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