PART I

An introduction to immunobiology
and innate immunity
1 Basic Concepts in Immunology
2 Innate Immunity: The First Lines of Defense
3 The Induced Response of Innate Immunity

Basic Concepts in
Immunology
Immunology is the study of the body’s defense against infection. We are con-
1
IN THIS CHAPTER
tinually exposed to microorganisms, many of which cause disease, and yet The origins of vertebrate immune
become ill only rarely. How does the body defend itself? When infection does cells.
occur, how does the body eliminate the invader and cure itself? And why do we
develop long-lasting immunity to many infectious diseases encountered once Principles of innate immunity.
and overcome? These are the questions addressed by immunology, which we Principles of adaptive immunity.
study to understand our body’s defenses against infection at the cellular and
The effector mechanisms
molecular levels. of immunity.
The beginning of immunology as a science is usually attributed to Edward
Jenner for his work in the late 18th century (Fig. 1.1). The notion of immunity—
that surviving a disease confers greater protection against it later—was known
since ancient Greece. Variolation—the inhalation or transfer into superficial
skin wounds of material from smallpox pustules—had been practiced since
at least the 1400s in the Middle East and China as a form of protection against
that disease and was known to Jenner. Jenner had observed that the relatively
mild disease of cowpox, or vaccinia, seemed to confer protection against the
often fatal disease of smallpox, and in 1796, he demonstrated that inoculation
with cowpox protected the recipient against smallpox. His scientific proof
relied on the deliberate exposure of the inoculated individual to infectious
smallpox material two months after inoculation. This scientific test was his
original contribution.
Jenner called the procedure vaccination. This term is still used to describe
the inoculation of healthy individuals with weakened or attenuated strains of
disease-causing agents in order to provide protection from disease. Although
Jenner’s bold experiment was successful, it took almost two centuries for
smallpox vaccination to become universal. This advance enabled the World
Health Organization to announce in 1979 that smallpox had been eradicated
(Fig. 1.2), arguably the greatest triumph of modern medicine.
Immunobiology
Fig. 1.1 Edward | chapter 1 | 01_001
Jenner. Portrait by John
Jenner’s strategy of vaccination was extended in the late 19th century by the Murphy et al | Ninth edition
Raphael Smith. Reproduced courtesy of
© Garland Science design by blink studio limited
discoveries of many great microbiologists. Robert Koch proved that infectious Yale University, Harvey Cushing/John Hay
diseases are caused by specific microorganisms. In the 1880s, Louis Pasteur Whitney Medical Library.

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 2 Chapter 1: Basic Concepts in Immunology

