- 1.Overview of theImmune Systemchapter 1T defense system that
has evolved to protect animalsfrom invading pathogenic
microorganisms andcancer. It is able to generate an enormous
variety of cells andmolecules capable of specifically recognizing
and eliminat-ing an apparently limitless variety of foreign
invaders. Thesecells and molecules act together in a dynamic
network whosecomplexity rivals that of the nervous system.
Functionally, an immune response can be divided into Numerous T
Lymphocytes Interacting with a Singletwo related
activitiesrecognition and response. ImmuneMacrophagerecognition is
remarkable for its specificity. The immunesystem is able to
recognize subtle chemical differences thatdistinguish one foreign
pathogen from another. Further-I Historical Perspectivemore, the
system is able to discriminate between foreign I Innate
Immunitymolecules and the bodys own cells and proteins. Once a
for-eign organism has been recognized, the immune system I Adaptive
Immunityrecruits a variety of cells and molecules to mount an
appro- I Comparative Immunitypriate response, called an effector
response, to eliminate orneutralize the organism. In this way the
system is able to I Immune Dysfunction and Its Consequencesconvert
the initial recognition event into a variety of effectorresponses,
each uniquely suited for eliminating a particulartype of pathogen.
Later exposure to the same foreign organ-ism induces a memory
response, characterized by a morerapid and heightened immune
reaction that serves to elimi-Like the later chapters covering
basic topics in immu-nate the pathogen and prevent disease. nology,
this one includes a section called Clinical Focus This chapter
introduces the study of immunology fromthat describes human disease
and its relation to immunity.an historical perspective and presents
a broad overview of These sections investigate the causes,
consequences, or treat-the cells and molecules that compose the
immune system,ments of diseases rooted in impaired or hyperactive
immunealong with the mechanisms they use to protect the body
function.against foreign invaders. Evidence for the presence of
verysimple immune systems in certain invertebrate organismsthen
gives an evolutionary perspective on the mammalianimmune system,
which is the major subject of this book. El- Historical
Perspectiveements of the primitive immune system persist in
verte-The discipline of immunology grew out of the
observationbrates as innate immunity along with a more highly
evolved that individuals who had recovered from certain
infectioussystem of specific responses termed adaptive immunity.
diseases were thereafter protected from the disease. TheThese two
systems work in concert to provide a high degree Latin term
immunis, meaning exempt, is the source of theof protection for
vertebrate species. Finally, in some circum- English word immunity,
meaning the state of protectionstances, the immune system fails to
act as protector because from infectious disease.of some deficiency
in its components; at other times, it be- Perhaps the earliest
written reference to the phenomenoncomes an aggressor and turns its
awesome powers against itsof immunity can be traced back to
Thucydides, the great his-own host. In this introductory chapter,
our description of torian of the Peloponnesian War. In describing a
plague inimmunity is simplified to reveal the essential structures
andAthens, he wrote in 430 BC that only those who had
recov-function of the immune system. Substantive discussions,
ex-ered from the plague could nurse the sick because theyperimental
approaches, and in-depth definitions are left towould not contract
the disease a second time. Although earlythe chapters that
follow.societies recognized the phenomenon of immunity, almost
2. 2PART I Introductiontwo 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
crustsderived from smallpox pustules were either inhaled into
thenostrils or inserted into small cuts in the skin (a
techniquecalled variolation). In 1718, Lady Mary Wortley Montagu,
thewife of the British ambassador to Constantinople, observedthe
positive effects of variolation on the native populationand had the
technique performed on her own children. Themethod was
significantly improved by the English physicianEdward Jenner, in
1798. Intrigued by the fact that milkmaidswho 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 froma cowpox pustule into people (i.e.,
inoculating them) mightprotect them from smallpox. To test this
idea, he inoculatedan eight-year-old boy with fluid from a cowpox
pustule andlater intentionally infected the child with smallpox. As
pre-dicted, the child did not develop smallpox.Jenners technique of
inoculating with cowpox to protectagainst smallpox spread quickly
throughout Europe. How-ever, for many reasons, including a lack of
obvious diseasetargets 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
incombination with astute observation led to the next majoradvance
in immunology, the induction of immunity toFIGURE 1-1 Wood
engraving of Louis Pasteur watching Josephcholera. Louis Pasteur
had succeeded in growing the bac-Meister receive the rabies
vaccine. [From Harpers Weekly 29:836;terium thought to cause fowl
cholera in culture and then hadcourtesy of the National Library of
Medicine.]shown that chickens injected with the cultured bacterium
de-veloped cholera. After returning from a summer vacation,
heinjected some chickens with an old culture. The chickens be-1885,
Pasteur administered his first vaccine to a human, acame ill, but,
to Pasteurs surprise, they recovered. Pasteur young boy who had
been bitten repeatedly by a rabid dogthen grew a fresh culture of
the bacterium with the intention (Figure 1-1). The boy, Joseph
Meister, was inoculated with aof injecting it into some fresh
chickens. But, as the story goes, series of attenuated rabies virus
preparations. He lived andhis supply of chickens was limited, and
therefore he used the later became a custodian at the Pasteur
Institute.previously injected chickens. Again to his surprise, the
chick-ens were completely protected from the disease. Pasteur Early
Studies Revealed Humoral and Cellularhypothesized and proved that
aging had weakened the viru-lence of the pathogen and that such an
attenuated strainComponents of the Immune Systemmight be
administered to protect against the disease. HeAlthough Pasteur
proved that vaccination worked, he did notcalled this attenuated
strain a vaccine (from the Latin vacca,understand how. The
experimental work of Emil vonmeaning cow), in honor of Jenners work
with cowpox Behring and Shibasaburo Kitasato in 1890 gave the first
in-inoculation.sights into the mechanism of immunity, earning von
BehringPasteur extended these findings to other diseases, demon-
the Nobel prize in medicine in 1901 (Table 1-1). Von
Behringstrating that it was possible to attenuate, or weaken, aand
Kitasato demonstrated that serum (the liquid, noncellu-pathogen and
administer the attenuated strain as a vaccine. lar component of
coagulated blood) from animals previouslyIn a now classic
experiment at Pouilly-le-Fort in 1881, Pas-immunized to diphtheria
could transfer the immune state toteur first vaccinated one group
of sheep with heat-attenuated unimmunized animals. In search of the
protective agent, var-anthrax bacillus (Bacillus anthracis); he
then challenged the ious researchers during the next decade
demonstrated thatvaccinated sheep and some unvaccinated sheep with
a viru- an active component from immune serum could neutralizelent
culture of the bacillus. All the vaccinated sheep lived, and
toxins, precipitate toxins, and agglutinate (clump) bacteria.all
the unvaccinated animals died. These experimentsIn each case, the
active agent was named for the activity it ex-marked the beginnings
of the discipline of immunology. In hibited: antitoxin, precipitin,
and agglutinin, respectively. 3. Overview of the Immune
SystemCHAPTER 13 TABLE 1-1 Nobel Prizes for immunologic research
YearRecipient CountryResearch 1901Emil von BehringGermanySerum
antitoxins 1905Robert Koch GermanyCellular immunity to tuberculosis
1908Elie MetchnikoffRussia Role of phagocytosis (Metchnikoff) and
Paul EhrlichGermany antitoxins (Ehrlich) in immunity 1913Charles
RichetFrance Anaphylaxis 1919Jules BorderBelgiumComplement-mediated
bacteriolysis 1930Karl LandsteinerUnited StatesDiscovery of human
blood groups 1951Max Theiler South Africa Development of yellow
fever vaccine 1957Daniel BovetSwitzerlandAntihistamines 1960F.
Macfarlane BurnetAustraliaDiscovery of acquired immunological Peter
Medawar Great Britain tolerance 1972Rodney R. PorterGreat
BritainChemical structure of antibodies Gerald M. Edelman United
States 1977Rosalyn R. YalowUnited StatesDevelopment of
radioimmunoassay 1980George SnellUnited StatesMajor
histocompatibility complex Jean DaussctFrance Baruj
BenacerrafUnited States 1984Cesar MilsteinGreat BritainMonoclonal
antibody Georges E. Khler Germany Niels K. JerneDenmarkImmune
regulatory theories 1987Susumu Tonegawa JapanGene rearrangement in
antibody production 1991E. Donnall Thomas United
StatesTransplantation immunology Joseph Murray United States
1996Peter C. DohertyAustraliaRole of major histocompatibility
complex Rolf M. Zinkernagel Switzerland in antigen recognition by
by T cellsInitially, a different serum component was thought to be
re-In due course, a controversy developed between thosesponsible
for each activity, but during the 1930s, mainlywho held to the
concept of humoral immunity and thosethrough the efforts of Elvin
Kabat, a fraction of serum firstwho agreed with Metchnikoff s
concept of cell-mediated im-called gamma-globulin (now
immunoglobulin) was shown munity. It was later shown that both are
correctimmunityto be responsible for all these activities. The
active molecules requires both cellular and humoral responses. It
was difficultin the immunoglobulin fraction are called antibodies.
Be-to study the activities of immune cells before the develop-cause
immunity was mediated by antibodies contained in ment of modern
tissue culture techniques, whereas studiesbody fluids (known at the
time as humors), it was called hu- with serum took advantage of the
ready availability of bloodmoral immunity.and established
biochemical techniques. Because of these In 1883, even before the
discovery that a serum compo-technical problems, information about
cellular immunitynent could transfer immunity, Elie Metchnikoff
demon-lagged behind findings that concerned humoral
immunity.strated that cells also contribute to the immune state of
anIn a key experiment in the 1940s, Merrill Chase succeededanimal.
