1.chapter 1I Historical PerspectiveI Innate ImmunityI Adaptive ImmunityI Comparative ImmunityI Immune Dysfunction and Its ConsequencesNumerous T Lymphocytes Interacting with a SingleMacrophageOverview of theImmune SystemT 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 intotwo related activitiesrecognition and response. Immunerecognition is remarkable for its specificity. The immunesystem is able to recognize subtle chemical differences thatdistinguish one foreign pathogen from another. Further-more, the system is able to discriminate between foreignmolecules and the bodys own cells and proteins. Once a for-eign organism has been recognized, the immune systemrecruits a variety of cells and molecules to mount an appro-priate response, called an effector response, to eliminate orneutralize the organism. In this way the system is able toconvert 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-nate the pathogen and prevent disease.This chapter introduces the study of immunology froman historical perspective and presents a broad overview ofthe cells and molecules that compose the immune system,along with the mechanisms they use to protect the bodyagainst 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-ements of the primitive immune system persist in verte-brates as innate immunity along with a more highly evolvedsystem of specific responses termed adaptive immunity.These two systems work in concert to provide a high degreeof protection for vertebrate species. Finally, in some circum-stances, the immune system fails to act as protector becauseof some deficiency in its components; at other times, it be-comes an aggressor and turns its awesome powers against itsown host. In this introductory chapter, our description ofimmunity is simplified to reveal the essential structures andfunction of the immune system. Substantive discussions, ex-perimental approaches, and in-depth definitions are left tothe chapters that follow.Like the later chapters covering basic topics in immu-nology, this one includes a section called Clinical Focusthat describes human disease and its relation to immunity.These sections investigate the causes, consequences, or treat-ments of diseases rooted in impaired or hyperactive immunefunction.Historical PerspectiveThe discipline of immunology grew out of the observationthat individuals who had recovered from certain infectiousdiseases were thereafter protected from the disease. TheLatin term immunis, meaning exempt, is the source of theEnglish word immunity, meaning the state of protectionfrom infectious disease.Perhaps the earliest written reference to the phenomenonof immunity can be traced back to Thucydides, the great his-torian of the Peloponnesian War. In describing a plague inAthens, he wrote in 430 BC that only those who had recov-ered from the plague could nurse the sick because theywould not contract the disease a second time.Although earlysocieties recognized the phenomenon of immunity, almost8536d_ch01_001-023 8/1/02 4:25 PM Page 1 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:Digitally signedby RohitJhawer

2. two thousand years passed before the concept was success-fully converted into medically effective practice.The first recorded attempts to induce immunity deliber-ately were performed by the Chinese and Turks in the fif-teenth century. Various reports suggest that the dried 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 tocholera. Louis Pasteur had succeeded in growing the bac-terium thought to cause fowl cholera in culture and then hadshown 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-came ill, but, to Pasteurs surprise, they recovered. Pasteurthen grew a fresh culture of the bacterium with the intentionof injecting it into some fresh chickens. But, as the story goes,his supply of chickens was limited, and therefore he used thepreviously injected chickens. Again to his surprise, the chick-ens were completely protected from the disease. Pasteurhypothesized and proved that aging had weakened the viru-lence of the pathogen and that such an attenuated strainmight be administered to protect against the disease. Hecalled this attenuated strain a vaccine (from the Latin vacca,meaning cow), in honor of Jenners work with cowpoxinoculation.Pasteur extended these findings to other diseases, demon-strating that it was possible to attenuate, or weaken, apathogen and administer the attenuated strain as a vaccine.In a now classic experiment at Pouilly-le-Fort in 1881, Pas-teur first vaccinated one group of sheep with heat-attenuatedanthrax bacillus (Bacillus anthracis); he then challenged thevaccinated sheep and some unvaccinated sheep with a viru-lent culture of the bacillus.All the vaccinated sheep lived, andall the unvaccinated animals died. These experimentsmarked the beginnings of the discipline of immunology. In1885, Pasteur administered his first vaccine to a human, ayoung boy who had been bitten repeatedly by a rabid dog(Figure 1-1). The boy, Joseph Meister, was inoculated with aseries of attenuated rabies virus preparations. He lived andlater became a custodian at the Pasteur Institute.Early Studies Revealed Humoral and CellularComponents of the Immune SystemAlthough Pasteur proved that vaccination worked, he did notunderstand how. The experimental work of Emil vonBehring and Shibasaburo Kitasato in 1890 gave the first in-sights into the mechanism of immunity, earning von Behringthe Nobel prize in medicine in 1901 (Table 1-1).Von Behringand Kitasato demonstrated that serum (the liquid, noncellu-lar component of coagulated blood) from animals previouslyimmunized to diphtheria could transfer the immune state tounimmunized animals. In search of the protective agent, var-ious researchers during the next decade demonstrated thatan active component from immune serum could neutralizetoxins, precipitate toxins, and agglutinate (clump) bacteria.In each case, the active agent was named for the activity it ex-hibited: antitoxin, precipitin, and agglutinin, respectively.2 P A R T I IntroductionFIGURE 1-1 Wood engraving of Louis Pasteur watching JosephMeister receive the rabies vaccine. [From Harpers Weekly 29:836;courtesy of the National Library of Medicine.]8536d_ch01_001-023 8/1/02 4:25 PM Page 2 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: 3. Initially, a different serum component was thought to be re-sponsible for each activity, but during the 1930s, mainlythrough the efforts of Elvin Kabat, a fraction of serum firstcalled gamma-globulin (now immunoglobulin) was shownto be responsible for all these activities. The active moleculesin the immunoglobulin fraction are called antibodies. Be-cause immunity was mediated by antibodies contained inbody fluids (known at the time as humors), it was called hu-moral immunity.In 1883, even before the discovery that a serum compo-nent could transfer immunity, Elie Metchnikoff demon-strated that cells also contribute to the immune state of ananimal. He observed that certain white blood cells, which hetermed phagocytes, were able to ingest (phagocytose) mi-croorganisms and other foreign material. Noting that thesephagocytic cells were more active in animals that had beenimmunized, Metchnikoff hypothesized that cells, rather thanserum components, were the major effector of immunity.The active phagocytic cells identified by Metchnikoff werelikely blood monocytes and neutrophils (see Chapter 2).In due course, a controversy developed between thosewho held to the concept of humoral immunity and thosewho agreed with Metchnikoffs concept of cell-mediated im-munity. It was later shown that both are correctimmunityrequires both cellular and humoral responses. It was difficultto study the activities of immune cells before the develop-ment of modern tissue culture techniques, whereas studieswith serum took advantage of the ready availability of bloodand established biochemical techniques. Because of thesetechnical problems, information about cellular immunitylagged behind findings that concerned humoral immunity.In a key experiment in the 1940s, Merrill Chase succeededin transferring immunity against the tuberculosis organismby transferring white blood cells between guinea pigs. Thisdemonstration helped to rekindle interest in cellular immu-nity.With the emergence of improved cell culture techniquesin the 1950s, the lymphocyte was identified as the cell re-sponsible for both cellular and humoral immunity. Soonthereafter, experiments with chickens pioneered by BruceGlick at Mississippi State University indicated that there wereOverview of the Immune System C H A P T E R 1 3TABLE 1-1 Nobel Prizes for immunologic researchYear Recipient Country Research1901 Emil von Behring Germany Serum antitoxins1905 Robert Koch Germany Cellular immunity to tuberculosis1908 Elie Metchnikoff Russia Role of phagocytosis (Metchnikoff) andPaul Ehrlich Germany antitoxins (Ehrlich) in immunity1913 Charles Richet France Anaphylaxis1919 Jules Border Belgium Complement-mediated bacteriolysis1930 Karl Landsteiner United States Discovery of human blood groups1951 Max Theiler South Africa Development of yellow fever vaccine1957 Daniel Bovet Switzerland Antihistamines1960 F. Macfarlane Burnet Australia Discovery of acquired immunologicalPeter Medawar Great Britain tolerance1972 Rodney R. Porter Great Britain Chemical structure of antibodiesGerald M. Edelman United States1977 Rosalyn R. Yalow United States Development of radioimmunoassay1980 George Snell United States Major histocompatibility complexJean Daussct FranceBaruj Benacerraf United States1984 Cesar Milstein Great Britain Monoclonal antibodyGeorges E. Khler GermanyNiels K. Jerne Denmark Immune regulatory theories1987 Susumu Tonegawa Japan Gene rearrangement in antibodyproduction1991 E. Donnall Thomas United States Transplantation immunologyJoseph Murray United States1996 Peter C. Doherty Australia Role of major histocompatibility complexRolf M. Zinkernagel Switzerland in antigen recognition by by T cells8536d_ch01_001-023 8/1/02 4:25 PM Page 3 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: 4. two types of lymphocytes: T lymphocytes derived from thethymus mediated cellular immunity, and B lymphocytesfrom the bursa of Fabricius (an outgrowth of the cloaca inbirds) were involved in humoral immunity. The controversyabout the roles of humoral and cellular immunity was re-solved when the two systems were shown to be intertwined,and that both systems were necessary for the immuneresponse.Early Theories Attempted to Explainthe Specificity