devised a vaccine against cholera in chickens, and developed a rabies vaccine

Number of 30
countries that proved to be a spectacular success upon its first trial in a boy bitten by a
with one or
more cases rabid dog.
per month
15 smallpox These practical triumphs led to a search for vaccination’s mechanism of
officially
eradicated
protection and to the development of the science of immunology. In the
early 1890s, Emil von Behring and Shibasaburo Kitasato discovered that
0 the serum of animals immune to diphtheria or tetanus contained a specific
1965 1970 1975 1980
‘antitoxic activity’ that could confer short-lived protection against the effects
Year
of diphtheria or tetanus toxins in people. This activity was later determined
to be due to the proteins we now call antibodies, which bind specifically to
the toxins and neutralize their activity. That these antibodies might have a
crucial role in immunity was reinforced by Jules Bordet’s discovery in 1899 of
complement, a component of serum that acts in conjunction with antibodies
to destroy pathogenic bacteria.
A specific response against infection by potential pathogens, such as the pro-
duction of antibodies against a particular pathogen, is known as adaptive
immunity, because it develops during the lifetime o­­f an individual as an adap-
tation to infection with that pathogen. Adaptive immunity is distinguished
from innate immunity, which was already known at the time von Behring was
developing serum therapy for diphtheria chiefly through the work of the great
Russian immunologist Elie Metchnikoff, who discovered that many micro-
Fig. 1.2 The| eradication
Immunobiology chapter 1 | 01_002 of smallpox by organisms could be engulfed and digested by phagocytic cells, which thus
Murphy et al | NinthAfter
vaccination. editiona period of 3 years in
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provide defenses against infection that are nonspecific. Whereas these cells—
which no cases of smallpox were recorded, which Metchnikoff called 'macrophages'—are always present and ready to act,
the World Health Organization was able
adaptive immunity requires time to develop but is highly specific.
to announce in 1979 that smallpox had
been eradicated, and vaccination stopped It was soon clear that specific antibodies could be induced against a vast range
(upper panel). A few laboratory stocks of substances, called antigens because they could stimulate antibody genera-
have been retained, however, and some
tion. Paul Ehrlich advanced the development of an antiserum as a treatment
fear that these are a source from which
the virus might reemerge. Ali Maow Maalin for diphtheria and developed methods to standardize therapeutic serums.
(lower panel) contracted and survived the Today the term antigen refers to any substance recognized by the adaptive
last case of smallpox in Somalia in 1977. immune system. Typically antigens are common proteins, glycoproteins, and
Photograph courtesy of Dr. Jason Weisfeld. polysaccharides of pathogens, but they can include a much wider range of
chemical structures, for example, metals such as nickel, drugs such as peni-
cillin, and organic chemicals such as the urushiol (a mix of pentadecylcatech-
ols) in the leaves of poison ivy. Metchnikoff and Ehrlich shared the 1908 Nobel
Prize for their respective work on immunity.
This chapter introduces the principles of innate and adaptive immunity, the
cells of the immune system, the tissues in which they develop, and the tissues
through which they circulate. We then outline the specialized functions of the
different types of cells by which they eliminate infection.

The origins of vertebrate immune cells.

The body is protected from infectious agents, their toxins, and the damage they
cause by a variety of effector cells and molecules that together make up the
immune system. Both innate and adaptive immune responses depend upon
the activities of white blood cells or leukocytes. Most cells of the immune sys-
tem arise from the bone marrow, where many of them develop and mature.
But some, particularly certain tissue-resident macrophage populations (for
example, the microglia of the central nervous system), originate from the yolk
sack or fetal liver during embryonic development. They seed tissues before
birth and are maintained throughout life as independent, self-renewing pop-
ulations. Once mature, immune cells reside within peripheral tissues, circu-
late in the bloodstream, or circulate in a specialized system of vessels called

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 Principles of innate immunity. 3

the lymphatic system. The lymphatic system drains extracellular fluid and
immune cells from tissues and transports them as lymph that is eventually
emptied back into the blood system.
All the cellular elements of blood, including the red blood cells that transport
oxygen, the platelets that trigger blood clotting in damaged tissues, and the
white blood cells of the immune system, ultimately derive from the hemato-
poietic stem cells (HSCs) of the bone marrow. Because these can give rise
to all the different types of blood cells, they are often known as pluripotent
hematopoietic stem cells. The hematopoietic stem cells give rise to cells of
more limited developmental potential, which are the immediate progenitors
of red blood cells, platelets, and the two main categories of white blood cells,
the lymphoid and myeloid lineages. The different types of blood cells and
their lineage relationships are summarized in Fig. 1.3.

Principles of innate immunity.

In this part of the chapter we will outline the principles of innate immunity
and describe the molecules and cells that provide continuous defense against
invasion by pathogens. Although the white blood cells known as lymphocytes
possess the most powerful ability to recognize and target pathogenic microor-
ganisms, they need the participation of the innate immune system to initiate
and mount their offensive. Indeed, the adaptive immune response and innate
immunity use many of the same destructive mechanisms to eliminate invad-
ing microorganisms.

1-1 Commensal organisms cause little host damage while

pathogens damage host tissues by a variety of mechanisms.

