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Chapter 1 Elements of the Immune System and
Their Roles in Defense The small intestine is the major
site in the human body that interacts with
microorganisms. Immunology is the study of the
physiological mechanisms that humans and other
mammals use to defend their bodies from invasion by
other organisms. The origins of the subject lie in the
practice of medicine, with historical observations that
people who survived an epidemic disease were
untouched when faced with that disease again—they
had become immune to infection. Infectious diseases
are caused by microorganisms, which reproduce and
evolve more rapidly than their human hosts. During an
infection, the microorganism pits a vast population of
its species against an individual Homo sapiens. In
response, the human body invests heavily in cells that
are dedicated to defense and collectively form the
immune system. An immune system is crucial to
human survival. In the absence of a working immune
system, even minor infections take hold and prove
fatal. Without intensive treatment, children born
without an immune system die in early childhood from
common infections. However, all humans suffer
infectious diseases, especially when young. To
provide an immunity that gives long-lasting future
protection, the immune system must first do battle
with the causative microorganism. This places
children at highest risk during their first infection with
a microorganism and, without modern medicine,
leads to substantial child mortality, as occurs in the
developing world. When entire populations face a new
infection, the outcome can be catastrophic, as
experienced by indigenous peoples who were killed in
large numbers by European diseases that were
imported with the arrival of Europeans in the Americas
in 1492 and the subsequent initiation of transatlantic
trade. New diseases are still emerging. The
coronavirus SARS-CoV-2, which causes the
respiratory disease COVID-19, was first detected in
Wuhan, China, in December 2019, although the virus
is thought to have been circulating for a few months
before that, according to both retrospective testing of
earlier samples collected for other purposes and
variations in the genome sequences of viruses from
different samples. Within a few weeks, infected
individuals had carried the virus around the globe
along the modern trading routes of the jet airliner and
cruise ship, resulting in a pandemic. By early
September 2020, more than 27 million people had
been infected with SARS-CoV-2 and nearly 900,000 of
them had perished. In many countries, normal life and
commerce ground to a standstill as people stayed at
home to reduce the spread of the virus. In medicine,
the greatest triumph of immunology is vaccination, a
procedure that prevents severe disease by exposing
healthy infants to the infectious agent in a form that
does not cause disease. Vaccination provides human
immune systems with the experience they need to
make a strong response, but one with little risk to
health and life. Vaccination was first used against
smallpox, a viral scourge that for centuries decimated
human populations and disfigured the faces of the
survivors. In Asia, a small dose of smallpox virus was
used to induce immunity long before 1721, when Lady
Mary Wortley Montagu introduced the method to
Europeans. In 1796, Edward Jenner, a doctor in rural
England, showed how inoculation with cowpox virus
protected against the related smallpox virus, but with
less risk of causing disease than the earlier method.
Jenner called his procedure vaccination, vaccinia
being the name of the mild disease caused by
cowpox. Since Jenner’s time, vaccination
progressively reduced the incidence of smallpox
worldwide, until it was eventually eliminated in the
1970s (Figure 1.1). Figure 1.1 Vaccination led to the
eradication of smallpox. The modern era of smallpox
vaccination began in 1796. By December 1979, after 2
years during which no case of smallpox was recorded,
the World Health Organization announced the
eradication of the virus. Since then, the proportion of
the human population that has either been vaccinated
against smallpox or acquired immunity by being
infected with smallpox virus has steadily decreased.
The result is that the human population has become
increasingly vulnerable should the virus emerge again,
either naturally or as a deliberate act of human
malevolence. The 3-year-old girl in the photograph
was the last recorded person in the world to be
naturally infected with the variola major strain of the
smallpox virus; this occurred in Bangladesh in
October 1975. She recovered fully. The last case of the
variola minor strain of smallpox was recorded in
Somalia in 1977. Effective vaccines have been made
for only a fraction of the infectious diseases, and for
some vaccines the application has been limited by
cost. The widely used vaccines were developed by
trial and error, in an era when little was known of the
immune system’s components and how they work.
