chapter 1
a73 Historical Perspective
a73 Innate Immunity
a73 Adaptive Immunity
a73 Comparative Immunity
a73 Immune Dysfunction and Its Consequences
Numerous T Lymphocytes Interacting with a Single
Macrophage
Overview of the
Immune System
T
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defense system that has evolved to protect animals
from invading pathogenic microorganisms and
cancer. It is able to generate an enormous variety of cells and
molecules capable of specifically recognizing and eliminat-
ing an apparently limitless variety of foreign invaders. These
cells and molecules act together in a dynamic network whose
complexity rivals that of the nervous system.
Functionally, an immune response can be divided into
two related activities—recognition and response. Immune
recognition is remarkable for its specificity. The immune
system is able to recognize subtle chemical differences that
distinguish one foreign pathogen from another. Further-
more, the system is able to discriminate between foreign
molecules and the body’s own cells and proteins. Once a for-
eign organism has been recognized, the immune system
recruits a variety of cells and molecules to mount an appro-
priate response, called an effector response, to eliminate or
neutralize the organism. In this way the system is able to
convert the initial recognition event into a variety of effector
responses, each uniquely suited for eliminating a particular
type of pathogen. Later exposure to the same foreign organ-
ism induces a memory response, characterized by a more
rapid and heightened immune reaction that serves to elimi-
nate the pathogen and prevent disease.
This chapter introduces the study of immunology from
an historical perspective and presents a broad overview of
the cells and molecules that compose the immune system,
along with the mechanisms they use to protect the body
against foreign invaders. Evidence for the presence of very
simple immune systems in certain invertebrate organisms
then gives an evolutionary perspective on the mammalian
immune system, which is the major subject of this book. El-
ements of the primitive immune system persist in verte-
brates as innate immunity along with a more highly evolved
system of specific responses termed adaptive immunity.
These two systems work in concert to provide a high degree
of protection for vertebrate species. Finally, in some circum-
stances, the immune system fails to act as protector because
of some deficiency in its components; at other times, it be-
comes an aggressor and turns its awesome powers against its
own host. In this introductory chapter, our description of
immunity is simplified to reveal the essential structures and
function of the immune system. Substantive discussions, ex-
perimental approaches, and in-depth definitions are left to
the chapters that follow.
Like the later chapters covering basic topics in immu-
nology, this one includes a section called “Clinical Focus”
that describes human disease and its relation to immunity.
These sections investigate the causes, consequences, or treat-
ments of diseases rooted in impaired or hyperactive immune
function.
Historical Perspective
The discipline of immunology grew out of the observation
that individuals who had recovered from certain infectious
diseases were thereafter protected from the disease. The
Latin term immunis, meaning “exempt,” is the source of the
English word immunity, meaning the state of protection
from infectious disease.
Perhaps the earliest written reference to the phenomenon
of immunity can be traced back to Thucydides, the great his-
torian of the Peloponnesian War. In describing a plague in
Athens, he wrote in 430 BC that only those who had recov-
ered from the plague could nurse the sick because they
would not contract the disease a second time. Although early
societies recognized the phenomenon of immunity, almost
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two thousand years passed before the concept was success-
fully converted into medically effective practice.
The first recorded attempts to induce immunity deliber-
ately were performed by the Chinese and Turks in the fif-
teenth century. Various reports suggest that the dried crusts
derived from smallpox pustules were either inhaled into the
nostrils or inserted into small cuts in the skin (a technique
called variolation). In 1718, Lady Mary Wortley Montagu, the
wife of the British ambassador to Constantinople, observed
the positive effects of variolation on the native population
and had the technique performed on her own children. The
method was significantly improved by the English physician
Edward Jenner, in 1798. Intrigued by the fact that milkmaids
who had contracted the mild disease cowpox were subse-
quently immune to smallpox, which is a disfiguring and of-
ten fatal disease, Jenner reasoned that introducing fluid from
a cowpox pustule into people (i.e., inoculating them) might
protect them from smallpox. To test this idea, he inoculated
an eight-year-old boy with fluid from a cowpox pustule and
later intentionally infected the child with smallpox. As pre-
dicted, the child did not develop smallpox.
Jenner’s technique of inoculating with cowpox to protect
against smallpox spread quickly throughout Europe. How-
ever, for many reasons, including a lack of obvious disease
targets and knowledge of their causes, it was nearly a hun-
dred years before this technique was applied to other dis-
eases. As so often happens in science, serendipity in
combination with astute observation led to the next major
advance in immunology, the induction of immunity to
cholera. Louis Pasteur had succeeded in growing the bac-
terium thought to cause fowl cholera in culture and then had
shown that chickens injected with the cultured bacterium de-
veloped cholera. After returning from a summer vacation, he
injected some chickens with an old culture. The chickens be-
came ill, but, to Pasteur’s surprise, they recovered. Pasteur
then grew a fresh culture of the bacterium with the intention
of injecting it into some fresh chickens. But, as the story goes,
his supply of chickens was limited, and therefore he used the
previously injected chickens. Again to his surprise, the chick-
ens were completely protected from the disease. Pasteur
hypothesized and proved that aging had weakened the viru-
lence of the pathogen and that such an attenuated strain
might be administered to protect against the disease. He
called this attenuated strain a vaccine (from the Latin vacca,
meaning “cow”), in honor of Jenner’s work with cowpox
inoculation.
Pasteur extended these findings to other diseases, demon-
strating that it was possible to attenuate, or weaken, a
pathogen and administer the attenuated strain as a vaccine.
In a now classic experiment at Pouilly-le-Fort in 1881, Pas-
teur first vaccinated one group of sheep with heat-attenuated
anthrax bacillus (Bacillus anthracis); he then challenged the
vaccinated sheep and some unvaccinated sheep with a viru-
lent culture of the bacillus. All the vaccinated sheep lived, and
all the unvaccinated animals died. These experiments
marked the beginnings of the discipline of immunology. In
1885, Pasteur administered his first vaccine to a human, a
young boy who had been bitten repeatedly by a rabid dog
(Figure 1-1). The boy, Joseph Meister, was inoculated with a
series of attenuated rabies virus preparations. He lived and
later became a custodian at the Pasteur Institute.
Early Studies Revealed Humoral and Cellular
Components of the Immune System
Although Pasteur proved that vaccination worked, he did not
understand how. The experimental work of Emil von
Behring and Shibasaburo Kitasato in 1890 gave the first in-
sights into the mechanism of immunity, earning von Behring
the Nobel prize in medicine in 1901 (Table 1-1). Von Behring
and Kitasato demonstrated that serum (the liquid, noncellu-
lar component of coagulated blood) from animals previously
immunized to diphtheria could transfer the immune state to
unimmunized animals. In search of the protective agent, var-
ious researchers during the next decade demonstrated that
an active component from immune serum could neutralize
toxins, precipitate toxins, and agglutinate (clump) bacteria.
In each case, the active agent was named for the activity it ex-
hibited: antitoxin, precipitin, and agglutinin, respectively.
2 PART I Introduction
FIGURE 1-1 Wood engraving of Louis Pasteur watching Joseph
Meister receive the rabies vaccine. [From Harper’s Weekly 29:836;
courtesy of the National Library of Medicine.]
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Initially, a different serum component was thought to be re-
sponsible for each activity, but during the 1930s, mainly
through the efforts of Elvin Kabat, a fraction of serum first
called gamma-globulin (now immunoglobulin) was shown
to be responsible for all these activities. The active molecules
in the immunoglobulin fraction are called antibodies. Be-
cause immunity was mediated by antibodies contained in
body fluids (known at the time as humors), it was called hu-
moral immunity.
In 1883, even before the discovery that a serum compo-
nent could transfer immunity, Elie Metchnikoff demon-
strated that cells also contribute to the immune state of an
animal. He observed that certain white blood cells, which he
termed phagocytes, were able to ingest (phagocytose) mi-
croorganisms and other foreign material. Noting that these
phagocytic cells were more active in animals that had been
immunized, Metchnikoff hypothesized that cells, rather than
serum components, were the major effector of immunity.
The active phagocytic cells identified by Metchnikoff were
likely blood monocytes and neutrophils (see Chapter 2).
In due course, a controversy developed between those
who held to the concept of humoral immunity and those
who agreed with Metchnikoff’s concept of cell-mediated im-
munity. It was later shown that both are correct—immunity
requires both cellular and humoral responses. It was difficult
to study the activities of immune cells before the develop-
ment of modern tissue culture techniques, whereas studies
with serum took advantage of the ready availability of blood
and established biochemical techniques. Because of these
technical problems, information about cellular immunity
lagged behind findings that concerned humoral immunity.
In a key experiment in the 1940s, Merrill Chase succeeded
in transferring immunity against the tuberculosis organism
by transferring white blood cells between guinea pigs. This
demonstration helped to rekindle interest in cellular immu-
nity. With the emergence of improved cell culture techniques
in the 1950s, the lymphocyte was identified as the cell re-
sponsible for both cellular and humoral immunity. Soon
thereafter, experiments with chickens pioneered by Bruce
Glick at Mississippi State University indicated that there were
Overview of the Immune System CHAPTER 1 3
TABLE 1-1 Nobel Prizes for immunologic research
Year Recipient Country Research
1901 Emil von Behring Germany Serum antitoxins
1905 Robert Koch Germany Cellular immunity to tuberculosis
1908 Elie Metchnikoff Russia Role of phagocytosis (Metchnikoff) and
Paul Ehrlich Germany antitoxins (Ehrlich) in immunity
1913 Charles Richet France Anaphylaxis
1919 Jules Border Belgium Complement-mediated bacteriolysis
1930 Karl Landsteiner United States Discovery of human blood groups
1951 Max Theiler South Africa Development of yellow fever vaccine
1957 Daniel Bovet Switzerland Antihistamines
1960 F. Macfarlane Burnet Australia Discovery of acquired immunological
Peter Medawar Great Britain tolerance
1972 Rodney R. Porter Great Britain Chemical structure of antibodies
Gerald M. Edelman United States
1977 Rosalyn R. Yalow United States Development of radioimmunoassay
1980 George Snell United States Major histocompatibility complex
Jean Daussct France
Baruj Benacerraf United States
1984 Cesar Milstein Great Britain Monoclonal antibody
Georges E. K?hler Germany
Niels K. Jerne Denmark Immune regulatory theories
1987 Susumu Tonegawa Japan Gene rearrangement in antibody
production
1991 E. Donnall Thomas United States Transplantation immunology
Joseph Murray United States
1996 Peter C. Doherty Australia Role of major histocompatibility complex
Rolf M. Zinkernagel Switzerland in antigen recognition by by T cells
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two types of lymphocytes: T lymphocytes derived from the
thymus mediated cellular immunity, and B lymphocytes
from the bursa of Fabricius (an outgrowth of the cloaca in
birds) were involved in humoral immunity. The controversy
about the roles of humoral and cellular immunity was re-
solved when the two systems were shown to be intertwined,
and that both systems were necessary for the immune
response.