of the AntibodyAntigen InteractionOne of the greatest enigmas facing early immunologists wasthe specificity of the antibody molecule for foreign material,or antigen (the general term for a substance that binds witha specific antibody).Around 1900, Jules Bordet at the PasteurInstitute expanded the concept of immunity by demonstrat-ing specific immune reactivity to nonpathogenic substances,such as red blood cells from other species. Serum from an an-imal inoculated previously with material that did not causeinfection would react with this material in a specific manner,and this reactivity could be passed to other animals by trans-ferring serum from the first. The work of Karl Landsteinerand those who followed him showed that injecting an animalwith almost any organic chemical could induce productionof antibodies that would bind specifically to the chemical.These studies demonstrated that antibodies have a capacityfor an almost unlimited range of reactivity, including re-sponses to compounds that had only recently been synthe-sized in the laboratory and had not previously existed innature. In addition, it was shown that molecules differing inthe smallest detail could be distinguished by their reactivitywith different antibodies. Two major theories were proposedto account for this specificity: the selective theory and the in-structional theory.The earliest conception of the selective theory dates to PaulEhrlich in 1900. In an attempt to explain the origin of serumantibody, Ehrlich proposed that cells in the blood expressed avariety of receptors, which he called side-chain receptors,that could react with infectious agents and inactivate them.Borrowing a concept used by Emil Fischer in 1894 to explainthe interaction between an enzyme and its substrate, Ehrlichproposed that binding of the receptor to an infectious agentwas like the fit between a lock and key. Ehrlich suggested thatinteraction between an infectious agent and a cell-boundreceptor would induce the cell to produce and release morereceptors with the same specificity. According to Ehrlichstheory, the specificity of the receptor was determined beforeits exposure to antigen, and the antigen selected the appro-priate receptor. Ultimately all aspects of Ehrlichs theorywould be proven correct with the minor exception that thereceptorexists as both a soluble antibody molecule and as acell-bound receptor; it is the soluble form that is secretedrather than the bound form released.In the 1930s and 1940s, the selective theory was chal-lenged by various instructional theories, in which antigenplayed a central role in determining the specificity of the an-tibody molecule. According to the instructional theories, aparticular antigen would serve as a template around whichantibody would fold. The antibody molecule would therebyassume a configuration complementary to that of the antigentemplate. This concept was first postulated by FriedrichBreinl and Felix Haurowitz about 1930 and redefined in the1940s in terms of protein folding by Linus Pauling. The in-structional theories were formally disproved in the 1960s, bywhich time information was emerging about the structure ofDNA, RNA, and protein that would offer new insights intothe vexing problem of how an individual could make anti-bodies against almost anything.In the 1950s, selective theories resurfaced as a result ofnew experimental data and, through the insights of NielsJerne, David Talmadge, and F. Macfarlane Burnet, were re-fined into a theory that came to be known as the clonal-selection theory. According to this theory, an individuallymphocyte expresses membrane receptors that are specificfor a distinct antigen. This unique receptor specificity is de-termined before the lymphocyte is exposed to the antigen.Binding of antigen to its specific receptor activates the cell,causing it to proliferate into a clone of cells that have thesame immunologic specificity as the parent cell. The clonal-selection theory has been further refined and is now acceptedas the underlying paradigm of modern immunology.The Immune System Includes Innate andAdaptive ComponentsImmunitythe state of protection from infectious diseasehas both a less specific and more specific component. Theless specific component, innate immunity, provides the firstline of defense against infection. Most components of innateimmunity are present before the onset of infection and con-stitute a set of disease-resistance mechanisms that are notspecific to a particular pathogen but that include cellular andmolecular components that recognize classes of moleculespeculiar to frequently encountered pathogens. Phagocyticcells, such as macrophages and neutrophils, barriers such asskin, and a variety of antimicrobial compounds synthesizedby the host all play important roles in innate immunity. Incontrast to the broad reactivity of the innate immune sys-tem, which is uniform in all members of a species, the spe-cific component, adaptive immunity, does not come intoplay until there is an antigenic challenge to the organism.Adaptive immunity responds to the challenge with a high de-gree of specificity as well as the remarkable property ofmemory. Typically, there is an adaptive immune responseagainst an antigen within five or six days after the initial ex-posure to that antigen. Exposure to the same antigen sometime in the future results in a memory response: the immuneresponse to the second challenge occurs more quickly than4 P A R T I Introduction8536d_ch01_001-023 8/1/02 4:25 PM Page 4 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: 5. the first, is stronger, and is often more effective in neutraliz-ing and clearing the pathogen. The major agents of adaptiveimmunity are lymphocytes and the antibodies and othermolecules they produce.Because adaptive immune responses require some time tomarshal, innate immunity provides the first line of defenseduring the critical period just after the hosts exposure to apathogen. In general, most of the microorganisms encoun-tered by a healthy individual are readily cleared within a fewdays by defense mechanisms of the innate immune systembefore they activate the adaptive immune system.Innate ImmunityInnate immunity can be seen to comprise four types of de-fensive barriers: anatomic, physiologic, phagocytic, and in-flammatory (Table 1-2).The Skin and the Mucosal Surfaces ProvideProtective Barriers Against InfectionPhysical and anatomic barriers that tend to prevent the entryof pathogens are an organisms first line of defense against in-fection. The skin and the surface of mucous membranes areincluded in this category because they are effective barriers tothe entry of most microorganisms. The skin consists of twodistinct layers: a thinner outer layerthe epidermisand athicker layerthe dermis. The epidermis contains severallayers of tightly packed epithelial cells. The outer epidermallayer consists of dead cells and is filled with a waterproofingprotein called keratin. The dermis, which is composed ofconnective tissue, contains blood vessels, hair follicles, seba-ceous glands, and sweat glands. The sebaceous glands are as-sociated with the hair follicles and produce an oily secretioncalled sebum. Sebum consists of lactic acid and fatty acids,which maintain the pH of the skin between 3 and 5; this pHinhibits the growth of most microorganisms. A few bacteriathat metabolize sebum live as commensals on the skin andsometimes cause a severe form of acne. One acne drug,isotretinoin (Accutane), is a vitamin A derivative that pre-vents the formation of sebum.Breaks in the skin resulting from scratches, wounds, orabrasion are obvious routes of infection. The skin may alsobe penetrated by biting insects (e.g., mosquitoes, mites, ticks,fleas, and sandflies); if these harbor pathogenic organisms,they can introduce the pathogen into the body as they feed.The protozoan that causes malaria, for example, is depositedin humans by mosquitoes when they take a blood meal. Sim-ilarly, bubonic plague is spread by the bite of fleas, and Lymedisease is spread by the bite of ticks.The conjunctivae and the alimentary, respiratory, andurogenital tracts are lined by mucous membranes, not by thedry, protective skin that covers the exterior of the body. TheseOverview of the Immune System C H A P T E R 1 5TABLE 1-2 Summary of nonspecific host defensesType MechanismAnatomic barriersSkin Mechanical barrier retards entry of microbes.Acidic environment (pH 35) retards growth of microbes.Mucous membranes Normal flora compete with microbes for attachment sites and nutrients.Mucus entraps foreign microorganisms.Cilia propel microorganisms out of body.Physiologic barriersTemperature Normal body temperature inhibits growth of some pathogens.Fever response inhibits growth of some pathogens.Low pH Acidity of stomach contents kills most ingested microorganisms.Chemical mediators Lysozyme cleaves bacterial cell wall.Interferon induces antiviral state in uninfected cells.Complement lyses microorganisms or facilitates phagocytosis.Toll-like receptors recognize microbial molecules, signal cell to secrete immunostimulatory cytokines.Collectins disrupt cell wall of pathogen.Phagocytic/endocytic barriers Various cells internalize (endocytose) and break down foreign macromolecules.Specialized cells (blood monocytes, neutrophils, tissue macrophages) internalize(phagocytose), kill, and digest whole microorganisms.Inflammatory barriers Tissue damage and infection induce leakage of vascular fluid, containing serum proteins withantibacterial activity, and influx of phagocytic cells into the affected area.8536d_ch01_001-023 8/1/02 4:25 PM Page 5 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: 6. membranes consist of an outer epithelial layer and an under-lying layer of connective tissue. Although many pathogensenter the body by binding to and penetrating mucous mem-branes, a number of nonspecific defense mechanisms tend toprevent this entry. For example, saliva, tears, and mucous se-cretions act to wash away potential invaders and also containantibacterial or antiviral substances. The viscous fluid calledmucus, which is secreted by epithelial cells of mucous mem-branes, entraps foreign microorganisms. In the lower respi-ratory tract, the mucous membrane is covered by cilia,hairlike protrusions of the epithelial-cell membranes. Thesynchronous movement of cilia propels mucus-entrappedmicroorganisms from these tracts. In addition, nonpatho-genic organisms tend to colonize the epithelial cells of mu-cosal surfaces. These normal flora