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against helminths

Fig. 8.1 Effector functions of antibodies. Antibodies are produced by the activation of B lymphocytes by

antigens and other signals (not shown). Antibodies of different heavy-chain classes (isotypes) perform different effector functions, as illustrated schematically in (A) and summarized in (B). (Some properties of antibodies are listed in Chapter 4, Fig. 4.3.) Ig, Immunoglobulin; NK, natural killer.

CHAPTER 8 Effector Mechanisms of Humoral Immunity 161

have a half-life of about 3 weeks, much longer than that

of other Ig isotypes and most other plasma proteins.

This property of Fc regions of IgG has been exploited to

increase the half-life of other proteins by coupling the

proteins to an IgG Fc region (Fig. 8.3). One of several

therapeutic agents based on this principle is the tumor

necrosis factor (TNF) receptor–Fc fusion protein, which

functions as an antagonist of TNF and is used to treat

various inflammatory diseases. By coupling the extracellular domain of the TNF receptor to the Fc portion

of a human IgG molecule using a genetic engineering

approach, the half-life of the hybrid protein becomes

much greater than that of the soluble receptor by itself.

With this introduction, we proceed to a discussion of

the mechanisms used by antibodies to combat infections.

Much of the chapter is devoted to effector mechanisms

that are not influenced by anatomic considerations; that

is, they may be active anywhere in the body. At the end

of the chapter, we describe the special features of antibody functions at particular anatomic locations.

NEUTRALIZATION OF MICROBES AND

MICROBIAL TOXINS

Antibodies bind to and block, or neutralize, the infectivity of microbes and the interactions of microbial

toxins with host cells (Fig. 8.4). Antibodies in mucosal secretions in the gut and airways block the entry of

ingested and inhaled microbes (discussed later in the

chapter). After microbes enter the host, they use molecules in their envelopes or cell walls to bind to and

gain entry into host cells. Antibodies may attach to

these microbial surface molecules, thereby preventing

the microbes from infecting host cells. The most effective vaccines available today work by stimulating the

production of neutralizing antibodies that block initial

infection. Microbes that are able to enter host cells may

replicate inside the cells and then be released and go on

to infect other neighboring cells. Antibodies can neutralize the microbes during their transit from cell to cell

and thus also limit the spread of infection. If an infectious microbe does colonize the host, its harmful effects

may be caused by endotoxins or exotoxins, which often

bind to specific receptors on host cells in order to mediate their effects. Antibodies prevent binding of the toxins

to host cells and thus block their harmful effects. Emil

von Behring and Shibasaburo Kitasato’s demonstration

of this type of protection mediated by the administration of antibodies against diphtheria toxin was the first

IgG

Plasma

protein

Endosome pH <7

IgG binds to FcRn

in endosome

IgG-FcRn complexes

sorted to recycling

endosome

Recycling

endosome

Endocytic

vesicle

FcRn

Other proteins

degraded in lysosomes

IgG released

from FcRn by

extracellular pH >7

Lysosome

Fig. 8.2 Neonatal Fc receptor (FcRn) contributes to the

long half-life of IgG molecules. Circulating or extravascular

IgG antibodies (mainly of the IgG1, IgG2, and IgG4 subclasses)

are ingested by endothelial cells and phagocytes and bind the

FcRn, a receptor present in the acidic environment of endosomes. In these cells, FcRn sequesters the IgG molecules in

endosomal vesicles (pH ~4). The FcRn-IgG complexes recycle

back to the cell surface, where they are exposed to the neutral

pH (~7) of the blood, which releases the bound antibody back

into the circulation or tissue fluid. Ig, Immunoglobulin.

TNF

receptor

Anti-TNF IgG TNFR-IgG Fc

fusion protein

Fc

TNF

Fig. 8.3 Antibodies and Fc-containing fusion proteins. An

antibody specific for the cytokine tumor necrosis factor (TNF)

(left) can bind to and block the activity of the cytokine and

remain in the circulation for a long time (weeks) due to recycling by the neonatal Fc receptor (FcRn). The soluble extracellular domain of the TNF receptor (right) can also act as an

antagonist of the cytokine, and coupling the soluble receptor

to an IgG Fc domain, using a genetic engineering approach,

results in a prolonged half-life of the fusion protein in the blood

by the same FcRn-dependent mechanism. Ig, Immunoglobulin.

162 CHAPTER 8 Effector Mechanisms of Humoral Immunity

formal demonstration of therapeutic immunity against

a microbe or its toxin, then called serum therapy, and

the basis for awarding Behring the first Nobel Prize in

Physiology or Medicine in 1901.

OPSONIZATION AND PHAGOCYTOSIS

Antibodies coat microbes and promote their ingestion

by phagocytes (Fig. 8.5). The process of coating particles

for subsequent phagocytosis is called opsonization, and the

molecules that coat microbes and enhance their phagocytosis are called opsonins. When several IgG molecules

bind to a microbe, an array of their Fc regions projects

away from the microbial surface. If the antibodies belong

to certain isotypes (IgG1 and IgG3 in humans), their Fc

regions bind to a high-affinity receptor for the Fc regions

of ? heavy chains, called Fc?RI (CD64), which is expressed

on neutrophils and macrophages (Fig. 8.6). The phagocyte extends its plasma membrane around the attached

microbe and ingests the microbe into a vesicle called a

phagosome, which fuses with lysosomes. The binding of

antibody Fc tails to Fc?RI also activates the phagocytes,

because the Fc?RI contains a signaling chain that triggers numerous biochemical pathways in the phagocytes.

