Properties of Antibodies that Determine Effector

Function, 158

Neutralization of Microbes and Microbial Toxins, 161

Opsonization and Phagocytosis, 162

Antibody-Dependent Cellular Cytotoxicity, 164

Immunoglobulin E– and Eosinophil/Mast Cell–

Mediated Reactions, 164

The Complement System, 164

Pathways of Complement Activation, 165

Functions of the Complement System, 168

Regulation of Complement Activation, 170

Functions of Antibodies at Special Anatomic Sites, 171

Mucosal Immunity, 171

Neonatal Immunity, 173

Evasion of Humoral Immunity by Microbes, 174

Vaccination, 174

Summary, 176

8

CHAPTER 8 Effector Mechanisms of Humoral Immunity 159

Antibodies function in the circulation, in tissues

throughout the body, and in the lumens of mucosal

organs. Antibodies are produced after stimulation of B

lymphocytes by antigens in peripheral (secondary) lymphoid organs (lymph nodes, spleen, mucosal lymphoid

tissues) and at tissue sites of inflammation. Many of the

antigen-stimulated B lymphocytes differentiate into antibody-secreting plasma cells, some of which remain in

lymphoid organs or inflamed tissues and others migrate

to and reside in the bone marrow. Different plasma cells

synthesize and secrete antibodies of different heavy-chain

isotypes (classes). These secreted antibodies enter the

blood, from where they may reach any peripheral site of

infection, or enter mucosal secretions, where they prevent

infections by microbes that try to enter through epithelia.

Protective antibodies are produced during the

first (primary) response to a microbe and in larger

amounts during subsequent (secondary) responses

(see Fig. 7.3 in Chapter 7). Antibody production begins

within the first week after infection or vaccination.

The plasma cells that migrate to the bone marrow continue to produce antibodies for months or years. If the

microbe again tries to infect the host, the continuously

secreted antibodies provide immediate protection. At

the same time, memory cells that had developed during

the initial B cell response rapidly differentiate into antibody-producing cells upon encounter with the antigen,

providing a large burst of antibody for more effective

defense against the infection. A goal of vaccination is

to stimulate the development of long-lived plasma cells

and memory cells.

Antibodies use their antigen-binding (Fab) regions

to bind to and block the harmful effects of microbes

and toxins, and they use their Fc regions to activate

diverse effector mechanisms that eliminate these

microbes and toxins (Fig. 8.1). This spatial segregation of the antigen recognition and effector functions

of antibody molecules was introduced in Chapter 4.

Antibodies block the infectivity of microbes and the

injurious effects of microbial toxins simply by binding

to the microbes and toxins, using only their Fab regions

to do so. Other functions of antibodies require the participation of various components of host defense, such

as phagocytes and the complement system. The Fc portions of immunoglobulin (Ig) molecules, made up of

the heavy-chain constant regions, contain the binding

sites for Fc receptors on phagocytes and for complement

proteins. The binding of antibodies to Fc receptors and

complement proteins occurs only after several Ig molecules recognize and become attached to a microbe or

microbial antigen. Therefore, even the Fc-dependent

functions of antibodies require antigen recognition by

the Fab regions. This feature of antibodies ensures that

they activate effector mechanisms only when needed—

that is, when they recognize their target antigens.

Heavy-chain isotype (class) switching and affinity

maturation enhance the protective functions of antibodies. Isotype switching and affinity maturation are

two changes that occur in the antibodies produced by

antigen-stimulated B lymphocytes, especially during

responses to protein antigens (see Chapter 7). Heavychain isotype switching results in the production of

antibodies with distinct Fc regions, capable of different

effector functions (see Fig. 8.1). By switching to different antibody isotypes in response to various microbes,

the humoral immune system is able to engage diverse

host mechanisms that are optimal for combating those

microbes. Affinity maturation is induced by prolonged

or repeated stimulation with protein antigens, and it

leads to the production of antibodies with higher and

higher affinities for the antigen, compared to the antibodies initially secreted. This change increases the ability of antibodies to bind to and neutralize or eliminate

microbes. The progressive increase in antibody affinity

with repeated stimulation of B cells is one of the reasons

for the recommended practice of giving multiple rounds

of immunizations with the same antigen for generating

protective immunity.

Switching to the IgG isotype prolongs the duration

that an antibody remains in the blood and therefore

increases the functional activity of the antibody. Most

circulating proteins have half-lives of hours to days

in the blood, but IgG has an unusually long half-life

because of a special mechanism involving a particular Fc

receptor. The neonatal Fc receptor (FcRn) is expressed

in placenta, endothelium, phagocytes, and a few other

cell types. In the placenta, the FcRn transports antibodies from the mother’s circulation to the fetus (discussed

later). In other cell types, the FcRn protects IgG antibodies from intracellular catabolism (Fig. 8.2). FcRn is

found in the endosomes of endothelial cells and phagocytes, where it binds to IgG that has been taken up by

the cells. Once bound to the FcRn, the IgG is recycled

back into the circulation or tissue fluids, thus avoiding

lysosomal degradation. This unique mechanism for protecting a blood protein is the reason why IgG antibodies

160 CHAPTER 8 Effector Mechanisms of Humoral Immunity

Lysis of microbes

B cell

Microbe

Antibodies

Neutralization of

microbes and toxins

Fc receptor

Opsonization and

phagocytosis

of microbes

Phagocytosis of

microbes opsonized

with complement

fragments (e.g., C3b) C3b

receptor Complement

activation

Inflammation

NK cell

Phagocyte

Antibodydependent cellular

cytotoxicity

Antibody

isotype

Effector functions

IgG

IgM

IgA

IgE

Neutralization of microbes and toxins

Opsonization of antigens for phagocytosis by

macrophages and neutrophils

Activation of the classical pathway of complement

Antibody-dependent cellular cytotoxicity mediated

by NK cells

Neonatal immunity: transfer of maternal antibody

across placenta and gut

Feedback inhibition of B cell activation

Mucosal immunity: secretion of IgA into lumens of

gastrointestinal and respiratory tracts, neutralization

of microbes and toxins

Activation of the classical pathway of complement

Eosinophil- and mast cell-mediated defense

A

B