generally outcompetepathogens for attachment sites on the epithelial cell surfaceand for necessary nutrients.Some organisms have evolved ways of escaping these de-fense mechanisms and thus are able to invade the bodythrough mucous membranes. For example, influenza virus(the agent that causes flu) has a surface molecule that enablesit to attach firmly to cells in mucous membranes of the respi-ratory tract, preventing the virus from being swept out by theciliated epithelial cells. Similarly, the organism that causesgonorrhea has surface projections that allow it to bind to ep-ithelial cells in the mucous membrane of the urogenital tract.Adherence of bacteria to mucous membranes is due to inter-actions between hairlike protrusions on a bacterium, calledfimbriae or pili, and certain glycoproteins or glycolipids thatare expressed only by epithelial cells of the mucous mem-brane of particular tissues (Figure 1-2). For this reason, sometissues are susceptible to bacterial invasion, whereas othersare not.Physiologic Barriers to Infection IncludeGeneral Conditions and Specific MoleculesThe physiologic barriers that contribute to innate immu-nity include temperature, pH, and various soluble and cell-associated molecules.Many species are not susceptible to cer-tain diseases simply because their normal body temperatureinhibits growth of the pathogens. Chickens, for example,have innate immunity to anthrax because their high bodytemperature inhibits the growth of the bacteria. Gastric acid-ity is an innate physiologic barrier to infection because veryfew ingested microorganisms can survive the low pH of thestomach contents. One reason newborns are susceptible tosome diseases that do not afflict adults is that their stomachcontents are less acid than those of adults.A variety of soluble factors contribute to innate immu-nity, among them the soluble proteins lysozyme, interferon,and complement. Lysozyme, a hydrolytic enzyme found inmucous secretions and in tears, is able to cleave the peptido-glycan layer of the bacterial cell wall. Interferon comprises agroup of proteins produced by virus-infected cells. Amongthe many functions of the interferons is the ability to bind tonearby cells and induce a generalized antiviral state.Comple-ment, examined in detail in Chapter 13, is a group of serumproteins that circulate in an inactive state. A variety of spe-cific and nonspecific immunologic mechanisms can convertthe inactive forms of complement proteins into an activestate 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 effectorsystem that is triggered by binding of antibodies to certaincell surfaces, or it may be activated by reactions betweencomplement molecules and certain components of microbialcell walls. Reactions between complement molecules or frag-ments of complement molecules and cellular receptors trig-ger activation of cells of the innate or adaptive immunesystems. 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 thebacteria to enhance their susceptibility to phagocytosis.Many of the molecules involved in innate immunity havethe property of pattern recognition, the ability to recognize agiven 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 andcombat invaders displaying such molecules is a strong featureof innate immunity. Molecules with pattern recognition abilitymay be soluble, like lysozyme and the complement compo-nents described above,or they may be cell-associated receptors.Among the class of receptors designated the toll-like receptors(TLRs), TLR2 recognizes the lipopolysaccharide (LPS) foundon Gram-negative bacteria. It has long been recognized that6 P A R T I IntroductionFIGURE 1-2 Electron micrograph of rod-shaped Escherichia colibacteria adhering to surface of epithelial cells of the urinary tract.[From N. Sharon and H. Lis, 1993, Sci. Am. 268(1):85; photographcourtesy of K. Fujita.]8536d_ch01_001-023 8/1/02 4:25 PM Page 6 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: 7. 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.Cells That Ingest and Destroy PathogensMake Up a Phagocytic Barrier to InfectionAnother important innate defense mechanism is the inges-tion of extracellular particulate material by phagocytosis.Phagocytosis is one type of endocytosis, the general term forthe uptake by a cell of material from its environment. Inphagocytosis, a cells plasma membrane expands around theparticulate material, which may include whole pathogenicmicroorganisms, to form large vesicles called phagosomes(Figure 1-3). Most phagocytosis is conducted by specializedcells, such as blood monocytes, neutrophils, and tissuemacrophages (see Chapter 2). Most cell types are capable ofother forms of endocytosis, such as receptor-mediated endo-cytosis, in which extracellular molecules are internalized afterbinding by specific cellular receptors, and pinocytosis, theprocess by which cells take up fluid from the surroundingmedium along with any molecules contained in it.Inflammation Represents a ComplexSequence of Events That StimulatesImmune ResponsesTissue damage caused by a wound or by an invading patho-genic microorganism induces a complex sequence of eventscollectively known as the inflammatory response. As de-scribed above, a molecular component of a microbe, such asLPS, may trigger an inflammatory response via interactionwith cell surface receptors. The end result of inflammationmay be the marshalling of a specific immune response to theinvasion or clearance of the invader by components of theinnate immune system. Many of the classic features of theinflammatory response were described as early as 1600 BC, inEgyptian papyrus writings. In the first century AD, theRoman physician Celsus described the four cardinal signsOverview of the Immune System C H A P T E R 1 7FIGURE 1-3 (a) Electronmicrograph of macrophage (pink) attack-ing Escherichia coli (green). The bacteria are phagocytized as de-scribed in part b and breakdown products secreted. The monocyte(purple) has been recruited to the vicinity of the encounter by 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.]Bacterium becomes attachedto membrane evaginationscalled pseudopodiaBacterium is ingested,forming phagosomePhagosome fuses withlysosomeLysosomal enzymes digestcaptured materialDigestion products arereleased from cell32451(a)(b)of inflammation as rubor (redness), tumor (swelling),calor (heat), and dolor (pain). In the second century AD, an-other physician, Galen, added a fifth sign: functio laesa (lossof function). The cardinal signs of inflammation reflect thethree major events of an inflammatory response (Figure 1-4):1. Vasodilationan increase in the diameter of bloodvesselsof nearby capillaries occurs as the vessels thatcarry blood away from the affected area constrict,resulting in engorgement of the capillary network. Theengorged capillaries are responsible for tissue redness(erythema) and an increase in tissue temperature.8536d_ch01_007 9/5/02 11:47 AM Page 7 mac46 mac46:385_reb: 8. 2. An increase in capillary permeability facilitates an influxof fluid and cells from the engorged capillaries into thetissue. The fluid that accumulates (exudate) has a muchhigher protein content than fluid normally released fromthe vasculature. Accumulation of exudate contributes totissue swelling (edema).3. Influx of phagocytes from the capillaries into the tissues isfacilitated by the increased permeability of the capil-laries. The emigration of phagocytes is a multistepprocess that includes adherence of the cells to theendothelial wall of the blood vessels (margination),followed by their emigration between the capillary-endothelial cells into the tissue (diapedesis or extrava-sation), and, finally, their migration through the tissue tothe site of the invasion (chemotaxis). As phagocytic cellsaccumulate at the site and begin to phagocytose bacteria,they release lytic enzymes, which can damage nearbyhealthy cells. The accumulation of dead cells, digestedmaterial, and fluid forms a substance called pus.The events in the inflammatory response are initiated by acomplex series of events involving a variety of chemical me-diators whose interactions are only partly understood. Someof these mediators are derived from invading microorgan-isms,some are released from damaged cells in response to tis-sue injury, some are generated by several plasma enzyme sys-tems, and some are products of various white blood cellsparticipating in the inflammatory response.Among the chemical mediators released in response to tis-sue damage are various serum proteins called acute-phaseproteins. The concentrations of these proteins increase dra-matically in tissue-damaging infections. C-reactive protein isa major acute-phase protein produced by the liver in re-sponse to tissue damage. Its name derives from its pattern-recognition activity: C-reactive protein binds to theC-polysaccharide cell-wall component found on a variety ofbacteria and fungi. This binding activates the complementsystem, resulting in increased clearance of the pathogen ei-ther by complement-mediated lysis or by a complement-mediated increase in phagocytosis.One of the principal mediators of the inflammatory re-sponse is histamine, a chemical released by a variety of cellsin response to tissue injury. Histamine binds to receptors onnearby capillaries and venules, causing vasodilation and in-creased permeability. Another important group of inflam-matory mediators, small peptides called kinins, are normallypresent in blood plasma in an inactive form. Tissue injury ac-tivates these peptides, which then cause vasodilation and in-8 P A R T I IntroductionTissue damage causes release ofvasoactive and chemotactic factorsthat trigger a local increase in bloodflow and capillary permeabilityPermeable capillaries allow aninflux of fluid (exudate) and cellsPhagocytes and antibacterialexudate destroy bacteriaPhagocytes migrate to site ofinflammation (chemotaxis)2134Exudate(complement, antibody,C-reactive protein)CapillaryMargination ExtravasationTissue damageBacteriaFIGURE 1-4 Major events in the inflammatory response. A bacte-rial infection causes tissue damage with release of various vasoactiveand chemotactic factors. These factors induce increased blood flowto the area, increased capillary permeability, and an influx of whiteblood cells, including phagocytes and lymphocytes, from the bloodinto the tissues. The serum proteins contained in the exudate haveantibacterial properties, and the phagocytes begin to engulf the bac-teria, as illustrated in Figure 1-3.8536d_ch01_001-023 