We recognize four broad categories of disease-causing microorganisms, or

pathogens: viruses, bacteria and archaea, fungi, and the unicellular and mul-
ticellular eukaryotic organisms collectively termed parasites (Fig. 1.4). These
microorganisms vary tremendously in size and in how they damage host tis-
sues. The smallest are viruses, which range from five to a few hundred nanom-
eters in size and are obligate intracellular pathogens. Viruses can directly kills
cells by inducing lysis during their replication. Somewhat larger are intracel-
lular bacteria and mycobacteria. These can kill cells directly or damage cells
by producing toxins. Many single-celled intracellular parasites, such as mem-
bers of the Plasmodium genus that cause malaria, also directly kill infected
cells. Pathogenic bacteria and fungi growing in extracellular spaces can induce
shock and sepsis by releasing toxins into the blood or tissues. The largest path-
ogens—parasitic worms, or helminths—are too large to infect host cells but
can injure tissues by forming cysts that induce damaging cellular responses in
the tissues into which the worms migrate.
Not all microbes are pathogens. Many tissues, especially the skin, oral mucosa,
conjunctiva, and gastrointestinal tract, are constantly colonized by microbial
communities—called the microbiome—that consist of archaea, bacteria, and
fungi but cause no damage to the host. These are also called commensal
microorganisms, since they can have a symbiotic relationship with the host.
Indeed, some commensal organisms perform important functions, as in the
case of the bacteria that aid in cellulose digestion in the stomachs of rumi-
nants. The difference between commensal organisms and pathogens lies in
whether they induce damage. Even enormous numbers of microbes in the
intestinal microbiome normally cause no damage and are confined within the
intestinal lumen by a protective layer of mucus, whereas pathogenic bacteria
can penetrate this barrier, injure intestinal epithelial cells, and spread into the
underlying tissues.

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 4 Chapter 1: Basic Concepts in Immunology

Bone marrow

pluripotent hematopoietic stem cell

Bone marrow

common common granulocyte/ megakaryocyte/

lymphoid myeloid macrophage erythrocyte megakaryocyte erythroblast
progenitor progenitor progenitor progenitor

Blood

Granulocytes
(or polymorphonuclear leukocytes)

immature unknown
B cell T cell NK cell ILC dendritic cell neutrophil eosinophil basophil precursor monocyte platelets erythrocyte
of mast cell

Lymph nodes Tissues

mature immature
B cell T cell NK cell ILC dendritic cell dendritic cell mast cell macrophage

Effector cells

activated activated activated

plasma cell T cell NK cell ILC

Fig. 1.3 All the

Immunobiology cellular
| chapter elements of the blood, including
1 | 01_003 T cells differentiate into effector T cells with a variety of functions.
the
Murphycells
et al |of the
Ninth immune system, arise from pluripotent
edition Unlike T and B cells, ILCs and NK cells lack antigen specificity.
hematopoietic
© Garland Science design stem cells
by blink studio in the bone marrow. These pluripotent
limited The remaining leukocytes are the monocytes, the dendritic cells,
cells divide to produce two types of stem cells. A common lymphoid and the neutrophils, eosinophils, and basophils. The last three of
progenitor gives rise to the lymphoid lineage (blue background) of these circulate in the blood and are termed granulocytes, because
white blood cells or leukocytes—the innate lymphoid cells (ILCs) and of the cytoplasmic granules whose staining gives these cells a
natural killer (NK) cells and the T and B lymphocytes. A common distinctive appearance in blood smears, or polymorphonuclear
myeloid progenitor gives rise to the myeloid lineage (pink and leukocytes, because of their irregularly shaped nuclei. Immature
yellow backgrounds), which comprises the rest of the leukocytes, dendritic cells (yellow background) are phagocytic cells that enter
the erythrocytes (red blood cells), and the megakaryocytes that the tissues; they mature after they have encountered a potential
produce platelets important in blood clotting. T and B lymphocytes pathogen. The majority of dendritic cells are derived from the
are distinguished from the other leukocytes by having antigen common myeloid progenitor cells, but some may also arise from the
receptors and from each other by their sites of differentiation—the common lymphoid progenitor. Monocytes enter tissues, where they
thymus and bone marrow, respectively. After encounter with antigen, differentiate into phagocytic macrophages or dendritic cells. Mast
B cells differentiate into antibody-secreting plasma cells, while cells also enter tissues and complete their maturation there.