Early Theories Attempted to Explain
the Specificity of the Antibody–
Antigen Interaction
One of the greatest enigmas facing early immunologists was
the specificity of the antibody molecule for foreign material,
or antigen (the general term for a substance that binds with
a specific antibody). Around 1900, Jules Bordet at the Pasteur
Institute expanded the concept of immunity by demonstrat-
ing specific immune reactivity to nonpathogenic substances,
such as red blood cells from other species. Serum from an an-
imal inoculated previously with material that did not cause
infection would react with this material in a specific manner,
and this reactivity could be passed to other animals by trans-
ferring serum from the first. The work of Karl Landsteiner
and those who followed him showed that injecting an animal
with almost any organic chemical could induce production
of antibodies that would bind specifically to the chemical.
These studies demonstrated that antibodies have a capacity
for an almost unlimited range of reactivity, including re-
sponses to compounds that had only recently been synthe-
sized in the laboratory and had not previously existed in
nature. In addition, it was shown that molecules differing in
the smallest detail could be distinguished by their reactivity
with different antibodies. Two major theories were proposed
to account for this specificity: the selective theory and the in-
structional theory.
The earliest conception of the selective theory dates to Paul
Ehrlich in 1900. In an attempt to explain the origin of serum
antibody, Ehrlich proposed that cells in the blood expressed a
variety of receptors, which he called “side-chain receptors,”
that could react with infectious agents and inactivate them.
Borrowing a concept used by Emil Fischer in 1894 to explain
the interaction between an enzyme and its substrate, Ehrlich
proposed that binding of the receptor to an infectious agent
was like the fit between a lock and key. Ehrlich suggested that
interaction between an infectious agent and a cell-bound
receptor would induce the cell to produce and release more
receptors with the same specificity. According to Ehrlich’s
theory, the specificity of the receptor was determined before
its exposure to antigen, and the antigen selected the appro-
priate receptor. Ultimately all aspects of Ehrlich’s theory
would be proven correct with the minor exception that the
“receptor” exists as both a soluble antibody molecule and as a
cell-bound receptor; it is the soluble form that is secreted
rather than the bound form released.
In the 1930s and 1940s, the selective theory was chal-
lenged by various instructional theories, in which antigen
played a central role in determining the specificity of the an-
tibody molecule. According to the instructional theories, a
particular antigen would serve as a template around which
antibody would fold. The antibody molecule would thereby
assume a configuration complementary to that of the antigen
template. This concept was first postulated by Friedrich
Breinl and Felix Haurowitz about 1930 and redefined in the
1940s in terms of protein folding by Linus Pauling. The in-
structional theories were formally disproved in the 1960s, by
which time information was emerging about the structure of
DNA, RNA, and protein that would offer new insights into
the vexing problem of how an individual could make anti-
bodies against almost anything.
In the 1950s, selective theories resurfaced as a result of
new experimental data and, through the insights of Niels
Jerne, David Talmadge, and F. Macfarlane Burnet, were re-
fined into a theory that came to be known as the clonal-
selection theory. According to this theory, an individual
lymphocyte expresses membrane receptors that are specific
for a distinct antigen. This unique receptor specificity is de-
termined before the lymphocyte is exposed to the antigen.
Binding of antigen to its specific receptor activates the cell,
causing it to proliferate into a clone of cells that have the
same immunologic specificity as the parent cell. The clonal-
selection theory has been further refined and is now accepted
as the underlying paradigm of modern immunology.
The Immune System Includes Innate and
Adaptive Components
Immunity—the state of protection from infectious disease
—has both a less specific and more specific component. The
less specific component, innate immunity, provides the first
line of defense against infection. Most components of innate
immunity are present before the onset of infection and con-
stitute a set of disease-resistance mechanisms that are not
specific to a particular pathogen but that include cellular and
molecular components that recognize classes of molecules
peculiar to frequently encountered pathogens. Phagocytic
cells, such as macrophages and neutrophils, barriers such as
skin, and a variety of antimicrobial compounds synthesized
by the host all play important roles in innate immunity. In
contrast to the broad reactivity of the innate immune sys-
tem, which is uniform in all members of a species, the spe-
cific component, adaptive immunity, does not come into
play until there is an antigenic challenge to the organism.
Adaptive immunity responds to the challenge with a high de-
gree of specificity as well as the remarkable property of
“memory.” Typically, there is an adaptive immune response
against an antigen within five or six days after the initial ex-
posure to that antigen. Exposure to the same antigen some
time in the future results in a memory response: the immune
response to the second challenge occurs more quickly than
4 PART I Introduction
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the first, is stronger, and is often more effective in neutraliz-
ing and clearing the pathogen. The major agents of adaptive
immunity are lymphocytes and the antibodies and other
molecules they produce.
Because adaptive immune responses require some time to
marshal, innate immunity provides the first line of defense
during the critical period just after the host’s exposure to a
pathogen. In general, most of the microorganisms encoun-
tered by a healthy individual are readily cleared within a few
days by defense mechanisms of the innate immune system
before they activate the adaptive immune system.
Innate Immunity
Innate immunity can be seen to comprise four types of de-
fensive barriers: anatomic, physiologic, phagocytic, and in-
flammatory (Table 1-2).
The Skin and the Mucosal Surfaces Provide
Protective Barriers Against Infection
Physical and anatomic barriers that tend to prevent the entry
of pathogens are an organism’s first line of defense against in-
fection. The skin and the surface of mucous membranes are
included in this category because they are effective barriers to
the entry of most microorganisms. The skin consists of two
distinct layers: a thinner outer layer—the epidermis—and a
thicker layer—the dermis. The epidermis contains several
layers of tightly packed epithelial cells. The outer epidermal
layer consists of dead cells and is filled with a waterproofing
protein called keratin. The dermis, which is composed of
connective tissue, contains blood vessels, hair follicles, seba-
ceous glands, and sweat glands. The sebaceous glands are as-
sociated with the hair follicles and produce an oily secretion
called sebum. Sebum consists of lactic acid and fatty acids,
which maintain the pH of the skin between 3 and 5; this pH
inhibits the growth of most microorganisms. A few bacteria
that metabolize sebum live as commensals on the skin and
sometimes cause a severe form of acne. One acne drug,
isotretinoin (Accutane), is a vitamin A derivative that pre-
vents the formation of sebum.
Breaks in the skin resulting from scratches, wounds, or
abrasion are obvious routes of infection. The skin may also
be penetrated by biting insects (e.g., mosquitoes, mites, ticks,
fleas, and sandflies); if these harbor pathogenic organisms,
they can introduce the pathogen into the body as they feed.
The protozoan that causes malaria, for example, is deposited
in humans by mosquitoes when they take a blood meal. Sim-
ilarly, bubonic plague is spread by the bite of fleas, and Lyme
disease is spread by the bite of ticks.
The conjunctivae and the alimentary, respiratory, and
urogenital tracts are lined by mucous membranes, not by the
dry, protective skin that covers the exterior of the body. These
Overview of the Immune System CHAPTER 1 5
TABLE 1-2 Summary of nonspecific host defenses
Type Mechanism
Anatomic barriers
Skin Mechanical barrier retards entry of microbes.
Acidic environment (pH 3–5) retards growth of microbes.
Mucous membranes Normal flora compete with microbes for attachment sites and nutrients.
Mucus entraps foreign microorganisms.
Cilia propel microorganisms out of body.
Physiologic barriers
Temperature Normal body temperature inhibits growth of some pathogens.
Fever response inhibits growth of some pathogens.
Low pH Acidity of stomach contents kills most ingested microorganisms.
Chemical mediators Lysozyme cleaves bacterial cell wall.
Interferon induces antiviral state in uninfected cells.
Complement lyses microorganisms or facilitates phagocytosis.
Toll-like receptors recognize microbial molecules, signal cell to secrete immunostimulatory cytokines.
Collectins disrupt cell wall of pathogen.
Phagocytic/endocytic barriers Various cells internalize (endocytose) and break down foreign macromolecules.
Specialized cells (blood monocytes, neutrophils, tissue macrophages) internalize
(phagocytose), kill, and digest whole microorganisms.
Inflammatory barriers Tissue damage and infection induce leakage of vascular fluid, containing serum proteins with
antibacterial activity, and influx of phagocytic cells into the affected area.
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membranes consist of an outer epithelial layer and an under-
lying layer of connective tissue. Although many pathogens
enter the body by binding to and penetrating mucous mem-
branes, a number of nonspecific defense mechanisms tend to
prevent this entry. For example, saliva, tears, and mucous se-
cretions act to wash away potential invaders and also contain
antibacterial or antiviral substances. The viscous fluid called
mucus, which is secreted by epithelial cells of mucous mem-
branes, entraps foreign microorganisms. In the lower respi-
ratory tract, the mucous membrane is covered by cilia,
hairlike protrusions of the epithelial-cell membranes. The
synchronous movement of cilia propels mucus-entrapped
microorganisms from these tracts. In addition, nonpatho-
genic organisms tend to colonize the epithelial cells of mu-
cosal surfaces. These normal flora generally outcompete
pathogens for attachment sites on the epithelial cell surface
and for necessary nutrients.
Some organisms have evolved ways of escaping these de-
fense mechanisms and thus are able to invade the body
through mucous membranes. For example, influenza virus
(the agent that causes flu) has a surface molecule that enables
it to attach firmly to cells in mucous membranes of the respi-
ratory tract, preventing the virus from being swept out by the
ciliated epithelial cells. Similarly, the organism that causes
gonorrhea has surface projections that allow it to bind to ep-
ithelial cells in the mucous membrane of the urogenital tract.
Adherence of bacteria to mucous membranes is due to inter-
actions between hairlike protrusions on a bacterium, called
fimbriae or pili, and certain glycoproteins or glycolipids that
are expressed only by epithelial cells of the mucous mem-
brane of particular tissues (Figure 1-2). For this reason, some
tissues are susceptible to bacterial invasion, whereas others
are not.
Physiologic Barriers to Infection Include
General Conditions and Specific Molecules
The physiologic barriers that contribute to innate immu-
nity include temperature, pH, and various soluble and cell-
associated molecules. Many species are not susceptible to cer-
tain diseases simply because their normal body temperature
inhibits growth of the pathogens. Chickens, for example,
have innate immunity to anthrax because their high body
temperature inhibits the growth of the bacteria. Gastric acid-
ity is an innate physiologic barrier to infection because very
few ingested microorganisms can survive the low pH of the
stomach contents. One reason newborns are susceptible to
some diseases that do not afflict adults is that their stomach
contents are less acid than those of adults.