8/1/02 4:25 PM Page 8 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: 9. creased permeability of capillaries. A particular kinin, calledbradykinin, also stimulates pain receptors in the skin. Thiseffect probably serves a protective role, because pain nor-mally causes an individual to protect the injured area.Vasodilation and the increase in capillary permeability inan injured tissue also enable enzymes of the blood-clottingsystem to enter the tissue. These enzymes activate an enzymecascade that results in the deposition of insoluble strands offibrin, which is the main component of a blood clot. The fib-rin strands wall off the injured area from the rest of the bodyand serve to prevent the spread of infection.Once the inflammatory response has subsided and mostof the debris has been cleared away by phagocytic cells, tissuerepair and regeneration of new tissue begins. Capillariesgrow into the fibrin of a blood clot. New connective tissuecells, called fibroblasts, replace the fibrin as the clot dissolves.As fibroblasts and capillaries accumulate, scar tissue forms.The inflammatory response is described in more detail inChapter 15.Adaptive ImmunityAdaptive immunity is capable of recognizing and selectivelyeliminating specific foreign microorganisms and molecules(i.e., foreign antigens). Unlike innate immune responses,adaptive immune responses are not the same in all membersof a species but are reactions to specific antigenic challenges.Adaptive immunity displays four characteristic attributes:I Antigenic specificityI DiversityI Immunologic memoryI Self/nonself recognitionThe antigenic specificity of the immune system permits it todistinguish subtle differences among antigens. Antibodiescan distinguish between two protein molecules that differ inonly a single amino acid. The immune system is capable ofgenerating tremendous diversity in its recognition molecules,allowing it to recognize billions of unique structures on for-eign antigens. Once the immune system has recognized andresponded to an antigen, it exhibits immunologic memory;that is, a second encounter with the same antigen induces aheightened state of immune reactivity. Because of this at-tribute, the immune system can confer life-long immunity tomany infectious agents after an initial encounter. Finally, theimmune system normally responds only to foreign antigens,indicating that it is capable of self/nonself recognition. Theability of the immune system to distinguish self from nonselfand respond only to nonself molecules is essential, for, as de-scribed below, the outcome of an inappropriate response toself molecules can be fatal.Adaptive immunity is not independent of innate immu-nity. The phagocytic cells crucial to nonspecific immune re-sponses are intimately involved in activating the specific im-mune response. Conversely, various soluble factors producedby a specific immune response have been shown to augmentthe activity of these phagocytic cells. As an inflammatory re-sponse develops, for example, soluble mediators are pro-duced that attract cells of the immune system. The immuneresponse will, in turn, serve to regulate the intensity of the in-flammatory response. Through the carefully regulated inter-play of adaptive and innate immunity, the two systems worktogether to eliminate a foreign invader.The Adaptive Immune System RequiresCooperation Between Lymphocytes andAntigen-Presenting CellsAn effective immune response involves two major groups ofcells: T lymphocytes and antigen-presenting cells. Lympho-cytes are one of many types of white blood cells produced inthe bone marrow by the process of hematopoiesis (see Chap-ter 2). Lymphocytes leave the bone marrow, circulate in theblood and lymphatic systems, and reside in various lym-phoid organs. Because they produce and display antigen-binding cell-surface receptors, lymphocytes mediate thedefining immunologic attributes of specificity, diversity,memory, and self/nonself recognition. The two major popu-lations of lymphocytesB lymphocytes (B cells) and T lym-phocytes (T cells)are described briefly here and in greaterdetail in later chapters.B LYMPHOCYTESB lymphocytes mature within the bone marrow; when theyleave it, each expresses a unique antigen-binding receptor onits membrane (Figure 1-5a). This antigen-binding or B-cellreceptor is a membrane-bound antibody molecule. Anti-bodies are glycoproteins that consist of two identical heavypolypeptide chains and two identical light polypeptidechains. Each heavy chain is joined with a light chain by disul-fide bonds, and additional disulfide bonds hold the two pairstogether. The amino-terminal ends of the pairs of heavy andlight chains form a cleft within which antigen binds. When anaive B cell (one that has not previously encountered anti-gen) first encounters the antigen that matches its membrane-bound antibody, the binding of the antigen to the antibodycauses the cell to divide rapidly; its progeny differentiate intomemory B cells and effector B cells called plasma cells.Memory B cells have a longer life span than naive cells, andthey express the same membrane-bound antibody as theirparent B cell. Plasma cells produce the antibody in a formthat can be secreted and have little or no membrane-boundantibody. Although plasma cells live for only a few days, theysecrete enormous amounts of antibody during this time.It has been estimated that a single plasma cell can secretemore than 2000 molecules of antibody per second. Secretedantibodies are the major effector molecules of humoralimmunity.Overview of the Immune System C H A P T E R 1 98536d_ch01_001-023 8/1/02 4:25 PM Page 9 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: 10. T LYMPHOCYTEST lymphocytes also arise in the bone marrow. Unlike B cells,which mature within the bone marrow, T cells migrate to thethymus gland to mature. During its maturation within thethymus, the T cell comes to express a unique antigen-bindingmolecule,called the T-cell receptor, on its membrane.Unlikemembrane-bound antibodies on B cells, which can recognizeantigen alone, T-cell receptors can recognize only antigenthat is bound to cell-membrane proteins called major histo-compatibility complex (MHC) molecules. MHC moleculesthat function in this recognition event,which is termedanti-gen presentation, are polymorphic (genetically diverse) gly-coproteins found on cell membranes (see Chapter 7). Thereare two major types of MHC molecules: Class I MHC mole-cules, which are expressed by nearly all nucleated cells of ver-tebrate species, consist of a heavy chain linked to a smallinvariant protein called 2-microglobulin. Class II MHCmolecules, which consist of an alpha and a beta glycoproteinchain, are expressed only by antigen-presenting cells.When anaive T cell encounters antigen combined with a MHC mol-ecule on a cell, the T cell proliferates and differentiates intomemory T cells and various effector T cells.There are two well-defined subpopulations of T cells: Thelper (TH) and T cytotoxic (TC) cells. Although a third typeof T cell, called a T suppressor (TS) cell, has been postulated,recent evidence suggests that it may not be distinct from THand TC subpopulations. T helper and T cytotoxic cells can bedistinguished from one another by the presence of eitherCD4 or CD8 membrane glycoproteins on their surfaces (Fig-ure 1-5b,c). T cells displaying CD4 generally function as THcells, whereas those displaying CD8 generally function as TCcells (see Chapter 2).After a TH cell recognizes and interacts with an anti-genMHC class II molecule complex, the cell is activateditbecomes an effector cell that secretes various growth factorsknown collectively as cytokines. The secreted cytokines playan important role in activating B cells, TC cells, macrophages,and various other cells that participate in the immune re-sponse. Differences in the pattern of cytokines produced byactivated TH cells result in different types of immuneresponse.Under the influence of TH-derived cytokines, a TC cellthat recognizes an antigenMHC class I molecule complexproliferates and differentiates into an effector cell called a cy-totoxic T lymphocyte (CTL). In contrast to the TC cell, theCTL generally does not secrete many cytokines and insteadexhibits cell-killing or cytotoxic activity. The CTL has a vitalfunction in monitoring the cells of the body and eliminatingany that display antigen, such as virus-infected cells, tumorcells, and cells of a foreign tissue graft. Cells that display for-eign antigen complexed with a class I MHC molecule arecalled altered self-cells; these are targets of CTLs.ANTIGEN-PRESENTING CELLSActivation of both the humoral and cell-mediated branchesof the immune system requires cytokines produced by THcells. It is essential that activation of TH cells themselves becarefully regulated, because an inappropriate T-cell responseto self-components can have fatal autoimmune conse-quences. To ensure carefully regulated activation of TH cells,they can recognize only antigen that is displayed togetherwith class MHC II molecules on the surface of antigen-pre-senting cells (APCs). These specialized cells, which includemacrophages, B lymphocytes, and dendritic cells, are distin-guished by two properties: (1) they express class II MHCmolecules on their membranes, and (2) they are able todeliver a co-stimulatory signal that is necessary for TH-cellactivation.Antigen-presenting cells first internalize antigen, either byphagocytosis or by endocytosis, and then display a part ofthat antigen on their membrane bound to a class II MHCmolecule. The TH cell recognizes and interacts with the10 P A R T I Introduction(a) B cellAntigen-bindingreceptor(antibody)(b) TH cell (c) TC cellCD4 TCR CD8TCRFIGURE 1-5 Distinctive membrane molecules on lymphocytes. (a)B cells have about 105molecules of membrane-bound antibody percell. All the antibody molecules on a given B cell have the same anti-genic specificity and can interact directly with antigen. (b) T cellsbearing CD4 (CD4+cells) recognize only antigen bound to class IIMHC molecules. (c) T cells bearing CD8 (CD8+cells) recognize onlyantigen associated with class I MHC molecules. In general, CD4+cells act as helper cells and CD8+cells act as cytotoxic cells. Bothtypes of T cells express about 105identical molecules of the antigen-binding T-cell receptor (TCR) per cell, all with the same antigenicspecificity.8536d_ch01_001-023 8/1/02 4:25 PM Page 10 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: 11. antigenclass II MHC molecule complex on the membraneof