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  • 1. 1C H A P T E R1Introduction to the Immune SystemNomenclature, General Properties, and ComponentsImmunity is defined as resistance to disease,specifically infectious disease. The collectionof cells, tissues, and molecules that mediateresistance to infections is called the immunesystem, and the coordinated reaction of thesecells and molecules to infectious microbes isthe immune response. Immunology is thestudy of the immune system, including itsresponses to microbial pathogens and damagedtissues and its role in disease. The mostimportant physiologic function of theimmune system is to prevent infectionsand to eradicate established infections,and this is the principal context in whichimmune responses are discussed throughoutthis book.The importance of the immune system forhealth is dramatically illustrated by the frequentobservation that individuals with defectiveimmune responses are susceptible to serious,often life-threatening infections (Fig. 1–1). Con-versely, stimulating immune responses againstmicrobes through vaccination is the most effec­tive method for protecting individuals againstinfections; this approach has led to the world-wide eradication of smallpox, the only diseasethat has been eliminated from civilization byhuman intervention (Fig. 1–2). The emergenceof acquired immunodeficiency syndrome (AIDS)in the 1980s tragically emphasized the impor-tance of the immune system for defendingindividuals against infection. The impact of im-munology, however, goes beyond infectiousdisease (see Fig. 1–1). The immune systemINNATE AND ADAPTIVE IMMUNITY  3TYPES OF ADAPTIVE IMMUNITY  4PROPERTIES OF ADAPTIVE IMMUNE RESPONSES  5Specificity and Diversity  6Memory  6Other Features of Adaptive Immunity  7CELLS OF THE IMMUNE SYSTEM  7Lymphocytes  8Antigen-Presenting Cells  13Effector Cells  13TISSUES OF THE IMMUNE SYSTEM  13Peripheral Lymphoid Organs  13Lymphocyte Recirculation and Migration into Tissues  17OVERVIEW OF IMMUNE RESPONSES TO MICROBES  18Early Innate Immune Response to Microbes  18Adaptive Immune Response  19Decline of Immune Responses and ImmunologicMemory  21SUMMARY  21
  • 2. 2 Chapter 1 – Introduction to the Immune SystemFIGURE 1–1 Importance of the immune system in health and disease. This table summarizes some of the physiologicfunctions of the immune system and its role in disease; AIDS, Acquired immunodeficiency syndrome.Role of the immune system ImplicationsDefense against infections Deficient immunity results in increased susceptibility toinfections; exemplified by AIDSVaccination boosts immune defenses and protects againstinfectionsThe immune systemrecognizes and respondsto tissue grafts and newlyintroduced moleculesImmune responses are barriers to transplantation and genetherapyThe immune system caninjure cells and inducepathologic inflammationImmune responses are the cause of allergic, autoimmune,and other inflammatory diseasesDefense against tumors Potential for immunotherapy of cancerFIGURE 1–2 Effectiveness of vaccination for some common infectious diseases. This table illustrates the strikingdecrease in the incidence of selected infectious diseases for which effective vaccines have been developed. For some infections, suchas hepatitis B, a vaccine has become available recently, and the incidence of the disease is continuing to decline. (Modified fromOrenstein WA, Hinman AR, Bart KJ, Hadler SC: Immunization. In Mandell GL, Bennett JE, Dolin R, editors: Principles and practices of infectiousdiseases, ed 4, New York, 1995, Churchill Livingstone; and MMWR 58:1458-1469, 2010.)Disease Maximum numberof cases (year)Number ofcases in 2009PercentchangeDiphtheriaMeaslesMumpsPertussisPolio(paralytic)RubellaTetanusHemophilusinfluenzatype BHepatitis B206,939 (1921)894,134 (1941)152,209 (1968)265,269 (1934)21,269 (1952)57,686 (1969)1,560 (1923)~20,000 (1984)26,611 (1985)06198213,5060414253,020-99.99-99.99-99.35-94.72-100.0-99.99-99.10-99.88-87.66prevents the growth of some tumors, and severalmethods to treat cancers by stimulating immuneresponses against tumor cells are in develop-ment. Immune responses also participate in theclearance of dead cells and in initiating tissuerepair.In contrast to these beneficial roles, abnormalimmune responses are the causes of manyinflammatory diseases with serious morbidityand mortality. The immune response is the majorbarrier to successful organ transplantation totreat organ failure. The products of immune
  • 3. Chapter 1 – Introduction to the Immune System 3l How are the cells and tissues of the immunesystem organized to find and respond tomicrobes in ways that lead to theirelimination?We conclude the chapter with a brief overviewof immune responses against microbes. Thebasic principles introduced here set the stagefor more detailed discussions of immuneresponses in later chapters. A glossary of theimportant terms used in this book is providedin Appendix I.INNATE AND ADAPTIVE IMMUNITYHost defense mechanisms consist of innateimmunity, which mediates the initial pro-tection against infections, and adaptiveimmunity, which develops more slowly andprovides more specialized and effectivedefense against infections (Fig. 1–3). Innateimmunity, also called natural immunity ornative immunity, is always present in healthyindividuals (hence the term innate), preparedcells are also of great practical use. For example,antibodies, which are proteins made by certaincells of the immune system, are used in clinicallaboratory testing and in research as highly spe-cific reagents for detecting a wide variety of mol-ecules in the circulation and in cells and tissues.Antibodies designed to block or eliminate poten-tially harmful molecules and cells are in wide-spread use for the treatment of immunologicdiseases, cancers, and other types of disorders.For all these reasons, the field of immunologyhas captured the attention of clinicians, scien-tists, and the lay public.This chapter introduces the nomenclature ofimmunology, important general properties of allimmune responses, and the cells and tissues thatare the principal components of the immunesystem. In particular, the following questions areaddressed:l What types of immune responses protect indi-viduals from infections?l What are the important characteristics ofimmunity, and what mechanisms are respon-sible for these characteristics?FIGURE 1–3 Principal mechanisms of innate and adaptive immunity. The mechanisms of innate immunity providethe initial defense against infections. Some mechanisms (e.g., epithelial barriers) prevent infections, and other mechanisms (e.g.,phagocytes, natural killer [NK] cells, the complement system) eliminate microbes. Adaptive immune responses develop later andare mediated by lymphocytes and their products. Antibodies block infections and eliminate microbes, and T lymphocytes eradicateintracellular microbes. The kinetics of the innate and adaptive immune responses are approximations and may vary in differentinfections.MicrobeInnate immunity Adaptive immunityEpithelialbarriersPhagocytes DendriticcellsNK cellsComplementB lymphocytesT lymphocytesTime after infection0 6 12 1 3 5AntibodiesEffector T cellsHours Days
  • 4. 4 Chapter 1 – Introduction to the Immune Systemand adaptive immunity are discussed in laterchapters.TYPES OF ADAPTIVE IMMUNITYThe two types of adaptive immunity,humoral immunity and cell-mediatedimmunity, are mediated by different cellsand molecules and provide defense againstextracellular microbes and intracellularmicrobes, respectively (Fig. 1–4). Humoralimmunity is mediated by proteins called anti-bodies, which are produced by cells called Blymphocytes. Antibodies are secreted into thecirculation and mucosal fluids, and they neutral-ize and eliminate microbes and microbial toxinsthat are present outside of host cells, in the bloodand in the lumens of mucosal organs, such as thegastrointestinal and respiratory tracts. One of themost important functions of antibodies is to stopmicrobes that are present at mucosal surfacesand in the blood from gaining access to and colo-nizing host cells and connective tissues. In thisway, antibodies prevent infections from everbeing established. Antibodies cannot gain accessto microbes that live and divide inside infectedcells. Defense against such intracellular microbesis called cell-mediated immunity because it ismediated by cells, which are called T lympho-cytes. Some T lymphocytes activate phagocytesto destroy microbes that have been ingested bythe phagocytes into intracellular vesicles. OtherT lymphocytes kill any type of host