Introduction to the Immune System PDF

CHAPTER 1 Introduction to the Immune System Nomenclature, General Properties, and Components INNATE AND ADAPTIVE IMMUNITY, 3 Lymphocyte Recirculation and Migration into TYPES OF ADAPTIVE IMMUNITY, 4 Tissues, 19 PROPERTIES OF ADAP...

CHAPTER 1 Introduction to the Immune System Nomenclature, General Properties, and Components INNATE AND ADAPTIVE IMMUNITY, 3 Lymphocyte Recirculation and Migration into TYPES OF ADAPTIVE IMMUNITY, 4 Tissues, 19 PROPERTIES OF ADAPTIVE IMMUNE RESPONSES, 6 OVERVIEW OF IMMUNE RESPONSES TO Specificity and Diversity, 6 MICROBES, 21 Memory, 8 Early Innate Immune Response to Microbes, 21 Other Features of Adaptive Immunity, 9 Adaptive Immune Response, 21 CELLS OF THE IMMUNE SYSTEM, 9 Decline of Immune Responses and Immunologic Lymphocytes, 10 Memory, 24 Antigen-Presenting Cells, 14 SUMMARY, 24 TISSUES OF THE IMMUNE SYSTEM, 15 Peripheral Lymphoid Organs, 15 Immunity is defined as resistance to disease, are susceptible to serious, often life-threaten- specifically infectious disease. The collection of ing infections. Conversely, stimulating immune cells, tissues, and molecules that mediate resis- responses against microbes through vaccina- tance to infections is called the immune system, tion is the most effective method for protecting and the coordinated reaction of these cells and individuals against infections; this approach has molecules to infectious microbes comprises an led to the worldwide eradication of smallpox, immune response. Immunology is the study the only disease that has been eliminated from of the immune system, including its responses to civilization by human intervention (Fig. 1-2). microbial pathogens and damaged tissues and its Unfortunately, interruptions of vaccination pro- role in disease. grams in developing countries and in regions of The most important physiologic function social conflict have led to local reemergence of of the immune system is to prevent or erad- some infectious diseases, such as polio, that have icate infections (Fig. 1-1), and this is the prin- been largely eliminated from other parts of the cipal context in which immune responses are world. The appearance of acquired immunode- discussed throughout this book. The importance ficiency syndrome (AIDS) in the 1980s tragically of the immune system for health is dramati- emphasized the importance of the immune sys- cally illustrated by the frequent observation that tem for defending individuals against infection. individuals with defective immune responses The immune system does more than provide 1 2 CHAPTER 1 Introduction to the Immune System Role of the immune system Implications Defense against infections Deficient immunity results in increased susceptibility to infections; exemplified by AIDS Vaccination boosts immune defenses and protects against infections Defense against tumors Potential for immunotherapy of cancer The immune system can Immune responses are the cause injure cells and induce of allergic, autoimmune, and other pathologic inflammation inflammatory diseases The immune system Immune responses are barriers to recognizes and responds transplantation and gene therapy to tissue grafts and newly introduced proteins FIGURE 1-1 Importance of the immune system in health and disease. This table summarizes some of the physiologic functions of the immune system and its role in disease. AIDS, Acquired immunodeficiency syndrome. protection against infections (see Fig. 1-1). It the attention of clinicians, scientists, and the lay prevents the growth of some tumors, and some public. cancers can be treated by stimulating immune This chapter introduces the nomenclature of responses against tumor cells. Immune responses immunology, important general properties of also participate in the clearance of dead cells and all immune responses, and the cells and tissues in initiating tissue repair. that are the principal components of the immune In contrast to these beneficial roles, abnormal system. In particular, the following questions are immune responses cause many inflammatory addressed: diseases with serious morbidity and mortal- What types of immune responses protect indi- ity. The immune response is the major barrier viduals from infections? to the success of organ transplantation, which What are the important characteristics of im- is often used to treat organ failure. The prod- munity, and what mechanisms are responsible ucts of immune cells can also be of great prac- for these characteristics? tical use. For example, antibodies, which are How are the cells and tissues of the immune proteins made by certain cells of the immune system organized to find and respond to mi- system, are used in clinical laboratory testing crobes in ways that lead to their elimina- and in research as highly specific reagents for tion? detecting a wide variety of molecules in the We conclude the chapter with a brief over- circulation and in cells and tissues. Antibod- view of immune responses against microbes. ies designed to block or eliminate potentially The basic principles introduced here set the harmful molecules and cells are used widely stage for more detailed discussions of immune for the treatment of immunologic diseases, can- responses in later chapters. A glossary of the cers, and other types of disorders. For all these important terms used in this book is provided in reasons, the field of immunology has captured Appendix I.  Innate and Adaptive Immunity 3 Disease Maximum number Number of Percent of cases (year) cases in 2014 change Diphtheria 206,939 (1921) 0 –100 Measles 894,134 (1941) 669 –99.93 Mumps 152,209 (1968) 737 –99.51 Pertussis 265,269 (1934) 10,631 –95.99 Polio 21,269 (1952) 0 –100 (paralytic) Rubella 57,686 (1969) 2 –99.99 Tetanus 1560 (1923) 8 –99.48 Hemophilus ~20,000 (1984) 34 –99.83 influenza type B Hepatitis B 26,611 (1985) 1,098 –95.87 FIGURE 1-2 Effectiveness of vaccination for some common infectious diseases. The striking decrease in the incidence of selected infectious diseases in the United States for which effective vaccines have been developed. (Modified from Orenstein WA, Hinman AR, Bart KJ, Hadler SC: Immunization. In Mandell GL, Bennett JE, Dolin R, editors: Principles and practices of infectious diseases, 4th edition, New York, 1995, Churchill Livingstone; and MMWR 64, No. 20, 2015.) In innate immunity, the first line of defense INNATE AND ADAPTIVE IMMUNITY is provided by epithelial barriers of the skin and Host defenses are grouped under innate mucosal tissues and by cells and natural antibiot- immunity, which provides immediate pro- ics present in epithelia, all of which function to tection against microbial invasion, and block the entry of microbes. If microbes do breach adaptive immunity, which develops more epithelia and enter the tissues or circulation, they slowly and provides more specialized are attacked by phagocytes, specialized lympho- defense against infections (Fig. 1-3). Innate cytes called innate lymphoid cells, which include immunity, also called natural immunity or native natural killer cells, and several plasma proteins, immunity, is always present in healthy individu- including the proteins of the complement system. als (hence the term innate), prepared to block All these mechanisms of innate immunity spe- the entry of microbes and to rapidly eliminate cifically recognize and react against microbes. In microbes that do succeed in entering host tissues. addition to providing early defense against infec- Adaptive immunity, also called specific immu- tions, innate immune responses enhance adaptive nity or acquired immunity, requires expansion immune responses against the infectious agents. and differentiation of lymphocytes in response to The components and mechanisms of innate microbes before it can provide effective defense; immunity are discussed in detail in Chapter 2. that is, it adapts to the presence of microbial The adaptive immune system consists invaders. Innate immunity is phylogenetically of lymphocytes and their products, such older, and the more specialized and powerful as antibodies. Adaptive immune responses adaptive immune response evolved later. are especially important for defense against 4 CHAPTER 1 Introduction to the Immune System Microbe Innate immunity Adaptive immunity Antibodies Epithelial barriers B lymphocytes Plasma cells Mast Dendritic cells cells Phagocytes NK cells T lymphocytes Complement and ILCs Effector T cells Hours Days 0 6 12 1 3 5 Time after infection FIGURE 1-3 Principal mechanisms of innate and adaptive immunity. The mechanisms of innate