That approach is no longer successful in vaccine
development; all the easily won vaccines seem to
have been made. Today’s greater knowledge and
deeper understanding of the mechanisms of immunity
are spawning new ideas for vaccines against
infectious diseases, and also for noninfectious
diseases such as cancer. All these new ideas and
technology are being applied to the development and
manufacture of vaccines and therapeutics for the
purpose of ending the SARS-CoV-2 pandemic. To that
end, 52,000 papers on SARS-CoV-2 were published in
the biomedical journals in the 6 months from January
to June 2020, and many more have been published
since then. The casualties of SARS-CoV-2 include
vaccination programs in 23 African countries that
were suspended because of the chaos. In 2020, 13.5
million children missed out on vaccinations against
polio, measles, human papilloma virus, yellow fever,
cholera, and meningitis. In this chapter, we consider
the microorganisms that infect human beings and the
defenses the microorganisms must overcome to start
and propagate an infection. The individual cells and
tissues of the immune system and how they integrate
with the rest of the human body are described. The
first line of defense is innate immunity, which
combines physical and chemical barriers with rapid
responses that eliminate infecting microorganisms
before they disrupt human tissue. These mechanisms
stop most infections, but when they fail, the targeted
and forceful defenses of adaptive immunity are
brought into play. These adapt to the particular
microorganism and are continually refined in the
course of infection. Usually successful, the adaptive
immune response clears the infection and has a long-
lasting memory that prevents its recurrence. 1-1
Numerous commensal microorganisms inhabit
healthy human bodies The remit of the immune
system is to protect the human body from infectious
disease. Most infectious diseases of humans are
caused by microorganisms, which are smaller than a
human cell. For both benign and dangerous
microorganisms, the human body constitutes an
extensive resource-rich environment in which to feed,
live, and reproduce. More than 1000 different
microbial species dwell in a healthy adult human’s
gut, and they constitute about 4.5 kg of the body’s
weight. They are called commensal microorganisms
because they ‘eat at the same table’ as their human
host. The entire community of microbial species that
inhabits the human body—skin, mouth, gut, or
vagina—is called the microbiota. Different ecological
niches within the body have distinctive microbiota and
are described as the ‘gut microbiota,’ the ‘oral
microbiota,’ and so on. The biology of many
commensal species has yet to be studied in any depth
because they cannot yet be grown in the laboratory.
We know they are there, because their distinctive
nucleic acid sequences were discovered from
analyses of human feces. Animals coevolve with their
commensal species and become both tolerant of
them and dependent on them. Commensal organisms
enhance human nutrition by processing digested food
and making some of our essential vitamins. They also
protect against disease, because their presence helps
to prevent colonization by disease-causing
microorganisms. For example, as well as competing
for space, the bacterium Escherichia coli, a major
component of the healthy human gut microbiota,
secretes antibacterial proteins called colicins that
incapacitate other bacterial species and prevent their
colonization of the human gut. When a person with a
bacterial infection is treated with antibiotics, much of
the gut microbiota is killed along with the disease-
causing bacteria. After such treatment, the body
recolonizes with a new population of commensal
bacteria, a situation in which opportunistic bacteria,
such as Clostridium difficile, can become established
and cause disease. Clostridium difficile is present in
small numbers in healthy individuals, but in patients
treated with antibiotics it can proliferate (Figure 1.2). It
secretes a toxin that inflames the colon. This causes
diarrhea and bleeding and can lead to the serious and
potentially fatal condition of pseudomembranous
colitis. Figure 1.2 Antibiotic treatments disrupt the
natural ecology of the colon. When antibiotics are
taken orally to counter infection with pathogenic
bacteria, symbiotic populations of commensal
bacteria in the colon are also exterminated. With
completion of the treatment, there is an opportunity
for potentially disease-causing strains of bacteria to
populate the colon and cause further disease.
Clostridium difficile is an example of such a
bacterium; it produces a toxin that can cause severe
diarrhea in patients treated with antibiotics. In
hospitals, acquired C. difficile infections are the
cause of death for many elderly patients. 1-2
Pathogens are infectious organisms that cause
disease Any microorganism that causes disease is
termed a pathogen. This definition includes microbes
such as the influenza virus and the typhoid bacillus
that habitually cause disease, and also
microorganisms that are usually harmless but cause
disease if a person’s immune system and other
defenses of the body are weakened. The latter
category comprises the opportunistic pathogens. In
the early years of the human immunodeficiency virus
(HIV) pandemic, when there was no effective therapy,
almost all people who became infected died. Their
immune systems became worn out by the HIV
infection, but their deaths were caused by various
opportunistic pathogens. Pathogens are of four kinds.
