in an efficient and professional manner. To all of them
we owe our many thanks. Finally, we owe an enormous
debt of gratitude to our families, whose support and
encouragement have been unwavering.
1 Introduction to the Immune System, 1
Nomenclature, General Properties, and Components
The Early Defense Against Infections
3 Antigen Capture and Presentation to
4 Antigen Recognition in the Adaptive
Structure of Lymphocyte Antigen Receptors and Development
5 T Cell–Mediated Immunity, 96
6 Effector Mechanisms of T Cell–Mediated
Functions of T Cells in Host Defense
7 Humoral Immune Responses, 137
Activation of B Lymphocytes and Production of Antibodies
8 Effector Mechanisms of Humoral Immunity, 158
Elimination of Extracellular Microbes and Toxins
9 Immunologic Tolerance and Autoimmunity, 177
Self–Nonself Discrimination in the Immune System and Its
10 Immunology of Tumors and Transplantation, 196
Immune Responses to Cancer Cells and Normal Foreign Cells
Disorders Caused by Immune Responses
12 Congenital and Acquired Immunodeficiencies, 235
Diseases Caused by Defective Immunity
Appendix I: Principal Features of Selected
Appendix III: Clinical Cases, 300
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FUNCTIONS AND DISORDERS OF THE IMMUNE SYSTEM
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reactions to some noninfectious substances including
harmless environmental molecules, tumors, and even
unaltered host components are also considered forms of
immunity (allergy, tumor immunity, and autoimmunity,
system, and the coordinated response of these cells and
molecules to pathogens and other substances comprises
The most important physiologic function of the
immune system is to prevent or eradicate infections
(Fig. 1.1), and this is the principal context in which immune
responses are discussed throughout this book. In addition,
it prevents the growth of some tumors, and some cancers
can be treated by stimulating immune responses against
tumor cells. The immune system also plays a major role in
the repair of damaged tissues. Because the immune system
can respond to microbial and nonmicrobial substances
and also can cause disease under some circumstances,
a more inclusive definition of the immune response is a
reaction to microbes, as well as to other molecules that
are recognized as foreign, regardless of the physiologic or
pathologic consequence of such a reaction. Immunology is
the study of immune responses in this broader sense and of
The importance of the immune system for health
is dramatically illustrated by the frequent observation
that individuals with defective immune responses are
susceptible to serious, often life-threatening infections.
Conversely, stimulating immune responses against
microbes through vaccination is the most effective
method for protecting individuals against infections;
this approach has led to the worldwide eradication of
smallpox, the only disease that has been eliminated
from civilization by human intervention (Fig. 1.2). The
appearance of acquired immunodeficiency syndrome
Innate and Adaptive Immunity, 3
Properties of Adaptive Immune Responses, 6
Other Features of Adaptive Immunity, 8
Cells of the Adaptive Immune System, 9
Tissues of the Immune System, 15
Peripheral (Secondary) Lymphoid Organs and
Lymphocyte Recirculation and Migration into
2 CHAPTER 1 Introduction to the Immune System
In contrast to these beneficial roles, abnormal immune
the major barrier to the success of organ transplantation,
which is often used to treat organ failure. The products
of immune cells can also be of great practical use. For
example, antibodies, which are proteins made by certain
block or eliminate potentially harmful molecules and
cells are used widely for the treatment of immunologic
diseases, cancers, and other types of disorders. For all
these reasons, the field of immunology has captured the
attention of clinicians, scientists, and the lay public.
This chapter introduces the nomenclature of immunology, important general properties of all immune
responses, and the cells and tissues that are the principal
components of the immune system. In particular, the
following questions are addressed:
• What types of immune responses protect individuals
• What are the important characteristics of immunity,
and what mechanisms are responsible for these characteristics?
• How are the cells and tissues of the immune system
organized to find and respond to microbes in ways
that lead to their elimination?
The basic principles introduced here set the stage for
more detailed discussions of immune responses in later
chapters. A Glossary of the important terms used in this
book is provided near the end of the book.
Host defenses are grouped under innate immunity,
more slowly and provides more specialized defense
against infections (Fig. 1.3). Innate immunity, also
called natural immunity or native immunity, is always
present in healthy individuals (hence the term innate),
prepared to block the entry of microbes and to rapidly
adaptive immune response evolved later.