A variety of soluble factors contribute to innate immu-
nity, among them the soluble proteins lysozyme, interferon,
and complement. Lysozyme, a hydrolytic enzyme found in
mucous secretions and in tears, is able to cleave the peptido-
glycan layer of the bacterial cell wall. Interferon comprises a
group of proteins produced by virus-infected cells. Among
the many functions of the interferons is the ability to bind to
nearby cells and induce a generalized antiviral state. Comple-
ment, examined in detail in Chapter 13, is a group of serum
proteins that circulate in an inactive state. A variety of spe-
cific and nonspecific immunologic mechanisms can convert
the inactive forms of complement proteins into an active
state with the ability to damage the membranes of patho-
genic organisms, either destroying the pathogens or facilitat-
ing their clearance. Complement may function as an effector
system that is triggered by binding of antibodies to certain
cell surfaces, or it may be activated by reactions between
complement molecules and certain components of microbial
cell walls. Reactions between complement molecules or frag-
ments of complement molecules and cellular receptors trig-
ger activation of cells of the innate or adaptive immune
systems. Recent studies on collectins indicate that these sur-
factant proteins may kill certain bacteria directly by disrupt-
ing their lipid membranes or, alternatively, by aggregating the
bacteria to enhance their susceptibility to phagocytosis.
Many of the molecules involved in innate immunity have
the property of pattern recognition, the ability to recognize a
given class of molecules. Because there are certain types of mol-
ecules that are unique to microbes and never found in multi-
cellular organisms, the ability to immediately recognize and
combat invaders displaying such molecules is a strong feature
of innate immunity. Molecules with pattern recognition ability
may be soluble, like lysozyme and the complement compo-
nents described above, or they may be cell-associated receptors.
Among the class of receptors designated the toll-like receptors
(TLRs), TLR2 recognizes the lipopolysaccharide (LPS) found
on Gram-negative bacteria. It has long been recognized that
6 PART I Introduction
FIGURE 1-2 Electron micrograph of rod-shaped Escherichia coli
bacteria adhering to surface of epithelial cells of the urinary tract.
[From N. Sharon and H. Lis, 1993, Sci. Am. 268(1):85; photograph
courtesy of K. Fujita.]
8536d_ch01_001-023 8/1/02 4:25 PM Page 6 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
systemic exposure of mammals to relatively small quantities of
purified LPS leads to an acute inflammatory response (see be-
low). The mechanism for this response is via a TLR on
macrophages that recognizes LPS and elicits a variety of mole-
cules in the inflammatory response upon exposure. When the
TLR is exposed to the LPS upon local invasion by a Gram-neg-
ative bacterium, the contained response results in elimination
of the bacterial challenge.
Cells That Ingest and Destroy Pathogens
Make Up a Phagocytic Barrier to Infection
Another important innate defense mechanism is the inges-
tion of extracellular particulate material by phagocytosis.
Phagocytosis is one type of endocytosis, the general term for
the uptake by a cell of material from its environment. In
phagocytosis, a cell’s plasma membrane expands around the
particulate material, which may include whole pathogenic
microorganisms, to form large vesicles called phagosomes
(Figure 1-3). Most phagocytosis is conducted by specialized
cells, such as blood monocytes, neutrophils, and tissue
macrophages (see Chapter 2). Most cell types are capable of
other forms of endocytosis, such as receptor-mediated endo-
cytosis, in which extracellular molecules are internalized after
binding by specific cellular receptors, and pinocytosis, the
process by which cells take up fluid from the surrounding
medium along with any molecules contained in it.
Inflammation Represents a Complex
Sequence of Events That Stimulates
Immune Responses
Tissue damage caused by a wound or by an invading patho-
genic microorganism induces a complex sequence of events
collectively known as the inflammatory response. As de-
scribed above, a molecular component of a microbe, such as
LPS, may trigger an inflammatory response via interaction
with cell surface receptors. The end result of inflammation
may be the marshalling of a specific immune response to the
invasion or clearance of the invader by components of the
innate immune system. Many of the classic features of the
inflammatory response were described as early as 1600 BC,in
Egyptian papyrus writings. In the first century AD, the
Roman physician Celsus described the “four cardinal signs
Overview of the Immune System CHAPTER 1 7
FIGURE 1-3 (a) Electronmicrograph of macrophage (pink) attack-
ing Escherichia coli (green). The bacteria are phagocytized as de-
scribed in part b and breakdown products secreted. The monocyte
(purple) has been recruited to the vicinity of the encounter by soluble
factors secreted by the macrophage. The red sphere is an erythrocyte.
(b) Schematic diagram of the steps in phagocytosis of a bacterium.
[Part a, Dennis Kunkel Microscopy, Inc./Dennis Kunkel.]
Bacterium becomes attached
to membrane evaginations
called pseudopodia
Bacterium is ingested,
forming phagosome
Phagosome fuses with
lysosome
Lysosomal enzymes digest
captured material
Digestion products are
released from cell
3
2
4
5
1
(a)
(b)
of inflammation” as rubor (redness), tumor (swelling),
calor (heat), and dolor (pain). In the second century AD,an-
other physician, Galen, added a fifth sign: functio laesa (loss
of function). The cardinal signs of inflammation reflect the
three major events of an inflammatory response (Figure 1-4):
1. Vasodilation—an increase in the diameter of blood
vessels—of nearby capillaries occurs as the vessels that
carry blood away from the affected area constrict,
resulting in engorgement of the capillary network. The
engorged capillaries are responsible for tissue redness
(erythema) and an increase in tissue temperature.
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2. An increase in capillary permeability facilitates an influx
of fluid and cells from the engorged capillaries into the
tissue. The fluid that accumulates (exudate) has a much
higher protein content than fluid normally released from
the vasculature. Accumulation of exudate contributes to
tissue swelling (edema).
3. Influx of phagocytes from the capillaries into the tissues is
facilitated by the increased permeability of the capil-
laries. The emigration of phagocytes is a multistep
process that includes adherence of the cells to the
endothelial wall of the blood vessels (margination),
followed by their emigration between the capillary-
endothelial cells into the tissue (diapedesis or extrava-
sation), and, finally, their migration through the tissue to
the site of the invasion (chemotaxis). As phagocytic cells
accumulate at the site and begin to phagocytose bacteria,
they release lytic enzymes, which can damage nearby
healthy cells. The accumulation of dead cells, digested
material, and fluid forms a substance called pus.
The events in the inflammatory response are initiated by a
complex series of events involving a variety of chemical me-
diators whose interactions are only partly understood. Some
of these mediators are derived from invading microorgan-
isms, some are released from damaged cells in response to tis-
sue injury, some are generated by several plasma enzyme sys-
tems, and some are products of various white blood cells
participating in the inflammatory response.
Among the chemical mediators released in response to tis-
sue damage are various serum proteins called acute-phase
proteins. The concentrations of these proteins increase dra-
matically in tissue-damaging infections. C-reactive protein is
a major acute-phase protein produced by the liver in re-
sponse to tissue damage. Its name derives from its pattern-
recognition activity: C-reactive protein binds to the
C-polysaccharide cell-wall component found on a variety of
bacteria and fungi. This binding activates the complement
system, resulting in increased clearance of the pathogen ei-
ther by complement-mediated lysis or by a complement-
mediated increase in phagocytosis.
One of the principal mediators of the inflammatory re-
sponse is histamine, a chemical released by a variety of cells
in response to tissue injury. Histamine binds to receptors on
nearby capillaries and venules, causing vasodilation and in-
creased permeability. Another important group of inflam-
matory mediators, small peptides called kinins, are normally
present in blood plasma in an inactive form. Tissue injury ac-
tivates these peptides, which then cause vasodilation and in-
8 PART I Introduction
Tissue damage causes release of
vasoactive and chemotactic factors
that trigger a local increase in blood
flow and capillary permeability
Permeable capillaries allow an
influx of fluid (exudate) and cells
Phagocytes and antibacterial
exudate destroy bacteria
Phagocytes migrate to site of
inflammation (chemotaxis)
2
1
3
4
Exudate
(complement, antibody,
C-reactive protein)
Capillary
Margination Extravasation
Tissue damage
Bacteria
FIGURE 1-4 Major events in the inflammatory response. A bacte-
rial infection causes tissue damage with release of various vasoactive
and chemotactic factors. These factors induce increased blood flow
to the area, increased capillary permeability, and an influx of white
blood cells, including phagocytes and lymphocytes, from the blood
into the tissues. The serum proteins contained in the exudate have
antibacterial properties, and the phagocytes begin to engulf the bac-
teria, as illustrated in Figure 1-3.
8536d_ch01_001-023 8/1/02 4:25 PM Page 8 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
creased permeability of capillaries. A particular kinin, called
bradykinin, also stimulates pain receptors in the skin. This
effect probably serves a protective role, because pain nor-
mally causes an individual to protect the injured area.
Vasodilation and the increase in capillary permeability in
an injured tissue also enable enzymes of the blood-clotting
system to enter the tissue. These enzymes activate an enzyme
cascade that results in the deposition of insoluble strands of
fibrin, which is the main component of a blood clot. The fib-
rin strands wall off the injured area from the rest of the body
and serve to prevent the spread of infection.
Once the inflammatory response has subsided and most
of the debris has been cleared away by phagocytic cells, tissue
repair and regeneration of new tissue begins. Capillaries
grow into the fibrin of a blood clot. New connective tissue
cells, called fibroblasts, replace the fibrin as the clot dissolves.
As fibroblasts and capillaries accumulate, scar tissue forms.
The inflammatory response is described in more detail in
Chapter 15.
Adaptive Immunity
Adaptive immunity is capable of recognizing and selectively
eliminating specific foreign microorganisms and molecules
(i.e., foreign antigens). Unlike innate immune responses,
adaptive immune responses are not the same in all members
of a species but are reactions to specific antigenic challenges.
Adaptive immunity displays four characteristic attributes:
a73
Antigenic specificity
a73
Diversity
a73
Immunologic memory
a73
Self/nonself recognition
The antigenic specificity of the immune system permits it to
distinguish subtle differences among antigens. Antibodies
can distinguish between two protein molecules that differ in
only a single amino acid. The immune system is capable of
generating tremendous diversity in its recognition molecules,
allowing it to recognize billions of unique structures on for-
eign antigens. Once the immune system has recognized and
responded to an antigen, it exhibits immunologic memory;
that is, a second encounter with the same antigen induces a
heightened state of immune reactivity. Because of this at-
tribute, the immune system can confer life-long immunity to
many infectious agents after an initial encounter. Finally, the
immune system normally responds only to foreign antigens,
indicating that it is capable of self/nonself recognition. The
ability of the immune system to distinguish self from nonself
and respond only to nonself molecules is essential, for, as de-
scribed below, the outcome of an inappropriate response to
self molecules can be fatal.