cells that areharboring infectious microbes in the cytoplasm.Thus, the antibodies produced by B lymphocytesrecognize extracellular microbial antigens,whereas T lymphocytes recognize antigens pro-duced by intracellular microbes. Another impor-tant difference between B and T lymphocytes isthat most T cells recognize only protein antigens,whereas B cells and antibodies are able to recog-nize many different types of molecules, includingproteins, carbohydrates, nucleic acids, and lipids.Immunity may be induced in an indi­vidual by infection or vaccination (activeimmunity) or conferred on an individual bytransfer of antibodies or lymphocytes froman actively immunized individual (passiveimmunity). In active immunity, an individualexposed to the antigens of a microbe mounts anactive response to eradicate the infection anddevelops resistance to later infection by thatto block the entry of microbes and rapidly elimi-nate microbes that do succeed in entering hosttissues. Adaptive immunity, also called spe-cific immunity or acquired immunity, requiresexpansion and differentiation of lymphocytesin response to microbes before it can provideeffective defense; that is, it adapts to the pres-ence of microbial invaders. Innate immunity isphylogenetically older, and the more specializedand powerful adaptive immune system evolvedlater.The first line of defense in innate immunity isprovided by epithelial barriers and by cells andnatural antibiotics present in epithelia, all ofwhich function to block the entry of microbes.If microbes do breach epithelia and enterthe tissues or circulation, they are attacked byphagocytes, specialized lymphocytes callednatural killer cells, and several plasma proteins,including the proteins of the complementsystem. All these mechanisms of innate immu-nity specifically recognize and react againstmicrobes. In addition to providing early defenseagainst infections, innate immune responsesenhance adaptive immune responses against theinfectious agents. The components and mecha-nisms of innate immunity are discussed in detailin Chapter 2.Defense against infectious microbes addition-ally requires adaptive immune responses, espe-cially with microbes that are pathogenic forhumans (i.e., capable of causing disease) andmay have evolved to resist innate immunity.The adaptive immune system consists oflymphocytes and their products, such asantibodies. Whereas the mechanisms of innateimmunity recognize structures shared by classesof microbes, the cells of adaptive immunity(lymphocytes) express receptors that specificallyrecognize a much wider variety of moleculesproduced by microbes as well as noninfectioussubstances. These substances are called anti-gens. Adaptive immune responses often usethe cells and molecules of the innate immunesystem to eliminate microbes, and adaptiveimmunity functions to greatly enhance theseantimicrobial mechanisms of innate immunity.For example, antibodies (a component of adap-tive immunity) bind to microbes, and thesecoated microbes avidly bind to and activatephagocytes (a component of innate immunity),which ingest and destroy the microbes. Similarexamples of the cooperation between innate
  • 5. Chapter 1 – Introduction to the Immune System 5the infection. The only physiologic example ofpassive immunity is seen in newborns, whoseimmune systems are not mature enough torespond to many pathogens but who are pro-tected against infections by acquiring antibodiesfrom their mothers through the placenta andbreast milk.PROPERTIES OF ADAPTIVEIMMUNE RESPONSESSeveral properties of adaptive immune responsesare crucial for the effectiveness of these responsesin combating infections (Fig. 1–5).microbe. Such an individual is said to be immuneto that microbe, in contrast with a naive indi-vidual, not previously exposed to that microbe’santigens. We are concerned mainly with themechanisms of active immunity. In passiveimmunity, a naive individual receives antibod-ies or cells (e.g., lymphocytes, feasible only ingenetically identical [inbred] animals) fromanother individual already immune to an infec-tion; for the lifetime of the transferred antibodiesor cells, the recipient is able to combat the infec-tion. Passive immunity is therefore useful forrapidly conferring immunity even before theindividual is able to mount an active response,but it does not induce long-lived resistance toFIGURE 1– 4 Types of adaptive immunity. In humoral immunity, B lymphocytes secrete antibodies that eliminate extracellularmicrobes. In cell-mediated immunity, different types of T lymphocytes recruit and activate phagocytes to destroy ingested microbesand kill infected cells.HumoralimmunityCell-mediatedimmunityMicrobeFunctionsRespondinglymphocytesEffectormechanismExtracellularmicrobesB lymphocyteSecretedantibodyActivatedmacrophageKilled infected cellPhagocytosedmicrobes inmacrophageHelperT lymphocyteIntracellularmicrobes(e.g., viruses)replicating withininfected cellCytotoxicT lymphocyteBlockinfections andeliminateextracellularmicrobesEliminatephagocytosedmicrobesKill infected cellsand eliminatereservoirsof infection
  • 6. 6 Chapter 1 – Introduction to the Immune SystemSpecificity and DiversityThe adaptive immune system is capable of dis-tinguishing among millions of different antigensor portions of antigens. Specificity is the abilityto distinguish between many different antigens.It implies that the total collection of lymphocytespecificities, sometimes called the lymphocyterepertoire, is extremely diverse. The basis forthis remarkable specificity and diversity is thatlymphocytes express clonally distributed recep-tors for antigens, meaning that the total popula-tion of lymphocytes consists of many differentclones (each made up of one cell and its progeny),and each clone expresses an antigen receptorthat is different from the receptors of all otherclones. The clonal selection hypothesis,formulated in the 1950s, correctly predicted thatclones of lymphocytes specific for differentantigens develop before an encounter with theseantigens, and each antigen elicits an immuneresponse by selecting and activating thelymphocytes of a specific clone (Fig. 1–6). Wenow know the molecular basis for how the speci-ficity and diversity of lymphocytes are generated(see Chapter 4).The diversity of the lymphocyte repertoire,which enables the immune system to respondto a vast number and variety of antigens, alsomeans that very few cells, perhaps as few as onein 100,000 or one in 1 million lymphocytes, arespecific for any one antigen. The total numberof naive (unactivated) lymphocytes that can rec-ognize and react against any one antigen rangesfrom about 1,000 to 10,000 cells. To mount aneffective defense against microbes, these fewcells have to give rise to a large number of lym-phocytes capable of destroying the microbes. Theremarkable effectiveness of immune responsesis attributable to several features of adaptiveimmunity, including (1) marked expansion ofthe pool of lymphocytes specific for any antigenon exposure to that antigen, (2) positive feed-back loops that amplify immune responses, and(3) selection mechanisms that preserve the mostuseful lymphocytes. These characteristics of theadaptive immune system are described in laterchapters.MemoryThe immune system mounts larger and moreeffective responses to repeated exposures tothe same antigen. The response to the first expo­sure to antigen, called the primary immuneresponse, is mediated by lymphocytes callednaive lymphocytes that are seeing antigen for thefirst time (Fig. 1–7). The term naive refers tothese cells being immunologically inexperienced,not having previously responded to antigens.Subsequent encounters with the same antigenlead to responses called secondary immuneresponses that usually are more rapid, larger,and better able to eliminate the antigen thanprimary responses. Secondary responses are theresult of the activation of memory lymphocytes,which are long-lived cells that were inducedduring the primary immune response. Immu-nologic memory optimizes the ability of theimmune system to combat persistent and recur-rent infections, because each encounter witha microbe generates more memory cells andactivates previously generated memory cells.Memory also is one of the reasons why vaccinesconfer long-lasting protection against infections.FIGURE 1–5 Properties of adaptive immune re­sponses. This table summarizes the important properties ofadaptive immune responses and how each feature contributesto host defense against microbes.Feature Functional significanceSpecificityDiversityMemoryNonreactivityto selfEnsures that distinct antigenselicit responses that targetthose antigensEnables immune systemto respond to a largevariety of antigensLeads to rapid and enhancedresponses to repeatedexposures to the sameantigensClonalexpansionSpecializationContraction andhomeostasisIncreases number ofantigen-specific lymphocytesto keep pace with microbesGenerates responses that areoptimal for defense againstdifferent types of microbesAllows immune systemto respond to newlyencountered antigensPrevents injury to thehost during responses toforeign antigens