immunity provide the initial defense against infections. Some mechanisms (e.g., epithelial barriers) prevent infections, and other mechanisms (e.g., phagocytes, natural killer [NK] cells and other innate lymphoid cells [ILCs], the complement system) eliminate microbes. Adaptive immune responses develop later and are mediated by lymphocytes and their products. Antibodies block infections and eliminate microbes, and T lymphocytes eradicate intracellular microbes. The kinetics of the innate and adaptive immune responses are approximations and may vary in different infections. infectious microbes that are pathogenic for innate and adaptive immunity are discussed in humans (i.e., capable of causing disease) and may later chapters. have evolved to resist innate immunity. Whereas By convention, the terms immune response and the mechanisms of innate immunity recognize immune system generally refer to adaptive immu- structures shared by classes of microbes, the cells nity, and that is the focus of most of this chapter. of adaptive immunity (lymphocytes) express receptors that specifically recognize a much wider variety of molecules produced by microbes TYPES OF ADAPTIVE IMMUNITY as well as noninfectious substances. Any sub- The two types of adaptive immunity, called stance that is specifically recognized by lympho- humoral immunity and cell-mediated cytes or antibodies is called an antigen. Adaptive immunity, are mediated by different cells immune responses often use the cells and mol- and molecules and provide defense against ecules of the innate immune system to eliminate extracellular microbes and intracellular microbes, and adaptive immunity functions to microbes, respectively (Fig. 1-4). greatly enhance these antimicrobial mechanisms Humoral immunity is mediated by proteins of innate immunity. For example, antibod- called antibodies, which are produced by cells ies (a component of adaptive immunity) bind called B lymphocytes. Secreted antibodies to microbes, and these coated microbes avidly enter the circulation and mucosal fluids, and bind to and activate phagocytes (a component of they neutralize and eliminate microbes and innate immunity), which ingest and destroy the microbial toxins that are present outside host microbes. Examples of the cooperation between cells, in the blood, extracellular fluid derived  Types of Adaptive Immunity 5 Humoral Cell-mediated immunity immunity Microbe Phagocytosed Intracellular microbes Extracellular (e.g., viruses) microbes microbes that can live within replicating within macrophages infected cell Responding lymphocytes Helper Cytotoxic B lymphocyte T lymphocyte T lymphocyte Secreted antibody Effector mechanism Block Activated Killed infected cell infections macrophage and Kill infected cells Functions eliminate Elimination of and eliminate extracellular phagocytosed reservoirs microbes microbes of infection FIGURE 1-4 Types of adaptive immunity. In humoral immunity, B lymphocytes secrete antibodies that elim- inate extracellular microbes. In cell-mediated immunity, different types of T lymphocytes recruit and activate phagocytes to destroy ingested microbes and kill infected cells. from plasma, and in the lumens of mucosal to destroy microbes that have been ingested by organs such as the gastrointestinal and re- the phagocytes into intracellular vesicles. Other spiratory tracts. One of the most important T lymphocytes kill any type of host cells that are functions of antibodies is to stop microbes that harboring infectious microbes in the cytoplasm. are present at mucosal surfaces and in the blood In both cases, the T cells recognize microbial from gaining access to and colonizing host cells ­antigens that are displayed on host cell surfaces, and connective tissues. In this way, antibodies which indicates there is a microbe inside the cell. prevent infections from ever being established. The specificities of B and T lymphocytes ­differ Antibodies cannot gain access to microbes that in important respects. Most T cells recognize only live and divide inside infected cells. protein antigens, whereas B cells and antibod-  Defense against such intracellular microbes is ies are able to recognize many different types called cell-mediated immunity because it is of molecules, including proteins, carbohydrates, mediated by cells, which are called T lympho- nucleic acids, and lipids. These and other differ- cytes. Some T lymphocytes activate phagocytes ences are discussed in more detail later. 6 CHAPTER 1 Introduction to the Immune System Immunity may be induced in an indi- Feature Functional significance vidual by infection or vaccination (active immunity) or conferred on an individual by Specificity Ensures that distinct antigens transfer of antibodies or lymphocytes from elicit specific responses an actively immunized individual (passive Diversity Enables immune system immunity). to respond to a large variety of antigens In active immunity, an individual exposed to the antigens of a microbe mounts an ac- Memory Leads to enhanced responses to repeated exposures to the tive response to eradicate the infection and same antigens develops resistance to later infection by that microbe. Such an individual is said to be im- Clonal Increases number of expansion antigen-specific lymphocytes mune to that microbe, in contrast with a naive from a small number of individual, not previously exposed to that mi- naive lymphocytes crobe’s antigens. Generates responses that are Specialization In passive immunity, a naive individual re- optimal for defense against ceives antibodies or cells (e.g., lymphocytes, different types of microbes feasible only in animal experiments) from Contraction and Allows immune system another individual already immune to an in- homeostasis to respond to newly encountered antigens fection. The recipient acquires the ability to combat the infection for as long as the trans- Nonreactivity Prevents injury to the ferred antibodies or cells last. Passive immu- to self host during responses to foreign antigens nity is therefore useful for rapidly conferring immunity even before the individual is able to mount an active response, but it does not FIGURE 1-5 Properties of adaptive immune re- induce long-lived resistance to the infection. sponses. This table summarizes the important The only physiologic example of passive im- properties of adaptive immune responses and how munity is seen in newborns, whose immune each feature contributes to host defense against mi- crobes. systems are not mature enough to respond to many pathogens but who are protected against infections by acquiring antibodies from antigens or portions of antigens. Specificity their mothers through the placenta and breast is the ability to distinguish between many differ- milk. Clinically, passive immunity is limited to ent antigens. It implies that the total collection treatment of some immunodeficiency diseases of lymphocyte specificities, sometimes called the with antibodies pooled from multiple donors, lymphocyte repertoire, is extremely diverse. and for emergency treatment of some viral in- The basis for this remarkable specificity and fections and snakebites using serum from im- diversity is that lymphocytes express clonally dis- munized donors. tributed receptors for antigens, meaning that the total population of lymphocytes consists of many PROPERTIES OF ADAPTIVE IMMUNE different clones (each made up of one cell and its progeny), and each clone expresses an antigen RESPONSES receptor that is different from the receptors of Several properties of adaptive immune responses all other clones. The clonal selection hypoth- are crucial for the effectiveness of these responses esis, formulated in the 1950s, correctly predicted in combating infections (Fig. 1-5). that clones of lymphocytes specific for different antigens develop before an encounter with these Specificity and Diversity antigens, and each antigen elicits an immune The adaptive immune system is capable of response by selecting and activating the lym- distinguishing among millions of different phocytes of a specific clone (Fig. 1-6). We now  Properties of Adaptive Immune Responses 7 Lymphocyte Mature precursor lymphocyte Lymphocyte clones with diverse receptors arise in generative lymphoid organs Clones of mature lymphocytes specific for many antigens enter lymphoid tissues Antigen X Antigen Y Antigen-specific clones are activated ("selected") by antigens Antigen-specific immune responses occur Anti-X Anti-Y antibody antibody FIGURE 1-6 Clonal selection. Mature lymphocytes with receptors for many antigens