Adaptive immunity is not independent of innate immu-
nity. The phagocytic cells crucial to nonspecific immune re-
sponses are intimately involved in activating the specific im-
mune response. Conversely, various soluble factors produced
by a specific immune response have been shown to augment
the activity of these phagocytic cells. As an inflammatory re-
sponse develops, for example, soluble mediators are pro-
duced that attract cells of the immune system. The immune
response will, in turn, serve to regulate the intensity of the in-
flammatory response. Through the carefully regulated inter-
play of adaptive and innate immunity, the two systems work
together to eliminate a foreign invader.
The Adaptive Immune System Requires
Cooperation Between Lymphocytes and
Antigen-Presenting Cells
An effective immune response involves two major groups of
cells: T lymphocytes and antigen-presenting cells. Lympho-
cytes are one of many types of white blood cells produced in
the bone marrow by the process of hematopoiesis (see Chap-
ter 2). Lymphocytes leave the bone marrow, circulate in the
blood and lymphatic systems, and reside in various lym-
phoid organs. Because they produce and display antigen-
binding cell-surface receptors, lymphocytes mediate the
defining immunologic attributes of specificity, diversity,
memory, and self/nonself recognition. The two major popu-
lations of lymphocytes—B lymphocytes (B cells) and T lym-
phocytes (T cells)—are described briefly here and in greater
detail in later chapters.
B LYMPHOCYTES
B lymphocytes mature within the bone marrow; when they
leave it, each expresses a unique antigen-binding receptor on
its membrane (Figure 1-5a). This antigen-binding or B-cell
receptor is a membrane-bound antibody molecule. Anti-
bodies are glycoproteins that consist of two identical heavy
polypeptide chains and two identical light polypeptide
chains. Each heavy chain is joined with a light chain by disul-
fide bonds, and additional disulfide bonds hold the two pairs
together. The amino-terminal ends of the pairs of heavy and
light chains form a cleft within which antigen binds. When a
naive B cell (one that has not previously encountered anti-
gen) first encounters the antigen that matches its membrane-
bound antibody, the binding of the antigen to the antibody
causes the cell to divide rapidly; its progeny differentiate into
memory B cells and effector B cells called plasma cells.
Memory B cells have a longer life span than naive cells, and
they express the same membrane-bound antibody as their
parent B cell. Plasma cells produce the antibody in a form
that can be secreted and have little or no membrane-bound
antibody. Although plasma cells live for only a few days, they
secrete enormous amounts of antibody during this time.
It has been estimated that a single plasma cell can secrete
more than 2000 molecules of antibody per second. Secreted
antibodies are the major effector molecules of humoral
immunity.
Overview of the Immune System CHAPTER 1 9
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T LYMPHOCYTES
T lymphocytes also arise in the bone marrow. Unlike B cells,
which mature within the bone marrow, T cells migrate to the
thymus gland to mature. During its maturation within the
thymus, the T cell comes to express a unique antigen-binding
molecule, called the T-cell receptor, on its membrane. Unlike
membrane-bound antibodies on B cells, which can recognize
antigen alone, T-cell receptors can recognize only antigen
that is bound to cell-membrane proteins called major histo-
compatibility complex (MHC) molecules. MHC molecules
that function in this recognition event, which is termed “anti-
gen presentation,” are polymorphic (genetically diverse) gly-
coproteins found on cell membranes (see Chapter 7). There
are two major types of MHC molecules: Class I MHC mole-
cules, which are expressed by nearly all nucleated cells of ver-
tebrate species, consist of a heavy chain linked to a small
invariant protein called H9252
2
-microglobulin. Class II MHC
molecules, which consist of an alpha and a beta glycoprotein
chain, are expressed only by antigen-presenting cells. When a
naive T cell encounters antigen combined with a MHC mol-
ecule on a cell, the T cell proliferates and differentiates into
memory T cells and various effector T cells.
There are two well-defined subpopulations of T cells: T
helper (T
H
) and T cytotoxic (T
C
) cells. Although a third type
of T cell, called a T suppressor (T
S
) cell, has been postulated,
recent evidence suggests that it may not be distinct from T
H
and T
C
subpopulations. T helper and T cytotoxic cells can be
distinguished from one another by the presence of either
CD4 or CD8 membrane glycoproteins on their surfaces (Fig-
ure 1-5b,c). T cells displaying CD4 generally function as T
H
cells, whereas those displaying CD8 generally function as T
C
cells (see Chapter 2).
After a T
H
cell recognizes and interacts with an anti-
gen–MHC class II molecule complex, the cell is activated—it
becomes an effector cell that secretes various growth factors
known collectively as cytokines. The secreted cytokines play
an important role in activating B cells, T
C
cells, macrophages,
and various other cells that participate in the immune re-
sponse. Differences in the pattern of cytokines produced by
activated T
H
cells result in different types of immune
response.
Under the influence of T
H
-derived cytokines, a T
C
cell
that recognizes an antigen–MHC class I molecule complex
proliferates and differentiates into an effector cell called a cy-
totoxic T lymphocyte (CTL). In contrast to the T
C
cell, the
CTL generally does not secrete many cytokines and instead
exhibits cell-killing or cytotoxic activity. The CTL has a vital
function in monitoring the cells of the body and eliminating
any that display antigen, such as virus-infected cells, tumor
cells, and cells of a foreign tissue graft. Cells that display for-
eign antigen complexed with a class I MHC molecule are
called altered self-cells; these are targets of CTLs.
ANTIGEN-PRESENTING CELLS
Activation of both the humoral and cell-mediated branches
of the immune system requires cytokines produced by T
H
cells. It is essential that activation of T
H
cells themselves be
carefully regulated, because an inappropriate T-cell response
to self-components can have fatal autoimmune conse-
quences. To ensure carefully regulated activation of T
H
cells,
they can recognize only antigen that is displayed together
with class MHC II molecules on the surface of antigen-pre-
senting cells (APCs). These specialized cells, which include
macrophages, B lymphocytes, and dendritic cells, are distin-
guished by two properties: (1) they express class II MHC
molecules on their membranes, and (2) they are able to
deliver a co-stimulatory signal that is necessary for T
H
-cell
activation.
Antigen-presenting cells first internalize antigen, either by
phagocytosis or by endocytosis, and then display a part of
that antigen on their membrane bound to a class II MHC
molecule. The T
H
cell recognizes and interacts with the
10 PART I Introduction
(a) B cell
Antigen-
binding
receptor
(antibody)
(b) T
H
cell (c) T
C
cell
CD4
TCR
CD8
TCR
FIGURE 1-5 Distinctive membrane molecules on lymphocytes. (a)
B cells have about 10
5
molecules of membrane-bound antibody per
cell. All the antibody molecules on a given B cell have the same anti-
genic specificity and can interact directly with antigen. (b) T cells
bearing CD4 (CD4
+
cells) recognize only antigen bound to class II
MHC molecules. (c) T cells bearing CD8 (CD8
+
cells) recognize only
antigen associated with class I MHC molecules. In general, CD4
+
cells act as helper cells and CD8
+
cells act as cytotoxic cells. Both
types of T cells express about 10
5
identical molecules of the antigen-
binding T-cell receptor (TCR) per cell, all with the same antigenic
specificity.
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antigen–class II MHC molecule complex on the membrane
of the antigen-presenting cell (Figure 1-6). An additional co-
stimulatory signal is then produced by the antigen-present-
ing cell, leading to activation of the T
H
cell.
Humoral Immunity But Not Cellular
Immunity Is Transferred
with Antibody
As mentioned earlier, immune responses can be divided into
humoral and cell-mediated responses. Humoral immunity
refers to immunity that can be conferred upon a nonimmune
individual by administration of serum antibodies from an
immune individual. In contrast, cell-mediated immunity can
be transferred only by administration of T cells from an im-
mune individual.
The humoral branch of the immune system is at work in
the interaction of B cells with antigen and their subsequent
proliferation and differentiation into antibody-secreting
plasma cells (Figure 1-7). Antibody functions as the effector
of the humoral response by binding to antigen and neutraliz-
ing it or facilitating its elimination. When an antigen is
coated with antibody, it can be eliminated in several ways.
For example, antibody can cross-link several antigens, form-
ing clusters that are more readily ingested by phagocytic cells.
Binding of antibody to antigen on a microorganism can also
activate the complement system, resulting in lysis of the for-
eign organism. Antibody can also neutralize toxins or viral
particles by coating them, which prevents them from binding
to host cells.
Effector T cells generated in response to antigen are re-
sponsible for cell-mediated immunity (see Figure 1-7). Both
activated T
H
cells and cytotoxic T lymphocytes (CTLs) serve
as effector cells in cell-mediated immune reactions. Cy-
tokines secreted by T
H
cells can activate various phagocytic
cells, enabling them to phagocytose and kill microorganisms
more effectively. This type of cell-mediated immune re-
sponse is especially important in ridding the host of bacteria
and protozoa contained by infected host cells. CTLs partici-
pate in cell-mediated immune reactions by killing altered
self-cells; they play an important role in the killing of virus-
infected cells and tumor cells.
Antigen Is Recognized Differently by
B and T Lymphocytes
Antigens, which are generally very large and complex, are not
recognized in their entirety by lymphocytes. Instead, both B
and T lymphocytes recognize discrete sites on the antigen
called antigenic determinants, or epitopes. Epitopes are the
immunologically active regions on a complex antigen, the re-
gions that actually bind to B-cell or T-cell receptors.
Although B cells can recognize an epitope alone, T cells
can recognize an epitope only when it is associated with an
MHC molecule on the surface of a self-cell (either an anti-
gen-presenting cell or an altered self-cell). Each branch of the
immune system is therefore uniquely suited to recognize
antigen in a different milieu. The humoral branch (B cells)
recognizes an enormous variety of epitopes: those displayed
on the surfaces of bacteria or viral particles, as well as those
displayed on soluble proteins, glycoproteins, polysaccha-
rides, or lipopolysaccharides that have been released from in-
vading pathogens. The cell-mediated branch (T cells)
recognizes protein epitopes displayed together with MHC
molecules on self-cells, including altered self-cells such as
virus-infected self-cells and cancerous cells.