  • 7. Chapter 1 – Introduction to the Immune System 7Other Features of Adaptive ImmunityAdaptive immune responses have other charac-teristics that are important for their functions(see Fig. 1–5). When lymphocytes are activatedby antigens, they undergo proliferation, generat-ing many thousands of clonal progeny cells, allwith the same antigen specificity. This process,called clonal expansion, rapidly increases thenumber of cells specific for the antigen encoun-tered, enabling few antigen-specific lymphocytesto serve their defensive role, and ensures thatadaptive immunity keeps pace with rapidly pro-liferating microbes. Immune responses are spe-cialized, and different responses are designed todefend best against different classes of microbes.All immune responses are self-limited and declineas the infection is eliminated, allowing the systemFIGURE 1–6 Clonal selection. Mature lymphocytes with receptors for many antigens develop before encountering these anti-gens. A clone refers to a population of lymphocytes with identical antigen receptors and therefore speci­ficities; all these cells arepresumably derived from one precursor cell. Each antigen (e.g., X and Y) selects a preexisting clone of specific lymphocytes and stimu-lates the proliferation and differentiation of that clone. The diagram shows only B lymphocytes giving rise to antibody-secreting cells,but the same principle applies to T lymphocytes. The antigens shown are surface molecules of microbes, but clonal selection also istrue for extracellular soluble and intracellular antigens.Lymphocyteclones withdiverse receptorsarise in generativelymphoid organsClones of maturelymphocytesspecific for manyantigens enterlymphoid tissuesAntigen-specificclones areactivated(“selected”)by antigensAntigen-specificimmuneresponses occurLymphocyteprecursorMaturelymphocytesAntigen X Antigen YAnti-XantibodyAnti-Yantibodyto return to a resting state, prepared to respondto another infection.The immune system is able to react against anenormous number and variety of microbes andother foreign antigens, but it normally does notreact against the host’s own potentially antigenicsubstances—so-called self antigens. This unre-sponsiveness to self is called immunologicaltolerance, referring to the ability of the immunesystem to coexist with (tolerate) potentially anti-genic self molecules, cells, and tissues.CELLS OF THE IMMUNE SYSTEMThe cells of the adaptive immune system consistof lymphocytes, antigen-presenting cells that
  • 8. 8 Chapter 1 – Introduction to the Immune Systemcluster or group of antibodies. (A list of CDmolecules mentioned in the book is providedin Appendix II.)As alluded to earlier, B lymphocytes are theonly cells capable of producing antibodies; there-fore they are the cells that mediate humoralimmunity. B cells express membrane formsof antibodies that serve as the receptors thatrecognize antigens and initiate the process ofactivation of the cells. Soluble antigens and anti-gens on the surface of microbes and other cellsmay bind to these B lymphocyte antigen recep-tors, initiating the process of B cell activation.This leads to the secretion of soluble forms ofantibodies with the same antigen specificity asthe membrane receptors.T lymphocytes are responsible for cell-mediated immunity. The antigen receptors ofmost T lymphocytes recognize only peptide frag-ments of protein antigens that are bound tospecialized peptide display molecules calledmajor histocompatibility complex (MHC) mole-cules on the surface of specialized cells calledantigen-presenting cells (see Chapter 3). AmongT lymphocytes, CD4+T cells are called helper Tcells because they help B lymphocytes toproduce antibodies and help phagocytes todestroy ingested microbes. CD8+T lymphocytescapture and display microbial antigens, andeffector cells (which include activated lympho-cytes and other cells, particularly other leuko-cytes) that eliminate microbes (Fig. 1–8). Thissection describes the important functional prop-erties of the major cell populations; a discussionof cellular morphology may be found in histol-ogy textbooks. The cells of innate immunity aredescribed in Chapter 2.LymphocytesLymphocytes are the only cells thatproduce receptors specific for diverse anti-gens and are the key mediators of adaptiveimmunity. Although all lymphocytes aremorpho­logically similar and rather unremark-able in appearance, they are heterogeneous inlineage, function, and phenotype and arecapable of complex biologic responses and activi-ties (Fig. 1–9). These cells often are distinguish-able by surface proteins that may be identifiedusing panels of monoclonal antibodies. The stan-dard nomenclature for these proteins is the CD(cluster of differentiation) numerical designa-tion, which is used to delineate surface proteinsthat define a particular cell type or stage of celldifferentiation and that are recognized by aFIGURE 1–7 Primary and sec­ondary immune responses.Antigens X and Y induce the produc-tion of different antibodies (a reflectionof specificity). The secondary responseto antigen X is more rapid and largerthan the primary response (illustratingmemory) and is different from theprimary response to antigen Y (againreflecting specificity). Antibody levelsdecline with time after each immuniza-tion. The level of antibody producedis shown as arbitrary values and varieswith the type of antigen exposure.Only B cells are shown, but the samefeatures are seen with T cell responsesto antigens. The time after immuniza-tion may be 1-3 weeks for a primaryresponse and 2-7 days for a secondaryresponse, but the kinetics vary depend-ing on the antigen and nature ofimmunization.AntibodyresponseAnti-X B cellAnti-Y B cellAntigen XPrimaryanti-XresponseAntigen X +Antigen YSecondaryanti-XresponseTime after immunizationPrimaryanti-YresponseNaiveB cellsMemoryB cellsPlasmacellPlasma cellsPlasmacells
  • 9. Chapter 1 – Introduction to the Immune System 9FIGURE 1–8 Principal cells of the immune system. This table shows the major cell types involved in immune responses,and the key functions of these cells. Micrographs in the left panels illustrate the morphology of some cells of each type. Note thattissue macrophages are derived from blood monocytes.Cell type Principal function(s)Lymphocytes:B lymphocytes;T lymphocytes;natural killer cellsAntigen-presenting cells:dendritic cells;macrophages;follicular dendritic cellsEffector cells:T lymphocytes;macrophages;granulocytesSpecific recognition of antigens:B lymphocytes: mediators ofhumoral immunityT lymphocytes: mediators ofcell-mediated immunityNatural killer cells: cells ofinnate immunityCapture of antigens for displayto lymphocytes:Dendritic cells: initiation ofT cell responsesMacrophages: effector phase ofcell-mediated immunityFollicular dendritic cells: display ofantigens to B lymphocytes inhumoral immune responsesElimination of antigens:T lymphocytes: helper T cells andcytotoxic T lymphocytesMacrophages and monocytes:cells of the mononuclearphagocyte systemGranulocytes: neutrophils,eosinophilsBlood lymphocyteDendritic cell Blood monocyteNeutrophilare called cytotoxic T lymphocytes (CTLs)because they kill cells harboring intracellularmicrobes. Some CD4+T cells belong to a specialsubset that functions to prevent or limit immuneresponses; these are called regulatory T lym-phocytes. Another class of lymphocytes is callednatural killer (NK) cells, which also killinfected host cells, but unlike B and T cells, theydo not express clonally distributed antigen recep-tors. NK cells are components of innate immu-nity, capable of rapidly attacking infected cells.All lymphocytes arise from stem cells in thebone marrow (Fig. 1–10). B lymphocytesmature in the bone marrow, and T lympho-cytes mature in an organ called the thymus.These sites in which mature lymphocytes areproduced (generated) are called the generativelymphoid organs. Mature lymphocytes leavethe generative lymphoid organs and enter thecirculation and the peripheral lymphoidorgans, where they may encounter antigen forwhich they express specific receptors.