the antigen-presenting cell (Figure 1-6). An additional co-stimulatory signal is then produced by the antigen-present-ing cell, leading to activation of the TH cell.Humoral Immunity But Not CellularImmunity Is Transferredwith AntibodyAs mentioned earlier, immune responses can be divided intohumoral and cell-mediated responses. Humoral immunityrefers to immunity that can be conferred upon a nonimmuneindividual by administration of serum antibodies from animmune individual. In contrast, cell-mediated immunity canbe transferred only by administration of T cells from an im-mune individual.The humoral branch of the immune system is at work inthe interaction of B cells with antigen and their subsequentproliferation and differentiation into antibody-secretingplasma cells (Figure 1-7). Antibody functions as the effectorof the humoral response by binding to antigen and neutraliz-ing it or facilitating its elimination. When an antigen iscoated with antibody, it can be eliminated in several ways.For example, antibody can cross-link several antigens, form-ing clusters that are more readily ingested by phagocytic cells.Binding of antibody to antigen on a microorganism can alsoactivate the complement system, resulting in lysis of the for-eign organism. Antibody can also neutralize toxins or viralparticles by coating them, which prevents them from bindingto host cells.Effector T cells generated in response to antigen are re-sponsible for cell-mediated immunity (see Figure 1-7). Bothactivated TH cells and cytotoxic T lymphocytes (CTLs) serveas effector cells in cell-mediated immune reactions. Cy-tokines secreted by TH cells can activate various phagocyticcells, enabling them to phagocytose and kill microorganismsmore effectively. This type of cell-mediated immune re-sponse is especially important in ridding the host of bacteriaand protozoa contained by infected host cells. CTLs partici-pate in cell-mediated immune reactions by killing alteredself-cells; they play an important role in the killing of virus-infected cells and tumor cells.Antigen Is Recognized Differently byB and T LymphocytesAntigens, which are generally very large and complex, are notrecognized in their entirety by lymphocytes. Instead, both Band T lymphocytes recognize discrete sites on the antigencalled antigenic determinants, or epitopes. Epitopes are theimmunologically active regions on a complex antigen, the re-gions that actually bind to B-cell or T-cell receptors.Although B cells can recognize an epitope alone, T cellscan recognize an epitope only when it is associated with anMHC molecule on the surface of a self-cell (either an anti-gen-presenting cell or an altered self-cell). Each branch of theimmune system is therefore uniquely suited to recognizeantigen in a different milieu. The humoral branch (B cells)recognizes an enormous variety of epitopes: those displayedon the surfaces of bacteria or viral particles, as well as thosedisplayed on soluble proteins, glycoproteins, polysaccha-rides, or lipopolysaccharides that have been released from in-vading pathogens. The cell-mediated branch (T cells)recognizes protein epitopes displayed together with MHCmolecules on self-cells, including altered self-cells such asvirus-infected self-cells and cancerous cells.Thus, four related but distinct cell-membrane moleculesare responsible for antigen recognition by the immunesystem:I Membrane-bound antibodies on B cellsI T-cell receptorsI Class I MHC moleculesI Class II MHC moleculesEach of these molecules plays a unique role in antigen recog-nition, ensuring that the immune system can recognize andrespond to the different types of antigen that it encounters.B and T Lymphocytes Utilize SimilarMechanisms To Generate Diversityin Antigen ReceptorsThe antigenic specificity of each B cell is determined by themembrane-bound antigen-binding receptor (i.e., antibody)expressed by the cell. As a B cell matures in the bone marrow,its specificity is created by random rearrangements of a seriesOverview of the Immune System C H A P T E R 1 11FIGURE 1-6 Electron micrograph of an antigen-presenting macro-phage (right) associating with a T lymphocyte. [From A. S. Rosenthalet al., 1982, in PhagocytosisPast and Future, Academic Press, p.239.]8536d_ch01_001-023 8/1/02 4:25 PM Page 11 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: 12. 12 P A R T I IntroductionV I S U A L I Z I N G C O N C E P T SFIGURE 1-7 Overview of the humoral and cell-mediatedbranches of the immune system. In the humoral response, B cellsinteract with antigen and then differentiate into antibody-secret-ing plasma cells. The secreted antibody binds to the antigen andfacilitates its clearance from the body. In the cell-mediated re-sponse, various subpopulations of T cells recognize antigen pre-sented on self-cells. TH cells respond to antigen by producing cy-tokines. TC cells respond to antigen by developing into cytotoxic Tlymphocytes (CTLs), which mediate killing of altered self-cells(e.g., virus-infected cells).B cell Ab-secretingplasma cells+AntigenActivatedTH cellTC cellTH cellCytotoxic T lymphocyte (CTL)Class IMHCClass IIMHCInternalized antigendigested by cell1T cell receptorsrecognize antigen boundto MHC moleculesAltered self-cellpresents antigen3Binding antigen-MHCactivates T cells2Activated CTLsrecognize and killaltered self-cells4Activated TH cell secretescytokines that contribute toactivation of B cells, TC cells,and other cells5B cells interact with antigenand differentiate intoantibody-secreting plasma cells7Antibody binds antigenand facilitates its clearancefrom the body86AntigensBacteriaVirusesForeignproteinsParasites FungiCell-mediated responseHumoral response8536d_ch01_001-023 8/1/02 4:25 PM Page 12 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: 13. of gene segments that encode the antibody molecule (seeChapter 5).As a result of this process, each mature B cell pos-sesses a single functional gene encoding the antibody heavychain and a single functional gene encoding the antibodylight chain; the cell therefore synthesizes and displays anti-body with one specificity on its membrane. All antibodymolecules on a given B lymphocyte have identical specificity,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 beantigenically committed.The random gene rearrangements during B-cell matura-tion in the bone marrow generate an enormous number ofdifferent antigenic specificities. The resulting B-cell popula-tion, which consists of individual B cells each expressing aunique antibody, is estimated to exhibit collectively morethan 1010different antigenic specificities. The enormous di-versity in the mature B-cell population is later reduced by aselection process in the bone marrow that eliminates any Bcells with membrane-bound antibody that recognizes self-components. The selection process helps to ensure that self-reactive antibodies (auto-antibodies) are not produced.The attributes of specificity and diversity also characterizethe antigen-binding T-cell receptor (TCR) on T cells.As in B-cell maturation, the process of T-cell maturation includesrandom rearrangements of a series of gene segments that en-code the cells antigen-binding receptor (see Chapter 9).EachT lymphocyte cell expresses about 105receptors, and all ofthe receptors on the cell and its clonal progeny have identicalspecificity for antigen. The random rearrangement of theTCR genes is capable of generating on the order of 109unique antigenic specificities. This enormous potential di-versity is later diminished through a selection process in thethymus that eliminates any T cell with self-reactive receptorsand ensures that only T cells with receptors capable of recog-nizing antigen associated with MHC molecules will be ableto mature (see Chapter 10).The Major Histocompatibility MoleculesBind Antigenic PeptidesThe major histocompatibility complex (MHC) is a large ge-netic complex with multiple loci. The MHC loci encode twomajor classes of membrane-bound glycoproteins: class I andclass II MHC molecules. As noted above, TH cells generallyrecognize antigen combined with class II molecules, whereasTC cells generally recognize antigen combined with class Imolecules (Figure 1-8).MHC molecules function as antigen-recognition mole-cules, but they do not possess the fine specificity for antigencharacteristic of antibodies and T-cell receptors. Rather, eachMHC molecule can bind to a spectrum of antigenic peptidesderived from the intracellular degradation of antigen mole-cules. In both class I and class II MHC molecules the distalregions (farthest from the membrane) of different alleles dis-play wide variation in their amino acid sequences. Thesevariable regions form a cleft within which the antigenic pep-tide sits and is presented to T lymphocytes (see Figure 1-8).Different allelic forms of the genes encoding class I and classOverview of the Immune System C H A P T E R 1 13Antigen-presenting cellTH cellTH cellVirus-infected cellTC cellTC cellAntigenicpeptideClass IMHCClass IIMHCCD8T cellreceptorCD4FIGURE 1-8 The role of MHC molecules in antigen recognition byT cells. (a) Class I MHC molecules are expressed on nearly all nucle-ated cells. Class II MHC molecules are expressed only on antigen-presenting cells. T cells that recognize only antigenic peptidesdisplayed with a class II MHC molecule generally function as T helper(TH) cells. T cells that recognize only antigenic peptides displayedwith a class I MHC molecule generally function as T cytotoxic (TC)cells. (b) This scanning electron micrograph reveals numerous Tlymphocytes interacting with a single macrophage. The macrophagepresents processed antigen combined with class II MHC moleculesto the T cells. [Photograph from W. E. Paul (ed.), 1991, Immunology:Recognition and Response, W. H. Freeman and Company, New York;micrograph courtesy of M. H. Nielsen and O. Werdelin.](b)(a)8536d_ch01_013 9/5/02 11:48 AM Page 13 mac46 mac46:385_reb: 14. II molecules confer different structures on the antigen-bind-ing cleft with different specificity. Thus the ability to presentan antigen to T lymphocytes is influenced by the particularset of alleles that an individual inherits.Complex Antigens Are Degraded (Processed)and Displayed (Presented) with MHCMolecules on the Cell SurfaceIn order for a foreign protein antigen to be recognized by a Tcell, it must be degraded into small antigenic peptides thatform complexes with class I or class II MHC molecules. Thisconversion of proteins into MHC-associated peptide frag-ments is called antigen processing and presentation. Whether