Thus, four related but distinct cell-membrane molecules
are responsible for antigen recognition by the immune
system:
a73
Membrane-bound antibodies on B cells
a73
T-cell receptors
a73
Class I MHC molecules
a73
Class II MHC molecules
Each of these molecules plays a unique role in antigen recog-
nition, ensuring that the immune system can recognize and
respond to the different types of antigen that it encounters.
B and T Lymphocytes Utilize Similar
Mechanisms To Generate Diversity
in Antigen Receptors
The antigenic specificity of each B cell is determined by the
membrane-bound antigen-binding receptor (i.e., antibody)
expressed by the cell. As a B cell matures in the bone marrow,
its specificity is created by random rearrangements of a series
Overview of the Immune System CHAPTER 1 11
FIGURE 1-6 Electron micrograph of an antigen-presenting macro-
phage (right) associating with a T lymphocyte. [From A. S. Rosenthal
et al., 1982, in Phagocytosis—Past and Future, Academic Press, p.
239.]
8536d_ch01_001-023 8/1/02 4:25 PM Page 11 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
12 PART I Introduction
VISUALIZING CONCEPTS
FIGURE 1-7 Overview of the humoral and cell-mediated
branches of the immune system. In the humoral response, B cells
interact with antigen and then differentiate into antibody-secret-
ing plasma cells. The secreted antibody binds to the antigen and
facilitates its clearance from the body. In the cell-mediated re-
sponse, various subpopulations of T cells recognize antigen pre-
sented on self-cells. T
H
cells respond to antigen by producing cy-
tokines. T
C
cells respond to antigen by developing into cytotoxic T
lymphocytes (CTLs), which mediate killing of altered self-cells
(e.g., virus-infected cells).
B cell Ab-secreting
plasma cells
+
Antigen
Activated
T
H
cell
T
C
cellT
H
cell
Cytotoxic T lymphocyte (CTL)
Class I
MHC
Class II
MHC
Internalized antigen
digested by cell
1
T cell receptors
recognize antigen bound
to MHC molecules
Altered self-cell
presents antigen
3
Binding antigen-MHC
activates T cells
2
Activated CTLs
recognize and kill
altered self-cells
4
Activated T
H
cell secretes
cytokines that contribute to
activation of B cells, T
C
cells,
and other cells
5
B cells interact with antigen
and differentiate into
antibody-secreting plasma cells
7
Antibody binds antigen
and facilitates its clearance
from the body
8
6
Antigens
BacteriaVirusesForeign
proteins
Parasites Fungi
Cell-mediated response
Humoral response
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of gene segments that encode the antibody molecule (see
Chapter 5). As a result of this process, each mature B cell pos-
sesses a single functional gene encoding the antibody heavy
chain and a single functional gene encoding the antibody
light chain; the cell therefore synthesizes and displays anti-
body with one specificity on its membrane. All antibody
molecules on a given B lymphocyte have identical specificity,
giving each B lymphocyte, and the clone of daughter cells to
which it gives rise, a distinct specificity for a single epitope on
an antigen. The mature B lymphocyte is therefore said to be
antigenically committed.
The random gene rearrangements during B-cell matura-
tion in the bone marrow generate an enormous number of
different antigenic specificities. The resulting B-cell popula-
tion, which consists of individual B cells each expressing a
unique antibody, is estimated to exhibit collectively more
than 10
10
different antigenic specificities. The enormous di-
versity in the mature B-cell population is later reduced by a
selection process in the bone marrow that eliminates any B
cells with membrane-bound antibody that recognizes self-
components. The selection process helps to ensure that self-
reactive antibodies (auto-antibodies) are not produced.
The attributes of specificity and diversity also characterize
the antigen-binding T-cell receptor (TCR) on T cells. As in B-
cell maturation, the process of T-cell maturation includes
random rearrangements of a series of gene segments that en-
code the cell’s antigen-binding receptor (see Chapter 9). Each
T lymphocyte cell expresses about 10
5
receptors, and all of
the receptors on the cell and its clonal progeny have identical
specificity for antigen. The random rearrangement of the
TCR genes is capable of generating on the order of 10
9
unique antigenic specificities. This enormous potential di-
versity is later diminished through a selection process in the
thymus that eliminates any T cell with self-reactive receptors
and ensures that only T cells with receptors capable of recog-
nizing antigen associated with MHC molecules will be able
to mature (see Chapter 10).
The Major Histocompatibility Molecules
Bind Antigenic Peptides
The major histocompatibility complex (MHC) is a large ge-
netic complex with multiple loci. The MHC loci encode two
major classes of membrane-bound glycoproteins: class I and
class II MHC molecules. As noted above, T
H
cells generally
recognize antigen combined with class II molecules, whereas
T
C
cells generally recognize antigen combined with class I
molecules (Figure 1-8).
MHC molecules function as antigen-recognition mole-
cules, but they do not possess the fine specificity for antigen
characteristic of antibodies and T-cell receptors. Rather, each
MHC molecule can bind to a spectrum of antigenic peptides
derived from the intracellular degradation of antigen mole-
cules. In both class I and class II MHC molecules the distal
regions (farthest from the membrane) of different alleles dis-
play wide variation in their amino acid sequences. These
variable regions form a cleft within which the antigenic pep-
tide sits and is presented to T lymphocytes (see Figure 1-8).
Different allelic forms of the genes encoding class I and class
Overview of the Immune System CHAPTER 1 13
Antigen-presenting cell
T
H
cell
T
H
cell
Virus-infected cell
T
C
cell
T
C
cell
Antigenic
peptide
Class I
MHC
Class II
MHC
CD8
T cell
receptor
CD4
FIGURE 1-8 The role of MHC molecules in antigen recognition by
T cells. (a) Class I MHC molecules are expressed on nearly all nucle-
ated cells. Class II MHC molecules are expressed only on antigen-
presenting cells. T cells that recognize only antigenic peptides
displayed with a class II MHC molecule generally function as T helper
(T
H
) cells. T cells that recognize only antigenic peptides displayed
with a class I MHC molecule generally function as T cytotoxic (T
C
)
cells. (b) This scanning electron micrograph reveals numerous T
lymphocytes interacting with a single macrophage. The macrophage
presents processed antigen combined with class II MHC molecules
to the T cells. [Photograph from W. E. Paul (ed.), 1991, Immunology:
Recognition and Response, W. H. Freeman and Company, New York;
micrograph courtesy of M. H. Nielsen and O. Werdelin.]
(b)
(a)
8536d_ch01_013 9/5/02 11:48 AM Page 13 mac46 mac46:385_reb:
II molecules confer different structures on the antigen-bind-
ing cleft with different specificity. Thus the ability to present
an antigen to T lymphocytes is influenced by the particular
set of alleles that an individual inherits.
Complex Antigens Are Degraded (Processed)
and Displayed (Presented) with MHC
Molecules on the Cell Surface
In order for a foreign protein antigen to be recognized by a T
cell, it must be degraded into small antigenic peptides that
form complexes with class I or class II MHC molecules. This
conversion of proteins into MHC-associated peptide frag-
ments is called antigen processing and presentation. Whether a
particular antigen will be processed and presented together
with class I MHC or class II MHC molecules appears to be
determined by the route that the antigen takes to enter a cell
(Figure 1-9).
Exogenous antigen is produced outside of the host cell
and enters the cell by endocytosis or phagocytosis. Antigen-
presenting cells (macrophages, dendritic cells, and B cells)
degrade ingested exogenous antigen into peptide fragments
within the endocytic processing pathway. Experiments sug-
gest that class II MHC molecules are expressed within the en-
docytic processing pathway and that peptides produced by
degradation of antigen in this pathway bind to the cleft
within the class II MHC molecules. The MHC molecules
bearing the peptide are then exported to the cell surface.
Since expression of class II MHC molecules is limited to anti-
gen-presenting cells, presentation of exogenous peptide–
class II MHC complexes is limited to these cells. T cells dis-
playing CD4 recognize antigen combined with class II MHC
molecules and thus are said to be class II MHC restricted.
These cells generally function as T helper cells.
Endogenous antigen is produced within the host cell it-
self. Two common examples are viral proteins synthesized
within virus-infected host cells and unique proteins synthe-
sized by cancerous cells. Endogenous antigens are degraded
into peptide fragments that bind to class I MHC molecules
within the endoplasmic reticulum. The peptide–class I MHC
complex is then transported to the cell membrane. Since all
nucleated cells express class I MHC molecules, all cells pro-
ducing endogenous antigen use this route to process the anti-
gen. T cells displaying CD8 recognize antigen associated with
class I MHC molecules and thus are said to be class I MHC re-
stricted. These cytotoxic T cells attack and kill cells displaying
the antigen–MHC class I complexes for which their receptors
are specific.
Antigen Selection of Lymphocytes
Causes Clonal Expansion
A mature immunocompetent animal contains a large num-
ber of antigen-reactive clones of T and B lymphocytes; the
antigenic specificity of each of these clones is determined by
the specificity of the antigen-binding receptor on the mem-
14 PART I Introduction
FIGURE 1-9 Processing and presentation of exogenous and en-
dogenous antigens. (a) Exogenous antigen is ingested by endocyto-
sis or phagocytosis and then enters the endocytic processing
pathway. Here, within an acidic environment, the antigen is degraded
into small peptides, which then are presented with class II MHC mol-
ecules on the membrane of the antigen-presenting cell. (b) Endoge-
Viral DNA
Virus
Viral mRNA
Polysomes
Rough
endoplasmic
reticulum
Golgi complex
Vesicle
Viral
peptides
Viral
protein
Antigen ingested
by endocytosis
or phagocytosis
Peptide–class II
MHC complex
(a) (b)
Peptides of
antigen
Class II
MHC
Peptide–class I MHC complex
Class I MHC
viral peptide
Nucleus
Lysosome
Endosome
Endocytic processing pathway
Ribosome
nous antigen, which is produced within the cell itself (e.g., in a virus-
infected cell), is degraded within the cytoplasm into peptides, which
move into the endoplasmic reticulum, where they bind to class I
MHC molecules. The peptide–class I MHC complexes then move
through the Golgi complex to the cell surface.
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brane of the clone’s lymphocytes. As noted above, the speci-
ficity of each T and B lymphocyte is determined before its
contact with antigen by random gene rearrangements during
maturation in the thymus or bone marrow.
The role of antigen becomes critical when it interacts with
and activates mature, antigenically committed T and B lym-
phocytes, bringing about expansion of the population of
cells with a given antigenic specificity. In this process of
clonal selection, an antigen binds to a particular T or B cell
and stimulates it to divide repeatedly into a clone of cells with
the same antigenic specificity as the original parent cell (Fig-
ure 1-10).
