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Overview of theImmune System chapter 1T defense system that has evolved to protect animals from 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 activities—recognition and response. Immune Macrophagerecognition 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 body’s 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 from that 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 its of 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 and Athens, 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 to would not contract the disease a second time. Although earlythe chapters that follow. societies recognized the phenomenon of immunity, almost
2 PART 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. Jenner’s 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 to FIGURE 1-1 Wood engraving of Louis Pasteur watching Josephcholera. Louis Pasteur had succeeded in growing the bac- Meister receive the rabies vaccine. [From Harper’s Weekly 29:836;terium thought to cause fowl cholera in culture and then had courtesy 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 Pasteur’s 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 strain Components of the Immune Systemmight be administered to protect against the disease. He Although 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 Jenner’s work with cowpox Behring and Shibasaburo Kitasato in 1890 gave the first in-inoculation. sights into the mechanism of immunity, earning von Behring Pasteur 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, a and 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 experiments In 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.
Overview of the Immune System CHAPTER 1 3 TABLE 1-1 Nobel Prizes for immunologic research Year Recipient Country Research 1901 Emil von Behring Germany Serum antitoxins 1905 Robert Koch Germany Cellular immunity to tuberculosis 1908 Elie Metchnikoff Russia Role of phagocytosis (Metchnikoff) and Paul Ehrlich Germany antitoxins (Ehrlich) in immunity 1913 Charles Richet France Anaphylaxis 1919 Jules Border Belgium Complement-mediated bacteriolysis 1930 Karl Landsteiner United States Discovery of human blood groups 1951 Max Theiler South Africa Development of yellow fever vaccine 1957 Daniel Bovet Switzerland Antihistamines 1960 F. Macfarlane Burnet Australia Discovery of acquired immunological Peter Medawar Great Britain tolerance 1972 Rodney R. Porter Great Britain Chemical structure of antibodies Gerald M. Edelman United States 1977 Rosalyn R. Yalow United States Development of radioimmunoassay 1980 George Snell United States Major histocompatibility complex Jean Daussct France Baruj Benacerraf United States 1984 Cesar Milstein Great Britain Monoclonal antibody Georges E. Köhler Germany Niels K. Jerne Denmark Immune regulatory theories 1987 Susumu Tonegawa Japan Gene rearrangement in antibody production 1991 E. Donnall Thomas United States Transplantation immunology Joseph Murray United States 1996 Peter C. Doherty Australia Role 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, mainly who held to the concept of humoral immunity and thosethrough the efforts of Elvin Kabat, a fraction of serum first who agreed with Metchnikoff ’s concept of cell-mediated im-called gamma-globulin (now immunoglobulin) was shown munity. It was later shown that both are correct—immunityto 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 an In 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 than in 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 PART I Introductiontwo types of lymphocytes: T lymphocytes derived from the In the 1930s and 1940s, the selective theory was chal-thymus mediated cellular immunity, and B lymphocytes lenged by various instructional theories, in which antigenfrom the bursa of Fabricius (an outgrowth of the cloaca in played 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 Friedrich Breinl 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 Antibody– structional theories were formally disproved in the 1960s, by which 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 was the 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 with In the 1950s, selective theories resurfaced as a result ofa specific antibody). Around 1900, Jules Bordet at the Pasteur new 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 Landsteiner Binding of antigen to its specific receptor activates the cell,and those who followed him showed that injecting an animal causing it to proliferate into a clone of cells that have thewith almost any organic chemical could induce production same 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 capacity as 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 in Adaptive Componentsthe smallest detail could be distinguished by their reactivity Immunity—the 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 innate The 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 a specific 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, Ehrlich skin, and a variety of antimicrobial compounds synthesizedproposed that binding of the receptor to an infectious agent by 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-bound tem, which is uniform in all members of a species, the spe-receptor would induce the cell to produce and release more cific component, adaptive immunity, does not come intoreceptors with the same specificity. According to Ehrlich’s 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 Ehrlich’s 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 a posure to that antigen. Exposure to the same antigen somecell-bound receptor; it is the soluble form that is secreted time in the future results in a memory response: the immunerather than the bound form released. response to the second challenge occurs more quickly than
Overview of the Immune System CHAPTER 1 5the first, is stronger, and is often more effective in neutraliz- distinct layers: a thinner outer layer—the epidermis—and aing and clearing the pathogen. The major agents of adaptive thicker layer—the dermis. The epidermis contains severalimmunity are lymphocytes and the antibodies and other layers 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 to protein called keratin. The dermis, which is composed ofmarshal, innate immunity provides the first line of defense connective tissue, contains blood vessels, hair follicles, seba-during the critical period just after the host’s 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 Immunity vents 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 Provide they can introduce the pathogen into the body as they feed. The protozoan that causes malaria, for example, is depositedProtective Barriers Against Infection in humans by mosquitoes when they take a blood meal. Sim-Physical and anatomic barriers that tend to prevent the entry ilarly, bubonic plague is spread by the bite of fleas, and Lymeof pathogens are an organism’s first line of defense against in- disease is spread by the bite of ticks.fection. The skin and the surface of mucous membranes are The 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 barriers Skin Mechanical barrier retards entry of microbes. Acidic environment (pH 3–5) 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 barriers Temperature 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 with antibacterial activity, and influx of phagocytic cells into the affected area.