Role of the immune system Implications
Defense against infections Deficient immunity results in
infections; exemplified by AIDS
Immune responses are barriers to
transplantation and gene therapy
Immune responses are the cause
of allergic, autoimmune, and other
CHAPTER 1 Introduction to the Immune System 3
Fig. 1.2 Effectiveness of vaccination for some common infectious diseases in the United States. Many
4th ed. New York: Churchill Livingstone, 1995; and MMWR 66, No. 1, 2017.)
tissues and by cells and natural antibiotics present in
epithelia, all of which function to block the entry of
microbes. If microbes do breach epithelia and enter the
tissues or circulation, several other components of the
plasma proteins, such as the complement system. In
addition to providing early defense against infections,
The components and mechanisms of innate immunity
are discussed in detail in Chapter 2.
The adaptive immune system consists of lymphocytes with highly diverse and variable receptors for
foreign substances, and the products of these cells,
such as antibodies. Adaptive immune responses are
essential for defense against infectious microbes that are
pathogenic for humans (i.e., capable of causing disease)
and may have evolved to resist innate immunity. The cells
and molecules of innate immunity recognize structures
shared by classes of microbes, whereas the lymphocytes
of adaptive immunity express receptors that specifically
recognize a much wider variety of molecules produced
by microbes, as well as noninfectious molecules. Any
molecule that is specifically recognized by lymphocytes
or antibodies is called an antigen. Adaptive immune
responses often use the cells and molecules of the innate
immune system to eliminate microbes. For example,
antibodies (a component of adaptive immunity) bind to
microbes, and these coated microbes avidly bind to and
activate phagocytes (a component of innate immunity),
which ingest and destroy the microbes. Examples of the
cooperation between innate and adaptive immunity are
By convention, the term immune response generally
refers to adaptive immunity, and that is the focus of
all times. Some of these cells function mainly in innate
into two broad categories—lymphoid cells (most of
4 CHAPTER 1 Introduction to the Immune System
which are the mediators of adaptive immune responses)
and nonlymphoid cells, also called myeloid cells,
which play diverse roles, including in innate immune
• Tissue-resident dendritic cells, macrophages, and
mast cells serve as sentinels to detect the presence of
microbes in tissues and initiate immune responses.
Dendritic cells (DCs), so called because of their
many protruding membrane extensions, also have
called antigen-presenting cells (APCs, discussed
• Phagocytes ingest and destroy microbes. They are
myeloid cells and include neutrophils, which are
recruited from the blood, and macrophages, which
can develop from circulating monocytes and live in
tissues much longer than neutrophils do. Macrophages
are not only sentinels and destroyers of microbes,
they also help to repair damaged tissues. Because the
sentinels and phagocytes are primarily cells of innate
immunity, they are described in Chapter 2.
• Lymphocytes, including B and T cells, circulate
through lymphoid organs and nonlymphoid tissues.
They recognize foreign antigens and carry out adaptive immune responses. They are described further
The two types of adaptive immunity, called humoral
immunity and cell-mediated immunity, are mediated
by different cells and molecules and provide defense
against extracellular microbes and intracellular
microbes, respectively (Fig. 1.4).
• Humoral immunity is mediated by proteins called
antibodies, which are produced by cells called
Innate immunity Adaptive immunity
Fig. 1.3 Principal mechanisms of innate and adaptive immunity. The mechanisms of innate immunity
complement system) eliminate microbes. Adaptive immune responses develop later and are mediated by
and may vary in different infections.
CHAPTER 1 Introduction to the Immune System 5
present in these locations by preventing them from
invading tissue cells and by neutralizing toxins made
by the microbes. Microbes that live and divide outside cells but are readily killed once ingested by
phagocytes are called extracellular microbes, and
antibodies can enhance the uptake of these microbes
into phagocytes. However, many microbes, often
called intracellular microbes, can live and divide
inside infected cells, including phagocytes. Although
antibodies can prevent such microbes from infecting
tissue cells, they are not effective after the microbes
• Defense against microbes that have already entered
host cells is called cell-mediated immunity because
can survive and replicate inside cells. Some T lymphocytes activate phagocytes to destroy microbes
that have been ingested and live within intracellular
vesicles of these phagocytes. Other T lymphocytes
kill any type of host cells (including non-phagocytic
cell. Some T lymphocytes also help to defend against
extracellular microbes by recruiting large numbers of
6 CHAPTER 1 Introduction to the Immune System
phagocytes to sites of infection, and the phagocytes
ingest and destroy the microbes.
The specificities of B and T lymphocytes differ in
important respects. Most T cells recognize only peptide
fragments of protein antigens presented on cell surfaces,
whereas B cells and antibodies are able to recognize
many different types of molecules, including proteins,
carbohydrates, nucleic acids, and lipids. These and other
differences are discussed in more detail later.