He observed that certain white blood cells, which he in
transferring immunity against the tuberculosis organismtermed
phagocytes, were able to ingest (phagocytose) mi- by transferring
white blood cells between guinea pigs. Thiscroorganisms and other
foreign material. Noting that these demonstration helped to
rekindle interest in cellular immu-phagocytic cells were more
active in animals that had been nity. With the emergence of
improved cell culture techniquesimmunized, Metchnikoff hypothesized
that cells, rather thanin the 1950s, the lymphocyte was identified
as the cell re-serum components, were the major effector of
immunity. sponsible for both cellular and humoral immunity. SoonThe
active phagocytic cells identified by Metchnikoff were thereafter,
experiments with chickens pioneered by Brucelikely blood monocytes
and neutrophils (see Chapter 2).Glick at Mississippi State
University indicated that there were 4. 4PART I Introductiontwo
types of lymphocytes: T lymphocytes derived from theIn the 1930s
and 1940s, the selective theory was chal-thymus mediated cellular
immunity, and B lymphocyteslenged by various instructional
theories, in which antigenfrom the bursa of Fabricius (an outgrowth
of the cloaca inplayed a central role in determining the
specificity of the an-birds) were involved in humoral immunity. The
controversy tibody molecule. According to the instructional
theories, aabout the roles of humoral and cellular immunity was
re-particular antigen would serve as a template around whichsolved
when the two systems were shown to be intertwined, antibody would
fold. The antibody molecule would therebyand that both systems were
necessary for the immune assume a configuration complementary to
that of the antigenresponse. template. This concept was first
postulated by FriedrichBreinl and Felix Haurowitz about 1930 and
redefined in theEarly Theories Attempted to Explain 1940s in terms
of protein folding by Linus Pauling. The in-the Specificity of the
Antibodystructional theories were formally disproved in the 1960s,
bywhich time information was emerging about the structure ofAntigen
Interaction DNA, RNA, and protein that would offer new insights
intoOne of the greatest enigmas facing early immunologists wasthe
vexing problem of how an individual could make anti-the specificity
of the antibody molecule for foreign material,bodies against almost
anything.or antigen (the general term for a substance that binds
withIn the 1950s, selective theories resurfaced as a result ofa
specific antibody). Around 1900, Jules Bordet at the Pasteurnew
experimental data and, through the insights of NielsInstitute
expanded the concept of immunity by demonstrat- Jerne, David
Talmadge, and F. Macfarlane Burnet, were re-ing specific immune
reactivity to nonpathogenic substances, fined into a theory that
came to be known as the clonal-such as red blood cells from other
species. Serum from an an- selection theory. According to this
theory, an individualimal inoculated previously with material that
did not cause lymphocyte expresses membrane receptors that are
specificinfection would react with this material in a specific
manner,for a distinct antigen. This unique receptor specificity is
de-and this reactivity could be passed to other animals by
trans-termined before the lymphocyte is exposed to the
antigen.ferring serum from the first. The work of Karl
LandsteinerBinding of antigen to its specific receptor activates
the cell,and those who followed him showed that injecting an
animalcausing it to proliferate into a clone of cells that have
thewith almost any organic chemical could induce productionsame
immunologic specificity as the parent cell. The clonal-of
antibodies that would bind specifically to the chemical. selection
theory has been further refined and is now acceptedThese studies
demonstrated that antibodies have a capacityas the underlying
paradigm of modern immunology.for an almost unlimited range of
reactivity, including re-sponses to compounds that had only
recently been synthe-The Immune System Includes Innate andsized in
the laboratory and had not previously existed innature. In
addition, it was shown that molecules differing inAdaptive
Componentsthe smallest detail could be distinguished by their
reactivityImmunitythe state of protection from infectious
diseasewith different antibodies. Two major theories were proposed
has both a less specific and more specific component. Theto account
for this specificity: the selective theory and the in- less
specific component, innate immunity, provides the firststructional
theory. line of defense against infection. Most components of
innateThe earliest conception of the selective theory dates to Paul
immunity are present before the onset of infection and con-Ehrlich
in 1900. In an attempt to explain the origin of serum stitute a set
of disease-resistance mechanisms that are notantibody, Ehrlich
proposed that cells in the blood expressed aspecific to a
particular pathogen but that include cellular andvariety of
receptors, which he called side-chain receptors, molecular
components that recognize classes of moleculesthat could react with
infectious agents and inactivate them.peculiar to frequently
encountered pathogens. PhagocyticBorrowing a concept used by Emil
Fischer in 1894 to explain cells, such as macrophages and
neutrophils, barriers such asthe interaction between an enzyme and
its substrate, Ehrlichskin, and a variety of antimicrobial
compounds synthesizedproposed that binding of the receptor to an
infectious agentby the host all play important roles in innate
immunity. Inwas like the fit between a lock and key. Ehrlich
suggested that contrast to the broad reactivity of the innate
immune sys-interaction between an infectious agent and a
cell-boundtem, which is uniform in all members of a species, the
spe-receptor would induce the cell to produce and release morecific
component, adaptive immunity, does not come intoreceptors with the
same specificity. According to Ehrlichs play until there is an
antigenic challenge to the organism.theory, the specificity of the
receptor was determined before Adaptive immunity responds to the
challenge with a high de-its exposure to antigen, and the antigen
selected the appro-gree of specificity as well as the remarkable
property ofpriate receptor. Ultimately all aspects of Ehrlichs
theory memory. Typically, there is an adaptive immune responsewould
be proven correct with the minor exception that the against an
antigen within five or six days after the initial ex-receptor
exists as both a soluble antibody molecule and as aposure to that
antigen. Exposure to the same antigen somecell-bound receptor; it
is the soluble form that is secretedtime in the future results in a
memory response: the immunerather than the bound form
released.response to the second challenge occurs more quickly than
5. Overview of the Immune System CHAPTER 15the first, is stronger,
and is often more effective in neutraliz-distinct layers: a thinner
outer layerthe epidermisand aing and clearing the pathogen. The
major agents of adaptivethicker layerthe dermis. The epidermis
contains severalimmunity are lymphocytes and the antibodies and
otherlayers of tightly packed epithelial cells. The outer
epidermalmolecules they produce.layer consists of dead cells and is
filled with a waterproofing Because adaptive immune responses
require some time toprotein called keratin. The dermis, which is
composed ofmarshal, innate immunity provides the first line of
defenseconnective tissue, contains blood vessels, hair follicles,
seba-during the critical period just after the hosts exposure to a
ceous glands, and sweat glands. The sebaceous glands are
as-pathogen. In general, most of the microorganisms encoun-
sociated with the hair follicles and produce an oily secretiontered
by a healthy individual are readily cleared within a few called
sebum. Sebum consists of lactic acid and fatty acids,days by
defense mechanisms of the innate immune system which maintain the
pH of the skin between 3 and 5; this pHbefore they activate the
adaptive immune system. 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-Innate
Immunityvents the formation of sebum.Innate immunity can be seen to
comprise four types of de-Breaks in the skin resulting from
scratches, wounds, orfensive barriers: anatomic, physiologic,
phagocytic, and in- abrasion are obvious routes of infection. The
skin may alsoflammatory (Table 1-2).be penetrated by biting insects
(e.g., mosquitoes, mites, ticks, fleas, and sandflies); if these
harbor pathogenic organisms,The Skin and the Mucosal Surfaces
Providethey can introduce the pathogen into the body as they feed.
The protozoan that causes malaria, for example, is
depositedProtective Barriers Against Infectionin humans by
mosquitoes when they take a blood meal. Sim-Physical and anatomic
barriers that tend to prevent the entryilarly, bubonic plague is
spread by the bite of fleas, and Lymeof pathogens are an organisms
first line of defense against in- disease is spread by the bite of
ticks.fection. The skin and the surface of mucous membranes areThe
conjunctivae and the alimentary, respiratory, andincluded in this
category because they are effective barriers to urogenital tracts
are lined by mucous membranes, not by thethe entry of most
microorganisms. The skin consists of two dry, protective skin that
covers the exterior of the body. These TABLE 1-2 Summary of
nonspecific host defenses Type Mechanism Anatomic
barriersSkinMechanical barrier retards entry of microbes.Acidic
environment (pH 35) retards growth of microbes.Mucous
membranesNormal flora compete with microbes for attachment sites
and nutrients.Mucus entraps foreign microorganisms.Cilia propel
microorganisms out of body. Physiologic barriersTemperature Normal
body temperature inhibits growth of some pathogens.Fever response
inhibits growth of some pathogens.Low pHAcidity of stomach contents
kills most ingested microorganisms.Chemical mediatorsLysozyme
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 barriersVarious
cells internalize (endocytose) and break down foreign
macromolecules.Specialized cells (blood monocytes, neutrophils,
tissue macrophages) internalize (phagocytose), kill, and digest
whole microorganisms. Inflammatory barriersTissue damage and
infection induce leakage of vascular fluid, containing serum
proteins with antibacterial activity, and influx of phagocytic
cells into the affected area. 6. 6 PART I Introductionmembranes
consist of an outer epithelial layer and an under- tissues are
susceptible to bacterial invasion, whereas otherslying layer of
connective tissue. Although many pathogensare not.enter the body by
binding to and penetrating mucous mem-branes, a number of
nonspecific defense mechanisms tend to Physiologic Barriers to
Infection Includeprevent this entry. For example, saliva, tears,
and mucous se-cretions act to wash away potential invaders and also
contain General Conditions and Specific Moleculesantibacterial or
antiviral substances. The viscous fluid calledThe physiologic
barriers that contribute to innate immu-mucus, which is secreted by
epithelial cells of mucous mem-nity include temperature, pH, and
various soluble and cell-branes, entraps foreign microorganisms. In
the lower respi-associated molecules. Many species are not
susceptible to cer-ratory tract, the mucous membrane is covered by
cilia, tain diseases simply because their normal body
temperaturehairlike protrusions of the epithelial-cell membranes.