aparticular antigen will be processed and presented togetherwith class I MHC or class II MHC molecules appears to bedetermined by the route that the antigen takes to enter a cell(Figure 1-9).Exogenous antigen is produced outside of the host celland enters the cell by endocytosis or phagocytosis. Antigen-presenting cells (macrophages, dendritic cells, and B cells)degrade ingested exogenous antigen into peptide fragmentswithin the endocytic processing pathway. Experiments sug-gest that class II MHC molecules are expressed within the en-docytic processing pathway and that peptides produced bydegradation of antigen in this pathway bind to the cleftwithin the class II MHC molecules. The MHC moleculesbearing the peptide are then exported to the cell surface.Since expression of class II MHC molecules is limited to anti-gen-presenting cells, presentation of exogenous peptideclass II MHC complexes is limited to these cells. T cells dis-playing CD4 recognize antigen combined with class II MHCmolecules and thus are said to be class II MHC restricted.These cells generally function as T helper cells.Endogenous antigen is produced within the host cell it-self. Two common examples are viral proteins synthesizedwithin virus-infected host cells and unique proteins synthe-sized by cancerous cells. Endogenous antigens are degradedinto peptide fragments that bind to class I MHC moleculeswithin the endoplasmic reticulum. The peptideclass I MHCcomplex is then transported to the cell membrane. Since allnucleated cells express class I MHC molecules, all cells pro-ducing endogenous antigen use this route to process the anti-gen. T cells displaying CD8 recognize antigen associated withclass I MHC molecules and thus are said to be class I MHC re-stricted. These cytotoxic T cells attack and kill cells displayingthe antigenMHC class I complexes for which their receptorsare specific.Antigen Selection of LymphocytesCauses Clonal ExpansionA mature immunocompetent animal contains a large num-ber of antigen-reactive clones of T and B lymphocytes; theantigenic specificity of each of these clones is determined bythe specificity of the antigen-binding receptor on the mem-14 P A R T I IntroductionFIGURE 1-9 Processing and presentation of exogenous and en-dogenous antigens. (a) Exogenous antigen is ingested by endocyto-sis or phagocytosis and then enters the endocytic processingpathway. Here, within an acidic environment, the antigen is degradedinto small peptides, which then are presented with class II MHC mol-ecules on the membrane of the antigen-presenting cell. (b) Endoge-Viral DNAVirusViral mRNAPolysomesRoughendoplasmicreticulumGolgi complexVesicleViralpeptidesViralproteinAntigen ingestedby endocytosisor phagocytosisPeptideclass IIMHC complex(a) (b)Peptides ofantigenClass IIMHCPeptideclass I MHC complexClass I MHCviral peptideNucleusLysosomeEndosomeEndocytic processing pathwayRibosomenous antigen, which is produced within the cell itself (e.g., in a virus-infected cell), is degraded within the cytoplasm into peptides, whichmove into the endoplasmic reticulum, where they bind to class IMHC molecules. The peptideclass I MHC complexes then movethrough the Golgi complex to the cell surface.8536d_ch01_001-023 8/1/02 4:25 PM Page 14 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: 15. brane of the clones lymphocytes. As noted above, the speci-ficity of each T and B lymphocyte is determined before itscontact with antigen by random gene rearrangements duringmaturation in the thymus or bone marrow.The role of antigen becomes critical when it interacts withand activates mature, antigenically committed T and B lym-phocytes, bringing about expansion of the population ofcells with a given antigenic specificity. In this process ofclonal selection, an antigen binds to a particular T or B celland stimulates it to divide repeatedly into a clone of cells withthe same antigenic specificity as the original parent cell (Fig-ure 1-10).Clonal selection provides a framework for understandingthe specificity and self/nonself recognition that is character-istic of adaptive immunity. Specificity is shown because onlylymphocytes whose receptors are specific for a given epitopeon an antigen will be clonally expanded and thus mobilizedfor an immune response. Self/nonself discrimination is ac-complished by the elimination, during development, of lym-phocytes bearing self-reactive receptors or by the functionalsuppression of these cells in adults.Immunologic memory also is a consequence of clonal se-lection. During clonal selection, the number of lymphocytesspecific for a given antigen is greatly amplified. Moreover,many of these lymphocytes, referred to as memory cells, ap-pear to have a longer life span than the naive lymphocytesfrom which they arise. The initial encounter of a naive im-munocompetent lymphocyte with an antigen induces aOverview of the Immune System C H A P T E R 1 15FIGURE 1-10 Maturation and clonal selection of B lymphocytes.Maturation, which occurs in the absence of antigen, produces anti-genically committed B cells, each of which expresses antibody with asingle antigenic specificity (indicated by 1, 2, 3, and 4). Clonal selec-tion occurs when an antigen binds to a B cell whose membrane-bound antibody molecules are specific for epitopes on that antigen.Clonal expansion of an antigen-activated B cell (number 2 in this ex-Bone marrow Peripheral lymphoid tissueMemory cellAntibody2Plasma cellsStemcellGenerearrangement1 12 23 34 4Maturation into matureantigenetically committed B cellsAntigen 2MatureB cellsMatureB cells22222222222222Antigen-dependent proliferation anddifferentiation into plasma and memory cellsample) leads to a clone of memory B cells and effector B cells, calledplasma cells; all cells in the expanded clone are specific for the orig-inal antigen. The plasma cells secrete antibody reactive with the acti-vating antigen. Similar processes take place in the T-lymphocytepopulation, resulting in clones of memory T cells and effector T cells;the latter include activated TH cells, which secrete cytokines, and cy-totoxic T lymphocytes (CTLs).8536d_ch01_001-023 8/1/02 4:25 PM Page 15 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: 16. primary response; a later contact of the host with antigenwill induce a more rapid and heightened secondary re-sponse. The amplified population of memory cells accountsfor the rapidity and intensity that distinguishes a secondaryresponse from the primary response.In the humoral branch of the immune system, antigen in-duces the clonal proliferation of B lymphocytes into anti-body-secreting plasma cells and memory B cells. As seen inFigure 1-11a, the primary response has a lag of approxi-mately 57 days before antibody levels start to rise. This lag isthe time required for activation of naive B cells by antigenand TH cells and for the subsequent proliferation and differ-entiation of the activated B cells into plasma cells. Antibodylevels peak in the primary response at about day 14 and thenbegin to drop off as the plasma cells begin to die. In thesecondary response, the lag is much shorter (only 12 days),antibody levels are much higher, and they are sustained formuch longer. The secondary response reflects the activityof the clonally expanded population of memory B cells.These memory cells respond to the antigen more rapidlythan naive B cells; in addition, because there are manymore memory cells than there were naive B cells for theprimary response, more plasma cells are generated in thesecondary response, and antibody levels are consequently100- to 1000-fold higher.In the cell-mediated branch of the immune system, therecognition of an antigen-MHC complex by a specific ma-ture T lymphocyte induces clonal proliferation into variousT cells with effector functions (TH cells and CTLs) and intomemory T cells. The cell-mediated response to a skin graft isillustrated in Figure 1-11b by a hypothetical transplantationexperiment. When skin from strain C mice is grafted ontostrain A mice, a primary response develops and all the graftsare rejected in about 1014 days. If these same mice are againgrafted with strain C skin, it is rejected much more vigor-ously and rapidly than the first grafts. However, if animalspreviously engrafted with strain C skin are next given skinfrom an unrelated strain, strain B, the response to strain B istypical of the primary response and is rejected in 1014 days.That is, graft rejection is a specific immune response. Thesame mice that showed a secondary response to graft C willshow a primary response to graft B. The increased speed ofrejection of graft C reflects the presence of a clonally ex-panded population of memory TH and TC cells specific forthe antigens of the foreign graft. This expanded memorypopulation generates more effector cells, resulting in fastergraft rejection.The Innate and Adaptive Immune SystemsCollaborate, Increasing the Efficiency ofImmune ResponsivenessIt is important to appreciate that adaptive and innate immu-nity do not operate independentlythey function as a highlyinteractive and cooperative system, producing a combinedresponse more effective than either branch could produce byitself. Certain immune components play important roles inboth types of immunity.An example of cooperation is seen in the encounterbetween macrophages and microbes. Interactions betweenreceptors on macrophages and microbial components gen-erate soluble proteins that stimulate and direct adaptive im-mune responses, facilitating the participation of the adap-16 P A R T I IntroductionStrain CgraftrepeatedStrain BgraftAntigen ASerumantibodylevelAntigen A+ Antigen BPrimary anti-AresponseSecondaryanti-Aresponse Primaryanti-Bresponse60 14Time, days(a)140PercentageofmicerejectinggraftStrain Cgraft4Time, days(b)0 12204060801008 16 40 128 16FIGURE 1-11 Differences in the primary and secondary responseto injected antigen (humoral response) and to a skin graft (cell-me-diated response) reflect the phenomenon of immunologic memory.