develop before encounter- ing these antigens. A clone refers to a population of lymphocytes with identical antigen receptors and therefore specificities; all of these cells are presumably derived from one precursor cell. Each antigen (e.g., X and Y) selects a preexisting clone of specific lymphocytes and stimulates 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 lym- phocytes. The antigens shown are surface molecules of microbes, but clonal selection also is true for extracellular soluble and intracellular antigens. know the molecular basis for how the specificity To mount an effective defense against microbes, and diversity of lymphocytes are generated (see these few cells have to give rise to a large Chapter 4). number of lymphocytes capable of destroy- The diversity of the lymphocyte repertoire, ing the microbes. The remarkable effectiveness which enables the immune system to respond of immune responses is attributable to several to a vast number and variety of antigens, also features of adaptive immunity, including the means that very few cells, perhaps as few as 1 marked expansion of the pool of lymphocytes in 100,000 or 1 in 1,000,000 lymphocytes, are specific for any antigen upon exposure to that specific for any one antigen. Thus, the total antigen, and selection mechanisms that preserve number of naive (unactivated) lymphocytes the most useful lymphocytes. These characteris- that can recognize and react against any one tics of the adaptive immune system are described antigen ranges from about 1000 to 10,000 cells. in later chapters. 8 CHAPTER 1 Introduction to the Immune System Memory usually are more rapid, larger, and better able to The adaptive immune system mounts larger eliminate the antigen than primary responses. and more effective responses to repeated Secondary responses are the result of the acti- exposures to the same antigen. This feature vation of memory lymphocytes, which are of adaptive immune responses implies that the long-lived cells that were induced during the immune system remembers exposure to anti- primary immune response. The term memory gen, and this property of adaptive immunity is arose because of the realization that these cells therefore called immunologic memory. The must remember previous encounter with anti- response to the first exposure to antigen, called gen since they respond better upon subsequent the primary immune response, is initiated by encounters. Immunologic memory optimizes lymphocytes called naive lymphocytes that are the ability of the immune system to combat per- seeing antigen for the first time (Fig. 1-7). The sistent and recurrent infections, because each term naive refers to these cells being immuno- exposure to a microbe generates more memory logically inexperienced, not having previously cells and activates previously generated mem- responded to antigens. Subsequent encoun- ory cells. Memory also is one of the reasons why ters with the same antigen lead to responses vaccines confer long-lasting protection against called secondary immune responses that infections. Antigen X + Antigen X Antigen Y Plasma cells Anti-X B cell Anti-Y B cell Secondary Plasma anti-X Serum antibody titer cell response Plasma Memory cells B cells Naive Primary B cells Primary anti-X anti-Y response response 2 4 6 8 10 Weeks FIGURE 1-7 Primary and secondary immune responses. Antigens X and Y induce the production of differ- ent antibodies (a reflection of specificity). The secondary response to antigen X is more rapid and larger than the primary response (illustrating memory) and is different from the primary response to antigen Y (again reflecting specificity). Antibody levels decline with time after each immunization. The level of antibody produced is shown as arbitrary values and varies with the type of antigen exposure. Only B cells are shown, but the same features are seen with T cell responses to antigens. The time after immunization may be 1 to 3 weeks for a primary response and 2 to 7 days for a secondary response, but the kinetics vary, depending on the antigen and the nature of im- munization.  Cells of the Immune System 9 Other Features of Adaptive Immunity the system to return to a resting state, pre- Adaptive immune responses have other char- pared to respond to another infection. acteristics that are important for their functions The immune system is able to react against an (see Fig. 1-5). enormous number and variety of ­microbes and When lymphocytes are activated by antigens, other foreign antigens, but it normally does they undergo proliferation, generating many not react against the host’s own ­potentially thousands of clonal progeny cells, all with antigenic substances—so-called self antigens. the same antigen specificity. This process, This unresponsiveness to self is called immu- called clonal expansion, rapidly increases nological tolerance, referring to the ability the number of cells specific for the antigen of the immune system to coexist with (toler- encountered and ensures that adaptive im- ate) potentially antigenic self molecules, cells, munity keeps pace with rapidly proliferating and tissues. microbes. Immune responses are specialized, and dif- ferent responses are designed to defend best CELLS OF THE IMMUNE SYSTEM against different classes of microbes. The cells of the immune system are located in All immune responses are self-limited and de- different tissues and serve different roles in host cline as the infection is eliminated, allowing defense (Fig. 1-8). Cell type Principal function(s) Lymphocytes: Specific recognition of antigens B lymphocytes; B lymphocytes: mediators of T lymphocytes humoral immunity T lymphocytes: mediators of cell-mediated immunity Blood lymphocyte Antigen-presenting cells: Capture of antigens for display dendritic cells; to lymphocytes: macrophages; Dendritic cells: initiation of T cell responses B cells; follicular dendritic cells Macrophages: effector phase of cell-mediated immunity Dendritic cell Follicular dendritic cells: display of antigens to B lymphocytes in humoral immune responses Effector cells: Elimination of antigens: T lymphocytes; T lymphocytes: activation of macrophages; phagocytes, killing infected cells granulocytes Macrophages: phagocytosis and killing of microbes Macrophage Granulocytes: killing microbes FIGURE 1-8 Principal cells of the immune system. The major cell types involved in immune responses and the key functions of these cells. Micrographs illustrate the morphology of some cells of each type. 10 CHAPTER 1 Introduction to the Immune System Lymphocytes circulate through lymphoid or- and that are recognized by a cluster or group of gans and nonlymphoid tissues. They recognize antibodies. (A list of CD molecules mentioned in foreign antigens and initiate adaptive immune the book is provided in Appendix II.) responses. As alluded to earlier, B lymphocytes are the Cells resident in tissues detect the presence of only cells capable of producing antibodies; there- microbes and react against them. These cells fore, they are the cells that mediate humoral include macrophages, whose function is to immunity. B cells express membrane forms of ingest and destroy foreign substances; den- antibodies that serve as the receptors that recog- dritic cells, which capture microbes and dis- nize antigens and initiate the process of activa- play them to lymphocytes to initiate immune tion of the cells. Soluble antigens and antigens responses, and are therefore called antigen- on the surface of microbes and other cells may presenting cells; and mast cells, which help bind to these B lymphocyte antigen receptors, to recruit other leukocytes to destroy mi- initiating the process of B cell activation. This crobes. leads to the secretion of soluble forms of anti- Phagocytes that normally circulate in the bodies with the same antigen specificity as the blood, including neutrophils and monocytes, membrane receptors. are rapidly recruited to sites of infection in T lymphocytes are responsible for cell-medi- the process called inflammation. These leu- ated immunity. The antigen receptors of most T kocytes (white blood cells) ingest and de- lymphocytes recognize only peptide fragments stroy microbes and then start the process of of protein antigens that are bound to special- repairing damaged tissues. Because these ized peptide display molecules, called major phagocytes, as well as some T lymphocytes, histocompatibility complex (MHC) molecules, are responsible for the effect of the immune on the surface of specialized cells, called anti- response, which is to destroy