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 Principles of innate immunity. 5

Extracellular bacteria,
Viruses Intracellular bacteria Fungi Parasites
Archaea, Protozoa

10–7 10–6 10–5 10–4 10–3 10–2

Log scale of size in meters (1 cm)

Fig. 1.4 Pathogens

Immunobiology | chapter 1 vary greatly in size and lifestyle.
| 01_100 tissues, as do some archaea and protozoa (third panel). Many
Murphy et al | Ninth
Intracellular edition
pathogens include viruses, such as herpes simplex parasites, such as the nematode Strongyloides stercoralis
© Garland Science design by blink studio limited
(first panel), and various bacteria, such as Listeria monocytogenes (fifth panel), are large multicellular organisms that can move
(second panel). Many bacteria, such as Staphylococcus aureus throughout the body in a complex life cycle. Second panel courtesy
(third panel), or fungi, such as Aspergillus fumigates (fourth panel), of Dan Portnoy. Fifth panel courtesy of James Lok.
can grow in the extracellular spaces and directly invade through

1-2 Anatomic and chemical barriers are the first defense against
pathogens.

The host can adopt three strategies to deal with the threat posed by microbes:
avoidance, resistance, and tolerance. Avoidance mechanisms prevent
exposure to microbes, and include both anatomic barriers and behavior
modifications. If an infection is established, resistance is aimed at reducing
or eliminating pathogens. To defend against the great variety of microbes, the
immune system has numerous molecular and cellular functions, collectively
Anatomic barriers
called mediators, or effector mechanisms, suited to resist different categories
of pathogens. Their description is a major aspect of this book. Finally,
Skin, oral mucosa, respiratory epithelium, intestine
tolerance involves responses that enhance a tissue’s capacity to resist damage
induced by microbes. This meaning of the term ‘tolerance’ has been used
extensively in the context of disease susceptibility in plants rather than animal Complement/antimicrobial proteins
immunity. For example, increasing growth by activating dormant meristems,
the undifferentiated cells that generate new parts of the plant, is a common C3, defensins, RegIIIγ
tolerance mechanism in response to damage. This should be distinguished
from the term immunological tolerance, which refers to mechanisms that Innate immune cells
prevent an immune response from being mounted against the host’s own
tissues. Macrophages, granulocytes, natural killer cells
Anatomic and chemical barriers are the initial defenses against infection
(Fig. 1.5). The skin and mucosal surfaces represent a kind of avoidance strat- Adaptive immunity
egy that prevents exposure of internal tissues to microbes. At most anatomic
barriers, additional resistance mechanisms further strengthen host defenses. B cells/antibodies, T cells
For example, mucosal surfaces produce a variety of antimicrobial proteins
that act as natural antibiotics to prevent microbes from entering the body. Fig. 1.5 Protection
Immunobiology | chapter 1against
| 01_102 pathogens
relieseton
Murphy al | several
Ninth editionlevels of defense.
If these barriers are breached or evaded, other components of the innate © Garland Science design by blink studio limited
The first is the anatomic barrier
provided
immune system can immediately come into play. We mentioned earlier the by the body’s epithelial surfaces. Second,
discovery by Jules Bordet of complement, which acts with antibodies to various chemical and enzymatic systems,
lyse bacteria. Complement is a group of around 30 different plasma proteins including complement, act as an immediate
that act together and are one of the most important effector mechanisms in antimicrobial barrier near these epithelia.
If epithelia are breached, nearby various
serum and interstitial tissues. Complement not only acts in conjunction with
innate lymphoid cells can coordinate a rapid
antibodies, but can also target foreign organisms in the absence of a specific cell-mediated defense. If the pathogen
antibody; thus it contributes to both innate and adaptive responses. We will overcomes these barriers, the slower-acting
examine anatomic barriers, the antimicrobial proteins, and complement in defenses of the adaptive immune system
greater detail in Chapter 2. are brought to bear.