  • 10. 10 Chapter 1 – Introduction to the Immune SystemFIGURE 1–9 Classes of lymphocytes. Different classes of lymphocytes recognize distinct types of antigens and differentiateinto effector cells whose function is to eliminate the antigens. B lymphocytes recognize soluble or cell surface antigens and differentiateinto antibody-secreting cells. Helper T lymphocytes recognize antigens on the surfaces of antigen-presenting cells and secrete cytokines,which stimulate different mechanisms of immunity and inflammation. Cytotoxic T lymphocytes recognize antigens in infected cells andkill these cells. (Note that T lymphocytes recognize peptides that are displayed by MHC molecules, discussed in Chapter 3.) RegulatoryT cells limit the activation of other lymphocytes, especially of T cells, and prevent autoimmunity. Natural killer cells recognize changeson the surface of infected cells and kill these cells. NK cells are cells of innate immunity, and all the other lymphocytes are cells of theadaptive immune system.++MicrobeAntibodyMicrobial antigenpresentedby antigen-presenting cellInfected cellexpressingmicrobial antigenCytokinesTarget cellBlymphocyteHelper TlymphocyteCytotoxic Tlymphocyte(CTL)RegulatoryT lymphocyteNatural killer(NK) cellAntigen recognition Effector functionsNeutralizationof microbe,phagocytosis,complementactivationKilling ofinfected cellKilling ofinfected cellActivation ofmacrophagesInflammationActivation(proliferation anddifferentiation)of T and BlymphocytesSuppressionof immuneresponse
  • 11. Chapter 1 – Introduction to the Immune System 11FIGURE 1–10 Maturation of lymphocytes. Lymphocytes develop from precursors in the generative lymphoid organs (bonemarrow and thymus). Mature lymphocytes enter the peripheral lymphoid organs, where they respond to foreign antigens and recirculatein the blood and lymph.BlymphocytelineageTlymphocytelineageBonemarrowThymusImmatureB lymphocytesMatureB lymphocytesMature naiveT lymphocytesMatureT lymphocytesLymphnodesSpleenMucosal andcutaneouslymphoidtissuesRecirculationRecirculationGenerativelymphoidorgansPeripherallymphoid organsBlood,lymphCommonlymphoidprecursorWhen naive lymphocytes recognizemicrobial antigens and also receive addi-tional signals induced by microbes, theantigen-specific lymphocytes proliferateand differentiate into effector cells andmemory cells (Fig. 1–11). Naive lymphocytesexpress receptors for antigens but do not performthe functions that are required to eliminateantigens. These cells reside in and circulatebetween peripheral lymphoid organs and survivefor several weeks or months, waiting to findand respond to antigen. If they are not acti-vated by antigen, naive lymphocytes die bythe process of apoptosis and are replaced bynew cells that have arisen in the generativelymphoid organs. The differentiation of naivelymphocytes into effector cells and memorycells is initiated by antigen recognition, thusensuring that the immune response that devel-ops is specific for the antigen. Effector cellsare the differentiated progeny of naive cellsthat have the ability to produce molecules thatfunction to eliminate antigens. The effector cellsin the B lymphocyte lineage are antibody-secreting cells, called plasma cells. Plasma cellsdevelop in response to antigenic stimulationin the peripheral lymphoid organs, where theymay stay and produce antibodies. Antibody-secreting cells, called plasmablasts, are alsopresent in the blood. Some of these migrateto the bone marrow, where they mature intolong-lived plasma cells and continue to producesmall amounts of antibody long after the infec-tion is eradicated, providing immediate protec-tion in case the infection recurs.Effector CD4+T cells (helper T cells) produceproteins called cytokines that activate B cells,macrophages, and other cell types, therebymediating the helper function of this lineage.Effector CD8+T cells (CTLs) have the machineryto kill infected host cells. The development andfunctions of these effector cells are discussed inlater chapters. Effector T lymphocytes are short-lived and die as the antigen is eliminated.Memory cells, also generated from theprogeny of antigen-stimulated lymphocytes, dosurvive for long periods in the absence of antigen.Therefore, the frequency of memory cellsincreases with age, presumably because of expo-sure to environmental microbes. In fact, memorycells make up less than 5% of peripheral bloodT cells in a newborn, but 50% or more in anadult. Memory cells are functionally inactive;they do not perform effector functions unlessstimulated by antigen. When memory cellsencounter the same antigen that induced theirdevelopment, the cells rapidly respond to initiatesecondary immune responses. The signals that
  • 12. 12 Chapter 1 – Introduction to the Immune SystemFIGURE 1–11 Stages in the life history of lymphocytes. A, Naive lymphocytes recognize foreign antigens to initiateadaptive immune responses. Naive lymphocytes need signals in addition to antigens to proliferate and differentiate into effector cells;these additional signals are not shown. Effector cells, which develop from naive cells, function to eliminate antigens. The effector cellsof the B lymphocyte lineage are antibody-secreting plasma cells (some of which are long-lived). The effector cells of the CD4 T lym-phocyte lineage produce cytokines. (The effector cells of the CD8 lineage are CTLs; these are not shown.) Other progeny of theantigen-stimulated lymphocytes differentiate into long-lived memory cells. B, The important characteristics of naive, effector, andmemory cells in the B and T lymphocyte lineages are summarized. The generation and functions of effector cells, including changesin migration patterns and types of immunoglobulin produced, are described in later chapters.Cell type StageB lymphocytesHelper TlymphocytesT lymphocytesB lymphocytesMigration Preferentiallyto peripherallymph nodesPreferentially toinflamed tissuesHeterogenous: one subset tolymph nodes, one subset tomucosa and inflamed tissuesVery low High LowNone Cytokine secretion;cytotoxic activityNoneFrequency of cellsresponsive toparticular antigenEffector functionsABAntigenrecognitionAntigenrecognitionProliferationProliferationDifferentiationDifferentiationNaive cell Memory lymphocyteActivated oreffector lymphocyteNaive cellMemorylymphocyteActivated oreffector lymphocyteMembraneimmunoglobulin(Ig) isotypeAffinity ofIg producedIgM and IgD Typically IgG,IgA, or IgETypically IgG,IgA, or IgERelatively low Increases duringimmune responseRelatively highNone Antibody secretion NoneEffector functions
  • 13. Chapter 1 – Introduction to the Immune System 13organs and displays antigens that stimulate thedifferentiation of B cells in the follicles (seeChapter 7). Follicular dendritic cells (FDCs) donot present antigens to T cells and differ from thedendritic cells described earlier that function asAPCs for T lymphocytes.Effector CellsThe cells that eliminate microbes are calledeffector cells and consist of lymphocytesand other leukocytes. The effector cells of theB and T lymphocyte lineages were mentionedearlier. The elimination of microbes oftenrequires the participation of other, nonlymphoidleukocytes, such as granulocytes and macro-phages. These leukocytes may function as effec-tor cells in both innate immunity and adaptiveimmunity. In innate immunity, macrophagesand some granulocytes directly recognizemicrobes and eliminate them (see Chapter 2). Inadaptive immunity, the products of B and T lym-phocytes enhance the activities of macrophagesand recruit other leukocytes and activate themto kill microbes.TISSUES OF THE IMMUNE SYSTEMThe tissues of the immune system consistof the generative lymphoid organs, in whichT and B lymphocytes mature and becomecompetent to respond to antigens, and theperipheral lymphoid organs, in which adap-tive immune responses to microbes areinitiated (see Fig. 1–10). The generative (alsocalled primary or central) lymphoid