Clonal selection provides a framework for understanding
the specificity and self/nonself recognition that is character-
istic of adaptive immunity. Specificity is shown because only
lymphocytes whose receptors are specific for a given epitope
on an antigen will be clonally expanded and thus mobilized
for an immune response. Self/nonself discrimination is ac-
complished by the elimination, during development, of lym-
phocytes bearing self-reactive receptors or by the functional
suppression of these cells in adults.
Immunologic memory also is a consequence of clonal se-
lection. During clonal selection, the number of lymphocytes
specific for a given antigen is greatly amplified. Moreover,
many of these lymphocytes, referred to as memory cells, ap-
pear to have a longer life span than the naive lymphocytes
from which they arise. The initial encounter of a naive im-
munocompetent lymphocyte with an antigen induces a
Overview of the Immune System CHAPTER 1 15
FIGURE 1-10 Maturation and clonal selection of B lymphocytes.
Maturation, which occurs in the absence of antigen, produces anti-
genically committed B cells, each of which expresses antibody with a
single antigenic specificity (indicated by 1, 2, 3, and 4). Clonal selec-
tion occurs when an antigen binds to a B cell whose membrane-
bound antibody molecules are specific for epitopes on that antigen.
Clonal expansion of an antigen-activated B cell (number 2 in this ex-
Bone marrow Peripheral lymphoid tissue
Memory cell
Antibody
2
Plasma cells
Stem
cell
Gene
rearrangement
11
22
33
44
Maturation into mature
antigenetically committed B cells
Antigen 2
Mature
B cells
Mature
B cells
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Antigen-dependent proliferation and
differentiation into plasma and memory cells
ample) leads to a clone of memory B cells and effector B cells, called
plasma cells; all cells in the expanded clone are specific for the orig-
inal antigen. The plasma cells secrete antibody reactive with the acti-
vating antigen. Similar processes take place in the T-lymphocyte
population, resulting in clones of memory T cells and effector T cells;
the latter include activated T
H
cells, which secrete cytokines, and cy-
totoxic T lymphocytes (CTLs).
8536d_ch01_001-023 8/1/02 4:25 PM Page 15 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
primary response; a later contact of the host with antigen
will induce a more rapid and heightened secondary re-
sponse. The amplified population of memory cells accounts
for the rapidity and intensity that distinguishes a secondary
response from the primary response.
In the humoral branch of the immune system, antigen in-
duces the clonal proliferation of B lymphocytes into anti-
body-secreting plasma cells and memory B cells. As seen in
Figure 1-11a, the primary response has a lag of approxi-
mately 5–7 days before antibody levels start to rise. This lag is
the time required for activation of naive B cells by antigen
and T
H
cells and for the subsequent proliferation and differ-
entiation of the activated B cells into plasma cells. Antibody
levels peak in the primary response at about day 14 and then
begin to drop off as the plasma cells begin to die. In the
secondary response, the lag is much shorter (only 1–2 days),
antibody levels are much higher, and they are sustained for
much longer. The secondary response reflects the activity
of the clonally expanded population of memory B cells.
These memory cells respond to the antigen more rapidly
than naive B cells; in addition, because there are many
more memory cells than there were naive B cells for the
primary response, more plasma cells are generated in the
secondary response, and antibody levels are consequently
100- to 1000-fold higher.
In the cell-mediated branch of the immune system, the
recognition of an antigen-MHC complex by a specific ma-
ture T lymphocyte induces clonal proliferation into various
T cells with effector functions (T
H
cells and CTLs) and into
memory T cells. The cell-mediated response to a skin graft is
illustrated in Figure 1-11b by a hypothetical transplantation
experiment. When skin from strain C mice is grafted onto
strain A mice, a primary response develops and all the grafts
are rejected in about 10–14 days. If these same mice are again
grafted with strain C skin, it is rejected much more vigor-
ously and rapidly than the first grafts. However, if animals
previously engrafted with strain C skin are next given skin
from an unrelated strain, strain B, the response to strain B is
typical of the primary response and is rejected in 10–14 days.
That is, graft rejection is a specific immune response. The
same mice that showed a secondary response to graft C will
show a primary response to graft B. The increased speed of
rejection of graft C reflects the presence of a clonally ex-
panded population of memory T
H
and T
C
cells specific for
the antigens of the foreign graft. This expanded memory
population generates more effector cells, resulting in faster
graft rejection.
The Innate and Adaptive Immune Systems
Collaborate, Increasing the Efficiency of
Immune Responsiveness
It is important to appreciate that adaptive and innate immu-
nity do not operate independently—they function as a highly
interactive and cooperative system, producing a combined
response more effective than either branch could produce by
itself. Certain immune components play important roles in
both types of immunity.
An example of cooperation is seen in the encounter
between macrophages and microbes. Interactions between
receptors on macrophages and microbial components gen-
erate soluble proteins that stimulate and direct adaptive im-
mune responses, facilitating the participation of the adap-
16 PART I Introduction
Strain C
graft
repeated
Strain B
graft
Antigen A
Serum antibody level
Antigen A
+ Antigen B
Primary anti-A
response
Secondary
anti-A
response
Primary
anti-B
response
6014
Time, days
(a)
140
Percentage of mice rejecting graft
Strain C
graft
4
Time, days
(b)
012
20
40
60
80
100
816 4012816
FIGURE 1-11 Differences in the primary and secondary response
to injected antigen (humoral response) and to a skin graft (cell-me-
diated response) reflect the phenomenon of immunologic memory.
(a) When an animal is injected with an antigen, it produces a primary
serum antibody response of low magnitude and short duration,
peaking at about 10–17 days. A second immunization with the same
antigen results in a secondary response that is greater in magnitude,
peaks in less time (2–7 days), and lasts longer (months to years)
than the primary response. Compare the secondary response to anti-
gen A with the primary response to antigen B administered to the
same mice. (b) Results from a hypothetical experiment in which skin
grafts from strain C mice are transplanted to 20 mice of strain A; the
grafts are rejected in about 10–14 days. The 20 mice are rested for 2
months and then 10 are given strain C grafts and the other 10 are
given skin from strain B. Mice previously exposed to strain C skin re-
ject C grafts much more vigorously and rapidly than the grafts from
strain B. Note that the rejection of the B graft follows a time course
similar to that of the first strain C graft.
8536d_ch01_001-023 8/1/02 4:25 PM Page 16 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
tive immune system in the elimination of the pathogen.
Stimulated macrophages also secrete cytokines that can
direct adaptive immune responses against particular intra-
cellular pathogens.
Just as important, the adaptive immune system produces
signals and components that stimulate and increase the ef-
fectiveness of innate responses. Some T cells, when they en-
counter appropriately presented antigen, synthesize and
secrete cytokines that increase the ability of macrophages to
kill the microbes they have ingested. Also, antibodies pro-
duced against an invader bind to the pathogen, marking it as
a target for attack by complement and serving as a potent ac-
tivator of the attack.
A major difference between adaptive and innate immu-
nity is the rapidity of the innate immune response, which uti-
lizes a pre-existing but limited repertoire of responding
components. Adaptive immunity compensates for its slower
onset by its ability to recognize a much wider repertoire of
foreign substances, and also by its ability to improve during a
response, whereas innate immunity remains constant. It may
also be noted that secondary adaptive responses are consid-
erably faster than primary responses. Principle characteris-
tics of the innate and adaptive immune systems are
compared in Table 1-3. With overlapping roles, the two sys-
tems together form a highly effective barrier to infection.
Comparative Immunity
The field of immunology is concerned mostly with how in-
nate and adaptive mechanisms collaborate to protect verte-
brates from infection. Although many cellular and molecular
actors have important roles, antibodies and lymphocytes are
considered to be the principal players. Yet despite their
prominence in vertebrate immune systems, it would be a
mistake to conclude that these extraordinary molecules and
versatile cells are essential for immunity. In fact, a deter-
mined search for antibodies, T cells, and B cells in organisms
of the nonvertebrate phyla has failed to find them. The inte-
rior spaces of organisms as diverse as fruit flies, cockroaches,
and plants do not contain unchecked microbial populations,
however, which implies that some sort of immunity exists in
most, possibly all, multicellular organisms, including those
with no components of adaptive immunity.
Insects and plants provide particularly clear and dramatic
examples of innate immunity that is not based on lympho-
cytes. The invasion of the interior body cavity of the fruit fly,
Drosophila melanogaster, by bacteria or molds triggers the
synthesis of small peptides that have strong antibacterial or
antifungal activity. The effectiveness of these antimicrobial
peptides is demonstrated by the fate of mutants that are un-
able to produce them. For example, a fungal infection over-
whelms a mutant fruit fly that is unable to trigger the
synthesis of drosomycin, an antifungal peptide (Figure
1-12). Further evidence for immunity in the fruit fly is given
by the recent findings that cell receptors recognizing various
classes of microbial molecules (the toll-like receptors) were
first found in Drosophila.
Plants respond to infection by producing a wide variety
of antimicrobial proteins and peptides, as well as small
Overview of the Immune System CHAPTER 1 17
TABLE 1-3
Comparison of adaptive and
innate immunity
Innate Adaptive
Response time Hours Days
Specificity Limited and Highly diverse, improves
fixed during the course of
immune response
Response to Identical to Much more rapid than
repeat primary primary response
infection response
FIGURE 1-12 Severe fungal infection in a fruit fly (Drosophila
melanogaster) with a disabling mutation in a signal-transduction
pathway required for the synthesis of the antifungal peptide dro-
somycin. [From B. Lemaitre et al., 1996, Cell 86:973; courtesy of J. A.
Hoffman, University of Strasbourg.]
8536d_ch01_001-023 8/1/02 4:25 PM Page 17 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
nonpeptide organic molecules that have antibiotic activity.
Among these agents are enzymes that digest microbial cell
walls, peptides and a protein that damages microbial mem-
branes, and the small organic molecules phytoalexins. The
importance of the phytoalexins is shown by the fact that mu-
tations that alter their biosynthetic pathways result in loss of
resistance to many plant pathogens. In some cases, the re-
sponse of plants to pathogens goes beyond this chemical as-
sault to include an architectural response, in which the plant
isolates cells in the infected area by strengthening the walls of
surrounding cells. Table 1-4 compares the capabilities of im-
mune systems in a wide range of multicellular organisms,
both animals and plants.