(a) When an animal is injected with an antigen, it produces a primaryserum antibody response of low magnitude and short duration,peaking at about 1017 days. A second immunization with the sameantigen results in a secondary response that is greater in magnitude,peaks in less time (27 days), and lasts longer (months to years)than the primary response. Compare the secondary response to anti-gen A with the primary response to antigen B administered to thesame mice. (b) Results from a hypothetical experiment in which skingrafts from strain C mice are transplanted to 20 mice of strain A; thegrafts are rejected in about 1014 days. The 20 mice are rested for 2months and then 10 are given strain C grafts and the other 10 aregiven skin from strain B. Mice previously exposed to strain C skin re-ject C grafts much more vigorously and rapidly than the grafts fromstrain B. Note that the rejection of the B graft follows a time coursesimilar to that of the first strain C graft.8536d_ch01_001-023 8/1/02 4:25 PM Page 16 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: 17. tive immune system in the elimination of the pathogen.Stimulated macrophages also secrete cytokines that candirect adaptive immune responses against particular intra-cellular pathogens.Just 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-mined search for antibodies, T cells, and B cells in organismsof the nonvertebrate phyla has failed to find them. The inte-rior spaces of organisms as diverse as fruit flies, cockroaches,and plants do not contain unchecked microbial populations,however, which implies that some sort of immunity exists inmost, possibly all, multicellular organisms, including thosewith no components of adaptive immunity.Insects and plants provide particularly clear and dramaticexamples of innate immunity that is not based on lympho-cytes. The invasion of the interior body cavity of the fruit fly,Drosophila melanogaster, by bacteria or molds triggers thesynthesis of small peptides that have strong antibacterial orantifungal activity. The effectiveness of these antimicrobialpeptides is demonstrated by the fate of mutants that are un-able to produce them. For example, a fungal infection over-whelms a mutant fruit fly that is unable to trigger thesynthesis of drosomycin, an antifungal peptide (Figure1-12). Further evidence for immunity in the fruit fly is givenby the recent findings that cell receptors recognizing variousclasses of microbial molecules (the toll-like receptors) werefirst found in Drosophila.Plants respond to infection by producing a wide varietyof antimicrobial proteins and peptides, as well as smallOverview of the Immune System C H A P T E R 1 17TABLE 1-3Comparison of adaptive andinnate immunityInnate AdaptiveResponse time Hours DaysSpecificity Limited and Highly diverse, improvesfixed during the course ofimmune responseResponse to Identical to Much more rapid thanrepeat primary primary responseinfection responseFIGURE 1-12 Severe fungal infection in a fruit fly (Drosophilamelanogaster) with a disabling mutation in a signal-transductionpathway required for the synthesis of the antifungal peptide dro-somycin. [From B. Lemaitre et al., 1996, Cell 86:973; courtesy of J. A.Hoffman, University of Strasbourg.]8536d_ch01_001-023 8/1/02 4:25 PM Page 17 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: 18. nonpeptide organic molecules that have antibiotic activity.Among these agents are enzymes that digest microbial cellwalls, peptides and a protein that damages microbial mem-branes, and the small organic molecules phytoalexins. Theimportance of the phytoalexins is shown by the fact that mu-tations that alter their biosynthetic pathways result in loss ofresistance to many plant pathogens. In some cases, the re-sponse of plants to pathogens goes beyond this chemical as-sault to include an architectural response, in which the plantisolates cells in the infected area by strengthening the walls ofsurrounding cells. Table 1-4 compares the capabilities of im-mune systems in a wide range of multicellular organisms,both animals and plants.Immune Dysfunction andIts ConsequencesThe above overview of innate and adaptive immunity depictsa multicomponent interactive system that protects the hostfrom infectious diseases and from cancer. This overviewwould not be complete without mentioning that the immunesystem can function improperly.Sometimes the immune sys-tem fails to protect the host adequately or misdirects its ac-tivities to cause discomfort, debilitating disease, or evendeath. There are several common manifestations of immunedysfunction:I Allergy and asthmaI Graft rejection and graft-versus-host diseaseI Autoimmune diseaseI ImmunodeficiencyAllergy and asthma are results of inappropriate immune re-sponses, often to common antigens such as plant pollen,food, or animal dander. The possibility that certain sub-stances increased sensitivity rather than protection was rec-ognized in about 1902 by Charles Richet, who attempted toimmunize dogs against the toxins of a type of jellyfish,Physalia. He and his colleague Paul Portier observed thatdogs exposed to sublethal doses of the toxin reacted almostinstantly, and fatally, to subsequent challenge with minuteamounts of the toxin. Richet concluded that a successful im-munization or vaccination results in phylaxis, or protection,and that an opposite result may occuranaphylaxisinwhich exposure to antigen can result in a potentially lethalsensitivity to the antigen if the exposure is repeated. Richetreceived the Nobel Prize in 1913 for his discovery of the ana-phylactic response.Fortunately, most allergic reactions in humans are notrapidly fatal.A specific allergic or anaphylactic response usu-ally involves one antibody type, called IgE. Binding of IgE toits specific antigen (allergen) releases substances that causeirritation and inflammation. When an allergic individual isexposed to an allergen, symptoms may include sneezing,wheezing, and difficulty in breathing (asthma); dermatitis orskin eruptions (hives); and, in more extreme cases, strangu-lation due to blockage of airways by inflammation. A signifi-cant fraction of our health resources is expended to care forthose suffering from allergy and asthma. The frequency ofallergy and asthma in the United States place these com-plaints among the most common reasons for a visit to thedoctors office or to the hospital emergency room (see Clini-cal Focus).When the immune system encounters foreign cells or tis-sue, it responds strongly to rid the host of the invaders. How-ever, in some cases, the transplantation of cells or an organfrom 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 froma kidney transplant. Because the immune system will attackand reject any transplanted organ that it does not recognizeas self, it is a serious barrier to this potentially life-savingtreatment. An additional danger in transplantation is thatany transplanted cells with immune function may view thenew host as nonself and react against it. This reaction, whichis termed graft-versus-host disease, can be fatal. The rejec-tion reaction and graft-versus-host disease can be suppressedby drugs, but this type of treatment suppresses all immunefunction, so that the host is no longer protected by its im-mune system and becomes susceptible to infectious diseases.Transplantation studies have played a major role in the de-velopment of immunology. A Nobel prize was awarded toKarl Landsteiner, in 1930, for the discovery of human bloodgroups, a finding that allowed blood transfusions to be car-ried out safely. In 1980, G. Snell, J. Dausset, and B. Benacerrafwere recognized for discovery of the major histocompatibil-ity complex, and, in 1991, E. D. Thomas and J. Murray wereawarded Nobel Prizes for advances in transplantation immu-nity. To enable a foreign organ to be accepted without sup-pressing immunity to all antigens remains a challenge forimmunologists today.In certain individuals, the immune system malfunctionsby losing its sense of self and nonself, which permits an im-mune attack upon the host. This condition, autoimmunity,can cause a number of chronic debilitating diseases. Thesymptoms of autoimmunity differ depending on whichtissues and organs are under attack. For example, multiplesclerosis is due to an autoimmune attack on the brain andcentral nervous system, Crohns disease is an attack on thetissues in the gut, and rheumatoid arthritis is an attack onjoints of the arms and legs. The genetic and environmentalfactors that trigger and sustain autoimmune disease are veryactive areas of immunologic research, as is the search for im-proved treatments.If any of the many components of innate or specific im-munity is defective because of genetic abnormality, or if anyimmune function is lost because of damage by chemical,physical, or biological agents, the host suffers from immu-nodeficiency. The severity of the immunodeficiency disease18 P A R T I Introduction8536d_ch01_001-023 8/1/02 4:26 PM Page 18 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: 19. Overview of the Immune System C H A P T E R 1 19TABLE 1-4 Immunity in multicellular organismsInvasion-inducedprotectiveInnate Adaptive enzymes Pattern-immunity immunity and enzyme Antimicrobial recognition Graft T and BTaxonomic group (nonspecific) (specific) cascades Phagocytosis peptides receptors rejection cells AntibodiesHigher plants Invertebrate animalsPorifera ? ? ? (sponges)Annelids ? ? ? (earthworms)Arthropods ? (insects,crustaceans)Vertebrate animalsElasmobranchs 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.lems. Details of the mechanisms that un-derlie allergic and asthmatic responsesto environmental antigens (or allergens)will be considered in Chapter 16. Simplystated, allergic reactions are responsesto antigenic stimuli that result in immu-nity based mainly on the IgE class of im-munoglobulin. Exposure to the antigen(or allergen) triggers an IgE-mediated re-lease of molecules that cause symptomsranging from sneezing and dermatitis toinflammation of the lungs in an asth-matic attack. The sequence of events inan allergic response is depicted in the ac-companying figure.The discomfort from common aller-gies such as plant pollen allergy (oftencalled ragweed allergy) consists of aweek or two of sneezing and runny nose,which may seem trivial compared withhealth problems such as cancer, cardiacarrest, or life-threatening infections. Amore serious allergic reaction is asthma,Althoughthe im-mune system serves to protect the hostfrom infection and cancer, inappropriateresponses of this system can lead todisease. Common among the results ofimmune dysfunction are allergies andasthma, both serious public health prob-C L I N I C A L F O C U SAllergy and Asthma as SeriousPublic Health Problems(continued)8536d_ch01_001-023 8/1/02 4:26 PM Page 19 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: 20. 