organs aredescribed in Chapter 4, when we discuss theprocess of lymphocyte maturation. The followingsection highlights some of the features ofperipheral (or secondary) lymphoid organs thatare important for the development of adaptiveimmunity.Peripheral Lymphoid OrgansThe peripheral lymphoid organs, which consistof the lymph nodes, the spleen, and the mucosaland cutaneous immune systems, are organizedto optimize interactions of antigens, APCs, andlymphocytes in a way that promotes the devel-opment of adaptive immune responses. T and Blymphocytes must locate microbes that enter atgenerate and maintain memory cells are not wellunderstood but include cytokines.Antigen-Presenting CellsThe common portals of entry for microbes—the skin, gastrointestinal tract, and respi­ratory tract—contain specialized antigen-presenting cells (APCs) located in theepithelium that capture antigens, transportthem to peripheral lymphoid tissues, anddisplay (present) them to lymphocytes. Thisfunction of antigen capture and presentation isbest understood for a cell type that is calleddendritic cells because of their long surfacemembrane processes. Dendritic cells captureprotein antigens of microbes entering throughthe epithelia and transport the antigens to re-gional lymph nodes, where the antigen-bearingdendritic cells display portions of the antigens forrecognition by T lymphocytes. If a microbe hasinvaded through the epithelium, it may bephagocytosed by macrophages that live in tissuesand in various organs. Microbes or their antigensthat enter lymphoid organs may be captured bydendritic cells or macrophages that reside inthese organs and presented to lymphocytes.Dendritic cells are the most effective APCs forinitiating T cell responses. The process of antigenpresentation to T cells is described in Chapter 3.Cells that are specialized to display antigens toT lymphocytes have another important featurethat gives them the ability to trigger T cellresponses. These specialized cells respond tomicrobes by producing surface and secreted pro-teins that are required, together with antigen, toactivate naive T lymphocytes to proliferate anddifferentiate into effector cells. Specialized cellsthat display antigens to T cells and provide addi-tional activating signals sometimes are calledprofessional APCs. The prototypic professionalAPCs are dendritic cells, but macrophages, Bcells, and a few other cell types may serve thesame function in various immune responses.Less is known about cells that may captureantigens for display to B lymphocytes. B lympho-cytes may directly recognize the antigens ofmicrobes (either released or on the surface ofthe microbes), or macrophages lining lymphaticchannels may capture antigens and display themto B cells. A type of cell called the folliculardendritic cell resides in the germinal centers oflymphoid follicles in the peripheral lymphoid
  • 14. 14 Chapter 1 – Introduction to the Immune Systemany site in the body, then respond to thesemicrobes and eliminate them. In addition, as pre-viously discussed, in the normal immune systemvery few of these lymphocytes are specific forany one antigen. It is not possible for the fewlymphocytes specific for any antigen to patrol allpossible sites of antigen entry. The anatomicorganization of peripheral lymphoid organsenables APCs to concentrate antigens in theseorgans and lymphocytes to locate and respond tothe antigens. This organization is complementedby a remarkable ability of lymphocytes to circu-late throughout the body in such a way thatnaive lymphocytes preferentially go to the spe-cialized organs in which antigen is concentrated,and effector cells go to sites of infection wheremicrobes must be eliminated. Furthermore, dif-ferent types of lymphocytes often need to com-municatetogenerateeffectiveimmuneresponses.For example, helper T cells specific for an antigeninteract with and help B lymphocytes specific forthe same antigen, resulting in antibody produc-tion. An important function of lymphoid organsis to bring these rare cells together so that theyinteract productively.Lymph nodes are encapsulated nodularaggregates of lymphoid tissues located alonglymphatic channels throughout the body (Fig.1–12). Fluid constantly leaks out of blood vesselsin all epithelia and connective tissues and mostparenchymal organs. This fluid, called lymph, isdrained by lymphatic vessels from the tissues tothe lymph nodes and eventually back into theblood circulation. Therefore, the lymph containsa mixture of substances absorbed from epitheliaand tissues. As the lymph passes through lymphnodes, APCs in the nodes are able to sample theantigens of microbes that may enter through epi-thelia into tissues. In addition, dendritic cells pickup antigens of microbes from epithelia and othertissues and transport these antigens to the lymphnodes. The net result of these processes of antigencapture and transport is that the antigens ofmicrobes entering through epithelia or coloniz-ing tissues become concentrated in draininglymph nodes.The spleen is a highly vascularized abdomi-nal organ that serves the same role in immuneresponses to blood-borne antigens as that oflymph nodes in responses to lymph-borne anti-gens (Fig. 1–13). Blood entering the spleenflows through a network of channels (sinu-soids). Blood-borne antigens are trapped andFIGURE 1–12 Morphology of lymph nodes. A, Sche-matic diagram shows the structural organization of a lymph node.B, Light micrograph shows a cross section of a lymph node withnumerous follicles in the cortex, some of which contain lightlystained central areas (germinal centers).B cell zone(follicle)AfferentlymphaticvesselTrabeculaCapsuleVeinArteryEfferentlymphaticvesselMedullaT cellzoneGerminalcenterMedullarysinusPrimary lymphoidfollicle (B cell zone)Secondaryfollicle withgerminalcenterParafollicularcortex (T cell zone)AntigenLymphocytesSubcapsularsinusHighendothelialvenule (HEV)AB
  • 15. Chapter 1 – Introduction to the Immune System 15pharyngeal tonsils and Peyer’s patches of theintestine are two anatomically defined mucosallymphoid tissues (Fig. 1–14). At any time, at leasta quarter of the body’s lymphocytes are in themucosal tissues and skin (reflecting the large sizeof these tissues), and many of these are memorycells. Cutaneous and mucosal lymphoid tissuesare sites of immune responses to antigens thatbreach epithelia. A challenge for the cutaneousand mucosal immune systems is to be able torespond to pathogens but not react to the enor­mous numbers of usually harmless commensalmicrobes present at the epithelial barriers. Thisis accomplished by several incompletely under-stood mechanisms, including the action of regu-latory T cells and dendritic cells that suppressrather than activate T lymphocytes.Within the peripheral lymphoid organs, Tlymphocytes and B lymphocytes are segregatedinto different anatomic compartments (Fig.1–15). In lymph nodes, the B cells are concen-trated in discrete structures, called follicles,located around the periphery, or cortex, of eachnode. If the B cells in a follicle have recentlyresponded to an antigen, this follicle may containa central lightly staining region called a germi-nal center. The role of germinal centers in theproduction of antibodies is described in Chapter7. The T lymphocytes are concentrated outsidebut adjacent to the follicles, in the paracortex.The follicles contain the FDCs described earlierthat are involved in the activation of B cells, andthe paracortex contains the dendritic cells thatpresent antigens to T lymphocytes. In the spleen,T lymphocytes are concentrated in periarteriolarlymphoid sheaths surrounding small arterioles,and B cells reside in the follicles.The anatomic organization of peripheral lym-phoid organs is tightly regulated to allow immuneresponses to develop after stimulation by anti-gens. B lymphocytes are attracted to and retainedin the follicles because of the action of a class ofcytokines called