The inhibits growth of the pathogens. Chickens, for
example,synchronous movement of cilia propels mucus-entrappedhave
innate immunity to anthrax because their high bodymicroorganisms
from these tracts. In addition, nonpatho- temperature inhibits the
growth of the bacteria. Gastric acid-genic organisms tend to
colonize the epithelial cells of mu- ity is an innate physiologic
barrier to infection because verycosal surfaces. These normal flora
generally outcompetefew ingested microorganisms can survive the low
pH of thepathogens for attachment sites on the epithelial cell
surfacestomach contents. One reason newborns are susceptible toand
for necessary nutrients. some diseases that do not afflict adults
is that their stomachSome organisms have evolved ways of escaping
these de- contents are less acid than those of adults.fense
mechanisms and thus are able to invade the bodyA variety of soluble
factors contribute to innate immu-through mucous membranes. For
example, influenza virus nity, among them the soluble proteins
lysozyme, interferon,(the agent that causes flu) has a surface
molecule that enablesand complement. Lysozyme, a hydrolytic enzyme
found init to attach firmly to cells in mucous membranes of the
respi- mucous secretions and in tears, is able to cleave the
peptido-ratory tract, preventing the virus from being swept out by
the glycan layer of the bacterial cell wall. Interferon comprises
aciliated epithelial cells. Similarly, the organism that causes
group of proteins produced by virus-infected cells. Amonggonorrhea
has surface projections that allow it to bind to ep- the many
functions of the interferons is the ability to bind toithelial
cells in the mucous membrane of the urogenital tract. nearby cells
and induce a generalized antiviral state. Comple-Adherence of
bacteria to mucous membranes is due to inter- ment, examined in
detail in Chapter 13, is a group of serumactions between hairlike
protrusions on a bacterium, calledproteins that circulate in an
inactive state. A variety of spe-fimbriae or pili, and certain
glycoproteins or glycolipids thatcific and nonspecific immunologic
mechanisms can convertare expressed only by epithelial cells of the
mucous mem-the inactive forms of complement proteins into an
activebrane of particular tissues (Figure 1-2). For this reason,
somestate 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- FIGURE 1-2
Electron micrograph of rod-shaped Escherichia coli nents described
above, or they may be cell-associated receptors.bacteria adhering
to surface of epithelial cells of the urinary tract. Among the
class of receptors designated the toll-like receptors[From N.
Sharon and H. Lis, 1993, Sci. Am. 268(1):85; photograph (TLRs),
TLR2 recognizes the lipopolysaccharide (LPS) foundcourtesy of K.
Fujita.]on Gram-negative bacteria. It has long been recognized that
7. Overview of the Immune System CHAPTER 1 7 FIGURE 1-3 (a)
Electronmicrograph of macrophage (pink) attack- (a)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 solublefactors
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.]systemic exposure
of mammals to relatively small quantities ofpurified LPS leads to
an acute inflammatory response (see be-low). The mechanism for this
response is via a TLR onmacrophages that recognizes LPS and elicits
a variety of mole-cules in the inflammatory response upon exposure.
When theTLR is exposed to the LPS upon local invasion by a
Gram-neg-ative bacterium, the contained response results in
eliminationof the bacterial challenge.(b)Cells That Ingest and
Destroy PathogensMake Up a Phagocytic Barrier to Infection
1Bacterium becomes attachedAnother important innate defense
mechanism is the inges-to membrane evaginationscalled
pseudopodiation of extracellular particulate material by
phagocytosis.Phagocytosis is one type of endocytosis, the general
term for2the uptake by a cell of material from its environment. In
Bacterium is ingested,phagocytosis, a cells plasma membrane expands
around the forming phagosomeparticulate material, which may include
whole pathogenicmicroorganisms, to form large vesicles called
phagosomes3(Figure 1-3). Most phagocytosis is conducted by
specialized Phagosome fuses withlysosomecells, such as blood
monocytes, neutrophils, and tissuemacrophages (see Chapter 2). Most
cell types are capable ofother forms of endocytosis, such as
receptor-mediated endo- 4Lysosomal enzymes digestcytosis, in which
extracellular molecules are internalized aftercaptured
materialbinding by specific cellular receptors, and pinocytosis,
theprocess by which cells take up fluid from the surrounding
5medium along with any molecules contained in it.Digestion products
arereleased from cellInflammation Represents a ComplexSequence of
Events That StimulatesImmune ResponsesTissue damage caused by a
wound or by an invading patho-of inflammation as rubor (redness),
tumor (swelling),genic microorganism induces a complex sequence of
eventscalor (heat), and dolor (pain). In the second century AD,
an-collectively known as the inflammatory response. As de-other
physician, Galen, added a fifth sign: functio laesa (lossscribed
above, a molecular component of a microbe, such asof function). The
cardinal signs of inflammation reflect theLPS, may trigger an
inflammatory response via interactionthree major events of an
inflammatory response (Figure 1-4):with cell surface receptors. The
end result of inflammationmay be the marshalling of a specific
immune response to the 1. Vasodilationan increase in the diameter
of bloodinvasion or clearance of the invader by components of
thevesselsof nearby capillaries occurs as the vessels thatinnate
immune system. Many of the classic features of thecarry blood away
from the affected area constrict,inflammatory response were
described as early as 1600 BC, in resulting in engorgement of the
capillary network. TheEgyptian papyrus writings. In the first
century AD, theengorged capillaries are responsible for tissue
rednessRoman physician Celsus described the four cardinal
signs(erythema) and an increase in tissue temperature. 8. 8PART I
Introduction Tissue damage Bacteria 1 4 Tissue damage causes
release of Phagocytes and antibacterial vasoactive and chemotactic
factorsexudate destroy bacteria that trigger a local increase in
blood flow and capillary permeability Exudate32 Phagocytes migrate
to site ofPermeable capillaries allow an (complement,
antibody,inflammation (chemotaxis)influx of fluid (exudate) and
cellsC-reactive protein)MarginationExtravasation CapillaryFIGURE
1-4 Major events in the inflammatory response. A bacte- blood
cells, including phagocytes and lymphocytes, from the bloodrial
infection causes tissue damage with release of various vasoactive
into the tissues. The serum proteins contained in the exudate
haveand chemotactic factors. These factors induce increased blood
flow antibacterial properties, and the phagocytes begin to engulf
the bac-to the area, increased capillary permeability, and an
influx of whiteteria, as illustrated in Figure 1-3.2. An increase
in capillary permeability facilitates an influx isms, some are
released from damaged cells in response to tis- of fluid and cells
from the engorged capillaries into the sue injury, some are
generated by several plasma enzyme sys- tissue. The fluid that
accumulates (exudate) has a much tems, and some are products of
various white blood cells higher protein content than fluid
normally released fromparticipating in the inflammatory response.
the vasculature. Accumulation of exudate contributes toAmong the
chemical mediators released in response to tis- tissue swelling
(edema).sue damage are various serum proteins called acute-phase
proteins. The concentrations of these proteins increase dra-3.
Influx of phagocytes from the capillaries into the tissues is
matically in tissue-damaging infections. C-reactive protein is
facilitated by the increased permeability of the capil- a major
acute-phase protein produced by the liver in re- laries. The
emigration of phagocytes is a multistep sponse to tissue damage.
Its name derives from its pattern- process that includes adherence
of the cells to the recognition activity: C-reactive protein binds
to the endothelial wall of the blood vessels (margination),
C-polysaccharide cell-wall component found on a variety of followed
by their emigration between the capillary- bacteria and fungi. This
binding activates the complement endothelial cells into the tissue
(diapedesis or extrava- system, resulting in increased clearance of
the pathogen ei- sation), and, finally, their migration through the
tissue to ther by complement-mediated lysis or by a complement- the
site of the invasion (chemotaxis). As phagocytic cells mediated
increase in phagocytosis. accumulate at the site and begin to
phagocytose bacteria,One of the principal mediators of the
inflammatory re- they release lytic enzymes, which can damage
nearby sponse is histamine, a chemical released by a variety of
cells healthy cells. The accumulation of dead cells, digested in
response to tissue injury. Histamine binds to receptors on
material, and fluid forms a substance called pus. nearby
capillaries and venules, causing vasodilation and in-The events in
the inflammatory response are initiated by a creased permeability.
Another important group of inflam-complex series of events
involving a variety of chemical me- matory mediators, small
peptides called kinins, are normallydiators whose interactions are
only partly understood. Somepresent in blood plasma in an inactive
form. Tissue injury ac-of these mediators are derived from invading
microorgan- tivates these peptides, which then cause vasodilation
and in- 9. Overview of the Immune SystemCHAPTER 1 9creased
permeability of capillaries. A particular kinin, calledsponses are
intimately involved in activating the specific im-bradykinin, also
stimulates pain receptors in the skin. This mune response.
Conversely, various soluble factors producedeffect probably serves
a protective role, because pain nor-by a specific immune response
have been shown to augmentmally causes an individual to protect the
injured area.the activity of these phagocytic cells. As an
inflammatory re-Vasodilation and the increase in capillary
permeability in sponse develops, for example, soluble mediators are
pro-an injured tissue also enable enzymes of the
blood-clottingduced that attract cells of the immune system. The
immunesystem to enter the tissue. These enzymes activate an enzyme
response will, in turn, serve to regulate the intensity of the
in-cascade that results in the deposition of insoluble strands of
flammatory response. Through the carefully regulated inter-fibrin,
which is the main component of a blood clot. The fib-play of
adaptive and innate immunity, the two systems workrin strands wall
off the injured area from the rest of the bodytogether to eliminate
a foreign invader.and serve to prevent the spread of infection.Once
the inflammatory response has subsided and mostof the debris has
been cleared away by phagocytic cells, tissue The Adaptive Immune
System Requiresrepair and regeneration of new tissue begins.