microbes, they gen-presenting cells (see Chapter 3). Among T are sometimes called effector cells. lymphocytes, CD4+ T cells are called helper T This section describes the important prop- cells because they help B lymphocytes to pro- erties of the major cell populations of adaptive duce antibodies and help phagocytes to destroy immunity—namely, lymphocytes and antigen- ingested microbes. CD8+ T lymphocytes are called presenting cells. The cells of innate immunity are cytotoxic T lymphocytes (CTLs) because they described in Chapter 2. kill cells harboring intracellular microbes. Some CD4+ T cells belong to a special subset that func- Lymphocytes tions to prevent or limit immune responses; these Lymphocytes are the only cells that produce are called regulatory T lymphocytes. clonally distributed receptors specific for diverse All lymphocytes arise from stem cells in the bone antigens and are the key mediators of adaptive marrow (Fig. 1-10). B lymphocytes mature immunity. A healthy adult contains 0.5-1×1012 in the bone marrow, and T lymphocytes lymphocytes. Although all lymphocytes are mor- mature in an organ called the thymus. These phologically similar and rather unremarkable in sites in which mature lymphocytes are produced appearance, they are heterogeneous in lineage, (generated) are called the ­ generative lym- function, and phenotype and are capable of com- phoid organs. Mature lymphocytes leave the plex biologic responses and activities (Fig. 1-9). generative lymphoid organs and enter the circu- These cells often are distinguishable by surface lation and the peripheral lymphoid organs, proteins that may be identified using panels of where they may encounter antigen for which monoclonal antibodies. The standard nomen- they express specific receptors. clature for these proteins is the CD (cluster of When naive lymphocytes recognize differentiation) numerical designation, which is microbial antigens and also receive addi- used to delineate surface proteins that define a tional signals induced by microbes, the particular cell type or stage of cell differentiation antigen-specific lymphocytes proliferate  Cells of the Immune System 11 Antigen recognition Effector functions Neutralization of microbe, B lymphocyte + phagocytosis, complement activation Microbe Antibody Cytokines Activation of macrophages + Inflammation Helper T lymphocyte Activation (proliferation and differentiation) Microbial antigen of T and B presented by antigen presenting cell lymphocytes Cytotoxic T Killing of infected cell lymphocyte (CTL) Infected cell expressing microbial antigen Suppression Regulatory of immune T lymphocyte response FIGURE 1-9 Classes of lymphocytes. Different classes of lymphocytes in the adaptive immune system recog- nize distinct types of antigens and differentiate into effector cells whose function is to eliminate the antigens. B lymphocytes recognize soluble or cell surface antigens and differentiate into antibody-secreting cells. Helper T lymphocytes recognize antigens on the surfaces of antigen-presenting cells and secrete cytokines, which stimu- late different mechanisms of immunity and inflammation. Cytotoxic T lymphocytes recognize antigens in infected cells and kill these cells. (Note that T lymphocytes recognize peptides that are displayed by MHC molecules, dis- cussed in Chapter 3.) Regulatory T cells limit the activation of other lymphocytes, especially of T cells, and prevent autoimmunity. 12 CHAPTER 1 Introduction to the Immune System Generative Blood, Peripheral lymphoid lymph Mature lymphoid organs B lymphocytes organs Bone Recirculation Common marrow Lymph lymphoid B nodes precursor lymphocyte lineage Spleen T lymphocyte Mucosal and lineage cutaneous lymphoid Recirculation tissues Thymus Mature T lymphocytes FIGURE 1-10 Maturation of lymphocytes. Lymphocytes develop from precursors in the generative lymphoid organs (bone marrow and thymus). Mature lymphocytes enter the peripheral lymphoid organs, where they re- spond to foreign antigens and recirculate in the blood and lymph. Some immature B cells leave the bone marrow and complete their maturation in the spleen (not shown). and differentiate into effector cells and the peripheral lymphoid organs, where they memory cells (Fig. 1-11). may stay and produce antibodies. Small num- Naive lymphocytes express receptors for bers of antibody-secreting cells are also found antigens but do not perform the functions that in the blood; these are called plasmablasts. are required to eliminate antigens. These cells Some of these migrate to the bone marrow, reside in and circulate between ­ peripheral where they mature into long-lived plasma lymphoid organs and survive for several cells and continue to ­produce small amounts weeks or months, waiting to find and respond of antibody long after the infection is eradi- to antigen. If they are not activated by anti- cated, providing immediate protection in case gen, naive lymphocytes die by the process of the infection recurs. apoptosis and are replaced by new cells that Effector CD4+ T cells (helper T cells) pro- have arisen in the generative lymphoid or- duce proteins called cytokines that activate gans. The differentiation of naive lymphocytes B cells, macrophages, and other cell types, into effector cells and memory cells is initiated thereby mediating the helper function of this by antigen recognition, thus ensuring that the lineage. Effector CD8+ T cells (CTLs) have immune response that develops is specific for the machinery to kill infected host cells. The the antigen. development and functions of these effector Effector lymphocytes are the differenti- cells are discussed in later chapters. Effector ated progeny of naive cells that have the T lymphocytes are short-lived and die as the ability to produce molecules that function to antigen is eliminated. eliminate antigens. The effector cells in the Memory cells, also generated from the prog- B lymphocyte lineage are antibody-secreting eny of antigen-stimulated lymphocytes, do cells, called plasma cells. Plasma cells de- survive for long periods in the absence of anti- velop in response to antigenic stimulation in gen. Therefore, the frequency of memory cells  A Cell type Stage Naive cell Activated or Memory effector lymphocyte lymphocyte B lymphocytes Antigen Proliferation Differentiation recognition T lymphocytes Antigen Proliferation Differentiation recognition B Naive cell Activated or Memory lymphocyte effector lymphocyte T lymphocytes Migration Preferentially Preferentially to Heterogenous: one subset to to peripheral inflamed tissues lymph nodes, one subset to lymph nodes mucosa and inflamed tissues Frequency of cells Very low High Low responsive to particular antigen Effector functions None Cytokine secretion; None cytotoxic activity B lymphocytes Membrane IgM and IgD Frequently IgG, Frequently IgG, immunoglobulin IgA, and IgE IgA, and IgE (Ig) isotype Affinity of Relatively low Increases during Relatively high Ig produced immune response Effector functions None Antibody secretion None FIGURE 1-11 Stages in the life history of lymphocytes. A, Naive lymphocytes recognize foreign antigens to initiate adaptive 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 cells of the B lymphocyte lineage are antibody-secreting plasma cells (some of which are long-lived). The effector cells of the CD4 T lymphocyte lineage produce cytokines. (The effector cells of the CD8 lineage are CTLs; these are not shown.) Other progeny of the antigen-stimulated lympho- cytes differentiate into long-lived memory cells. B, The important characteristics of naive, effector, and memory cells in the B and T lymphocyte lineages are summarized. The generation and functions of effector cells, including changes in migration patterns and types of immunoglobulin produced, are described in later chapters. 