chemokines (chemoattractantcytokines; chemokines and other cytokines arediscussed in more detail in later chapters). FDCsin the follicles constantly secrete a particular che-mokine for which naive B cells express a recep-tor, called CXCR5. The chemokine that binds toCXCR5 attracts B cells from the blood into thefollicles of lymphoid organs. Similarly, T cells aresegregated in the paracortex of lymph nodes andthe periarteriolar lymphoid sheaths of the spleen,because naive T lymphocytes express a receptor,concentrated by dendritic cells and macrophagesin the spleen. The spleen contains abundantphagocytes, which ingest and destroy microbesin the blood.The cutaneous immune system andmucosal immune system are specialized col-lections of lymphoid tissues, APCs, and effectormolecules located in and under the epithelia ofthe skin and the gastrointestinal and respiratorytracts, respectively. Although most of the immunecells in these tissues are diffusely scatteredbeneath the epithelial barriers, there are discretecollections of lymphocytes and APCs organizedin a similar way as in lymph nodes. For example,FIGURE 1–13 Morphology of the spleen. A, Schematicdiagram shows a splenic arteriole surrounded by the periarteriolarlymphoid sheath (PALS) and attached follicle containing a promi-nent germinal center. The PALS and lymphoid follicles togetherconstitute the white pulp. B, Light micrograph of a section ofspleen shows an arteriole with the PALS and a follicle with agerminal center. These are surrounded by the red pulp, which isrich in vascular sinusoids.Periarteriolarlymphoidsheath (PALS)BGerminalcenter oflymphoidfollicleT cell zone(periarteriolarlymphoidsheath PALS)Red pulpB cell zone(follicle)MarginalzoneMarginalsinusFolliculararterioleTrabeculararteryCentralarterioleA
  • 16. 16 Chapter 1 – Introduction to the Immune Systemcalled CCR7, that recognizes chemokines thatare produced in these regions of the lymph nodesand spleen. As a result, T lymphocytes arerecruited from the blood into the parafollicularcortex region of the lymph node and the periar-teriolar lymphoid sheaths of the spleen. Whenthe lymphocytes are activated by antigens, theyalter their expression of chemokine receptors.The B cells and T cells then migrate toward eachother and meet at the edge of follicles, wherehelper T cells interact with and help B cells todifferentiate into antibody-producing cells (seeChapter 7). Thus, these lymphocyte populationsFIGURE 1–14 Mucosal immune system. Schematic diagram of the mucosal immune system uses the small bowel as anexample. Many commensal bacteria are present in the lumen. The mucus-secreting epithelium provides an innate barrier to microbialinvasion (discussed in Chapter 2). Specialized epithelial cells, such as M cells, promote the transport of antigens from the lumen intounderlying tissues. Cells in the lamina propria, including dendritic cells, T lymphocytes, and macrophages, provide innate and adaptiveimmune defense against invading microbes; some of these cells are organized into specialized structures, such as Peyer’s patches inthe small intestine. Immunoglobulin A (IgA) is a type of antibody abundantly produced in mucosal tissues that is transported into thelumen, where it binds and neutralizes microbes (Chapter 8).FollicleDendriticcellAfferentlymphaticPlasma cellT cellMacrophageB cellPeyer’spatchLaminapropriaMesenteryMucosalepitheliumM cellCommensalbacteriaMucusCryptIntraepitheliallymphocytes Intestinalepithelia cellDendriticcellLymphaticdrainageIntestinallumenVillusMesentericlymph nodeIgAare kept apart from each other until it is usefulfor them to interact, after exposure to an antigen.This is an excellent example of how the structureof lymphoid organs ensures that the cells thathave recognized and responded to an antigeninteract and communicate with one anotheronly when necessary.Many of the activated lymphocytes, especiallythe T cells, ultimately exit the node throughefferent lymphatic vessels and leave the spleenthrough veins. These activated lymphocytes endup in the circulation and can go to distant sitesof infection.
  • 17. Chapter 1 – Introduction to the Immune System 17Lymphocyte Recirculation andMigration into TissuesNaive lymphocytes constantly recirculatebetween the blood and peripheral lym-phoid organs, where they may be activatedby antigens to become effector cells, andthe effector lymphocytes migrate fromlymphoid tissues to sites of infection, wheremicrobes are eliminated (Fig. 1–16). Thus,lymphocytes at distinct stages of their livesmigrate to the different sites where they areneeded for their functions. Migration of effectorlymphocytes to sites of infection is most relevantfor T cells, because effector T cells have to locateand eliminate microbes at these sites. By con-trast, plasma cells do not need to migrate to sitesof infection; instead, they secrete antibodies, andthe antibodies enter the blood, where they maybind blood-borne pathogens or toxins. In addi-tion, antibodies may be carried to tissue sites ofinfection by the circulation.Naive T lymphocytes that have matured in thethymus and entered the circulation migrate tolymph nodes, where they can find antigens thatenter through lymphatic vessels that drain epi-thelia and parenchymal organs. These naive Tcells enter lymph nodes through specialized post-capillary venules, called high endothelialvenules (HEVs). The adhesion molecules usedby the T cells to bind to the endothelium aredescribed in Chapter 6. Chemokines produced inthe T cell zones of the lymph nodes and dis-played on HEV surfaces bind to the chemokinereceptor CCR7 expressed on naive T cells, whichcauses the T cells to bind tightly to HEVs. Thenaive T cells then migrate into the T cell zone,where antigens are displayed by dendritic cells.Naive B cells also enter lymphoid tissues, butthen migrate to follicles in response to chemo-kines that bind CXCR5, the chemokine receptorexpressed on these B cells.In the lymph node, if a T cell specifically rec-ognizes an antigen on a dendritic cell, that T cellforms stable conjugates with the dendritic celland is activated. Such an encounter between anantigen and a specific lymphocyte is likely to bea random event, but most T cells in the bodycirculate through some lymph nodes at leastonce a day. As mentioned earlier and describedfurther in Chapter 3, the likelihood of the correctT cell finding its antigen is increased in periph-eral lymphoid organs, particularly lymph nodes,FIGURE 1–15 Segregation of T and B lymphocytesin different regions of peripheral lymphoid organs.A, Schematic diagram illustrates the path by which naive T andB lymphocytes migrate to different areas of a lymph node. NaiveB and T lymphocytes enter through a high endothelial venule(HEV), shown in cross section, and are drawn to different areasof the node by chemokines that are produced in these areas andbind selectively to either cell type. Also shown is the migrationof dendritic cells, which pick up antigens from epithelia, enterthrough afferent lymphatic vessels, and migrate to the T cell–richareas of the node (Chapter 3). B, In this histologic section of alymph node, the B lymphocytes, located in the follicles, arestained green, and the T cells, in the parafollicular cortex, arestained red using immunofluorescence. In this technique, asection of the tissue is stained with antibodies specific for T orB cells coupled to fluorochromes that emit different colors whenexcited at the appropriate wavelengths. The anatomic segrega-tion of T and B cells also occurs in the spleen (not shown).(Courtesy Drs. Kathryn Pape and Jennifer Walter, University ofMinnesota Medical School, Minneapolis.)B cellzoneArteryAfferentlymphaticvesselDendriticcellT cellzoneB cellT cellT cell– anddendritic cell–specificchemokineB cell–specificchemokineHighendothelialvenuleB cell zone(lymphoidfollicle)T cell zone(parafollicularcortex)NaiveT cellNaiveB cellAB