CapillariesCooperation Between Lymphocytes andgrow into the fibrin
of a blood clot. New connective tissueAntigen-Presenting
Cellscells, called fibroblasts, replace the fibrin as the clot
dissolves. An effective immune response involves two major groups
ofAs fibroblasts and capillaries accumulate, scar tissue
forms.cells: T lymphocytes and antigen-presenting cells. Lympho-The
inflammatory response is described in more detail in cytes are one
of many types of white blood cells produced inChapter 15.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-Adaptive Immunitybinding
cell-surface receptors, lymphocytes mediate theAdaptive immunity is
capable of recognizing and selectivelydefining immunologic
attributes of specificity, diversity,eliminating specific foreign
microorganisms and moleculesmemory, and self/nonself recognition.
The two major popu-(i.e., foreign antigens). Unlike innate immune
responses,lations of lymphocytesB lymphocytes (B cells) and T
lym-adaptive immune responses are not the same in all
membersphocytes (T cells)are described briefly here and in
greaterof a species but are reactions to specific antigenic
challenges. detail in later chapters.Adaptive immunity displays
four characteristic attributes:I Antigenic specificityB LYMPHOCYTES
B lymphocytes mature within the bone marrow; when theyI Diversity
leave it, each expresses a unique antigen-binding receptor onI
Immunologic memory its membrane (Figure 1-5a). This antigen-binding
or B-cell receptor is a membrane-bound antibody molecule. Anti-I
Self/nonself recognition bodies are glycoproteins that consist of
two identical heavyThe antigenic specificity of the immune system
permits it to polypeptide chains and two identical light
polypeptidedistinguish subtle differences among antigens.
Antibodieschains. Each heavy chain is joined with a light chain by
disul-can distinguish between two protein molecules that differ in
fide bonds, and additional disulfide bonds hold the two pairsonly a
single amino acid. The immune system is capable oftogether. The
amino-terminal ends of the pairs of heavy andgenerating tremendous
diversity in its recognition molecules,light chains form a cleft
within which antigen binds. When aallowing it to recognize billions
of unique structures on for- naive B cell (one that has not
previously encountered anti-eign antigens. Once the immune system
has recognized and gen) first encounters the antigen that matches
its membrane-responded to an antigen, it exhibits immunologic
memory; bound antibody, the binding of the antigen to the
antibodythat is, a second encounter with the same antigen induces
acauses the cell to divide rapidly; its progeny differentiate
intoheightened state of immune reactivity. Because of this at-
memory B cells and effector B cells called plasma cells.tribute,
the immune system can confer life-long immunity toMemory B cells
have a longer life span than naive cells, andmany infectious agents
after an initial encounter. Finally, thethey express the same
membrane-bound antibody as theirimmune system normally responds
only to foreign antigens,parent B cell. Plasma cells produce the
antibody in a formindicating that it is capable of self/nonself
recognition. The that can be secreted and have little or no
membrane-boundability of the immune system to distinguish self from
nonselfantibody. Although plasma cells live for only a few days,
theyand respond only to nonself molecules is essential, for, as
de-secrete enormous amounts of antibody during this time.scribed
below, the outcome of an inappropriate response to It has been
estimated that a single plasma cell can secreteself molecules can
be fatal. more than 2000 molecules of antibody per second.
SecretedAdaptive immunity is not independent of innate immu-
antibodies are the major effector molecules of humoralnity. The
phagocytic cells crucial to nonspecific immune re- immunity. 10.
10PART I Introduction (a) B cell (b) TH cell(c) TC cell CD4TCR CD8
TCR Antigen- binding receptor (antibody) FIGURE 1-5 Distinctive
membrane molecules on lymphocytes. (a) antigen associated with
class I MHC molecules. In general, CD4+5B cells have about 10
molecules of membrane-bound antibody per cells act as helper cells
and CD8+ cells act as cytotoxic cells. Bothcell. All the antibody
molecules on a given B cell have the same anti- types of T cells
express about 105 identical molecules of the antigen-genic
specificity and can interact directly with antigen. (b) T
cellsbinding T-cell receptor (TCR) per cell, all with the same
antigenicbearing CD4 (CD4+ cells) recognize only antigen bound to
class IIspecificity.MHC molecules. (c) T cells bearing CD8 (CD8+
cells) recognize onlyT LYMPHOCYTESan important role in activating B
cells, TC cells, macrophages,T lymphocytes also arise in the bone
marrow. Unlike B cells, and various other cells that participate in
the immune re-which mature within the bone marrow, T cells migrate
to thesponse. Differences in the pattern of cytokines produced
bythymus gland to mature. During its maturation within the
activated TH cells result in different types of immunethymus, the T
cell comes to express a unique antigen-binding response.molecule,
called the T-cell receptor, on its membrane. Unlike Under the
influence of TH-derived cytokines, a TC cellmembrane-bound
antibodies on B cells, which can recognizethat recognizes an
antigenMHC class I molecule complexantigen alone, T-cell receptors
can recognize only antigen proliferates and differentiates into an
effector cell called a cy-that is bound to cell-membrane proteins
called major histo-totoxic T lymphocyte (CTL). In contrast to the
TC cell, thecompatibility complex (MHC) molecules. MHC molecules
CTL generally does not secrete many cytokines and insteadthat
function in this recognition event, which is termed anti-exhibits
cell-killing or cytotoxic activity. The CTL has a vitalgen
presentation, are polymorphic (genetically diverse) gly-function in
monitoring the cells of the body and eliminatingcoproteins found on
cell membranes (see Chapter 7). Thereany that display antigen, such
as virus-infected cells, tumorare two major types of MHC molecules:
Class I MHC mole-cells, and cells of a foreign tissue graft. Cells
that display for-cules, which are expressed by nearly all nucleated
cells of ver- eign antigen complexed with a class I MHC molecule
aretebrate species, consist of a heavy chain linked to a
smallcalled altered self-cells; these are targets of CTLs.invariant
protein called 2-microglobulin. Class II MHCmolecules, which
consist of an alpha and a beta glycoprotein ANTIGEN-PRESENTING
CELLSchain, are expressed only by antigen-presenting cells. When
aActivation of both the humoral and cell-mediated branchesnaive T
cell encounters antigen combined with a MHC mol- of the immune
system requires cytokines produced by THecule on a cell, the T cell
proliferates and differentiates into cells. It is essential that
activation of TH cells themselves bememory T cells and various
effector T cells. carefully regulated, because an inappropriate
T-cell response There are two well-defined subpopulations of T
cells: T to self-components can have fatal autoimmune conse-helper
(TH) and T cytotoxic (TC) cells. Although a third typequences. To
ensure carefully regulated activation of TH cells,of T cell, called
a T suppressor (TS) cell, has been postulated, they can recognize
only antigen that is displayed togetherrecent evidence suggests
that it may not be distinct from TH with class MHC II molecules on
the surface of antigen-pre-and TC subpopulations. T helper and T
cytotoxic cells can be senting cells (APCs). These specialized
cells, which includedistinguished from one another by the presence
of either macrophages, B lymphocytes, and dendritic cells, are
distin-CD4 or CD8 membrane glycoproteins on their surfaces
(Fig-guished by two properties: (1) they express class II MHCure
1-5b,c). T cells displaying CD4 generally function as TH molecules
on their membranes, and (2) they are able tocells, whereas those
displaying CD8 generally function as TC deliver a co-stimulatory
signal that is necessary for TH-cellcells (see Chapter 2).