The viruses, bacteria, and fungi are all groups of
related microorganisms. The internal parasites are a
heterogeneous group of unicellular protozoa and
multicellular invertebrates, mainly worms. In this book
we consider the functions of the human immune
system principally in the context of controlling
infection. For some pathogens this necessitates their
complete elimination, but for others it is sufficient to
limit the size of the pathogen population and its
anatomical location within the human host. Figure 1.3
illustrates the variety in shape and form of the four
kinds of pathogen. Figure 1.4 lists common or
wellknown infectious diseases and the pathogens that
cause them. Reference to many of these diseases and
the problems they pose for the immune system are
made throughout this book. Figure 1.3 Numerous
microorganisms have evolved to be human
pathogens. (a) The coronavirus SARS-CoV-2 is the
cause of a worldwide pandemic of an acute
respiratory disease (COVID-19) that started late in
2019 (×70,000). (b) Human immunodeficiency virus
(HIV), the cause of acquired immunodeficiency
syndrome (AIDS) (×80,000). (c) Staphylococcus
aureus, a bacterium that colonizes human skin, is the
common cause of pimples and boils and also causes
food poisoning (×5000). (d) Streptococcus
pneumoniae is the major cause of bacterial
pneumonia and a cause of meningitis in children and
the elderly (×5800). (e) Salmonella enterica serovar
Enteritidis, a bacterium that commonly causes food
poisoning (×6500). (f) Mycobacterium tuberculosis,
the bacterium that causes tuberculosis (×19,200). (g)
A human cell (colored green) containing Listeria
monocytogenes (colored yellow), a bacterium that
can contaminate processed food, causing disease
(listeriosis) in pregnant women and
immunosuppressed individuals (×1160). (h)
Pneumocystis jirovecii, an opportunistic fungus that
infects people with AIDS and other
immunosuppressed individuals. The fungal cells
(colored green) are in lung tissue (×720). (i)
Epidermophyton floccosum, the fungus that causes
ringworm (×500). (j) Candida albicans, a normally
commensal fungus, which occasionally causes thrush
and more severe systemic infections (×1270). (k)
Trypanosoma brucei (colored orange) is the protozoan
that causes African sleeping sickness. It is seen here
in a blood sample with erythrocytes (×2000). (l)
Schistosoma mansoni, the helminth worm that
causes schistosomiasis. The adult intestinal blood
fluke forms are shown: the male is thick and bluish,
the female thin and white (×8). All photos are false-
colored electron micrographs, the exception being (l),
a light micrograph. Figure 1.4 Diverse microorganisms
cause human disease. Pathogenic organisms are of
four main types—viruses, bacteria, fungi, and
parasites. The latter are mostly protozoans and
worms. Some important pathogens in each category
are listed along with the diseases they cause. *The
classifications are a guide and are not taxonomically
consistent: family names are given for the viruses;
general groupings used in medical bacteriology are
given for the bacteria; and higher taxonomic divisions
are given for the fungi and parasites. Bacteria are
classed as either Gram-positive or Gram-negative
according to whether they stain purple or pink using
the Gram staining procedure. Type Disease Pathogen
General classification* Route of infection Viruses
Coronavirus disease 2019 (COVID-19) SARS-CoV-2
Coronaviruses Oral/respiratory/ocular mucosa Severe
acute respiratory syndrome SARS-CoV Coronaviruses
Oral/respiratory/ocular mucosa West Nile
encephalitis West Nile virus Flaviviruses Bite of an
infected mosquito Type Disease Pathogen General
classification* Route of infection Yellow fever Yellow
fever virus Flaviviruses Bite of infected mosquito
(Aedes aegypti) Hepatitis B Hepatitis B virus
Hepadnaviruses Sexual transmission; infected blood
Chickenpox Varicella-zoster Herpesviruses
Oral/respiratory Mononucleosis Epstein–Barr virus
Herpesviruses Oral/respiratory Influenza Influenza
virus Orthomyxoviruses Oral/respiratory Measles
Measles virus Paramyxoviruses Oral/respiratory
Mumps Mumps virus Paramyxoviruses
Oral/respiratory Poliomyelitis Polio virus
Picornaviruses Oral Jaundice Hepatitis A virus
Picornaviruses Oral Smallpox Variola Poxviruses