Immunity may be induced in an individual by
lymphocytes from an actively immunized individual
• In active immunity, an individual exposed to the
antigens of a microbe mounts a response to eradicate
be immune to that microbe, in contrast with a naive
individual who has not previously been exposed to
antibodies that have been synthesized using modern
bioengineering techniques. The recipient acquires
the ability to combat the infection for as long as the
transferred antibodies or cells last. Passive immunity
is therefore useful for rapidly conferring immunity
even before the individual is able to mount an active
response, but it does not induce long-lived resistance
to the infection. The only physiologic example of passive immunity is seen in newborns, whose immune
systems are not mature enough to respond to many
pathogens but who are protected against infections by
using serum from immunized donors. Antibodies and
T cells designed to recognize tumors are now widely
used for passive immunotherapy of cancers.
Several properties of adaptive immune responses are
crucial for the effectiveness of these responses in combating infections (Fig. 1.5).
The adaptive immune system is capable of distinguishing millions of different antigens or portions
of antigens, a feature that is referred to as specificity.
is extremely diverse. The total population of B and T
lymphocytes consists of many different clones (each
basis for the generation of this remarkable diversity
of lymphocytes (see Chapter 4). The clonal selection
selecting and activating the lymphocytes of a specific
Feature Functional significance
Fig. 1.5 Properties of adaptive immune responses. This
table summarizes the important properties of adaptive immune
responses and how each feature contributes to host defense
CHAPTER 1 Introduction to the Immune System 7
The diversity of the lymphocyte repertoire, which
enables the immune system to respond to a vast number
and variety of antigens, also means that before exposure
to any one antigen, very few cells, perhaps as few as 1 in
100,000 or 1 in 1,000,000 lymphocytes, are specific for
that antigen. Thus, the total number of lymphocytes that
can recognize and react against any one antigen ranges
from approximately 1,000 to 10,000 cells. To mount an
effective defense against microbes, these few cells have
to give rise to a large number of lymphocytes capable of
destroying the microbes. Each unique lymphocyte that
recognizes a single antigen and its progeny constitute
an antigen-specific clone. The effectiveness of immune
responses is attributable to several features of adaptive
immunity, including the marked expansion of the clone
of lymphocytes specific for any antigen upon exposure
to that antigen, the selection and preservation of the
The adaptive immune system mounts faster, larger
and more effective responses to repeated exposure
to the same antigen. This feature of adaptive immune
responses implies that the immune system remembers
8 CHAPTER 1 Introduction to the Immune System
for the first time (Fig. 1.7). The term naive refers to these
cells being immunologically inexperienced, not having
larger, and better able to eliminate the antigen than
primary responses. Secondary responses are the result
of the activation of memory lymphocytes, which are
long-lived cells that were induced during the primary
immune response. Immunologic memory optimizes
the ability of the immune system to combat persistent
and recurrent infections, because each exposure to a
is one mechanism by which vaccines confer long-lasting
protection against infections.
Other Features of Adaptive Immunity
Adaptive immune responses have other characteristics
that are important for their functions (see Fig. 1.5).
• When naive or memory lymphocytes are activated
by antigens, they undergo proliferation, generating
many thousands of cells, all with the same antigen
receptors and specificity. This process, called clonal
expansion, rapidly increases the number of cells
specific for the antigen encountered and ensures
that adaptive immunity keeps pace with rapidly
• Immune responses are specialized, and different
responses are designed to defend best against different types of microbes.
• All immune responses are self-limited and decline
as the infection is eliminated, allowing the system to
return to a resting state (homeostasis), prepared to
Fig. 1.7 Primary and secondary immune responses. The properties of memory and specificity can be
demonstrated by repeated immunizations with defined antigens in animal experiments. Antigens X and Y
kinetics vary, depending on the antigen and the nature of immunization.
CHAPTER 1 Introduction to the Immune System 9
the host’s own potentially antigenic substances—
so-called self antigens. This unresponsiveness to self
is called immunological tolerance, referring to the
(Fig. 1.8). Phagocytes and other cells of innate immunity
Lymphocytes are the only cells that produce clonally
distributed receptors specific for diverse antigens and
are the key mediators of adaptive immunity. A healthy
adult contains 0.5 to 1 × 1012 lymphocytes. Although
all lymphocytes are morphologically similar and rather
unremarkable in appearance, they are heterogeneous
in lineage, function, and phenotype and are capable
of complex biologic responses and activities (Fig. 1.9).
These cells often are distinguished by the expression
of surface proteins that may be identified using panels
of monoclonal antibodies. The standard nomenclature
for these proteins is the CD (cluster of differentiation)
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