activation. After a TH cell recognizes and interacts with an anti-
Antigen-presenting cells first internalize antigen, either bygenMHC
class II molecule complex, the cell is activateditphagocytosis or
by endocytosis, and then display a part ofbecomes an effector cell
that secretes various growth factorsthat antigen on their membrane
bound to a class II MHCknown collectively as cytokines. The
secreted cytokines play molecule. The TH cell recognizes and
interacts with the 11. Overview of the Immune System CHAPTER 111
activated TH cells and cytotoxic T lymphocytes (CTLs) serve as
effector cells in cell-mediated immune reactions. Cy- tokines
secreted by TH 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 FIGURE
1-6 Electron micrograph of an antigen-presenting macro-called
antigenic determinants, or epitopes. Epitopes are thephage (right)
associating with a T lymphocyte. [From A. S. Rosenthal
immunologically active regions on a complex antigen, the re-et al.,
1982, in PhagocytosisPast and Future, Academic Press, p.gions that
actually bind to B-cell or T-cell receptors.239.] 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 theantigenclass II MHC molecule complex
on the membraneimmune system is therefore uniquely suited to
recognizeof the antigen-presenting cell (Figure 1-6). An additional
co- antigen in a different milieu. The humoral branch (B
cells)stimulatory signal is then produced by the
antigen-present-recognizes an enormous variety of epitopes: those
displayeding cell, leading to activation of the TH cell.on the
surfaces of bacteria or viral particles, as well as those displayed
on soluble proteins, glycoproteins, polysaccha-Humoral Immunity But
Not Cellularrides, or lipopolysaccharides that have been released
from in-Immunity Is Transferredvading pathogens. The cell-mediated
branch (T cells)with Antibodyrecognizes protein epitopes displayed
together with MHC molecules on self-cells, including altered
self-cells such asAs mentioned earlier, immune responses can be
divided into virus-infected self-cells and cancerous cells.humoral
and cell-mediated responses. Humoral immunity Thus, four related
but distinct cell-membrane moleculesrefers to immunity that can be
conferred upon a nonimmuneare responsible for antigen recognition
by the immuneindividual by administration of serum antibodies from
an system:immune individual. In contrast, cell-mediated immunity
canbe transferred only by administration of T cells from an im- I
Membrane-bound antibodies on B cellsmune individual. I T-cell
receptorsThe humoral branch of the immune system is at work inthe
interaction of B cells with antigen and their subsequent I Class I
MHC moleculesproliferation and differentiation into
antibody-secretingI Class II MHC moleculesplasma cells (Figure
1-7). Antibody functions as the effectorof the humoral response by
binding to antigen and neutraliz- Each of these molecules plays a
unique role in antigen recog-ing it or facilitating its
elimination. When an antigen is nition, ensuring that the immune
system can recognize andcoated with antibody, it can be eliminated
in several ways.respond to the different types of antigen that it
encounters.For example, antibody can cross-link several antigens,
form-ing clusters that are more readily ingested by phagocytic
cells. B and T Lymphocytes Utilize SimilarBinding of antibody to
antigen on a microorganism can also Mechanisms To Generate
Diversityactivate the complement system, resulting in lysis of the
for-eign organism. Antibody can also neutralize toxins or viral in
Antigen Receptorsparticles by coating them, which prevents them
from bindingThe antigenic specificity of each B cell is determined
by theto host cells. membrane-bound antigen-binding receptor (i.e.,
antibody)Effector T cells generated in response to antigen are
re-expressed by the cell. As a B cell matures in the bone
marrow,sponsible for cell-mediated immunity (see Figure 1-7).
Bothits specificity is created by random rearrangements of a series
12. 12 PART I IntroductionVISUALIZING CONCEPTSAntigens
ForeignVirusesBacteriaParasitesFungi proteins 1 Internalized
antigen digested by cell2Altered self-cellpresents antigen Class
IIClass I MHC MHCTH cellTC cell3T cell receptorsrecognize antigen
boundto MHC moleculesActivated6TH cellActivated CTLs4recognize and
killBinding antigen-MHCaltered self-cellsactivates T cells
Cytotoxic T lymphocyte (CTL) 5Activated TH cell secretes
Cell-mediated response cytokines that contribute toactivation of B
cells, TC cells, Humoral response and other cells +Antigen78B cellB
cells interact with antigen Ab-secreting Antibody binds antigenand
differentiate intoplasma cells and facilitates its
clearanceantibody-secreting plasma cellsfrom the bodyFIGURE 1-7
Overview of the humoral and cell-mediated sponse, various
subpopulations of T cells recognize antigen pre- branches of the
immune system. In the humoral response, B cells sented on
self-cells. TH cells respond to antigen by producing cy- interact
with antigen and then differentiate into antibody-secret-tokines.
TC cells respond to antigen by developing into cytotoxic T ing
plasma cells. The secreted antibody binds to the antigen
andlymphocytes (CTLs), which mediate killing of altered self-cells
facilitates its clearance from the body. In the cell-mediated re-
(e.g., virus-infected cells). 13. Overview of the Immune System
CHAPTER 1 13of gene segments that encode the antibody molecule
(seeTCR genes is capable of generating on the order of 109Chapter
5). As a result of this process, each mature B cell pos- unique
antigenic specificities. This enormous potential di-sesses a single
functional gene encoding the antibody heavyversity is later
diminished through a selection process in thechain and a single
functional gene encoding the antibody thymus that eliminates any T
cell with self-reactive receptorslight chain; the cell therefore
synthesizes and displays anti- and ensures that only T cells with
receptors capable of recog-body with one specificity on its
membrane. All antibodynizing antigen associated with MHC molecules
will be ablemolecules on a given B lymphocyte have identical
specificity,to mature (see Chapter 10).giving each B lymphocyte,
and the clone of daughter cells towhich it gives rise, a distinct
specificity for a single epitope onan antigen. The mature B
lymphocyte is therefore said to beThe Major Histocompatibility
Moleculesantigenically committed. The random gene rearrangements
during B-cell matura- Bind Antigenic Peptidestion in the bone
marrow generate an enormous number of The major histocompatibility
complex (MHC) is a large ge-different antigenic specificities. The
resulting B-cell popula-netic complex with multiple loci. The MHC
loci encode twotion, which consists of individual B cells each
expressing a major classes of membrane-bound glycoproteins: class I
andunique antibody, is estimated to exhibit collectively more class
II MHC molecules. As noted above, TH cells generallythan 1010
different antigenic specificities. The enormous di-recognize
antigen combined with class II molecules, whereasversity in the
mature B-cell population is later reduced by aTC cells generally
recognize antigen combined with class Iselection process in the
bone marrow that eliminates any B molecules (Figure 1-8).cells with
membrane-bound antibody that recognizes self-MHC molecules function
as antigen-recognition mole-components. The selection process helps
to ensure that self- cules, but they do not possess the fine
specificity for antigenreactive antibodies (auto-antibodies) are
not produced.characteristic of antibodies and T-cell receptors.
Rather, each The attributes of specificity and diversity also
characterize MHC molecule can bind to a spectrum of antigenic
peptidesthe antigen-binding T-cell receptor (TCR) on T cells. As in
B- derived from the intracellular degradation of antigen mole-cell
maturation, the process of T-cell maturation includes cules. In
both class I and class II MHC molecules the distalrandom
rearrangements of a series of gene segments that en-regions
(farthest from the membrane) of different alleles dis-code the
cells antigen-binding receptor (see Chapter 9). Each play wide
variation in their amino acid sequences. TheseT lymphocyte cell
expresses about 105 receptors, and all ofvariable regions form a
cleft within which the antigenic pep-the receptors on the cell and
its clonal progeny have identicaltide sits and is presented to T
lymphocytes (see Figure 1-8).specificity for antigen. The random
rearrangement of the Different allelic forms of the genes encoding
class I and class(a)(b)AntigenicpeptideTC cell TH cellClass
IMHCClass IIMHC TC cellT cellreceptorCD8 TH cellCD4Virus-infected
cell Antigen-presenting cell FIGURE 1-8 The role of MHC molecules
in antigen recognition bycells. (b) This scanning electron
micrograph reveals numerous TT cells. (a) Class I MHC molecules are
expressed on nearly all nucle-lymphocytes interacting with a single
macrophage. The macrophageated cells. Class II MHC molecules are
expressed only on antigen-presents processed antigen combined with
class II MHC moleculespresenting cells. T cells that recognize only
antigenic peptides to the T cells. [Photograph from W. E. Paul
(ed.), 1991, Immunology:displayed with a class II MHC molecule
generally function as T helperRecognition and Response, W. H.
Freeman and Company, New York;(TH) cells. T cells that recognize
only antigenic peptides displayed micrograph courtesy of M. H.