Oral/respiratory AIDS Human immunodeficiency virus
Retroviruses Sexual transmission, infected blood Type
Disease Pathogen General classification* Route of
infection Rabies Rabies virus Rhabdoviruses Bite of an
infected animal Common cold Rhinoviruses
Rhinoviruses Nasal Diarrhea Rotavirus Rotaviruses
Oral Rubella Rubella Togaviruses Oral/respiratory
Bacteria Trachoma Chlamydia trachomatis
Chlamydias Oral/respiratory/ocular mucosa Bacillary
dysentery Shigella flexneri Gram-negative bacilli Oral
Food poisoning Salmonella enterica serovar
Enteritidis, S. Typhimurium Gram-negative bacilli Oral
Plague Yersinia pestis Gram-negative bacilli Infected
flea bite, respiratory Tularemia Francisella tularensis
Gram-negative bacilli Handling infected animals
Typhoid fever Salmonella Typhi Gram-negative bacilli
Oral Type Disease Pathogen General classification*
Route of infection Gonorrhea Neisseria gonorrhoeae
Gram-negative cocci Sexually transmitted
Meningococcal meningitis Neisseria meningitidis
Gram-negative cocci Oral/respiratory Meningitis,
pneumonia Haemophilus influenzae Gram-negative
coccobacilli Oral/respiratory Legionnaire’s disease
Legionella pneumophila Gram-negative coccobacilli
Inhalation of contaminated aerosol Whooping cough
Bordetella pertussis Gram-negative coccobacilli
Oral/respiratory Cholera Vibrio cholerae Gram-
negative vibrios Oral Anthrax Bacillus anthracis Gram-
positive bacilli Oral/respiratory by contact with spores
Diphtheria Corynebacterium diphtheriae Gram-
positive bacilli Oral/respiratory Tetanus Clostridium
tetani Gram-positive bacilli (anaerobic) Infected
wound Boils, wound infections Staphylococcus
aureus Gram-positive cocci Wounds; oral/respiratory
Type Disease Pathogen General classification* Route
of infection Pneumonia, scarlet fever Streptococcus
pneumoniae Gram-positive cocci Oral/respiratory
Tonsillitis Streptococcus pyogenes Gram-positive
cocci Oral/respiratory Leprosy Mycobacterium leprae
Mycobacteria Infected respiratory droplets
Tuberculosis Mycobacterium tuberculosis
Mycobacteria Oral/respiratory Respiratory disease
Mycoplasma pneumoniae Mycoplasmas
Oral/respiratory Typhus Rickettsia prowazekii
Rickettsias Bite of infected tick Lyme disease Borrelia
burgdorferi Spirochetes Bite of infected deer tick
Syphilis Treponema pallidum Spirochetes Sexual
transmission Fungi Aspergillosis Aspergillus species
Ascomycetes Opportunistic pathogen, inhalation of
spores Type Disease Pathogen General classification*
Route of infection Athlete’s foot Trichophyton species
Ascomycetes Physical contact Candidiasis, thrush
Candida albicans Ascomycetes (yeasts) Opportunistic
pathogen, resident microbiota Pneumonia
Pneumocystis jirovecii Ascomycetes Opportunistic
pathogen, resident lung microbiota Protozoan
parasites Leishmaniasis Leishmania major Protozoa
Bite of an infected sand fly Malaria Plasmodium
falciparum Protozoa Bite of an infected mosquito
Toxoplasmosis Toxoplasma gondii Protozoa Oral,
from infected material Trypanosomiasis Trypanosoma
brucei Protozoa Bite of an infected tsetse fly Helminth
parasites (worms) Common roundworm Ascaris
lumbricoides Nematodes (roundworms) Oral, from
infected material Schistosomiasis Schistosoma
mansoni Trematodes Through skin by bathing in
infected water Over evolutionary time, the relationship
between a pathogen and its human host can change in
ways that affect disease severity. Pathogenic
organisms evolve adaptations that enable them to
invade their hosts, replicate within them, and be
propagated through a human population. Rapid death
of the human host is rarely in a microbe’s interest,
because this destroys its home and source of
sustenance. Consequently, those organisms with
potential to inflict severe and fatal disease often
evolve an accommodation with their host. In
complementary fashion, human populations evolve a
genetic resistance to common disease-causing
organisms; the diseases they cause are known as
endemic diseases. These diseases, such as measles,
chickenpox, and malaria, are ubiquitous in a given
population, with most people being exposed during
childhood. Because of the interplay between host and
pathogen, the nature and severity of infectious
diseases in human populations are always changing.