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 pathogens are 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 called The 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-entrapped have 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 outcompete few ingested microorganisms can survive the low pH of thepathogens for attachment sites on the epithelial cell surface stomach contents. One reason newborns are susceptible toand for necessary nutrients. some diseases that do not afflict adults is that their stomach Some 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 body A 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 enables and 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, called proteins that circulate in an inactive state. A variety of spe-fimbriae or pili, and certain glycoproteins or glycolipids that cific 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, some state 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
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 1 Bacterium becomes attachedAnother important innate defense mechanism is the inges- to membrane evaginations called pseudopodiation of extracellular particulate material by phagocytosis.Phagocytosis is one type of endocytosis, the general term for 2the uptake by a cell of material from its environment. In Bacterium is ingested,phagocytosis, a cell’s plasma membrane expands around the forming phagosomeparticulate material, which may include whole pathogenicmicroorganisms, to form large vesicles called phagosomes 3(Figure 1-3). Most phagocytosis is conducted by specialized Phagosome fuses with lysosomecells, such as blood monocytes, neutrophils, and tissuemacrophages (see Chapter 2). Most cell types are capable ofother forms of endocytosis, such as receptor-mediated endo- 4 Lysosomal enzymes digestcytosis, in which extracellular molecules are internalized after captured 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 are released 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 events calor (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 as of function). The cardinal signs of inflammation reflect theLPS, may trigger an inflammatory response via interaction three 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. Vasodilation—an increase in the diameter of bloodinvasion or clearance of the invader by components of the vessels—of nearby capillaries occurs as the vessels thatinnate immune system. Many of the classic features of the carry 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, the engorged capillaries are responsible for tissue rednessRoman physician Celsus described the “four cardinal signs (erythema) and an increase in tissue temperature.
8 PART I Introduction Tissue damage Bacteria 1 4 Tissue damage causes release of Phagocytes and antibacterial vasoactive and chemotactic factors exudate destroy bacteria that trigger a local increase in blood flow and capillary permeability Exudate 3 2 Phagocytes migrate to site of Permeable capillaries allow an (complement, antibody, inflammation (chemotaxis) influx of fluid (exudate) and cells C-reactive protein) Margination Extravasation Capillary FIGURE 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 white teria, 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 from participating in the inflammatory response. the vasculature. Accumulation of exudate contributes to Among 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. Some present 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-
Overview of the Immune System CHAPTER 1 9creased permeability of capillaries. A particular kinin, called sponses 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-clotting duced 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 body together 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. Capillaries Cooperation Between Lymphocytes andgrow into the fibrin of a blood clot. New connective tissue Antigen-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 Immunity binding cell-surface receptors, lymphocytes mediate theAdaptive immunity is capable of recognizing and selectively defining immunologic attributes of specificity, diversity,eliminating specific foreign microorganisms and molecules memory, and self/nonself recognition. The two major popu-(i.e., foreign antigens). Unlike innate immune responses, lations of lymphocytes—B lymphocytes (B cells) and T lym-adaptive immune responses are not the same in all members phocytes (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 specificity B 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. Antibodies chains. 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 of together. 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 a causes 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 to Memory B cells have a longer life span than naive cells, andmany infectious agents after an initial encounter. Finally, the they 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 nonself antibody. 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. Secreted Adaptive 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 PART I Introduction (a) B cell (b) TH cell (c) TC cell CD4 TCR 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 cells binding T-cell receptor (TCR) per cell, all with the same antigenicbearing CD4 (CD4+ cells) recognize only antigen bound to class II specificity.MHC molecules. (c) T cells bearing CD8 (CD8+ cells) recognize onlyT LYMPHOCYTES an 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 the sponse. 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 recognize that recognizes an antigen–MHC 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). There any 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 small called 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 a Activation 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 type quences. 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 bygen–MHC class II molecule complex, the cell is activated—it phagocytosis or by endocytosis, and then display a part ofbecomes an effector cell that secretes various growth factors that 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
Overview of the Immune System CHAPTER 1 11 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 Phagocytosis—Past 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 theantigen–class II MHC molecule complex on the membrane immune 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 Cellular rides, or lipopolysaccharides that have been released from in-Immunity Is Transferred vading pathogens. The cell-mediated branch (T cells)with Antibody recognizes 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 nonimmune are 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 receptors The 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-secreting I 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 binding The 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). Both its specificity is created by random rearrangements of a series
12 PART I Introduction VISUALIZING CONCEPTS Antigens Foreign Viruses Bacteria Parasites Fungi proteins 1 Internalized antigen digested by cell 2 Altered self-cell presents antigen Class II Class I MHC MHC TH cell TC cell 3 T cell receptors recognize antigen bound to MHC molecules Activated 6 TH cell Activated CTLs 4 recognize and kill Binding antigen-MHC altered self-cells activates T cells Cytotoxic T lymphocyte (CTL) 5 Activated TH cell secretes Cell-mediated response cytokines that contribute to activation of B cells, TC cells, Humoral response and other cells + Antigen 7 8 B cell B cells interact with antigen Ab-secreting Antibody binds antigen and differentiate into plasma cells and facilitates its clearance antibody-secreting plasma cells from the body FIGURE 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 and lymphocytes (CTLs), which mediate killing of altered self-cells facilitates its clearance from the body. In the cell-mediated re- (e.g., virus-infected cells).
