Fig. 8.11 The functions of complement. A, C3b opsonizes microbes and is recognized by the type 1
proteolysis of C5 and C3, respectively.
170 CHAPTER 8 Effector Mechanisms of Humoral Immunity
and antibody production. When C3 is activated by a
microbe by the alternative pathway, one of its breakdown products, C3d, is recognized by complement
the microbe. This process is described in Chapter 7
(see Fig. 7.5A) and is an example of an innate immune
cell activation and selection of high-affinity B cells. This
complement-dependent antigen display is another way
in which the complement system promotes antibody
Inherited deficiencies of complement proteins result
in immune deficiencies and, in some cases, increased
incidence of autoimmune disease. Deficiency of C3
results in increased susceptibility to bacterial infections
that may be fatal early in life. Deficiencies of the early
proteins of the classical pathway, C2 and C4, may have
incidence of systemic lupus erythematosus, an immune
complex-mediated autoimmune disease. The increased
incidence of lupus may be because the classical pathway
failure of B cell tolerance (see Chapter 9). Deficiencies
polymorphisms in the gene encoding MBL, leading to
production of a protein that is functionally defective;
pathway protein properdin also causes increased susceptibility to bacterial infection.
Regulation of Complement Activation
Mammalian cells express regulatory proteins that
inhibit complement activation, thus preventing complement-mediated damage to host cells (Fig. 8.12).
Many such regulatory proteins have been described,
and defects in these proteins are associated with
clinical syndromes caused by uncontrolled complement
• A regulatory protein called C1 inhibitor (C1 INH)
stops complement activation early, at the stage of
C1 activation. Deficiency of C1 INH is the cause of
a disease called hereditary angioedema. C1 INH is
a serine protease inhibitor that functions as a major
physiologic inhibitor of the cleavage of kallikrein,
increased complement activation but also increased
proteolytic activation of bradykinin, and this is the
main reason for the vascular changes that lead to
leakage of fluid (edema) in many tissues.
blocking C3 convertase formation and terminating
complement activation by both the alternative and
the classical pathways. A disease called paroxysmal nocturnal hemoglobinuria results from the
acquired deficiency in hematopoietic stem cells of
an enzyme that synthesizes the glycolipid anchor for
several cell-surface proteins, including the complement regulatory proteins DAF and CD59. In these
patients, unregulated complement activation occurs
on erythrocytes, leading to their lysis.
• A plasma enzyme called Factor I cleaves C3b into
inactive fragments, with membrane cofactor protein
(MCP) and the plasma protein Factor H serving as
cofactors in this enzymatic process. Deficiency of
the regulatory proteins Factors H and I results in
increased complement activation and reduced levels
of C3 because of its consumption, causing increased
susceptibility to infection. Mutations in Factor H that
compromise its binding to cells are associated with a
rare genetic disease called atypical hemolytic uremic
syndrome, in which there are clotting, vascular, and
These regulatory proteins are made by vertebrate host
cells but not by microbes. Because microbes lack these
activation. For instance, host cells can become targets
CHAPTER 8 Effector Mechanisms of Humoral Immunity 171
Fig. 8.12 Regulation of complement activation. A, C1 inhibitor (C1 INH) prevents the assembly of the
of complement if they are coated with large amounts
of antibodies, as in some hypersensitivity diseases (see
FUNCTIONS OF ANTIBODIES AT SPECIAL
The effector mechanisms of humoral immunity described
produced in peripheral lymphoid organs and bone marrow
two special anatomic sites: the mucosal organs and the fetus.
Immunoglobulin A (IgA) is produced in mucosal
lymphoid tissues, transported across epithelia, and
binds to and neutralizes microbes in the lumens of
the mucosal organs (Fig. 8.13). Microbes often are
inhaled or ingested, and antibodies that are secreted
into the lumens of the respiratory or gastrointestinal
tract bind to these microbes and prevent them from
colonizing the host. This type of immunity is called
is IgA. In fact, IgA accounts for about two-thirds of
the approximately 3 g of antibody produced daily by
a healthy adult, reflecting the vast surface area of the
intestines. The propensity of B cells in mucosal epithelial
tissues to produce IgA is because the cytokines that
IgA-producing B cells that are generated in regional
lymph nodes or spleen tend to home to mucosal tissues
172 CHAPTER 8 Effector Mechanisms of Humoral Immunity
Follicular dendritic cells; MAC, membrane attack complex.
CHAPTER 8 Effector Mechanisms of Humoral Immunity 173
in response to chemokines produced in these tissues.
Also, some of the IgA is produced by a subset of B cells,
called B-1 cells, best studied in rodents, which also
have a propensity to migrate to mucosal tissues; these
cells secrete IgA in response to nonprotein antigens,
Intestinal mucosal B cells are located in the lamina
pathogens in the lumen before they invade, the IgA
must be transported across the epithelial barrier into
the lumen. Transport through the epithelium is carried
out by a special Fc receptor, the poly-Ig receptor, which
is expressed on the basal surface of the epithelial cells.
This receptor binds IgA, endocytoses it into vesicles,
the lumen still carrying a portion of the bound poly-Ig
by proteases in the gut. The antibody can then recognize
microbes in the lumen and block their binding to and
entry through the epithelium. IgA-mediated mucosal
The gut contains a large number of commensal
bacteria that are essential for basic functions such as
absorption of food and, therefore, have to be tolerated
by the immune system. IgA antibodies are produced
epithelium. Harmless commensals are tolerated by the
immune system of the gut by mechanisms that are discussed in Chapter 9.
neonates, protecting the newborn from infections.