Immune Dysfunction and
Its Consequences
The above overview of innate and adaptive immunity depicts
a multicomponent interactive system that protects the host
from infectious diseases and from cancer. This overview
would not be complete without mentioning that the immune
system can function improperly. Sometimes the immune sys-
tem fails to protect the host adequately or misdirects its ac-
tivities to cause discomfort, debilitating disease, or even
death. There are several common manifestations of immune
dysfunction:
a73
Allergy and asthma
a73
Graft rejection and graft-versus-host disease
a73
Autoimmune disease
a73
Immunodeficiency
Allergy and asthma are results of inappropriate immune re-
sponses, often to common antigens such as plant pollen,
food, or animal dander. The possibility that certain sub-
stances increased sensitivity rather than protection was rec-
ognized in about 1902 by Charles Richet, who attempted to
immunize dogs against the toxins of a type of jellyfish,
Physalia. He and his colleague Paul Portier observed that
dogs exposed to sublethal doses of the toxin reacted almost
instantly, and fatally, to subsequent challenge with minute
amounts of the toxin. Richet concluded that a successful im-
munization or vaccination results in phylaxis, or protection,
and that an opposite result may occur—anaphylaxis—in
which exposure to antigen can result in a potentially lethal
sensitivity to the antigen if the exposure is repeated. Richet
received the Nobel Prize in 1913 for his discovery of the ana-
phylactic response.
Fortunately, most allergic reactions in humans are not
rapidly fatal. A specific allergic or anaphylactic response usu-
ally involves one antibody type, called IgE. Binding of IgE to
its specific antigen (allergen) releases substances that cause
irritation and inflammation. When an allergic individual is
exposed to an allergen, symptoms may include sneezing,
wheezing, and difficulty in breathing (asthma); dermatitis or
skin eruptions (hives); and, in more extreme cases, strangu-
lation due to blockage of airways by inflammation. A signifi-
cant fraction of our health resources is expended to care for
those suffering from allergy and asthma. The frequency of
allergy and asthma in the United States place these com-
plaints among the most common reasons for a visit to the
doctor’s office or to the hospital emergency room (see Clini-
cal Focus).
When the immune system encounters foreign cells or tis-
sue, it responds strongly to rid the host of the invaders. How-
ever, in some cases, the transplantation of cells or an organ
from another individual, although viewed by the immune
system as a foreign invasion, may be the only possible treat-
ment for disease. For example, it is estimated that more than
60,000 persons in the United States alone could benefit from
a kidney transplant. Because the immune system will attack
and reject any transplanted organ that it does not recognize
as self, it is a serious barrier to this potentially life-saving
treatment. An additional danger in transplantation is that
any transplanted cells with immune function may view the
new host as nonself and react against it. This reaction, which
is termed graft-versus-host disease, can be fatal. The rejec-
tion reaction and graft-versus-host disease can be suppressed
by drugs, but this type of treatment suppresses all immune
function, so that the host is no longer protected by its im-
mune system and becomes susceptible to infectious diseases.
Transplantation studies have played a major role in the de-
velopment of immunology. A Nobel prize was awarded to
Karl Landsteiner, in 1930, for the discovery of human blood
groups, a finding that allowed blood transfusions to be car-
ried out safely. In 1980, G. Snell, J. Dausset, and B. Benacerraf
were recognized for discovery of the major histocompatibil-
ity complex, and, in 1991, E. D. Thomas and J. Murray were
awarded Nobel Prizes for advances in transplantation immu-
nity. To enable a foreign organ to be accepted without sup-
pressing immunity to all antigens remains a challenge for
immunologists today.
In certain individuals, the immune system malfunctions
by losing its sense of self and nonself, which permits an im-
mune attack upon the host. This condition, autoimmunity,
can cause a number of chronic debilitating diseases. The
symptoms of autoimmunity differ depending on which
tissues and organs are under attack. For example, multiple
sclerosis is due to an autoimmune attack on the brain and
central nervous system, Crohn’s disease is an attack on the
tissues in the gut, and rheumatoid arthritis is an attack on
joints of the arms and legs. The genetic and environmental
factors that trigger and sustain autoimmune disease are very
active areas of immunologic research, as is the search for im-
proved treatments.
If any of the many components of innate or specific im-
munity is defective because of genetic abnormality, or if any
immune function is lost because of damage by chemical,
physical, or biological agents, the host suffers from immu-
nodeficiency. The severity of the immunodeficiency disease
18 PART I Introduction
8536d_ch01_001-023 8/1/02 4:26 PM Page 18 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
Overview of the Immune System CHAPTER 1 19
TABLE 1-4 Immunity in multicellular organisms
Invasion-
induced
protective
Innate Adaptive enzymes Pattern-
immunity immunity and enzyme Antimicrobial recognition Graft T and B
Taxonomic group (nonspecific) (specific) cascades Phagocytosis peptides receptors rejection cells Antibodies
Higher plants H11001H11002H11001 H11002 H11001 H11001H11002H11002H11002
Invertebrate animals
Porifera H11001H11002? H11001 ??H11001H11002 H11002
(sponges)
Annelids H11001H11002? H11001 ??H11001H11002 H11002
(earthworms)
Arthropods H11001H11002H11001 H11001 H11001 H11001? H11002H11002
(insects,
crustaceans)
Vertebrate animals
Elasmobranchs H11001H11001H11001 H11001equivalent H11001H11001H11001H11001
(cartilaginous agents
fish; e.g.,
sharks, rays)
Teleost fish and H11001H11001H11001 H11001probable H11001H11001H11001H11001
bony fish (e.g.,
salmon, tuna)
Amphibians H11001H11001H11001 H11001 H11001 H11001H11001H11001H11001
Reptiles H11001H11001H11001 H11001 ? H11001H11001H11001H11001
Birds H11001H11001H11001 H11001 ? H11001H11001H11001H11001
Mammals H11001H11001H11001 H11001 H11001 H11001H11001H11001H11001
KEY: H11001H11005definitive demonstration; H11002H11005failure to demonstrate thus far; ? H11005 presence or absence remains to be established.
SOURCES: L. Du Pasquier and M. Flajnik, 1999, “Origin and Evolution of the Vertebrate Immune System,” in Fundamental Immunology, 4th ed.
W. E. Paul (ed.), Lippincott, Philadelphia; B. Fritig, T. Heitz, and M. Legrand, 1998, Curr. Opin. Immunol. 10:16; K. Soderhall and L. Cerenius,
1998, Curr. Opin. Immunol. 10:23.
lems. Details of the mechanisms that un-
derlie allergic and asthmatic responses
to environmental antigens (or allergens)
will be considered in Chapter 16. Simply
stated, allergic reactions are responses
to antigenic stimuli that result in immu-
nity based mainly on the IgE class of im-
munoglobulin. Exposure to the antigen
(or allergen) triggers an IgE-mediated re-
lease of molecules that cause symptoms
ranging from sneezing and dermatitis to
inflammation of the lungs in an asth-
matic attack. The sequence of events in
an allergic response is depicted in the ac-
companying figure.
The discomfort from common aller-
gies such as plant pollen allergy (often
called ragweed allergy) consists of a
week or two of sneezing and runny nose,
which may seem trivial compared with
health problems such as cancer, cardiac
arrest, or life-threatening infections. A
more serious allergic reaction is asthma,
Although the im-
mune system serves to protect the host
from infection and cancer, inappropriate
responses of this system can lead to
disease. Common among the results of
immune dysfunction are allergies and
asthma, both serious public health prob-
CLINICAL FOCUS
Allergy and Asthma as Serious
Public Health Problems
(continued)
8536d_ch01_001-023 8/1/02 4:26 PM Page 19 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
20 PART I Introduction
a chronic disease of the lungs in which
inflammation, mediated by environmen-
tal antigens or infections, causes severe
difficulty in breathing. Approximately 15
million persons in the United States suf-
fer from asthma, and it causes about
5000 deaths per year. In the past twenty
years, the prevalence of asthma in the
Western World has doubled.*
Data on the frequency of care sought
for the most common medical com-
plaints in the United States show that
asthma and allergy together resulted in
more than 28 million visits to the doctor
in 1995. The importance of allergy as a
public health problem is underscored by
the fact that the annual number of doctor
visits for hypertension, routine medical
examinations, or normal pregnancy, are
each fewer than the number of visits for
allergic conditions. In fact, the most
common reason for a visit to a hospital
emergency room is an asthma attack, ac-
counting for one third of all visits. In ad-
dition to those treated in the ER, there
were about 160,000 hospitalizations for
asthma in the past year, with an average
stay of 3 to 4 days.
Although all ages and races are af-
fected, deaths from asthma are 3.5 times
more common among African-American
children. The reasons for the increases in
number of asthma cases and for the
higher death rate in African-American chil-
dren remain unknown, although some
clues may have been uncovered by recent
CLINICAL FOCUS (continued)
Allergy and Asthma as Serious
Public Health Problems
Sequence of events leading to an allergic
response. When the antibody produced
upon contact with an allergen is IgE, this
class of antibody reacts via its constant
region with a mast cell. Subsequent reac-
tion of the antibody binding site with the
allergen triggers the mast cell to which
the IgE is bound to secrete molecules
that cause the allergic symptoms.
Plasma cell
B cell
IgE
Production of
large amounts
of ragweed IgE
antibody
First contact
with an allergen (ragweed)
Subsequent contact
with allergen
IgE molecules
attach to mast
cells
IgE-primed mast
cell releases
molecules that
cause wheezing,
sneezing, runny nose,
watery eyes, and
other symptoms
Ragweed
pollen
Mast cell
studies of genetic factors in allergic dis-
ease (see Clinical Focus in Chapter 16).
An increasingly serious health prob-
lem is food allergy, especially to peanuts
and tree nuts (almonds, cashews, and
walnuts).
?
Approximately 3 million
Americans are allergic to these foods
and they are the leading causes of fatal
and near-fatal food allergic (anaphylac-
tic) reactions. While avoidance of these
foods can prevent harmful conse-
quences, the ubiquitous use of peanut
protein and other nut products in a vari-
ety of foods makes this very difficult for
the allergic individual. At least 50% of se-
rious reactions are caused by accidental
exposures to peanuts, tree nuts, or their
products. This has led to controversial
movements to ban peanuts from
schools and airplanes.
Anaphylaxis generally occurs within
an hour of ingesting the food allergen
and the most effective treatment is injec-
tion of the drug epinephrine. Those
prone to anaphylactic attacks often carry
injectable epinephrine to be used in case
of exposure.
In addition to the suffering and anxi-
ety caused by inappropriate immune re-
sponses or allergies to environmental
antigens, there is a staggering cost in
terms of lost work time for those affected
and for caregivers. These costs well justify
the extensive efforts by basic and clinical
immunologists and allergists to relieve
the suffering caused by these disorders.
?