Influenza is an example of a common viral disease
that has severe symptoms but is usually overcome by
the human immune system. The fever, aches, and
lassitude that accompany infection can seem
overwhelming, and it is difficult to imagine overcoming
foes or predators at the peak of a bout of influenza.
Nevertheless, despite the severity of the symptoms,
most strains of influenza pose no great danger to
healthy people in populations where influenza is
endemic. Warm, well-nourished, and otherwise
healthy people usually recover within 2 weeks and
assume that their immune system will accomplish
this task. Contrasting with influenza is Ebola virus, a
pathogen new to human populations and which
causes a high mortality of 60– 75% among those
infected. The effects of SARS-CoV-2 on human
populations are less severe than those of Ebola but
much greater than those of seasonal influenza and the
common colds caused by other strains of coronavirus.
COVID-19 is killing large numbers of people, but most
of them were vulnerable because of other, preexisting
conditions. 1-3 Skin and mucosal surfaces are barrier
defenses against infection The skin gives the human
body a formidable defense against infection. It is an
epithelium protected by a tough, impenetrable outer
barrier of layers of keratinized cells. Epithelium is a
general name for the layers of cells that line the outer
surface and the inner cavities of the body. However,
the skin can be breached by physical damage, such as
wounds, burns, or surgical procedures, which
exposes soft tissues and renders them vulnerable to
infection. Until the adoption of antiseptic procedures
in the 19th century, surgery was a risky business,
largely because of the life-threatening infections that
the procedures introduced. Consequently, far more
soldiers died from infected wounds than from the
direct effects of enemy action. Ironically, the need to
conduct increasingly sophisticated and wide-ranging
warfare has been the major force driving
improvements in surgery and medicine. As an
example from immunology, the horrific burns suffered
by fighter pilots during the Second World War
stimulated the study and application of skin
transplantation, which directly led to knowledge of the
cellular basis of the immune response. Continuous
with the skin are the epithelia that line the respiratory,
gastrointestinal, and urogenital tracts (Figure 1.5). On
these internal surfaces, the impermeable skin gives
way to specialized tissues that communicate with the
environment and are vulnerable to microbial invasion.
These tissues, the mucosal surfaces, or mucosae, are
coated with the mucus they constitutively secrete.
This thick fluid layer contains glycoproteins,
proteoglycans, and enzymes that protect the
epithelial cells from damage and contribute to limiting
infection. In the respiratory tract, mucus is continually
removed through the beating action of the cilia that
characterize this epithelium. The mucus bathing the
epithelium is replenished by goblet cells, specialized
in the synthesis and secretion of mucus. In this way
the respiratory mucosa is continually cleansed of
unwanted material, particularly infectious
microorganisms. Epithelial surfaces also secrete
antimicrobial substances. Sebum secreted by the
sebaceous glands associated with hair follicles
contains fatty acids and lactic acids, which cooperate
to inhibit bacterial growth at the skin surface. All
epithelia produce antimicrobial peptides that kill
bacteria, fungi, and enveloped viruses by the common
mechanism of perturbing their membranes. Tears and
saliva contain lysozyme, an enzyme that kills bacteria
by degrading their cell walls. Also deterring
microorganisms are the acidic environments of the
stomach, vagina, and skin. The fixed defenses of skin
and mucosa provide well-maintained mechanical,
chemical, and microbiological barriers that prevent
most pathogens from gaining access to the cells and
tissues of the body. When those barriers are breached
and pathogens gain entry to the body’s soft tissues,
the defense mechanisms of innate immunity are
aimed at the invaders. 1-4 The innate immune
response produces a state of inflammation at sites of
infection Cuts, abrasions, bites, and wounds provide
routes for pathogens to get through the skin. Touching,
rubbing, picking, and poking the eyes, nose, and
mouth help pathogens breach mucosal surfaces, as
does breathing polluted air, eating contaminated
food, and being around infected people. With few
exceptions, the infections remain localized and are
extinguished within a few days without incapacitation
or illness. Such infections are controlled and
terminated by the innate immune response, which is
always ready to react. The response consists of two
phases (Figure 1.6). The first is recognition that a
pathogen is present. This involves soluble proteins
and cell-surface receptors that bind either to the
pathogen or to human cells and plasma proteins that
have been altered by the pathogen’s presence. Once
the pathogen has been recognized, the second phase
of the response recruits effector mechanisms that kill