Overview of the Immune System CHAPTER 1 13of gene segments that encode the antibody molecule (see TCR 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 heavy versity 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 antibody nizing 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 be The 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 a TC 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 cell’s antigen-binding receptor (see Chapter 9). Each play wide variation in their amino acid sequences. TheseT lymphocyte cell expresses about 105 receptors, and all of variable regions form a cleft within which the antigenic pep-the receptors on the cell and its clonal progeny have identical tide 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) Antigenic peptide TC cell TH cell Class I MHC Class II MHC TC cell T cell receptor CD8 TH cell CD4 Virus-infected cell Antigen-presenting cell FIGURE 1-8 The role of MHC molecules in antigen recognition by cells. (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 helper Recognition 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 PART 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 present gen-presenting cells, presentation of exogenous peptide–an antigen to T lymphocytes is influenced by the particular class 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 Surface within 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. This within the endoplasmic reticulum. The peptide–class 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 together ducing 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 cell the antigen–MHC 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 fragments Antigen 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) Peptide–class II (b) Peptide–class I MHC complex MHC complex Antigen ingested Class I MHC by endocytosis viral peptide or phagocytosis Peptides of Vesicle antigen Class II MHC Golgi complex Viral Polysomes Lysosome peptides Endosome Rough Endocytic processing pathway endoplasmic Viral reticulum protein Ribosome Viral 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 peptide–class 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-
Overview of the Immune System CHAPTER 1 15brane of the clone’s 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 during on 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 with complished 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 of suppression 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 with specific 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 lymphocytes Clonal selection provides a framework for understanding from 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 a Bone marrow Peripheral lymphoid tissue Memory cell 2 Antibody 2 2 1 1 2 Plasma cells 2 2 Antigen 2 2 2 2 2 Gene rearrangement 2 Stem 2 cell 3 3 2 2 2 2 4 4 2 Mature Mature B cells B cells Maturation into mature Antigen-dependent proliferation and antigenetically committed B cells differentiation into plasma and memory cells FIGURE 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 a inal 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 PART I Introduction primary response; a later contact of the host with antigen body-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 5–7 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 1–2 days),(a) antibody levels are much higher, and they are sustained for Antigen A much longer. The secondary response reflects the activity Antigen A Secondary + Antigen B anti-A of the clonally expanded population of memory B cells. response Primary Serum antibody level anti-B These memory cells respond to the antigen more rapidly response than naive B cells; in addition, because there are many Primary anti-A more memory cells than there were naive B cells for the response 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 14 0 6 14 ture T lymphocyte induces clonal proliferation into various Time, days T 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 100 Strain C Strain C Strain B experiment. When skin from strain C mice is grafted ontoPercentage of mice rejecting graft graft graft graft strain A mice, a primary response develops and all the grafts repeated are rejected in about 10–14 days. If these same mice are again 80 grafted with strain C skin, it is rejected much more vigor- ously and rapidly than the first grafts. However, if animals 60 previously engrafted with strain C skin are next given skin from an unrelated strain, strain B, the response to strain B is 40 typical of the primary response and is rejected in 10–14 days. That is, graft rejection is a specific immune response. The 20 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, days panded population of memory TH and TC cells specific for the antigens of the foreign graft. This expanded memory FIGURE 1-11 Differences in the primary and secondary response population 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 10–17 days. A second immunization with the same antigen results in a secondary response that is greater in magnitude, Immune Responsiveness peaks in less time (2–7 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 independently—they function as a highly gen A with the primary response to antigen B administered to the interactive 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; the itself. Certain immune components play important roles in grafts are rejected in about 10–14 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 course erate 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-
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