14 CHAPTER 1 Introduction to the Immune System Thymic output This function of antigen capture and presen- tation is best understood for a cell type that is 100 called dendritic cells because of their long sur- face membrane processes. Dendritic cells capture 80 Naive T cells % Blood T cells protein antigens of microbes entering through Memory T cells 60 the epithelia and transport the antigens to regional lymph nodes, where the antigen-bear- 40 ing dendritic cells display portions of the antigens for recognition by T lymphocytes. If a microbe 20 has invaded through the epithelium, it may be 0 phagocytosed and presented by tissue macro- 0 10 20 30 40 50 60 70 80 phages. Microbes or their antigens that enter Age (Years) lymphoid organs may be captured by dendritic cells or macrophages that reside in these organs FIGURE 1-12 Change in proportions of naive and and presented to lymphocytes. Dendritic cells memory T cells with age. The proportions of naive are the most effective APCs for initiating T cell and memory T cells are based on data from m ­ ultiple responses. The process of antigen presentation to healthy individuals. The estimate of thymic output is T cells is described in Chapter 3. an approximation. (Courtesy of Dr. Donna L. F ­ arber, Cells that are specialized to display antigens Columbia University College of Physicians and ­ to T lymphocytes have another important fea- ­Surgeons, New York.) ture that gives them the ability to stimulate T cell responses. These specialized cells respond increases with age, presumably because of to microbes by producing surface and secreted exposure to environmental microbes. In fact, proteins that are required, together with anti- memory cells make up less than 5% of pe- gen, to activate naive T lymphocytes to pro- ripheral blood T cells in a newborn, but 50% liferate and differentiate into effector cells. or more in an adult (Fig. 1-12). As individu- Specialized cells that display antigens to T cells als age, the gradual accumulation of memory and provide additional activating signals some- cells compensates for the reduced output of times are called professional APCs. The pro- new, naive T cells from the thymus, which in- totypic professional APCs are dendritic cells, volutes after puberty (see Chapter 4). Memo- but macrophages, B cells, and a few other cell ry cells are functionally inactive; they do not types may serve the same function in various perform effector functions unless stimulated immune responses. by antigen. When memory cells encounter the Less is known about cells that may capture same antigen that induced their development, antigens for display to B lymphocytes. B lym- the cells rapidly respond to initiate secondary phocytes may directly recognize the antigens immune responses. The signals that generate of microbes (either released or on the surface and maintain memory cells are not well un- of the microbes), or macrophages lining lym- derstood but include cytokines. phatic channels may capture antigens and display them to B cells. A type of cell called Antigen-Presenting Cells the follicular dendritic cell (FDC) resides in The common portals of entry for the germinal centers of lymphoid follicles in microbes—the skin, gastrointestinal tract, the peripheral lymphoid organs and displays and respiratory tract—contain specialized antigens that stimulate the differentiation of B antigen-presenting cells (APCs) located in cells in the follicles (see Chapter 7). FDCs do the epithelium that capture antigens, trans- not present antigens to T cells and differ from port them to peripheral lymphoid tissues, the dendritic cells described earlier that func- and display (present) them to lymphocytes. tion as APCs for T lymphocytes.  Tissues of the Immune System 15 TISSUES OF THE IMMUNE SYSTEM Tissue Number of lymphocytes The tissues of the immune system consist of the generative lymphoid organs, in which Spleen 70 x 109 T and B lymphocytes mature and become competent to respond to antigens, and the Lymph nodes 190 x 109 peripheral lymphoid organs, in which adap- tive immune responses to microbes are Bone marrow 50 x 109 initiated (see Fig. 1-10). Most of the lympho- Blood 10 x 109 cytes in a healthy human are found in lymphoid organs and other tissues (Fig. 1-13). However, as Skin 20 x 109 we discuss later, lymphocytes are unique among Intestines 50 x 109 the cells of the body because of their ability to cir- culate among tissues. The generative (also called Liver 10 x 109 primary or central) lymphoid organs are described in Chapter 4, when we discuss the process of Lungs 30 x 109 lymphocyte maturation. The following section highlights some of the features of peripheral (or FIGURE 1-13 Distribution of lymphocytes in lym- secondary) lymphoid organs that are important phoid organs and other tissues. Approximate num- for the development of adaptive immunity. bers of lymphocytes in different organs of healthy adults are shown. Peripheral Lymphoid Organs The peripheral lymphoid organs, which con- help B lymphocytes specific for the same antigen, sist of the lymph nodes, the spleen, and the resulting in antibody production. An important mucosal and cutaneous immune systems, are function of lymphoid organs is to bring these rare organized in a way that promotes the devel- cells together after stimulation by antigen so they opment of adaptive immune responses. interact. T and B lymphocytes must locate microbes that The major peripheral lymphoid organs share enter at any site in the body, then respond to these many characteristics but also have some unique microbes and eliminate them. In addition, as pre- features. viously discussed, in the normal immune system, Lymph nodes are encapsulated nodular very few of these lymphocytes are specific for any ­aggregates of lymphoid tissues located along one antigen. It is not possible for the few lympho- lymphatic channels throughout the body cytes specific for any antigen to patrol all possible (Fig. 1-14). Fluid constantly leaks out of blood sites of antigen entry. The anatomic organization ­vessels in all epithelia and connective tissues of peripheral lymphoid organs enables APCs to and most parenchymal organs. This fluid, concentrate antigens in these organs and lympho- called lymph, is drained by lymphatic ves- cytes to locate and respond to the antigens. This sels from the tissues to the lymph nodes and organization is complemented by a remarkable eventually back into the blood circulation. ability of lymphocytes to circulate throughout the Therefore, the lymph contains a mixture of body in such a way that naive lymphocytes pref- ­substances absorbed from epithelia and tissues. erentially go to the specialized organs in which As the lymph passes through lymph nodes, antigen is concentrated, and effector cells go to APCs in the nodes are able to sample the an- sites of infection where microbes must be elimi- tigens of microbes that may enter through nated. Furthermore, different types of lympho- epithelia into tissues. In addition, dendritic cytes often need to communicate to generate cells pick up antigens of microbes from epi- effective immune responses. For example, helper thelia and other tissues and transport these T cells specific for an antigen interact with and antigens to the lymph nodes. The net result of 16 CHAPTER 1 Introduction to the Immune System A A Marginal Antigen Red pulp sinus B cell zone High Follicular (follicle) endothelial arteriole venule (HEV) Afferent lymphatic B cell zone Subcapsular (follicle) sinus vessel T cell zone (periarteriolar lymphoid sheath [PALS]) Trabecular Central Marginal artery arteriole zone Trabecula B T cell zone Capsule Germinal Medulla center Vein Medullary sinus Artery Efferent lymphatic vessel Lymphocytes B Primary lymphoid Germinal follicle (B cell zone) Periarteriolar center of lymphoid lymphoid sheath (PALS) follicle FIGURE 1-15 Morphology of the spleen. A, Sche- matic diagram shows a splenic arteriole surrounded by the periarteriolar lymphoid sheath (PALS) and attached follicle containing a prominent germinal center. The PALS and lymphoid follicles together constitute the white pulp. B, Light micrograph of a section of spleen Secondary shows an arteriole with the PALS and a follicle with Parafollicular follicle with a germinal center. These are surrounded by the red cortex (T cell zone) germinal pulp, which is rich in vascular sinusoids. center these processes of antigen capture and trans- FIGURE 1-14 Morphology of lymph nodes. A, Schematic diagram shows the structural organization port is that the antigens of microbes entering of a lymph node. B, Light micrograph shows a cross through epithelia or colonizing ­tissues become section of a lymph node with numerous follicles in the concentrated in draining lymph nodes. cortex, some of which contain lightly stained central The spleen is a highly vascularized abdomi- areas (germinal centers). nal organ that serves the same role in immune responses to blood-borne antigens as that of lymph nodes in responses to lymph-borne anti- gens (Fig. 1-15). Blood entering the spleen flows through a network of c­hannels ­ (sinusoids).  