20 P A R T I Introductiona chronic disease of the lungs in whichinflammation, mediated by environmen-tal antigens or infections, causes severedifficulty in breathing. Approximately 15million persons in the United States suf-fer from asthma, and it causes about5000 deaths per year. In the past twentyyears, the prevalence of asthma in theWestern World has doubled.*Data on the frequency of care soughtfor the most common medical com-plaints in the United States show thatasthma and allergy together resulted inmore than 28 million visits to the doctorin 1995. The importance of allergy as apublic health problem is underscored bythe fact that the annual number of doctorvisits for hypertension, routine medicalexaminations, or normal pregnancy, areeach fewer than the number of visits forallergic conditions. In fact, the mostcommon reason for a visit to a hospitalemergency room is an asthma attack, ac-counting for one third of all visits. In ad-dition to those treated in the ER, therewere about 160,000 hospitalizations forasthma in the past year, with an averagestay of 3 to 4 days.Although all ages and races are af-fected, deaths from asthma are 3.5 timesmore common among African-Americanchildren. The reasons for the increases innumber of asthma cases and for thehigher death rate in African-American chil-dren remain unknown, although someclues may have been uncovered by recentC L I N I C A L F O C U S (continued)Allergy and Asthma as SeriousPublic Health ProblemsSequence of events leading to an allergicresponse. When the antibody producedupon contact with an allergen is IgE, thisclass of antibody reacts via its constantregion with a mast cell. Subsequent reac-tion of the antibody binding site with theallergen triggers the mast cell to whichthe IgE is bound to secrete moleculesthat cause the allergic symptoms.Plasma cellB cellIgEProduction oflarge amountsof ragweed IgEantibodyFirst contactwith an allergen (ragweed)Subsequent contactwith allergenIgE moleculesattach to mastcellsIgE-primed mastcell releasesmolecules thatcause wheezing,sneezing, runny nose,watery eyes, andother symptomsRagweedpollenMast cellstudies of genetic factors in allergic dis-ease (see Clinical Focus in Chapter 16).An increasingly serious health prob-lem is food allergy, especially to peanutsand tree nuts (almonds, cashews, andwalnuts).Approximately 3 millionAmericans are allergic to these foodsand they are the leading causes of fataland near-fatal food allergic (anaphylac-tic) reactions. While avoidance of thesefoods can prevent harmful conse-quences, the ubiquitous use of peanutprotein and other nut products in a vari-ety of foods makes this very difficult forthe allergic individual. At least 50% of se-rious reactions are caused by accidentalexposures to peanuts, tree nuts, or theirproducts. This has led to controversialmovements to ban peanuts fromschools and airplanes.Anaphylaxis generally occurs withinan hour of ingesting the food allergenand the most effective treatment is injec-tion of the drug epinephrine. Thoseprone to anaphylactic attacks often carryinjectable epinephrine to be used in caseof exposure.In addition to the suffering and anxi-ety caused by inappropriate immune re-sponses or allergies to environmentalantigens, there is a staggering cost interms of lost work time for those affectedand for caregivers. These costs well justifythe extensive efforts by basic and clinicalimmunologists and allergists to relievethe suffering caused by these disorders.Hughes, D. A., and C. Mills. 2001. Food allergy:A problem on the rise. Biologist (London) 48:201.depends on the number of affected components.A commontype of immunodeficiency in North America is a selectiveimmunodeficiency in which only one type of immunoglob-ulin, IgA, is lacking; the symptoms may be minor or even gounnoticed. In contrast, a rarer immunodeficiency calledsevere combined immunodeficiency (SCID), which affectsboth B and T cells, if untreated, results in death from infec-tion at an early age. Since the 1980s, the most common formof immunodeficiency has been acquired immune deficiencysyndrome, or AIDS, which results from infection with the*Holgate, S. T. 1999. The epidemic of allergy andasthma, Nature Supp. to vol. 402, B2.8536d_ch01_020 9/5/02 11:48 AM Page 20 mac46 mac46:385_reb: 21. retrovirus human immunodeficiency virus, or HIV. In AIDS,T helper cells are infected and destroyed by HIV, causing acollapse of the immune system. It is estimated that 35 millionpersons worldwide suffer from this disease, which is usuallyfatal within 8 to 10 years after infection. Although certaintreatments can prolong the life of AIDS patients, there is noknown cure for this disease.This chapter has been a brief introduction to the immunesystem, and it has given a thumbnail sketch of how this com-plex system functions to protect the host from disease. Thefollowing chapters will concern the structure and function ofthe individual cells, organs, and molecules that make up thissystem. They will describe our current understanding of howthe components of immunity interact and the experimentsthat allowed discovery of these mechanisms. Specific areas ofapplied immunology, such as immunity to infectious dis-eases,cancer,and current vaccination practices are the subjectmatter of later chapters. Finally, to complete the descriptionof the immune system in all of its activities, a chapter ad-dresses each of the major types of immune dysfunction.SUMMARYI Immunity is the state of protection against foreign organ-isms or substances (antigens). Vertebrates have two typesof immunity, innate and adaptive.I Innate immunity is not specific to any one pathogen butrather constitutes a first line of defense, which includesanatomic, physiologic, endocytic and phagocytic, and in-flammatory barriers.I Innate and adaptive immunity operate in cooperative andinterdependent ways. The activation of innate immune re-sponses produces signals that stimulate and direct subse-quent adaptive immune responses.I Adaptive immune responses exhibit four immunologic at-tributes: specificity, diversity, memory, and self/nonselfrecognition.I The high degree of specificity in adaptive immunity arisesfrom the activities of molecules (antibodies and T-cellreceptors) that recognize and bind specific antigens.I Antibodies recognize and interact directly with antigen. T-cell receptors recognize only antigen that is combined witheither class I or class II major histocompatibility complex(MHC) molecules.I The two major subpopulations of T lymphocytes are theCD4T helper (TH) cells and CD8T cytotoxic (TC) cells.TH cells secrete cytokines that regulate immune responseupon recognizing antigen combined with class II MHC.TCcells recognize antigen combined with class I MHC andgive rise to cytotoxic T cells (CTLs), which display cyto-toxic ability.I Exogenous (extracellular) antigens are internalized anddegraded by antigen-presenting cells (macrophages, Bcells, and dendritic cells); the resulting antigenic peptidescomplexed with class II MHC molecules are then displayedon the cell surface.I Endogenous (intracellular) antigens (e.g., viral and tumorproteins produced in altered self-cells) are degraded in thecytoplasm and then displayed with class I MHC moleculeson the cell surface.I The immune system produces both humoral and cell-me-diated responses. The humoral response is best suited forelimination of exogenous antigens; the cell-mediated re-sponse, for elimination of endogenous antigens.I While an adaptive immune system is found only in verte-brates, innate immunity has been demonstrated in organ-isms as different as insects, earthworms, and higher plants.I Dysfunctions of the immune system include commonmaladies such as allergy or asthma. Loss of immune func-tion leaves the host susceptible to infection; in autoimmu-nity, the immune system attacks host cells or tissues,ReferencesAkira, S., K. Takeda, and T. Kaisho. 2001. Toll-like receptors:Critical proteins linking innate and acquired immunity. Na-ture Immunol. 2:675.Burnet, F. M. 1959. The Clonal Selection Theory of Acquired Im-munity. Cambridge University Press, Cambridge.Cohen, S. G., and M. Samter. 1992. Excerpts from Classics in Al-lergy. Symposia Foundation, Carlsbad, California.Desour, L. 1922. Pasteur and His Work (translated by A. F. andB. H. Wedd). T. Fisher Unwin Ltd., London.Fritig, B., T. Heitz, and M. Legrand. 1998.Antimicrobial proteinsin induced plant defense. Curr. Opin. Immunol. 10:12.Kimbrell, D. A., and B. Beutler. 2001. The evolution andgenetics of innate immunity. Nature Rev. Genet. 2:256.Kindt, T. J., and J. D. Capra. 1984. The Antibody Enigma.Plenum Press, New York.Landsteiner, K. 1947. The Specificity of Serologic Reactions. Har-vard University Press, Cambridge, Massachusetts.Lawson, P. R., and K. B. Reid. 2000. The roles of surfactantproteins A and D in innate immunity. Immunologic Reviews173:66.Medawar, P. B. 1958. The Immunology of Transplantation. TheHarvey Lectures 19561957. Academic Press, New York.Medzhitov, R., and C. A. Janeway. 2000. Innate immunity. N.Eng. J. Med. 343:338.Metchnikoff, E. 1905. Immunity in the Infectious Diseases.MacMillan, New York.Otvos, L. 2000. Antibacterial peptides isolated from insects. J.Peptide Sci. 6:497.Paul, W., ed. 1999. Fundamental Immunology, 4th ed. Lippin-cott-Raven, Philadelphia.Overview of the Immune System C H A P T E R 1 218536d_ch01_001-023 8/1/02 4:26 PM Page 21 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: 22. Roitt, I. M., and P. J. Delves, eds. 1998. An Encyclopedia of Im-munology, 2nd ed., vols. 14. Academic Press, London.USEFUL WEB SITEShttp://www.aaaai.org/The American Academy of Allergy Asthma and Immunologysite includes an extensive library of information about allergicdiseases.http://12.17.12.70/aai/default.aspThe Web site of the American Association of Immunologistscontains a good deal of information of interest to immunolo-gists.http://www.ncbi.nlm.nih.gov/PubMed/PubMed, the National Library of Medicine database of morethan 9 million publications, is the worlds most comprehen-sive bibliographic database for biological and biomedical lit-erature. It is also a highly user-friendly site.Study QuestionsCLINICAL FOCUS QUESTION You have a young nephew who hasdeveloped a severe allergy to tree nuts. What precautions wouldyou advise for him and for his parents? Should school officials beaware of this condition?1. Indicate to which branch(es) of the immune system the fol-lowing statements apply, using H for the humoral branchand CM for the cell-mediated branch. Some statements mayapply to both branches.a. Involves class I MHC moleculesb. Responds to viral infectionc. Involves T helper cellsd. Involves processed antigene. Most likely r