Large amounts of reactive oxygen species, nitric oxide,

and proteolytic enzymes are produced in the lysosomes of

the activated neutrophils and macrophages, all of which

contribute to the destruction of the ingested microbe.

Receptor

for microbe

Microbe

Infected

tissue cell

Infection of cell by microbe

Antibody blocks

penetration of

microbe through

epithelial barrier

Antibody blocks

binding of microbe

and infection of cells

Cell surface

receptor

for toxin Toxin

Pathologic effect of

toxin (e.g., cell necrosis)

Pathologic effect of toxin

Antibody blocks

binding of toxin

to cellular receptor

Microbe entry through epithelial barrier

Epithelial

barrier cells

Tissue

cell

Without antibody With antibody

A

B

C

Fig. 8.4 Neutralization of microbes and toxins by antibodies. A, Antibodies at epithelial surfaces, such as

in the gastrointestinal and respiratory tracts, block the entry of ingested and inhaled microbes, respectively. B,

Antibodies prevent the binding of microbes to cells, thereby blocking the ability of the microbes to infect host

cells. C, Antibodies block the binding of toxins to cells, thereby inhibiting the pathologic effects of the toxins.

CHAPTER 8 Effector Mechanisms of Humoral Immunity 163

Antibody-mediated phagocytosis is the major

mechanism of defense against encapsulated bacteria, such as pneumococci. The polysaccharide-rich

capsules of these bacteria protect the organisms

from phagocytosis in the absence of antibody, but

opsonization by antibody promotes phagocytosis

and destruction of the bacteria. The spleen contains

large numbers of phagocytes and is an important site

of phagocytic clearance of opsonized bacteria. This

is why patients who have undergone splenectomy are

susceptible to disseminated infections by encapsulated bacteria.

One of the Fc? receptors, Fc?RIIB, does not mediate

effector functions of antibodies but rather shuts down

antibody production and reduces inflammation. The

role of Fc?RIIB in feedback inhibition of B cell activation

was discussed in Chapter 7 (see Fig. 7.16). Fc?RIIB also

inhibits activation of macrophages and dendritic cells

and may thus serve an antiinflammatory function as well.

Pooled IgG from healthy donors is given intravenously

to treat various inflammatory diseases. This preparation

is called intravenous immune globulin (IVIG), and its

beneficial effect in these diseases is partly mediated by its

binding to Fc?RIIB on various cells.

Binding of

opsonized microbes

to phagocyte

Fc receptors (Fc?RI)

Fc receptor

signals

activate

phagocyte

Phagocytosis

of microbe

Killing of

ingested

microbe

Opsonization

of microbe

by IgG

IgG

antibody

Phagocyte

Fc?RI

Signals

Fig. 8.5 Antibody-mediated opsonization and phagocytosis of microbes. Antibodies of certain IgG subclasses (IgG1 and IgG3) bind to microbes and are then recognized by Fc receptors on phagocytes. Signals

from the Fc receptors promote the phagocytosis of the opsonized microbes and activate the phagocytes to

destroy these microbes. Ig, Immunoglobulin.

Fc Receptor Affinity for Ig Cell distribution Function

Fc?RI

(CD64)

Fc?RIIB

(CD32)

Fc?RIIIA

(CD16)

FceRI

High; binds IgG1

and IgG3

Low

Low

High; binds IgE

Macrophages,

neutrophils

B lymphocytes,

DCs, mast cells,

neutrophils,

macrophages

NK cells

Mast cells, basophils,

eosinophils

Phagocytosis;

activation of

phagocytes

Feedback inhibition

of B cells, attenuation of

inflammation

Antibody-dependent

cellular cytotoxicity (ADCC)

Activation (degranulation)

of mast cells and basophils

Fig. 8.6 Fc receptors. The cellular distribution and functions of different types of human Fc receptors. DCs,

Dendritic cells; Ig, immunoglobulin; NK, natural killer.

164 CHAPTER 8 Effector Mechanisms of Humoral Immunity

ANTIBODY-DEPENDENT CELLULAR

CYTOTOXICITY

Natural killer (NK) cells bind to antibody-coated cells

and destroy these cells (Fig. 8.7). NK cells express an

Fc? receptor called Fc?RIII (CD16), which is one of several kinds of NK cell–activating receptors (see Chapter

2). Fc?RIII binds to arrays of IgG antibodies attached to

the surface of a cell, generating signals that cause the NK

cell to discharge its granule proteins, which kill the antibody-coated cell by the same mechanisms that CD8+

cytotoxic T lymphocytes use to kill infected cells (see

Chapter 6). This process is called antibody-dependent

cellular cytotoxicity (ADCC). Cells infected with enveloped viruses typically express viral glycoproteins on

their surface that can be recognized by specific antibodies, and this may facilitate ADCC-mediated destruction

of the infected cells. ADCC is also one of the mechanisms by which therapeutic antibodies used to treat cancers eliminate tumor cells.

IMMUNOGLOBULIN E– AND EOSINOPHIL/

MAST CELL–MEDIATED REACTIONS