Tissues of the Immune System 17 Commensal Villus bacteria Intraepithelial lymphocytes Intestinal Intestinal M cell lumen epithelia cell Mucus Dendritic cell Peyer’s Crypt patch Mucosal epithelium Afferent IgA Lymphatic lymphatic drainage Follicle Lamina propria Dendritic B cell Macrophage T cell Plasma cell cell Mesentery Mesenteric lymph node FIGURE 1-16 Mucosal immune system. Schematic diagram of the mucosal immune system uses the small bowel as an example. Many commensal bacteria are present in the lumen. The mucus-secreting epithelium pro- vides an innate barrier to microbial invasion (discussed in Chapter 2). Specialized epithelial cells, such as M cells, promote the transport of antigens from the lumen into underlying tissues. Cells in the lamina propria, including dendritic cells, T lymphocytes, and macrophages, provide innate and adaptive immune defense against invading microbes; some of these cells are organized into specialized structures, such as Peyer’s patches in the small in- testine. Immunoglobulin A (IgA) is a type of antibody abundantly produced in mucosal tissues that is transported into the lumen, where it binds and neutralizes microbes (see Chapter 8). Blood-borne antigens are ­ captured and con- and the gastrointestinal and r­ espiratory tracts, centrated by dendritic cells and macrophages respectively. Although most of the immune ­ in the spleen. The spleen contains abundant cells in these tissues are diffusely scattered be- phagocytes, which ingest and destroy microbes neath the epithelial barriers, there are discrete in the blood. collections of lymphocytes and APCs orga- The cutaneous immune system and nized in a similar way as in lymph nodes. For ­mucosal immune system are specialized example, tonsils in the pharynx and Peyer’s collections of lymphoid tissues and APCs patches in the intestine are two anatomically ­located in and under the epithelia of the skin defined mucosal lymphoid tissues (Fig. 1-16). 18 CHAPTER 1 Introduction to the Immune System A Dendritic cell Naive High B cell B cell–specific endothelial chemokine venule B Afferent lymphatic vessel T cell zone (parafollicular cortex) B cell B cell zone zone (lymphoid T cell follicle) zone Artery Naive T cell B cell T cell and dendritic cell–specific chemokine T cell FIGURE 1-17 Segregation of T and B lymphocytes in different regions of peripheral lymphoid organs. A, Schematic diagram illustrates the path by which naive T and B lymphocytes migrate to different areas of a lymph node. Naive B and T lymphocytes enter through a high endothelial venule (HEV), shown in cross section, and are drawn to different areas of the node by chemokines that are produced in these areas and bind selectively to either cell type. Also shown is the migration of dendritic cells, which pick up antigens from epithelia, enter through afferent lymphatic vessels, and migrate to the T cell–rich areas of the node (see Chapter 3). B, In this histologic section of a lymph node, the B lymphocytes, located in the follicles, are stained green, and the T cells, in the parafollicular cortex, are stained red using immunofluorescence. In this technique, a section of the tissue is stained with antibodies specific for T or B cells coupled to fluorochromes that emit different colors when excited at the appropriate wavelengths. The anatomic segregation of T and B cells also occurs in the spleen (not shown). (Courtesy Drs. Kathryn Pape and Jennifer Walter, University of Minnesota Medical School, Minneapolis.) At any time, at least a ­quarter of the body’s several mechanisms, including the action of ­lymphocytes are in the mucosal tissues and regulatory T cells and other cells that suppress skin (reflecting the large size of these tissues) rather than activate T lymphocytes. (see Fig. 1-13), and many of these are memory Within the peripheral lymphoid organs, T cells. Cutaneous and mucosal lymphoid tissues lymphocytes and B lymphocytes are segre- are sites of immune responses to antigens that gated into different anatomic compartments breach epithelia. A remarkable property of the (Fig. 1-17). In lymph nodes, the B cells are concen- cutaneous and mucosal immune systems is trated in discrete structures, called follicles, located that they are able to respond to pathogens but around the periphery, or cortex, of each node. If do not react to the enormous numbers of usu- the B cells in a follicle have recently responded to ally harmless commensal microbes present at an antigen, this follicle may contain a central lightly the epithelial barriers. This is accomplished by staining region called a germinal center. The role  Tissues of the Immune System 19 of germinal centers in the production of antibodies the spleen through veins. These activated lympho- is described in Chapter 7. The T lymphocytes are cytes end up in the circulation and can go to distant concentrated outside but adjacent to the follicles, sites of infection. Some activated T cells remain in in the paracortex. The follicles contain the FDCs the lymphoid organ where they were generated described earlier that are involved in the activation and migrate into lymphoid follicles, where they of B cells, and the paracortex contains the dendritic help B cells to make high-affinity antibodies. cells that present antigens to T lymphocytes. In the spleen, T lymphocytes are concentrated in periar- teriolar lymphoid sheaths surrounding small arte- Lymphocyte Recirculation and Migration rioles, and B cells reside in the follicles. into Tissues The anatomic organization of peripheral lym- Naive lymphocytes constantly recirculate phoid organs is tightly regulated to allow immune between the blood and peripheral lym- responses to develop after stimulation by anti- phoid organs, where they may be a ­ ctivated gens. B lymphocytes are attracted to and retained by antigens to become effector cells, and in the follicles because of the action of a class of the effector lymphocytes migrate from cytokines called chemokines (chemoattractant lymphoid tissues to sites of infection, cytokines; chemokines and other cytokines are where microbes are eliminated (Fig. 1-18). discussed in more detail in later chapters). FDCs Thus, lymphocytes at distinct stages of their lives in the follicles secrete a particular chemokine migrate to the different sites where they are for which naive B cells express a receptor, called needed for their functions. Migration of effec- CXCR5. The chemokine that binds to CXCR5 tor lymphocytes to sites of infection is most rel- attracts B cells from the blood into the follicles of evant for T cells, because effector T cells have to lymphoid organs. Similarly, T cells are segregated locate and eliminate microbes at these sites. By in the paracortex of lymph nodes and the periar- contrast, plasma cells do not need to migrate to teriolar lymphoid sheaths of the spleen, because sites of infection; instead, they secrete antibod- naive T lymphocytes express a receptor, called ies, and the antibodies enter the blood, where CCR7, that recognizes chemokines that are pro- they may bind blood-borne pathogens or toxins. duced in these regions of the lymph nodes and Plasma cells in mucosal organs secrete antibod- spleen. As a result, T lymphocytes are recruited ies that enter the lumens of these organs, where from the blood into the paracortical region of they bind to and combat ingested and inhaled the lymph node and the periarteriolar lymphoid microbes. sheaths of the spleen. When the lymphocytes are Naive T lymphocytes that have matured in the activated by antigens, they alter their expression thymus and entered the circulation migrate to of chemokine receptors. The B cells and T cells lymph nodes, where they can find antigens then migrate toward each other and meet at the that are brought to the lymph nodes through edge of follicles, where helper T cells interact with lymphatic vessels that drain epithelia and pa- and help B cells to differentiate into antibody-pro- renchymal organs. These naive T cells enter ducing cells (see Chapter 7). Thus, these lympho- lymph nodes through specialized postcapillary cyte populations are kept apart from each other venules, called high endothelial venules until it is useful for them to interact, after expo- (HEVs). The adhesion molecules used by the sure to an antigen. This is an excellent example T cells to bind to the endothelium are described of how the structure of lymphoid organs ensures in Chapter 6. Chemokines produced in the that the cells that have recognized and responded T cell zones of the lymph nodes and displayed to an antigen interact and communicate with one on HEV surfaces bind to the chemokine recep- another only when necessary. tor CCR7 expressed on naive T cells, which Many of the activated lymphocytes, especially causes the T cells to bind tightly to HEVs. The the effector and memory T cells, ultimately exit the naive T cells then migrate into the T cell zone, node through efferent lymphatic vessels and leave where antigens are displayed by d ­ endritic cells. 