Nielsen and O. Werdelin.]with a class I MHC molecule generally
function as T cytotoxic (TC) 14. 14PART I IntroductionII molecules
confer different structures on the antigen-bind-Since expression of
class II MHC molecules is limited to anti-ing cleft with different
specificity. Thus the ability to presentgen-presenting cells,
presentation of exogenous peptidean antigen to T lymphocytes is
influenced by the particularclass II MHC complexes is limited to
these cells. T cells dis-set of alleles that an individual
inherits.playing CD4 recognize antigen combined with class II MHC
molecules and thus are said to be class II MHC restricted.Complex
Antigens Are Degraded (Processed)These cells generally function as
T helper cells.and Displayed (Presented) with MHC Endogenous
antigen is produced within the host cell it- self. Two common
examples are viral proteins synthesizedMolecules on the Cell
Surfacewithin virus-infected host cells and unique proteins
synthe-In order for a foreign protein antigen to be recognized by a
T sized by cancerous cells. Endogenous antigens are degradedcell,
it must be degraded into small antigenic peptides that into peptide
fragments that bind to class I MHC moleculesform complexes with
class I or class II MHC molecules. Thiswithin the endoplasmic
reticulum. The peptideclass I MHCconversion of proteins into
MHC-associated peptide frag- complex is then transported to the
cell membrane. Since allments is called antigen processing and
presentation. Whether a nucleated cells express class I MHC
molecules, all cells pro-particular antigen will be processed and
presented togetherducing endogenous antigen use this route to
process the anti-with class I MHC or class II MHC molecules appears
to be gen. T cells displaying CD8 recognize antigen associated
withdetermined by the route that the antigen takes to enter a cell
class I MHC molecules and thus are said to be class I MHC
re-(Figure 1-9).stricted. These cytotoxic T cells attack and kill
cells displaying Exogenous antigen is produced outside of the host
cellthe antigenMHC class I complexes for which their receptorsand
enters the cell by endocytosis or phagocytosis. Antigen- are
specific.presenting cells (macrophages, dendritic cells, and B
cells)degrade ingested exogenous antigen into peptide
fragmentsAntigen Selection of Lymphocyteswithin the endocytic
processing pathway. Experiments sug-gest that class II MHC
molecules are expressed within the en- Causes Clonal
Expansiondocytic processing pathway and that peptides produced by A
mature immunocompetent animal contains a large num-degradation of
antigen in this pathway bind to the cleft ber of antigen-reactive
clones of T and B lymphocytes; thewithin the class II MHC
molecules. The MHC molecules antigenic specificity of each of these
clones is determined bybearing the peptide are then exported to the
cell surface. the specificity of the antigen-binding receptor on
the mem- (a)Peptideclass II(b)Peptideclass I MHC complexMHC complex
Antigen ingested Class I MHC by endocytosis viral peptide or
phagocytosisPeptides ofVesicleantigenClass IIMHC Golgi complex
Viral PolysomesLysosome peptides EndosomeRough Endocytic processing
pathwayendoplasmicViralreticulumprotein RibosomeViral mRNA Nucleus
Viral DNA Virus FIGURE 1-9 Processing and presentation of exogenous
and en- nous antigen, which is produced within the cell itself
(e.g., in a virus-dogenous antigens. (a) Exogenous antigen is
ingested by endocyto-infected cell), is degraded within the
cytoplasm into peptides, whichsis or phagocytosis and then enters
the endocytic processing move into the endoplasmic reticulum, where
they bind to class Ipathway. Here, within an acidic environment,
the antigen is degraded MHC molecules. The peptideclass I MHC
complexes then moveinto small peptides, which then are presented
with class II MHC mol- through the Golgi complex to the cell
surface.ecules on the membrane of the antigen-presenting cell. (b)
Endoge- 15. Overview of the Immune System CHAPTER1 15brane of the
clones lymphocytes. As noted above, the speci- istic of adaptive
immunity. Specificity is shown because onlyficity of each T and B
lymphocyte is determined before its lymphocytes whose receptors are
specific for a given epitopecontact with antigen by random gene
rearrangements duringon an antigen will be clonally expanded and
thus mobilizedmaturation in the thymus or bone marrow. for an
immune response. Self/nonself discrimination is ac-The role of
antigen becomes critical when it interacts withcomplished by the
elimination, during development, of lym-and activates mature,
antigenically committed T and B lym- phocytes bearing self-reactive
receptors or by the functionalphocytes, bringing about expansion of
the population ofsuppression of these cells in adults.cells with a
given antigenic specificity. In this process of Immunologic memory
also is a consequence of clonal se-clonal selection, an antigen
binds to a particular T or B cell lection. During clonal selection,
the number of lymphocytesand stimulates it to divide repeatedly
into a clone of cells withspecific for a given antigen is greatly
amplified. Moreover,the same antigenic specificity as the original
parent cell (Fig- many of these lymphocytes, referred to as memory
cells, ap-ure 1-10). pear to have a longer life span than the naive
lymphocytesClonal selection provides a framework for
understandingfrom which they arise. The initial encounter of a
naive im-the specificity and self/nonself recognition that is
character-munocompetent lymphocyte with an antigen induces aBone
marrowPeripheral lymphoid tissueMemory cell 2Antibody2 211 2 Plasma
cells22 Antigen 2222 2Gene rearrangement 2 Stem 2cell33 22 2244 2
Mature Mature B cellsB cellsMaturation into matureAntigen-dependent
proliferation and antigenetically committed B cells differentiation
into plasma and memory cellsFIGURE 1-10 Maturation and clonal
selection of B lymphocytes. ample) leads to a clone of memory B
cells and effector B cells, calledMaturation, which occurs in the
absence of antigen, produces anti-plasma cells; all cells in the
expanded clone are specific for the orig-genically committed B
cells, each of which expresses antibody with ainal antigen. The
plasma cells secrete antibody reactive with the acti-single
antigenic specificity (indicated by 1, 2, 3, and 4). Clonal selec-
vating antigen. Similar processes take place in the
T-lymphocytetion occurs when an antigen binds to a B cell whose
membrane- population, resulting in clones of memory T cells and
effector T cells;bound antibody molecules are specific for epitopes
on that antigen. the latter include activated TH cells, which
secrete cytokines, and cy-Clonal expansion of an antigen-activated
B cell (number 2 in this ex- totoxic T lymphocytes (CTLs). 16.
16PART I Introduction primary response; a later contact of the host
with antigenbody-secreting plasma cells and memory B cells. As seen
in will induce a more rapid and heightened secondary re- Figure
1-11a, the primary response has a lag of approxi- sponse. The
amplified population of memory cells accounts mately 57 days before
antibody levels start to rise. This lag is for the rapidity and
intensity that distinguishes a secondary the time required for
activation of naive B cells by antigen response from the primary
response. and TH cells and for the subsequent proliferation and
differ-In the humoral branch of the immune system, antigen
in-entiation of the activated B cells into plasma cells. Antibody
duces the clonal proliferation of B lymphocytes into anti-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 12 days),(a)antibody levels are much
higher, and they are sustained forAntigen Amuch longer. The
secondary response reflects the activity Antigen ASecondary+
Antigen Banti-A of the clonally expanded population of memory B
cells.response PrimarySerum antibody levelanti-B These memory cells
respond to the antigen more rapidlyresponse than naive B cells; in
addition, because there are manyPrimary anti-A more memory cells
than there were naive B cells for theresponse 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- 0 140 614 ture T lymphocyte
induces clonal proliferation into various Time, daysT cells with
effector functions (TH cells and CTLs) and into memory T cells. The
cell-mediated response to a skin graft is(b)illustrated in Figure
1-11b by a hypothetical transplantation 100Strain CStrain CStrain B
experiment. When skin from strain C mice is grafted ontoPercentage
of mice rejecting graftgraft graft graftstrain A mice, a primary
response develops and all the graftsrepeated are rejected in about
1014 days. If these same mice are again80 grafted with strain C
skin, it is rejected much more vigor- ously and rapidly than the
first grafts. However, if animals60 previously engrafted with
strain C skin are next given skin from an unrelated strain, strain
B, the response to strain B is40 typical of the primary response
and is rejected in 1014 days. That is, graft rejection is a
specific immune response. The20 same mice that showed a secondary
response to graft C will show a primary response to graft B. The
increased speed of 0 4 8 12 16 0 4 8 12 16 rejection of graft C
reflects the presence of a clonally ex- Time, dayspanded population
of memory TH and TC cells specific for the antigens of the foreign
graft. This expanded memoryFIGURE 1-11 Differences in the primary
and secondary responsepopulation generates more effector cells,
resulting in faster to injected antigen (humoral response) and to a
skin graft (cell-me-graft rejection. diated response) reflect the
phenomenon of immunologic memory. (a) When an animal is injected
with an antigen, it produces a primary The Innate and Adaptive
Immune Systems serum antibody response of low magnitude and short
duration,Collaborate, Increasing the Efficiency of peaking at about
1017 days. A second immunization with the same antigen results in a
secondary response that is greater in magnitude, Immune
Responsiveness peaks in less time (27 days), and lasts longer
(months to years) It is important to appreciate that adaptive and
innate immu- than the primary response. Compare the secondary
response to anti-nity do not operate independentlythey function as
a highly gen A with the primary response to antigen B administered
to theinteractive and cooperative system, producing a combined same
mice. (b) Results from a hypothetical experiment in which skin
response more effective than either branch could produce by grafts
from strain C mice are transplanted to 20 mice of strain A;
theitself. Certain immune components play important roles in grafts
are rejected in about 1014 days. The 20 mice are rested for 2 both
types of immunity. months and then 10 are given strain C grafts and
the other 10 are An example of cooperation is seen in the encounter
given skin from strain B. Mice previously exposed to strain C skin
re-between macrophages and microbes. Interactions between ject C
grafts much more vigorously and rapidly than the grafts from
receptors on macrophages and microbial components gen- strain B.
Note that the rejection of the B graft follows a time courseerate
soluble proteins that stimulate and direct adaptive im- similar to
that of the first strain C graft.mune responses, facilitating the
participation of the adap- 17. Overview of the Immune SystemCHAPTER
117 however, which implies that some sort of immunity exists in
TABLE 1-3 Comparison of adaptive and most, possibly all,
multicellular organisms, including those innate immunity with no
components of adaptive immunity. InnateAdaptiveInsects and plants
provide particularly clear and dramatic examples of innate immunity
that is not based on lympho- Response time Hours Dayscytes. The
invasion of the interior body cavity of the fruit fly, Specificity
Limited and Highly diverse, improves Drosophila melanogaster, by
bacteria or molds triggers thefixed during the course of synthesis
of small peptides that have strong antibacterial orimmune
responseantifungal activity. The effectiveness of these
antimicrobial Response to Identical toMuch more rapid thanpeptides
is demonstrated by the fate of mutants that are un-repeat
primaryprimary response able to produce them. For example, a fungal
infection over-infectionresponsewhelms 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
varioustive immune system in the elimination of the pathogen.
classes of microbial molecules (the toll-like receptors)
wereStimulated macrophages also secrete cytokines that can first
found in Drosophila.direct adaptive immune responses against
particular intra- Plants respond to infection by producing a wide
varietycellular pathogens.of antimicrobial proteins and peptides,
as well as smallJust as important, the adaptive immune system
producessignals and components that stimulate and increase the
ef-fectiveness of innate responses. Some T cells, when they
en-counter appropriately presented antigen, synthesize andsecrete
cytokines that increase the ability of macrophages tokill the
microbes they have ingested. Also, antibodies pro-duced against an
invader bind to the pathogen, marking it asa 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 respondingcomponents. Adaptive immunity
compensates for its sloweronset by its ability to recognize a much
wider repertoire offoreign substances, and also by its ability to
improve during aresponse, whereas innate immunity remains constant.