Hughes, D. A., and C. Mills. 2001. Food allergy:
A problem on the rise. Biologist (London) 48:201.
depends on the number of affected components. A common
type of immunodeficiency in North America is a selective
immunodeficiency in which only one type of immunoglob-
ulin, IgA, is lacking; the symptoms may be minor or even go
unnoticed. In contrast, a rarer immunodeficiency called
severe combined immunodeficiency (SCID), which affects
both B and T cells, if untreated, results in death from infec-
tion at an early age. Since the 1980s, the most common form
of immunodeficiency has been acquired immune deficiency
syndrome, or AIDS, which results from infection with the
*Holgate, S. T. 1999. The epidemic of allergy and
asthma, Nature Supp. to vol. 402, B2.
8536d_ch01_020 9/5/02 11:48 AM Page 20 mac46 mac46:385_reb:
retrovirus human immunodeficiency virus, or HIV. In AIDS,
T helper cells are infected and destroyed by HIV, causing a
collapse of the immune system. It is estimated that 35 million
persons worldwide suffer from this disease, which is usually
fatal within 8 to 10 years after infection. Although certain
treatments can prolong the life of AIDS patients, there is no
known cure for this disease.
This chapter has been a brief introduction to the immune
system, and it has given a thumbnail sketch of how this com-
plex system functions to protect the host from disease. The
following chapters will concern the structure and function of
the individual cells, organs, and molecules that make up this
system. They will describe our current understanding of how
the components of immunity interact and the experiments
that allowed discovery of these mechanisms. Specific areas of
applied immunology, such as immunity to infectious dis-
eases, cancer, and current vaccination practices are the subject
matter of later chapters. Finally, to complete the description
of the immune system in all of its activities, a chapter ad-
dresses each of the major types of immune dysfunction.
SUMMARY
a73
Immunity is the state of protection against foreign organ-
isms or substances (antigens). Vertebrates have two types
of immunity, innate and adaptive.
a73
Innate immunity is not specific to any one pathogen but
rather constitutes a first line of defense, which includes
anatomic, physiologic, endocytic and phagocytic, and in-
flammatory barriers.
a73
Innate and adaptive immunity operate in cooperative and
interdependent ways. The activation of innate immune re-
sponses produces signals that stimulate and direct subse-
quent adaptive immune responses.
a73
Adaptive immune responses exhibit four immunologic at-
tributes: specificity, diversity, memory, and self/nonself
recognition.
a73
The high degree of specificity in adaptive immunity arises
from the activities of molecules (antibodies and T-cell
receptors) that recognize and bind specific antigens.
a73
Antibodies recognize and interact directly with antigen. T-
cell receptors recognize only antigen that is combined with
either class I or class II major histocompatibility complex
(MHC) molecules.
a73
The two major subpopulations of T lymphocytes are the
CD4
H11001
T helper (T
H
) cells and CD8
H11001
T cytotoxic (T
C
) cells.
T
H
cells secrete cytokines that regulate immune response
upon recognizing antigen combined with class II MHC. T
C
cells recognize antigen combined with class I MHC and
give rise to cytotoxic T cells (CTLs), which display cyto-
toxic ability.
a73
Exogenous (extracellular) antigens are internalized and
degraded by antigen-presenting cells (macrophages, B
cells, and dendritic cells); the resulting antigenic peptides
complexed with class II MHC molecules are then displayed
on the cell surface.
a73
Endogenous (intracellular) antigens (e.g., viral and tumor
proteins produced in altered self-cells) are degraded in the
cytoplasm and then displayed with class I MHC molecules
on the cell surface.
a73
The immune system produces both humoral and cell-me-
diated responses. The humoral response is best suited for
elimination of exogenous antigens; the cell-mediated re-
sponse, for elimination of endogenous antigens.
a73
While an adaptive immune system is found only in verte-
brates, innate immunity has been demonstrated in organ-
isms as different as insects, earthworms, and higher plants.
a73
Dysfunctions of the immune system include common
maladies such as allergy or asthma. Loss of immune func-
tion leaves the host susceptible to infection; in autoimmu-
nity, the immune system attacks host cells or tissues,
References
Akira, S., K. Takeda, and T. Kaisho. 2001. Toll-like receptors:
Critical proteins linking innate and acquired immunity. Na-
ture Immunol. 2:675.
Burnet, F. M. 1959. The Clonal Selection Theory of Acquired Im-
munity. Cambridge University Press, Cambridge.
Cohen, S. G., and M. Samter. 1992. Excerpts from Classics in Al-
lergy. Symposia Foundation, Carlsbad, California.
Desour, L. 1922. Pasteur and His Work (translated by A. F. and
B. H. Wedd). T. Fisher Unwin Ltd., London.
Fritig, B., T. Heitz, and M. Legrand. 1998. Antimicrobial proteins
in induced plant defense. Curr. Opin. Immunol. 10:12.
Kimbrell, D. A., and B. Beutler. 2001. The evolution and
genetics of innate immunity. Nature Rev. Genet. 2:256.
Kindt, T. J., and J. D. Capra. 1984. The Antibody Enigma.
Plenum Press, New York.
Landsteiner, K. 1947. The Specificity of Serologic Reactions. Har-
vard University Press, Cambridge, Massachusetts.
Lawson, P. R., and K. B. Reid. 2000. The roles of surfactant
proteins A and D in innate immunity. Immunologic Reviews
173:66.
Medawar, P. B. 1958. The Immunology of Transplantation. The
Harvey Lectures 1956–1957. Academic Press, New York.
Medzhitov, R., and C. A. Janeway. 2000. Innate immunity. N.
Eng. J. Med. 343:338.
Metchnikoff, E. 1905. Immunity in the Infectious Diseases.
MacMillan, New York.
Otvos, L. 2000. Antibacterial peptides isolated from insects. J.
Peptide Sci. 6:497.
Paul, W., ed. 1999. Fundamental Immunology, 4th ed. Lippin-
cott-Raven, Philadelphia.
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Roitt, I. M., and P. J. Delves, eds. 1998. An Encyclopedia of Im-
munology, 2nd ed., vols. 1–4. Academic Press, London.
USEFUL WEB SITES
http://www.aaaai.org/
The American Academy of Allergy Asthma and Immunology
site includes an extensive library of information about allergic
diseases.
http://12.17.12.70/aai/default.asp
The Web site of the American Association of Immunologists
contains a good deal of information of interest to immunolo-
gists.
http://www.ncbi.nlm.nih.gov/PubMed/
PubMed, the National Library of Medicine database of more
than 9 million publications, is the world’s most comprehen-
sive bibliographic database for biological and biomedical lit-
erature. It is also a highly user-friendly site.
Study Questions
CLINICAL FOCUS QUESTION You have a young nephew who has
developed a severe allergy to tree nuts. What precautions would
you advise for him and for his parents? Should school officials be
aware of this condition?
1. Indicate to which branch(es) of the immune system the fol-
lowing statements apply, using H for the humoral branch
and CM for the cell-mediated branch. Some statements may
apply to both branches.
a. Involves class I MHC molecules
b. Responds to viral infection
c. Involves T helper cells
d. Involves processed antigen
e. Most likely responds following an organ
transplant
f. Involves T cytotoxic cells
g. Involves B cells
h. Involves T cells
i. Responds to extracellular bacterial infection
j. Involves secreted antibody
k. Kills virus-infected self-cells
2. Specific immunity exhibits four characteristic attributes,
which are mediated by lymphocytes. List these four attrib-
utes and briefly explain how they arise.
3. Name three features of a secondary immune response that
distinguish it from a primary immune response.
4. Compare and contrast the four types of antigen-binding
molecules used by the immune system—antibodies, T-cell
receptors, class I MHC molecules, and class II MHC mole-
cules—in terms of the following characteristics:
a. Specificity for antigen
b. Cellular expression
c. Types of antigen recognized
5. Fill in the blanks in the following statements with the most
appropriate terms:
a. , , and all function as antigen-
presenting cells.
b. Antigen-presenting cells deliver a signal to
cells.
c. Only antigen-presenting cells express class
MHC molecules, whereas nearly all cells express class
MHC molecules.
d. antigens are internalized by antigen-presenting
cells, degraded in the , and displayed with class
MHC molecules on the cell surface.
e. antigens are produced in altered self-cells, de-
graded in the , and displayed with class
MHC molecules on the cell surface.
6. Briefly describe the three major events in the inflammatory
response.
7. The T cell is said to be class I restricted. What does this
mean?
8. Match each term related to innate immunity (a–p) with the
most appropriate description listed below (1–19). Each de-
scription may be used once, more than once, or not at all.
Terms
a. Fimbriae or pili
b. Exudate
c. Sebum
d. Margination
e. Dermis
f. Lysosome
g. Histamine
h. Macrophage
i. Lysozyme
j. Bradykinin
k. Interferon
l. Edema
m. Complement
n. Extravasation
o. C-reactive protein
p. Phagosome
Descriptions
(1) Thin outer layer of skin
(2) Layer of skin containing blood vessels and sebaceous
glands
(3) One of several acute-phase proteins
(4) Hydrolytic enzyme found in mucous secretions
(5) Migration of a phagocyte through the endothelial wall
into the tissues
(6) Acidic antibacterial secretion found on the skin
(7) Has antiviral activity
(8) Induces vasodilation
(9) Accumulation of fluid in intercellular space, resulting in
swelling
(10) Large vesicle containing ingested particulate material
(11) Accumulation of dead cells, digested material, and fluid
(12) Adherence of phagocytic cells to the endothelial wall
22 PART I Introduction
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Review and quiz of key terms
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(13) Structures involved in microbial adherence to mucous
membranes
(14) Stimulates pain receptors in the skin
(15) Phagocytic cell found in the tissues
(16) Phagocytic cell found in the blood
(17) Group of serum proteins involved in cell lysis and clear-
ance of antigen
(18) Cytoplasmic vesicle containing degradative enzymes
(19) Protein-rich fluid that leaks from the capillaries into the
tissues
9. Innate and adaptive immunity act in cooperative and inter-
dependent ways to protect the host. Discuss the collabora-
tion of these two forms of immunity.
10. How might an arthropod, such as a cockroach or beetle, pro-
tect itself from infection? In what ways might the innate im-
mune responses of an arthropod be similar to those of a
plant and how might they differ?
11. Give examples of mild and severe consequences of immune
dysfunction. What is the most common cause of immunod-
eficiency throughout the world today?
12. Adaptive immunity has evolved in vertebrates but they have
also retained innate immunity. What would be the disadvan-
tages of having only an adaptive immune system? Comment
on how possession of both types of immunity enhances pro-
tection against infection.
Overview of the Immune System CHAPTER 1 23
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