20 CHAPTER 1 Introduction to the Immune System Lymph node Peripheral tissue High endothelial venule Peripheral Blood blood vessel Artery vessel Effector or Efferent memory T cell lymphatic vessel Naive T cell FIGURE 1-18 Migration of T lymphocytes. Naive T lymphocytes migrate from the blood through high endo- thelial venules into 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 attachment of T cells to endothelial cells are described in Chapters 5 and 6. Naive B cells also enter lymphoid tissues but The effector cells that are generated upon T then migrate to follicles in response to chemo- cell activation preferentially migrate into the kines that bind CXCR5, the chemokine recep- tissues infected by microbes, where the T lym- tor expressed on these B cells. phocytes perform their function of eradicat- In the lymph node, if a T cell specifically recog- ing the infection. Specific signals control these nizes an antigen on a dendritic cell, that T cell precise patterns of migration of naive and ac- forms stable conjugates with the dendritic cell tivated T cells (see Chapter 6). and is activated. Such an encounter between B lymphocytes that recognize and respond an antigen and a specific lymphocyte is likely to antigen in lymph node follicles differenti- to be a random event, but most T cells in the ate into antibody-secreting cells, which either body circulate through some lymph nodes at remain in the lymph nodes or migrate to the least once a day. As mentioned earlier and bone marrow (see Chapter 7). described further in Chapter 3, the likeli- Memory T cells consist of different popula- hood of the correct T cell finding its antigen tions; some cells recirculate through lymph is increased in peripheral lymphoid o ­ rgans, nodes, where they can mount secondary re- particularly lymph nodes, because microbial sponses to captured antigens, and other cells antigens are concentrated in the same re- migrate to sites of infection, where they can gions of these organs through which naive respond rapidly to eliminate the infection. T cells circulate. Thus, T cells find the antigen We know less about lymphocyte circula- they can recognize, and these T cells are ac- tion through the spleen or other lymphoid tis- tivated to proliferate and differentiate. Naive sues. The spleen does not contain HEVs, but the cells that have not encountered specific anti- general pattern of naive lymphocyte migration gens leave the lymph nodes and reenter the through this organ probably is similar to migra- circulation. tion through lymph nodes.  Overview of Immune Responses to Microbes 21 OVERVIEW OF IMMUNE RESPONSES TO receptors are also present on epithelial barrier cells. The recognition of microbial products by MICROBES these cells induces biochemical changes inside Now that we have described the major compo- the cell that elicit the inflammatory and antiviral nents of the immune system, it is useful to sum- responses. marize the key features of immune responses to In addition to tissue-resident cells and cells microbes. The focus here is on the physiologic recruited from the circulation, soluble molecules function of the immune system—defense against are also present in blood and tissue fluids that infections. In subsequent chapters, each of these can recognize microbes and respond. For exam- features is discussed in more detail. ple, soluble complement proteins modify the surface of the microbes so the microbes are more Early Innate Immune Response to Microbes readily taken up by phagocytes. In healthy uninfected individuals, the innate In addition to recognizing microbial struc- immune system is constantly defending against tures, the innate immune system also recognizes infection by microbial organisms in our envi- and responds to dead or injured cells, which may ronment and against commensal organisms be because of microbial infection or, in the case that live on our epithelial barriers, including of sterile injury, may be a site where microbes skin and mucosal barriers (lung, gastrointestinal can readily enter and grow. The innate immune tract, urogenital tract). In large part, the innate response also initiates the process of tissue repair immune system prevents these organisms from that is critical for healing damaged tissues and getting across the barriers. If microbes do trans- restoring structure and function. gress the barriers, the innate immune system is Even though the innate immune system is always ready, rapidly responds, and attempts to essential for survival and often sufficient for eliminate the invaders. microbial defense, it may be inadequate to elimi- The two principal ways the innate immune nate or control pathogenic microbes that have system deals with microbes is by inducing evolved to evade the innate responses. Innate inflammation and by antiviral mechanisms. immunity may also be incapable of defending Inflammation, which is triggered by all classes of against organisms if they are introduced in great microbes, is the recruitment of circulating blood numbers through damaged barriers, such as in leukocytes (e.g., phagocytes and lymphocytes) trauma or burns. It is in these situations that the and various plasma proteins (e.g., complement, adaptive immune system plays a critical role. antibodies, fibrinogen) to sites of infection, where they function to destroy the microbes and repair Adaptive Immune Response damaged tissue. Several different cytokines are The adaptive immune system uses the following involved in the inflammatory response. The strategies to combat the majority of microbes: antiviral mechanisms render host cells inhospi- Secreted antibodies bind to extracellular mi- table for viral infection and reproduction. These crobes, block their ability to infect host cells, innate responses are often sufficient to prevent and promote their ingestion and subsequent infection within tissues or the blood. destruction by phagocytes. In order to maintain this state of readiness, Phagocytes ingest microbes and kill them, and the innate immune system populates all tissues helper T cells enhance the microbicidal abili- with sentinel cells, including macrophages, den- ties of the phagocytes. dritic cells and mast cells, which express many Helper T cells recruit leukocytes to destroy mi- different cell surface and intracellular molecules crobes and enhance epithelial barrier function that recognize thousands of common features to prevent the entry of microbes. of different classes of microbes, such as bacteria Cytotoxic T lymphocytes kill cells infected by cell walls, or viral nucleic acids. Some of these microbes.  22 CHAPTER 1 Introduction to the Immune System Antigen Lymphocyte Antigen Contraction recognition activation elimination (homeostasis) Memory Antibody- producing Effector T Elimination cell lymphocyte of antigens Relative number of antigen-specific lymphocytes Differentiation Humoral immunity Cell-mediated Surviving Antigen memory cells immunity Apoptosis presenting cell Clonal expansion Naive T lymphocyte Naive B lymphocyte 0 7 14 Days after antigen exposure FIGURE 1-19 Phases of adaptive immune response. An adaptive immune response consists of distinct phas- es; the first three are recognition of antigen, activation of lymphocytes, and elimination of antigen (effector phase). The response declines as antigen-stimulated lymphocytes die by apoptosis, restoring the baseline steady state called homeostasis, and the antigen-specific cells that survive are responsible for memory. The duration of each phase may vary in different immune responses. These principles apply to both humoral immunity (mediated by B lymphocytes) and cell-mediated immunity (mediated by T lymphocytes). Adaptive immune responses develop in steps, these different clones develop prior to exposure each of which corresponds to particular reactions to the antigens. These lymphocytes circulate of lymphocytes (Fig. 1-19). throughout the body, visiting secondary lym- phoid organs (lymph nodes, spleen. mucosal Initiation of Adaptive Immune Response lymphoid tissues). Given their diversity, there is If a microbe does get through the initial defenses a high likelihood that at any time, there will be a of the innate immune system, the adaptive small number of naive lymphocyte that can rec- immune system is alerted and responds. The ognize some molecules made by most