It mayalso be noted that secondary adaptive responses are
consid-erably faster than primary responses. Principle
characteris-tics of the innate and adaptive immune systems
arecompared in Table 1-3. With overlapping roles, the two sys-tems
together form a highly effective barrier to infection.Comparative
ImmunityThe field of immunology is concerned mostly with how
in-nate and adaptive mechanisms collaborate to protect verte-brates
from infection. Although many cellular and molecularactors have
important roles, antibodies and lymphocytes areconsidered to be the
principal players. Yet despite theirprominence in vertebrate immune
systems, it would be amistake to conclude that these extraordinary
molecules andversatile cells are essential for immunity. In fact, a
deter- FIGURE 1-12 Severe fungal infection in a fruit fly
(Drosophilamined search for antibodies, T cells, and B cells in
organisms melanogaster) with a disabling mutation in a
signal-transductionof the nonvertebrate phyla has failed to find
them. The inte-pathway required for the synthesis of the antifungal
peptide dro-rior spaces of organisms as diverse as fruit flies,
cockroaches, somycin. [From B. Lemaitre et al., 1996, Cell 86:973;
courtesy of J. A.and plants do not contain unchecked microbial
populations, Hoffman, University of Strasbourg.] 18. 18 PART I
Introductionnonpeptide organic molecules that have antibiotic
activity. wheezing, and difficulty in breathing (asthma);
dermatitis orAmong these agents are enzymes that digest microbial
cell skin eruptions (hives); and, in more extreme cases,
strangu-walls, peptides and a protein that damages microbial mem-
lation due to blockage of airways by inflammation. A
signifi-branes, and the small organic molecules phytoalexins. The
cant fraction of our health resources is expended to care
forimportance of the phytoalexins is shown by the fact that
mu-those suffering from allergy and asthma. The frequency oftations
that alter their biosynthetic pathways result in loss ofallergy and
asthma in the United States place these com-resistance to many
plant pathogens. In some cases, the re-plaints among the most
common reasons for a visit to thesponse of plants to pathogens goes
beyond this chemical as- doctors office or to the hospital
emergency room (see Clini-sault to include an architectural
response, in which the plantcal Focus).isolates cells in the
infected area by strengthening the walls of When the immune system
encounters foreign cells or tis-surrounding cells. Table 1-4
compares the capabilities of im- sue, it responds strongly to rid
the host of the invaders. How-mune systems in a wide range of
multicellular organisms,ever, in some cases, the transplantation of
cells or an organboth animals and plants.from another individual,
although viewed by the immunesystem as a foreign invasion, may be
the only possible treat-ment for disease. For example, it is
estimated that more than60,000 persons in the United States alone
could benefit fromImmune Dysfunction anda kidney transplant.
Because the immune system will attackIts Consequencesand reject any
transplanted organ that it does not recognizeas self, it is a
serious barrier to this potentially life-savingThe above overview
of innate and adaptive immunity depictstreatment. An additional
danger in transplantation is thata multicomponent interactive
system that protects the hostany transplanted cells with immune
function may view thefrom infectious diseases and from cancer. This
overviewnew host as nonself and react against it. This reaction,
whichwould not be complete without mentioning that the immuneis
termed graft-versus-host disease, can be fatal. The rejec-system
can function improperly. Sometimes the immune sys-tion reaction and
graft-versus-host disease can be suppressedtem fails to protect the
host adequately or misdirects its ac-by drugs, but this type of
treatment suppresses all immunetivities to cause discomfort,
debilitating disease, or evenfunction, so that the host is no
longer protected by its im-death. There are several common
manifestations of immunemune system and becomes susceptible to
infectious diseases.dysfunction:Transplantation studies have played
a major role in the de-I Allergy and asthmavelopment of immunology.
A Nobel prize was awarded toKarl Landsteiner, in 1930, for the
discovery of human bloodI Graft rejection and graft-versus-host
diseasegroups, a finding that allowed blood transfusions to be
car-I Autoimmune diseaseried out safely. In 1980, G. Snell, J.
Dausset, and B. Benacerrafwere recognized for discovery of the
major histocompatibil-I Immunodeficiencyity complex, and, in 1991,
E. D. Thomas and J. Murray wereAllergy and asthma are results of
inappropriate immune re-awarded Nobel Prizes for advances in
transplantation immu-sponses, often to common antigens such as
plant pollen, nity. To enable a foreign organ to be accepted
without sup-food, or animal dander. The possibility that certain
sub- pressing immunity to all antigens remains a challenge
forstances increased sensitivity rather than protection was rec-
immunologists today.ognized in about 1902 by Charles Richet, who
attempted to In certain individuals, the immune system
malfunctionsimmunize dogs against the toxins of a type of
jellyfish,by losing its sense of self and nonself, which permits an
im-Physalia. He and his colleague Paul Portier observed that mune
attack upon the host. This condition, autoimmunity,dogs exposed to
sublethal doses of the toxin reacted almost can cause a number of
chronic debilitating diseases. Theinstantly, and fatally, to
subsequent challenge with minute symptoms of autoimmunity differ
depending on whichamounts of the toxin. Richet concluded that a
successful im-tissues and organs are under attack. For example,
multiplemunization or vaccination results in phylaxis, or
protection, sclerosis is due to an autoimmune attack on the brain
andand that an opposite result may occuranaphylaxisincentral
nervous system, Crohns disease is an attack on thewhich exposure to
antigen can result in a potentially lethaltissues in the gut, and
rheumatoid arthritis is an attack onsensitivity to the antigen if
the exposure is repeated. Richetjoints of the arms and legs. The
genetic and environmentalreceived the Nobel Prize in 1913 for his
discovery of the ana-factors that trigger and sustain autoimmune
disease are veryphylactic response. active areas of immunologic
research, as is the search for im-Fortunately, most allergic
reactions in humans are notproved treatments.rapidly fatal. A
specific allergic or anaphylactic response usu-If any of the many
components of innate or specific im-ally involves one antibody
type, called IgE. Binding of IgE tomunity is defective because of
genetic abnormality, or if anyits specific antigen (allergen)
releases substances that causeimmune function is lost because of
damage by chemical,irritation and inflammation. When an allergic
individual is physical, or biological agents, the host suffers from
immu-exposed to an allergen, symptoms may include
sneezing,nodeficiency. The severity of the immunodeficiency disease
19. Overview of the Immune System CHAPTER119TABLE 1-4 Immunity in
multicellular organisms Invasion- induced protectiveInnateAdaptive
enzymes Pattern-immunityimmunity and enzymeAntimicrobial
recognition Graft T and BTaxonomic group (nonspecific) (specific)
cascades Phagocytosis peptidesreceptors rejection cells
AntibodiesHigher plants Invertebrate animals Porifera ?? ?
(sponges) Annelids ?? ? (earthworms) Arthropods ?
(insects,crustaceans)Vertebrate animals Elasmobranchs equivalent
(cartilaginous agentsfish; e.g.,sharks, rays) Teleost fish and
probable bony fish (e.g.,salmon, tuna) Amphibians Reptiles ? Birds
? Mammals KEY: definitive demonstration; failure to demonstrate
thus far; ? 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.CLINICAL FOCUS (or
allergen) triggers an IgE-mediated re- lease of molecules that
cause symptoms Allergy and Asthma as Serious ranging from sneezing
and dermatitis to inflammation of the lungs in an asth- Public
Health Problemsmatic attack. The sequence of events in an allergic
response is depicted in the ac- companying figure. Although the im-
mune system serves to protect the hostlems. Details of the
mechanisms that un-derlie allergic and asthmatic responsesto
environmental antigens (or allergens) The discomfort from common
aller- gies such as plant pollen allergy (often called ragweed
allergy) consists of a from infection and cancer, inappropriate
will be considered in Chapter 16. Simply week or two of sneezing
and runny nose, responses of this system can lead to stated,
allergic reactions are responses which may seem trivial compared
with disease. Common among the results of to antigenic stimuli that
result in immu-health problems such as cancer, cardiac immune
dysfunction are allergies and nity based mainly on the IgE class of
im-arrest, or life-threatening infections. A asthma, both serious
public health prob- munoglobulin. Exposure to the antigenmore
serious allergic reaction is asthma, (continued) 20. 20 PART I
IntroductionC L I N I C A L F O C U S (continued)First
contactAllergy and Asthma as Serious with an allergen (ragweed)
RagweedPublic Health Problems pollena chronic disease of the lungs
in which studies of genetic factors in allergic dis-inflammation,
mediated by environmen- ease (see Clinical Focus in Chapter 16). B
celltal antigens or infections, causes severe An increasingly
serious health prob-difficulty in breathing. Approximately 15 lem
is food allergy, especially to peanuts IgEmillion persons in the
United States suf- and tree nuts (almonds, cashews, andfer from
asthma, and it causes aboutwalnuts). Approximately 3 million
Production of large amounts5000 deaths per year. In the past
twentyAmericans are allergic to these foods of ragweed IgEyears,
the prevalence of asthma in theand they are the leading causes of
fatal antibodyWestern World has doubled.* and near-fatal food
allergic (anaphylac- Plasma cellData on the frequency of care
soughttic) reactions. While avoidance of thesefor the most common
medical com-foods can prevent harmful conse-plaints in the United
States show thatquences, the ubiquitous use of peanutasthma and
allergy together resulted in protein and other nut products in a
vari-IgE moleculesmore than 28 million visits to the doctor ety of
foods makes this very difficult for attach to mastin 1995. The
importance of allergy as a the allergic individual. At least 50% of
se- cellspublic health problem is underscored by rious reactions
are caused by accidentalthe fact that the annual number of doctor
exposures to peanuts, tree nuts, or theirvisits for hypertension,
routine medicalproducts. This has led to controversial Mast
cellexaminations, or normal pregnancy, aremovements to ban peanuts
fromeach fewer than the number of visits forschools and
airplanes.Subsequent contactallergic conditions. In fact, the
mostAnaphylaxis generally occurs withinwith allergencommon reason
for a visit to a hospital an hour of ingesting the food
allergenemergency room is an asthma attack, ac- and the most
effective treatment is injec- IgE-primed mastcounting for one third
of all visits. In ad-tion of the drug epinephrine. Thosecell
releasesdition to those treated in the ER, thereprone to
anaphylactic attacks often carrymolecules thatwere about 160,000
hospitalizations for injectable epinephrine to be used in casecause
wheezing,asthma in the past year, with an averageof exposure.
sneezing, runny nose,stay of 3 to 4 days.In addition to the
suffering and anxi- watery eyes, andAlthough all ages and races are
af- ety caused by inappropriate immune re- other symptomsfected,
deaths from asthma are 3.5 timessponses or allergies to
environmentalmore common among African-Americanantigens, there is a
staggering cost inchildren. The reasons for the increases interms
of lost work time for those affectedSequence of events leading to
an allergicnumber of asthma cases and for theand for caregivers.