or eliminate the pathogen. Mediating the effector
mechanisms are effector cells that engulf bacteria, kill
virus-infected cells, and attack protozoa. Guiding the
effector cells is complement, a system of plasma
proteins that commands the effector cells by tagging
pathogens with molecular flags. Complement
proteins can also kill pathogens without assistance
from effector cells by perturbing the integrity of the
pathogens’ membranes. Collectively, these defenses
comprise innate immunity, a genetically programmed
set of responses that can act immediately when an
infection occurs. Numerous families of receptor
proteins contribute to pathogen recognition in the
innate immune response. They are of many different
structural types and have binding specificities for
chemically diverse ligands. These ligands include
peptides, proteins, glycoproteins, proteoglycans,
peptidoglycans, carbohydrates, glycolipids,
phospholipids, nucleic acids, small molecules, and
metabolites. Figure 1.6 Immune defense involves
pathogen recognition followed by pathogen
destruction. A common strategy used to counter
microbial pathogens is shown. A protein of the
complement system (turquoise) is cleaved in two by a
protease (not shown). The large fragment attaches to
the bacterium (red) with a covalent bond. The
attached piece of complement is a flag that marks the
pathogen as dangerous. The small complement
fragment activates a phagocyte, an effector cell
bearing a receptor that engages the complement
fragment attached to the bacterium. The phagocyte
engulfs the complex of bacterium, complement, and
receptor and delivers it to the phagosome. This acidic
intracellular vesicle contains enzymes that degrade
and destroy the bacterium. A phagocyte is a cell that
eats, ‘phago’ derived from the Greek word for eat.
During play and exploration of the local environment,
small wounds to the skin can be a daily occurrence for
many children. On returning home, the grazes are
washed, which removes most of the dirt and the
bacteria associated with soil, plants, and wild and
domesticated animals, including other humans. Of
the bacteria that remain, some divide and start an
infection. The receptors of cells in the damaged tissue
detect the bacteria, and the cells send out small
messenger proteins called cytokines that bind
receptors on the effector cells of innate immunity to
trigger the innate immune response. The overall effect
of the innate immune response is to induce a state of
inflammation in the infected tissue. An ancient
concept in medicine, inflammation was defined by
calor, dolor, rubor, and tumor: the Latin words for
heat, pain, redness, and swelling. These symptoms
are not caused by the infecting pathogen but by the
human innate immune response to the pathogen.
Cytokines induce dilation of nearby blood capillaries,
which increases the blood flow, causing the skin to
warm and redden. Vascular dilation (vasodilation)
creates gaps between the cells of the endothelium,
the thin layer of specialized epithelium that lines the
interior of blood vessels. This makes the endothelium
more permeable, increasing the leakage of blood
plasma into connective tissue. Expansion of the local
fluid volume, or edema, causes swelling, putting
pressure on nerve endings and causing pain.
Cytokines alter the adhesive properties of the vascular
endothelium, permitting white blood cells to leave the
blood and enter the inflamed tissue (Figure 1.7). White
blood cells recruited to the infected tissue contribute
to the inflammation and in this context are called
inflammatory cells. Infiltration of cells into the
inflamed tissue increases the swelling, and the cells
release chemicals that cause pain. The upside of the
discomfort and disfigurement caused by inflammation
is that it enables an army of immune-system cells and
soluble effector molecules to be brought rapidly and
in quantity to the infected tissue. Figure 1.7 Innate
immune mechanisms establish a state of
inflammation at sites of infection. Illustrated here are
the events following an abrasion of the skin. Bacteria
invade the underlying connective tissue and stimulate
the innate immune response. Historically, the study of
immunology (adaptive immunity) and the study of
inflammation (innate immunity) were separate
medical disciplines, and they began to merge only in
the 1980s. Today, the terms inflammation and innate
immunity are used interchangeably. The mechanisms
of innate immunity are considered in Chapters 2 and
3. 1-5 The adaptive immune response builds on the
innate immune response Everybody is exposed to
pathogens every day. The intensity of exposure and
the diversity of the encountered pathogens increase
with crowded city living and the daily exchange of
people and pathogens in international airports and
other transport hubs. Despite the exposure, innate
immunity keeps most people healthy for most of the
time. Nevertheless, some infections outrun the innate
immune response, an event more frequent in people
who are poor, malnourished, badly housed, deprived
of sleep, or stressed and insecure in other ways.