  • 18. 18 Chapter 1 – Introduction to the Immune SystemOVERVIEW OF IMMUNERESPONSES TO MICROBESNow that we have described the major compo-nents of the immune system, it is useful to sum-marize the key features of immune responses tomicrobes. The focus here is on the physiologicfunction of the immune system—defense againstinfections. In subsequent chapters, each of thesefeatures is discussed in more detail.Early Innate Immune Response to MicrobesThe principal barriers between the host and theenvironment are the epithelia of the skin andthe gastrointestinal and respiratory tracts. Infec-tious microbes usually enter through theseroutes and attempt to colonize the host. Epitheliaserve as physical and functional barriers to infec-tions, simultaneously impeding the entry ofmicrobes and interfering with their growththrough production of natural antimicrobialagents. If microbes are able to traverse theseepithelia and enter tissues and the circulation,they encounter the defense mechanisms ofinnate immunity, which are designed to reactrapidly against microbes and their products.Phagocytes, including neutrophils and macro-phages, ingest microbes into vesicles and destroythem by producing microbicidal substances inthese vesicles. Macrophages and dendritic cellsbecause microbial antigens are concentrated inthe same regions of these organs through whichnaive T cells circulate. Thus, T cells find theantigen they can recognize, and these T cells areactivated to proliferate and differentiate. Naivecells that have not encountered specific antigensleave the lymph nodes and reenter the circula-tion. The effector cells that are generated uponT cell activation preferentially migrate into thetissues infected by microbes, where the T lym-phocytes perform their function of eradicatingthe infection. Specific signals control theseprecise patterns of migration of naive and acti-vated T cells (see Chapter 6).B lymphocytes that recognize and respond toantigen in lymph node follicles differentiate intoantibody-secreting cells, which either remain inthe lymph nodes or migrate to the bone marrow(see Chapter 7).Memory T cells consist of different popula-tions; some cells recirculate through lymphnodes, where they can mount secondaryresponses to captured antigens, and other cellsmigrate to sites of infection, where they canrespond rapidly to eliminate the infection.We know less about lymphocyte circulationthrough the spleen or other lymphoid tissues.The spleen does not contain HEVs, but thegeneral pattern of naive lymphocyte migrationthrough this organ probably is similar to migra-tion through lymph nodes.FIGURE 1–16 Migration of T lymphocytes. Naive T lymphocytes migrate from the blood through high endothelial venulesinto the T cell zones of lymph nodes, where the cells are activated by antigens. Activated T cells exit the nodes, enter the bloodstream,and migrate preferentially to peripheral tissues at sites of infection and inflammation. The adhesion molecules involved in the attach-ment of T cells to endothelial cells are described in Chapter 6.Lymph node PeripheraltissueArteryBloodvesselPeripheralblood vesselEfferentlymphaticvesselHighendothelialvenuleEffector ormemory T cellNaive T cell
  • 19. Chapter 1 – Introduction to the Immune System 19the dendritic cells to generate peptides that aredisplayed on the surface of the APCs bound toMHC molecules. Naive T cells recognize thesepeptide-MHC complexes, and this is the first stepin the initiation of T cell responses. Protein anti-gens also are recognized by B lymphocytes inthe lymphoid follicles of the peripheral lymphoidorgans. Polysaccharides and other nonproteinantigens are captured in the lymphoid organsand are recognized by B lymphocytes but notby T cells.As part of the innate immune response, thedendritic cells that present the antigen to naiveT cells are activated to express molecules calledcostimulators and to secrete cytokines, both ofwhich are needed, in addition to the antigen, tostimulate the proliferation and differentiation ofT lymphocytes. The innate immune response tosome microbes and polysaccharide antigens alsoresults in the activation of the complementsystem, which generates cleavage products ofproteins that have various immune functions.Some complement-generated products enhancethe proliferation and differentiation of B lym-phocytes. Thus, antigen (often referred to assignal 1) and molecules produced during innateimmune responses (signal 2) function coopera-tively to activate antigen-specific lymphocytes.The requirement for microbe-triggered signal 2ensures that the adaptive immune response isinduced by microbes and not by harmless sub-stances. Signals generated in lymphocytes by theengagement of antigen receptors and receptorsfor costimulators lead to the transcription ofvarious genes, which encode cytokines, cytokinereceptors, effector molecules, and proteins thatcontrol cell survival and cycling. All these mol-ecules are involved in the responses of thelymphocytes.Cell-Mediated Immunity: Activation of T Lymphocytesand Elimination of Cell-Associated MicrobesWhen activated by antigen and costimulators inlymphoid organs, naive T cells secrete cytokinesthat function as growth factors and respond toother cytokines secreted by APCs. The combina-tion of signals (antigen, costimulation, and cyto-kines) stimulates the proliferation of the T cellsand their differentiation into effector T cells. Theeffector T cells generated in the lymphoid organmay migrate back into the blood and then intoany site where the antigen (or microbe) ispresent. These effector cells are reactivated bythat encounter microbes also secrete cytokines,which serve numerous functions.The two major cellular reactions of innateimmunity are inflammation, which is inducedby cytokines and other molecules and serves tobring leukocytes and plasma proteins to the siteof infection or injury, and antiviral defense,which is mediated by type I interferons (a par-ticular family of cytokines) and NK cells. Manyplasma proteins are involved in host defense,including the proteins of the complement system,which are activated by microbes, and whoseproducts kill microbes and coat (opsonize) themfor phagocytosis by macrophages and neutro-phils. In addition to combating infections, innateimmune responses stimulate subsequent adap-tive immunity, providing signals that are essen-tial for initiating the responses of antigen-specificT and B lymphocytes. The combined actions ofthe mechanisms of innate immunity can eradi-cate some infections and keep other pathogensin check until the more powerful adaptiveimmune response is activated.Adaptive Immune ResponseThe adaptive immune system uses the followingstrategies to combat the majority of microbes:l Secreted antibodies bind to extracellularmicrobes, block their ability to infect host cells,and promote their ingestion and subsequentdestruction by phagocytes.l Phagocytes ingest microbes and kill them, andhelper T cells enhance the microbicidal abili-ties of the phagocytes.l Helper T cells recruit leukocytes to destroymicrobes and enhance epithelial barrier func-tion to expel microbes.l Cytotoxic T lymphocytes destroy cells infectedby microbes that are inaccessible to antibodies.Adaptive immune responses develop in steps,each of which corresponds to particular reactionsof lymphocytes (Fig. 1–17).Capture and Display of Microbial AntigensMicrobes that enter through epithelia, as well astheir protein antigens, are captured by dendriticcells residing in these epithelia, and the cell-bound antigens are transported to draininglymph nodes. Protein antigens are processed in