These costs well justifyresponse. When the antibody producedhigher
death rate in African-American chil- the extensive efforts by basic
and clinical upon contact with an allergen is IgE, thisdren remain
unknown, although someimmunologists and allergists to relieve class
of antibody reacts via its constantregion with a mast cell.
Subsequent reac-clues may have been uncovered by recent the
suffering caused by these disorders.tion of the antibody binding
site with theallergen triggers the mast cell to which*Holgate, S.
T. 1999. The epidemic of allergy and Hughes, D. A., and C. Mills.
2001. Food allergy: the IgE is bound to secrete moleculesasthma,
Nature Supp. to vol. 402, B2. A problem on the rise. Biologist
(London) 48:201. that cause the allergic symptoms.depends on the
number of affected components. A commonsevere combined
immunodeficiency (SCID), which affectstype of immunodeficiency in
North America is a selectiveboth B and T cells, if untreated,
results in death from infec-immunodeficiency in which only one type
of immunoglob-tion at an early age. Since the 1980s, the most
common formulin, IgA, is lacking; the symptoms may be minor or even
go of immunodeficiency has been acquired immune
deficiencyunnoticed. In contrast, a rarer immunodeficiency called
syndrome, or AIDS, which results from infection with the 21.
Overview of the Immune System CHAPTER 1 21retrovirus human
immunodeficiency virus, or HIV. In AIDS,cells, and dendritic
cells); the resulting antigenic peptidesT helper cells are infected
and destroyed by HIV, causing acomplexed with class II MHC
molecules are then displayedcollapse of the immune system. It is
estimated that 35 million on the cell surface.persons worldwide
suffer from this disease, which is usually I Endogenous
(intracellular) antigens (e.g., viral and tumorfatal within 8 to 10
years after infection. Although certain proteins produced in
altered self-cells) are degraded in thetreatments can prolong the
life of AIDS patients, there is nocytoplasm and then displayed with
class I MHC moleculesknown cure for this disease. on the cell
surface.This chapter has been a brief introduction to the immune I
The immune system produces both humoral and cell-me-system, and it
has given a thumbnail sketch of how this com- diated responses. The
humoral response is best suited forplex system functions to protect
the host from disease. The elimination of exogenous antigens; the
cell-mediated re-following chapters will concern the structure and
function of sponse, for elimination of endogenous antigens.the
individual cells, organs, and molecules that make up thissystem.
They will describe our current understanding of howI While an
adaptive immune system is found only in verte-the components of
immunity interact and the experimentsbrates, innate immunity has
been demonstrated in organ-that allowed discovery of these
mechanisms. Specific areas ofisms as different as insects,
earthworms, and higher plants.applied immunology, such as immunity
to infectious dis-I Dysfunctions of the immune system include
commoneases, cancer, and current vaccination practices are the
subject maladies such as allergy or asthma. Loss of immune
func-matter of later chapters. Finally, to complete the description
tion leaves the host susceptible to infection; in autoimmu-of the
immune system in all of its activities, a chapter ad- nity, the
immune system attacks host cells or tissues,dresses each of the
major types of immune dysfunction. References Akira, S., K. Takeda,
and T. Kaisho. 2001. Toll-like receptors:SUMMARY Critical proteins
linking innate and acquired immunity. Na-ture Immunol. 2:675.I
Immunity is the state of protection against foreign organ-isms or
substances (antigens). Vertebrates have two typesBurnet, F. M.
1959. The Clonal Selection Theory of Acquired Im-of immunity,
innate and adaptive. munity. Cambridge University Press,
Cambridge.I Innate immunity is not specific to any one pathogen
butCohen, S. G., and M. Samter. 1992. Excerpts from Classics in
Al-rather constitutes a first line of defense, which includeslergy.
Symposia Foundation, Carlsbad, California.anatomic, physiologic,
endocytic and phagocytic, and in- Desour, L. 1922. Pasteur and His
Work (translated by A. F. andflammatory barriers.B. H. Wedd). T.
Fisher Unwin Ltd., London.I Innate and adaptive immunity operate in
cooperative and Fritig, B., T. Heitz, and M. Legrand. 1998.
Antimicrobial proteinsinterdependent ways. The activation of innate
immune re-in induced plant defense. Curr. Opin. Immunol.
10:12.sponses produces signals that stimulate and direct
subse-quent adaptive immune responses. Kimbrell, D. A., and B.
Beutler. 2001. The evolution andgenetics of innate immunity. Nature
Rev. Genet. 2:256.I Adaptive immune responses exhibit four
immunologic at-tributes: specificity, diversity, memory, and
self/nonself Kindt, T. J., and J. D. Capra. 1984. The Antibody
Enigma.recognition.Plenum Press, New York.I The high degree of
specificity in adaptive immunity arises Landsteiner, K. 1947. The
Specificity of Serologic Reactions. Har-from the activities of
molecules (antibodies and T-cell vard University Press, Cambridge,
Massachusetts.receptors) that recognize and bind specific
antigens.Lawson, P. R., and K. B. Reid. 2000. The roles of
surfactantI Antibodies recognize and interact directly with
antigen. T- proteins A and D in innate immunity. Immunologic
Reviewscell receptors recognize only antigen that is combined with
173:66.either class I or class II major histocompatibility
complexMedawar, P. B. 1958. The Immunology of Transplantation.
The(MHC) molecules.Harvey Lectures 19561957. Academic Press, New
York.I The two major subpopulations of T lymphocytes are the
Medzhitov, R., and C. A. Janeway. 2000. Innate immunity. N.CD4 T
helper (TH) cells and CD8 T cytotoxic (TC) cells. Eng. J. Med.
343:338.TH cells secrete cytokines that regulate immune
responseupon recognizing antigen combined with class II MHC.
TCMetchnikoff, E. 1905. Immunity in the Infectious
Diseases.MacMillan, New York.cells recognize antigen combined with
class I MHC andgive rise to cytotoxic T cells (CTLs), which display
cyto- Otvos, L. 2000. Antibacterial peptides isolated from insects.
J.toxic ability.Peptide Sci. 6:497.I Exogenous (extracellular)
antigens are internalized andPaul, W., ed. 1999. Fundamental
Immunology, 4th ed. Lippin-degraded by antigen-presenting cells
(macrophages, Bcott-Raven, Philadelphia. 22. 22PART I Introduction
Roitt, I. M., and P. J. Delves, eds. 1998. An Encyclopedia of Im-5.
Fill in the blanks in the following statements with the
mostmunology, 2nd ed., vols. 14. Academic Press, London.appropriate
terms: a.,, andall function as antigen- USEFUL WEB SITES presenting
cells.b.Antigen-presenting cells deliver asignal tocells.
http://www.aaaai.org/ c. Only antigen-presenting cells express
classMHC molecules, whereas nearly all cells express classThe
American Academy of Allergy Asthma and Immunology MHC
molecules.site includes an extensive library of information about
allergicd. antigens are internalized by antigen-presentingdiseases.
cells, degraded in the, and displayed with classMHC molecules on
the cell surface. http://12.17.12.70/aai/default.asp e.antigens are
produced in altered self-cells, de-The Web site of the American
Association of Immunologists graded in the, and displayed with
classcontains a good deal of information of interest to
immunolo-MHC molecules on the cell surface.gists.6. Briefly
describe the three major events in the inflammatory
http://www.ncbi.nlm.nih.gov/PubMed/ response.PubMed, the National
Library of Medicine database of more 7. The T cell is said to be
class I restricted. What does thisthan 9 million publications, is
the worlds most comprehen-mean?sive bibliographic database for
biological and biomedical lit-erature. It is also a highly
user-friendly site.8. Match each term related to innate immunity
(ap) with the most appropriate description listed below (119). Each
de- scription may be used once, more than once, or not at all.
Study Questions CLINICAL FOCUS QUESTIONYou have a young nephew who
hasTerms developed a severe allergy to tree nuts. What precautions
woulda. Fimbriae or pili you advise for him and for his parents?
Should school officials be b. Exudate aware of this condition? c.
Sebum1. Indicate to which branch(es) of the immune system the fol-
d. Margination lowing statements apply, using H for the humoral
branche. Dermis and CM for the cell-mediated branch. Some
statements mayf.Lysosome apply to both branches.g. Histamineh.
Macrophagea.Involves class I MHC molecules i.Lysozymeb.Responds to
viral infectionj.Bradykininc.Involves T helper cells k.
Interferond.Involves processed antigen l.Edemae.Most likely
responds following an organm.Complementtransplantn.
Extravasationf.Involves T cytotoxic cellso. C-reactive
proteing.Involves B cellsp. Phagosomeh.Involves T cells i. Responds
to extracellular bacterial infection j. Involves secreted antibody
Descriptionsk.Kills virus-infected self-cells (1) Thin outer layer
of skin(2) Layer of skin containing blood v