microbes. adaptive immune system generates and main- In order for the adaptive immune response to be tains a diverse repertoire of clones of naive B initiated, an antigen made by the microbe selects and T lymphocytes, with millions of different a naive lymphocyte specific for the antigen specificities for microbial antigens, and all of (clonal selection), and the lymphocyte responds  Overview of Immune Responses to Microbes 23 by proliferating to produce tens of thousands of molecules, and proteins that control cell survival effector lymphocytes with the identical specific- and cycling. All of these molecules are involved ity that are capable of eliminating the microbial in the responses of the lymphocytes. infection. Cell-Mediated Immunity: Activation of T Capture and Display of Microbial Antigens Lymphocytes and Elimination of Cell-Associated In order for naive lymphocyte activation by Microbes antigen to occur efficiently, the immune sys- When activated by antigen and costimulators in tem collects antigens from tissue sites of infec- lymphoid organs, naive T cells secrete cytokines tion or blood and delivers them to the secondary that function as growth factors and respond to lymphoid organs though which the naive lym- other cytokines secreted by dendritic cells. The phocytes circulate. Microbes that enter through combination of signals (antigen, costimulation, epithelia, as well as their protein antigens, are and cytokines) stimulates the proliferation of captured by dendritic cells residing in these epi- the T cells and their differentiation into effector thelia, and the cell-bound antigens are trans- T cells. Some of the effector T cells generated in ported to draining lymph nodes. Microbial the lymphoid organ may migrate back into the protein antigens are processed in the dendritic blood and then into any site where the antigen cells to generate peptides that are displayed on (or microbe) is present. These effector cells are the cell surface bound to MHC molecules. Naive reactivated by antigen at sites of infection and T cells recognize these peptide-MHC complexes, perform the functions responsible for elimina- and this is the first step in the initiation of T cell tion of the microbes. Helper T cells secrete cyto- responses. Protein antigens also are recognized kines and express surface molecules that mediate by B lymphocytes in the lymphoid follicles of the their functions. Helper T cells differentiate into peripheral lymphoid organs. Polysaccharides and different subsets of effector cells with distinct other nonprotein antigens are captured in the functions. Some of these helper cells recruit neu- lymphoid organs and are recognized by B lym- trophils and other leukocytes to sites of infec- phocytes but not by T cells. tion; other helper cells activate macrophages to As part of the innate immune response, the kill ingested microbes; and still others stay in dendritic cells that present the antigen to naive the lymphoid organs and help B lymphocytes to T cells are activated to express molecules called produce antibodies. CTLs directly kill cells har- costimulators and to secrete cytokines, both of boring microbes in the cytoplasm. By destroying which are needed, in addition to the antigen, to the infected cells, CTLs eliminate the reservoirs stimulate the proliferation and differentiation of infection. of T lymphocytes. The innate immune response to some microbes also generates peptide frag- Humoral Immunity: Activation of B Lymphocytes ments of complement proteins that enhance the and Elimination of Extracellular Microbes response of naive B lymphocytes to antigen. Thus, On activation, B lymphocytes proliferate and then antigen (often referred to as signal 1) and mole- differentiate into plasma cells that secrete differ- cules produced during innate immune responses ent classes of antibodies with distinct functions. (signal 2) function cooperatively to activate anti- Many nonprotein antigens, such as polysaccha- gen-specific lymphocytes. The requirement for rides and lipids, have multiple identical antigenic microbe-triggered signal 2 ensures that the adap- determinants (epitopes) that are able to engage tive immune response is induced by microbes many antigen receptor molecules on each B cell and not by harmless substances. Signals gener- and initiate the process of B cell activation. Protein ated in lymphocytes by the engagement of anti- antigens are typically folded and do not contain gen receptors and receptors for costimulators multiple identical epitopes, so they are not able to lead to the transcription of various genes, which simultaneously bind to many antigen receptors, encode cytokines, cytokine receptors, effector and the full response of B cells to protein antigens 24 CHAPTER 1 Introduction to the Immune System requires help from CD4+ T cells. B cells ingest pro- The initial activation of lymphocytes generates tein antigens, degrade them, and display peptides ­long-lived memory cells, which may survive for bound to MHC molecules for recognition by and years after the infection and mount rapid and activation of helper T cells. The helper T cells then robust responses to a repeat encounter with the express cytokines and cell surface proteins, which antigen. work together to activate the B cells. Some of the progeny of the expanded B cell SUMMARY clones differentiate into antibody-secreting plasma cells. Each B cell secretes antibodies that n  he physiologic function of the immune sys- T have the same antigen-binding site as the cell tem is to protect individuals against infections. surface antibodies (B cell antigen receptors) that n Innate immunity is the early line of defense, first recognized the antigen. Nonprotein antigens mediated by cells and molecules that are al- stimulate secretion of antibodies with a limited ways present and ready to eliminate infectious range of functions and low affinity for the anti- microbes. gen. Protein antigens, by engaging the help of T n Adaptive immunity is mediated by lympho- cells, stimulate the production of several differ- cytes stimulated by microbial antigens, re- ent kinds of antibodies with different functions quires clonal expansion and differentiation and high affinity for antigen. In addition, protein of the lymphocytes before it is effective, and antigens induce very long-lived antibody secret- responds more effectively against each succes- ing cells and memory B cells. sive exposure to a microbe. The humoral immune response defends n Lymphocytes are the cells of adaptive immu- against microbes in many ways. Antibodies bind nity and are the only cells with clonally dis- to microbes and prevent them from infecting tributed receptors with fine specificities for cells, thereby neutralizing the microbes. Anti- different antigens. bodies coat (opsonize) microbes and target them n Adaptive immunity consists of humoral im- for phagocytosis, because phagocytes (neutro- munity, in which antibodies neutralize and phils and macrophages) express receptors for eradicate extracellular microbes and toxins, the antibodies. Additionally, antibodies activate and cell-mediated immunity, in which T lym- the complement system, generating protein frag- phocytes eradicate intracellular microbes. ments that promote phagocytosis and destruc- n Adaptive immune responses consist of se-  tion of microbes. Specialized types of antibodies quential phases: antigen recognition by lym- and specialized transport mechanisms for anti- phocytes, activation of the lymphocytes to bodies serve distinct roles at particular anatomic proliferate and to differentiate into effector sites, including the lumens of the respiratory and and memory cells, elimination of the mi- gastrointestinal tracts and the placenta and fetus. crobes, decline of the immune response, and long-lived memory. n Different populations of lymphocytes serve  Decline of Immune Responses distinct functions and may be distinguished by and Immunologic Memory the surface expression of particular membrane The majority of effector lymphocytes induced molecules. by an infectious pathogen die by apoptosis after n B lymphocytes are the only cells that produce the microbe is eliminated, thus returning the antibodies. B lymphocytes express membrane immune system to its basal resting state, called antibodies that recognize antigens, and the homeostasis. This occurs because microbes pro- progeny of activated B cells, called plasma vide essential stimuli for lymphocyte survival cells, secrete the antibodies that neutralize and activation, and effector cells are short-lived. and elimina