  • 20. 20 Chapter 1 – Introduction to the Immune Systemantigen at sites of infection and perform thefunctions responsible for elimination of themicrobes. Different classes of T cells differentiateinto effector cells with distinct functional proper-ties. Helper T cells secrete cytokines and expresssurface molecules that mediate their functions.Some of these activated helper T cells function torecruit neutrophils and other leukocytes to sitesof infection; other helper cells activate macro-phages to kill ingested microbes; and still otherhelper T cells stay in the lymphoid organs andhelp B lymphocytes. CTLs directly kill cells har-boring microbes in the cytoplasm. These microbesmay be viruses that infect many cell types or bac-teria that are ingested by macrophages but havelearned to escape from phagocytic vesicles intothe cytoplasm (where they are inaccessible to theFIGURE 1–17 Phases of adaptive immune response. An adaptive immune response consists of distinct phases; the firstthree are recognition of antigen, activation of lymphocytes, and elimination of antigen (effector phase). The response declines asantigen-stimulated lymphocytes die by apoptosis, restoring the baseline steady state called homeostasis, and the antigen-specific cellsthat survive are responsible for memory. The duration of each phase may vary in different immune responses. These principles applyto both humoral immunity (mediated by B lymphocytes) and cell-mediated immunity (mediated by T lymphocytes).Days afterantigen exposureAntibody-producingcellEffector TlymphocyteLymphocyteactivationAntigeneliminationContraction(homeostasis) MemoryAntigenrecognitionHumoralimmunityApoptosisEliminationof antigensSurvivingmemorycellsAntigen-presentingcellDifferentiationClonalexpansionNaive TlymphocyteNaive Blymphocyte0 7 14Cell-mediatedimmunitykilling machinery of phagocytes, which is largelyconfined to vesicles). By destroying the infectedcells, CTLs eliminate the reservoirs of infection.Humoral Immunity: Activation of B Lymphocytes andElimination of Extracellular MicrobesOn activation, B lymphocytes proliferate andthen differentiate into plasma cells that secretedifferent classes of antibodies with distinct func-tions. Many polysaccharide and lipid antigenshave multiple identical antigenic determinants(epitopes) that are able to engage many antigenreceptor molecules on each B cell and initiate theprocess of B cell activation. Typical globularprotein antigens are not able to bind to manyantigen receptors, and the full response of B cellsto protein antigens requires help from CD4+T
  • 21. Chapter 1 – Introduction to the Immune System 21cells. B cells ingest protein antigens, degradethem, and display peptides bound to MHC mol-ecules for recognition by helper T cells. Thehelper T cells express cytokines and cell surfaceproteins, which work together to activate theB cells.Some of the progeny of the expanded B cellclones differentiate into antibody-secreting cells.Each B cell secretes antibodies that have thesame antigen-binding site as the cell surface anti-bodies (B cell antigen receptors) that first recog-nized the antigen. Polysaccharides and lipidsstimulate secretion mainly of a class of antibodycalled immunoglobulin M (IgM). Protein anti-gens stimulate helper T cells, which induce theproduction of antibodies of different classes (IgG,IgA, and IgE). This production of different anti-bodies, all with the same specificity, is calledheavy-chain class (or isotype) switching; itincreases the defensive capability of the antibodyresponse, enabling antibodies to serve manyfunctions. Helper T cells also stimulate the pro-duction of antibodies with higher and higheraffinity for the antigen. This process, called affin-ity maturation, improves the quality of thehumoral immune response.The humoral immune response defendsagainst microbes in many ways. Antibodiesbind to microbes and prevent them frominfecting cells, thereby neutralizing the microbes.Antibodies coat (opsonize) microbes and targetthem for phagocytosis, because phagocytes(neutrophils and macrophages) express recep-tors for the antibodies. Additionally, antibodiesactivate the complement system, generatingprotein fragments that promote phagocytosisand destruction of microbes. Specialized typesof antibodies and specialized transport mecha-nisms for antibodies serve distinct roles atparticular anatomic sites, including the lumensof the respiratory and gastrointestinal tractsor the placenta and fetus.Decline of Immune Responsesand Immunologic MemoryThe majority of effector lymphocytes induced byan infectious pathogen die by apoptosis afterthe microbe is eliminated, thus returning theimmune system to its basal resting state, calledhomeostasis. This occurs because microbesprovide essential stimuli for lymphocyte survivaland activation and effector cells are short-lived.Therefore, as the stimuli are eliminated, the acti-vated lymphocytes are no longer kept alive. Theinitial activation of lymphocytes generates long-lived memory cells, which may survive for yearsafter the infection and mount rapid and robustresponses to a repeat encounter with the antigen.SUMMARY✹ The physiologic function of the immunesystem is to protect individuals againstinfections.✹ Innate immunity is the early line ofdefense, mediated by cells and moleculesthat are always present and ready to elimi-nate infectious microbes.✹ Adaptive immunity is mediated by lym-phocytes stimulated by microbial antigens,requires clonal expansion and differentia-tion of the lymphocytes before it is effec-tive, and responds more effectively againsteach successive exposure to a microbe.✹ Lymphocytes are the cells of adaptiveimmunity and are the only cells with clon-ally distributed receptors with fine speci-ficities for different antigens.✹ Adaptive immunity consists of humoralimmunity, in which antibodies neutralizeand eradicate extracellular microbes andtoxins, and cell-mediated immunity, inwhich T lymphocytes eradicate intracel-lular microbes.✹ Adaptive immune responses consist ofsequential phases: antigen recognition bylymphocytes, activation of the lympho-cytes to proliferate and to differentiate intoeffector and memory cells, elimination ofthe microbes, decline of the immuneresponse, and long-lived memory.✹ Different populations of lymphocytesserve distinct functions and may be distin-guished by the surface expression of par-ticular membrane molecules.✹ B lymphocytes are the only cells thatproduce antibodies. B lymphocytes expressmembrane antibodies that recognize anti-gens, and the progeny of activated B cells,called plasma cells, secrete the antibodiesthat neutralize and eliminate the antigen.✹ T lymphocytes recognize peptide frag-ments of protein antigens displayed on
  • 22. 22 Chapter 1 – Introduction to the Immune Systemother cells. Helper T lymphocytes producecytokines that acti­vate phagocytes todestroy ingested microbes, recruit leuko-cytes, and activate B lymphocytes toproduce antibodies. Cytotoxic T lympho-cytes (CTLs) kill infected cells harboringmicrobes in the cytoplasm.✹ Antigen-presenting cells (APCs) captureantigens of microbes that enter throughepithelia, concentrate these antigens inlymphoid organs, and display the antigensfor recognition by T cells.✹ Lymphocytes and APCs are organizedin peripheral lymphoid organs, whereimmune responses are initiated anddevelop.✹ Naive lymphocytes circulate throughperipheral lymphoid organs searching forforeign antigens. Effector T lymphocytesmigrate to peripheral sites of infection,where they function to eliminate infec-tious microbes. Plasma cells remain inlymphoid organs and the bone marrow,where they secrete antibodies that enterthe circulation and find and eliminatemicrobes.REVIEW QUESTIONS1. What are the two types of adaptive immunity,and what types of microbes do these adaptiveimmune responses combat?2. What are the principal classes of lymphocytes,and how do they differ in function?3. What are the important differences amongnaive, effector, and memory T and B lymph-ocytes?4. Where are T and B lymphocytes located inlymph nodes, and how is their anatomic sepa-ration maintained?5. How do naive and effector T lymphocytesdiffer in their patterns of migration?Answers to and discussion of the Review Questions areavailable at