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 6 Chapter 1: Basic Concepts in Immunology

1-3 The immune system is activated by inflammatory inducers that

Inflammatory inducers
indicate the presence of pathogens or tissue damage.
Bacterial lipopolysaccharides, ATP, urate crystals A pathogen that breaches the host’s anatomic and chemical barriers will
encounter the cellular defenses of innate immunity. Cellular immune
Sensor cells responses are initiated when sensor cells detect inflammatory inducers
(Fig. 1.6). Sensor cells include many cell types that detect inflammatory
Macrophages, neutrophils, dendritic cells mediators through expression of many innate recognition receptors, which
are encoded by a relatively small number of genes that remain constant over
an individual’s lifetime. Inflammatory inducers that trigger these receptors
Mediators include molecular components unique to bacteria or viruses, such as bacterial
lipopolysaccharides, or molecules such as ATP, which is not normally found in
Cytokines, cytotoxicity
the extracellular space. Triggering these receptors can activate innate immune
cells to produce various mediators that either act directly to destroy invading
Target tissues microbes, or act on other cells to propagate the immune response. For exam-
ple, macrophages can ingest microbes and produce toxic chemical mediators,
Production of antimicrobial proteins such as degradative enzymes or reactive oxygen intermediates, to kill them.
Induction of intracellular antiviral proteins Dendritic cells may produce cytokine mediators, including many cytokines
Killing of infected cells
that activate target tissues, such as epithelial or other immune cells, to resist
or kill invading microbes more efficiently. We will discuss these receptors and
Immunobiology | chapter 1 | 01_101
Fig. 1.6 Cell-mediated immunity mediators briefly below and in much greater detail in Chapter 3.
Murphy et al | Ninth edition
proceeds in a series of steps.
© Garland Science design by blink studio limited
Inflammatory inducers are chemical Innate immune responses occur rapidly on exposure to an infectious organ-
structures that indicate the presence of ism (Fig. 1.7). In contrast, responses by the adaptive immune system take days
invading microbes or the cellular damage rather than hours to develop. However, the adaptive immune system is capa-
produced by them. Sensor cells detect ble of eliminating infections more efficiently because of exquisite specificity
these inducers by expressing various innate
recognition receptors, and in response
produce a variety of mediators that act
directly in defense or that further propagate Phases of the immune response
the immune response. Mediators include
many cytokines, and they act on various Typical time
target tissues, such as epithelial cells, to Duration of
Response after infection to response
induce antimicrobial proteins and resist start of response
intracellular viral growth; or on other
immune cells, such as ILCs that produce Innate
other cytokines that amplify the immune immune Inflammation, complement activation, Minutes Days
response. response phagocytosis, and destruction of pathogen

Interaction between antigen-presenting

dendritic cells and antigen-specific T cells:
recognition of antigen, adhesion, co- Hours Days
stimulation, T-cell proliferation and
differentiation

Activation of antigen-specific B cells Hours Days

Formation of effector and memory T cells Days Weeks

Adaptive
immune Interaction of T cells with B cells, formation
response of germinal centers. Formation of effector
B cells (plasma cells) and memory B cells. Days Weeks
Production of antibody

Emigration of effector lymphocytes from A few days Weeks

peripheral lymphoid organs

Elimination of pathogen by effector cells A few days Weeks

and antibody

Immunological Maintenance of memory B cells and T cells Can be

and high serum or mucosal antibody levels. Days to weeks
memory lifelong
Protection against reinfection
Fig. 1.7 Phases of the immune response.
Immunobiology | chapter 1 | 01_034
Murphy et al | Ninth edition
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