When this occurs, the innate immune response works
to minimize the spread of infection while enlisting
white blood cells called lymphocytes to increase the
strength and focus of the immune response. The
unique contribution that lymphocytes make to the
defense of the human body is the adaptive immune
response. This is organized around the existing
infection and the innate immune response and adapts
that response to the unique characteristics of the
infecting pathogen. Consequently, the adaptive
immunity that is directed at the pathogen is powerful,
long lasting, and specific to that pathogen. Adaptive
immunity has evolved only in vertebrate animals,
where it complements the mechanisms of innate
immunity that vertebrates and invertebrates have in
common. The effector mechanisms of adaptive
immunity are largely those used in innate immunity.
The important differences between innate immunity
and adaptive immunity are in the receptors that
lymphocytes use to recognize pathogens (Figure 1.8).
The receptors of innate immunity are structurally of
many different types. Each receptor recognizes
molecular features shared by groups of pathogens,
and none is specific for a particular pathogen.
Conversely, the lymphocytes of adaptive immunity
recognize pathogens using only one type of cell-
surface receptor, but this is made in billions of
different versions. The adaptive immune response
becomes specific for a particular pathogen by
including only lymphocytes expressing a receptor that
recognizes the pathogen. Lymphocyte receptors are
not encoded by conventional genes, but by genes that
are cut, spliced, and modified during lymphocyte
development. By these mechanisms, each
lymphocyte is programmed to make one variant of the
basic receptor type. Billions of different receptor
variants are represented in the lymphocytes of a
person’s immune system, which enables all possible
pathogens to be recognized by the immune system.
Figure 1.8 Principal characteristics and distinguishing
features of innate immunity and adaptive immunity.
During infection, only lymphocytes bearing receptors
that recognize the infecting pathogen are recruited to
the adaptive immune response. They then proliferate
and differentiate to form an army of pathogen-specific
effector cells (Figure 1.9). The processes that select
pathogenspecific lymphocytes for proliferation and
differentiation are called clonal selection and clonal
expansion. Because of the time it takes to expand a
few selected lymphocytes into an army, the benefit of
the adaptive immune response cannot be felt until 7–
10 days after the onset of infection. Figure 1.9
Selection of lymphocytes by a pathogen. Top panel:
during its development from a progenitor cell (gray), a
lymphocyte is programmed to make one form of cell-
surface receptor that recognizes a particular
molecular structure. Each lymphocyte makes a
receptor of different specificity, and the population of
circulating lymphocytes includes billions of different
receptors, all recognizing different structures. This
arrangement enables all possible pathogens to be
recognized. Lymphocytes with different receptor
specificities are represented by different colors.
Center panel: upon infection by a particular pathogen,
only a few lymphocytes (represented by the yellow
cell) have receptors that bind to the pathogen or one
of its components. Bottom panel: these lymphocytes
are selected for stimulation, proliferation, and
differentiation. This produces an expanded population
of effector cells. The ‘flu’ is a global disease that most
people have experienced. It starts when epithelial
cells in the lower respiratory tract become infected
with influenza virus. The debilitating symptoms
emerge 3 or 4 days after the start of infection, when
the spread of the virus outruns the innate immune
response. The disease persists for 5–7 days while an
adaptive immune response is developed and then put
to work. As the adaptive immune response gains the
upper hand, fever subsides and a gradual
convalescence begins in the second week after
infection. Some of the lymphocytes that contributed
to a successful adaptive immune response persist in
the body and are selected to provide long-term
immunological memory of the pathogen. These
memory cells enable subsequent encounters with the
same pathogen to elicit a stronger and faster adaptive
immune response; one that terminates infection
before there are any significant symptoms of disease.
The adaptive immunity based on immunological
memory is also called acquired immunity, or
protective immunity. For some pathogens, such as
measles virus, one full-blown infection provides
immunity for decades, whereas for influenza virus the
protection is less effective. This is not due to faulty
memory but to the rapid evolution of the virus, which
allows it to escape the immunity acquired by its
human hosts. The first time that a person makes an
adaptive immune response to a pathogen is called the
primary immune response. During the primary
response, the person acquires the immunological
memory that enables subsequent encounters with the
pathogen to be met with a faster and stronger
secondary immune response. The purpose of
vaccination is to provide people with a good
immunological memory of the pathogen without them
having to experience the disease. To do this, any
vaccine must stimulate strong innate and adaptive
immune responses against the pathogen (Figure 1.10).
Immunological memory and vaccination are
considered in Chapter 11.

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