Newborn mammals have incompletely developed
immune systems and are unable to mount effective
immune responses against many microbes. During their
naturally occurring passive immunity. Neonates acquire
maternal antibodies by two routes. During pregnancy,
After birth, infants ingest maternal IgA antibodies that
are secreted into their mothers’ colostrum and milk.
infectious microbes to which the mothers were exposed
Lamina propria Mucosal epithelial cell Lumen
ingested or inhaled microbes and blocks their entry through the epithelium.
174 CHAPTER 8 Effector Mechanisms of Humoral Immunity
EVASION OF HUMORAL IMMUNITY BY
Microbes have evolved numerous mechanisms to evade
humoral immunity (Fig. 8.14). Many bacteria and viruses
mutate their antigenic surface molecules so that they can no
longer be recognized by antibodies produced in response to
the original microbe. Antigenic variation typically is seen in
viruses, such as influenza virus, human immunodeficiency
virus (HIV), and rhinovirus. HIV mutates its genome at
a high rate, and therefore different strains contain many
variant forms of the major antigenic surface glycoprotein of
HIV, called gp120. As a result, antibodies against exposed
determinants on gp120 in any one HIV subtype may not
protect against other virus subtypes that appear in infected
individuals. This is one reason why gp120 vaccines are not
their pili and thus evade antibody-mediated defense. The
trypanosome that causes sleeping sickness expresses new
surface glycoproteins whenever it encounters antibodies
against the original glycoprotein. As a result, infection with
the parasites in the preceding wave. Other microbes inhibit
Now that we have discussed the mechanisms of host
it is important to consider how these adaptive immune
responses can be induced with prophylactic vaccines.
Vaccination is the process of stimulating protective
adaptive immune responses against microbes by exposure to nonpathogenic forms or components of the
microbes. The development of vaccines against infections
has been one of the great successes of immunology. The only
human disease to be intentionally eradicated from the earth
is smallpox, and this was achieved by a worldwide program
Fig. 8.14 Evasion of humoral immunity by microbes. This figure shows some of the mechanisms by
CHAPTER 8 Effector Mechanisms of Humoral Immunity 175
of vaccination. Polio is likely to be the second such disease,
and as mentioned in Chapter 1, many other diseases have
been largely controlled by vaccination (see Fig. 1.2).
Several types of vaccines are in use and being developed (Fig. 8.15).
• Some of the most effective vaccines are composed of
microbial antigens that protect vaccinated individuals
from subsequent infections. For some infections, such
infection, which occurs by the oral route.
Some microbial polysaccharide antigens (which cannot
stimulate T cell help) are chemically coupled to proteins
so that helper T cells are activated and high-affinity
antibodies are produced against the polysaccharides.
Immunization with inactivated microbial toxins and
with microbial proteins synthesized in the laboratory
stimulates antibodies that bind to and neutralize the
native toxins and the microbes, respectively.
One of the continuing challenges in vaccination is to
develop vaccines that stimulate cell-mediated immunity
mainly antibody responses. Many newer approaches are
antigens into viral vectors, which will infect host cells and
produce the antigens inside the cells. Another technique is
to immunize individuals with DNA encoding a microbial
antigen in a bacterial plasmid. The plasmid is ingested by
host APCs, and the antigen is produced inside the cells.
Many of these strategies have been successfully tested in
animal models, but few have shown clinical efficacy to date.
Type of vaccine Examples Form of protection
176 CHAPTER 8 Effector Mechanisms of Humoral Immunity
to invade host cells, and they eliminate microbes by
activating several effector mechanisms.
• In antibody molecules, the antigen-binding (Fab)
regions are spatially separate from the effector (Fc)
regions. The ability of antibodies to neutralize microbes
are activated only after antibodies bind antigens.
• Antibodies are produced in lymphoid tissues and
bone marrow, but they enter the circulation and are
protective functions of antibodies.
• Antibodies neutralize the infectivity of microbes and
the pathogenicity of microbial toxins by binding to
and interfering with the ability of these microbes and
toxins to attach to host cells.
• Antibodies coat (opsonize) microbes and promote their
phagocytosis by binding to Fc receptors on phagocytes.
The binding of antibody Fc regions to Fc receptors also
stimulates the microbicidal activities of phagocytes.
• The complement system is a collection of circulating and cell surface proteins that play important
roles in host defense. The complement system may
innate immunity) and after the binding of antibodies
to antigens (classical pathway, a mechanism of adaptive humoral immunity).
• Complement proteins are sequentially cleaved, and
active components, in particular C4b and C3b,
become covalently attached to the surfaces on which
complement is activated. The late steps of complement
activation lead to the formation of the cytolytic MAC.
inappropriate complement activation on host cells.
• IgA antibody is produced in the lamina propria of
where it blocks the ability of microbes to invade the
• Neonates acquire IgG antibodies from their mothers through the placenta, using the FcRn to capture
and transport the maternal antibodies. Infants also
acquire IgA antibodies from the mother’s colostrum
• Microbes have developed strategies to resist or evade
humoral immunity, such as varying their antigens and
becoming resistant to complement and phagocytosis.
• Most vaccines in current use work by stimulating the
production of neutralizing antibodies.
1. What regions of antibody molecules are involved in
2. How do heavy-chain isotype (class) switching and
affinity maturation improve the ability of antibodies
to combat infectious pathogens?
3. In what situations does the ability of antibodies to
neutralize microbes protect the host from infections?
4. How do antibodies assist in the elimination of
5. How is the complement system activated?
6. Why is the complement system effective against
microbes but does not react against host cells and
7. What are the functions of the complement system,
and what components of complement mediate these
8. How do antibodies prevent infections by ingested
9. How are neonates protected from infection before
their immune system has reached maturity?
Answers to and discussion of the Review Questions are
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