Basic Immunology PDF - Functions and Disorders of the Immune System

1 Introduction to the Immune System Nomenclature, General Properties, and Components CHAPTER OUTLINE Infections and Immunity, 2 Other Features of Adaptive Immunity, 7 Immunologic Disorders, 3 Cells of the Adaptive Immune System, 8 Stages of Host Defense: Innate and Adaptive Lymphocytes, 8 Immunity, 4 Antigen-Presenting Cells, 14 Division of Labor: Types of Adaptive Tissues of the Immune System, 15 Immunity, 5 Secondary (Peripheral) Lymphoid Organs and Properties of Adaptive Immune Responses, 6 Tissues, 15 Speciﬁcity and Diversity, 6 Lymphocyte Recirculation and Migration into Memory, 7 Tissues, 19 Nonreactivity to Self, 7 Summary, 21 The term immunity usually refers to protection against learning how to harness immune responses. The im- infectious pathogens. However, reactions to some mune system prevents the growth of some tumors, and noninfectious substances, including harmless environ- some cancers can be treated by stimulating immune mental molecules, tumors, and even one’s own mole- responses against tumor cells. These concepts are the cules are also considered forms of immunity (allergy, foundation of cancer immunotherapy, a therapeutic tumor immunity, and autoimmunity, respectively). The modality that has transformed the treatment of many collection of cells, tissues, and molecules that mediate cancer patients. Immune responses may become these reactions is called the immune system, and the abnormal and cause inﬂammatory diseases with serious coordinated response of these cells and molecules to morbidity and mortality. Allergies and autoimmune pathogens and other substances makes up an immune diseases are examples of such disorders. The immune response. Immunology is the study of the immune sys- response damages transplanted tissues and is the major tem and its functions. This ﬁeld has captured the barrier to the success of organ transplantation. The attention of scientists, physicians, and the lay public for widespread adoption of transplantation as a therapy has many reasons (Fig. 1.1). As we will discuss later, the become possible because of the development of effective immune system is the primary defense against in- drugs to suppress these immune responses. fections. The devastating consequences of pandemics This chapter introduces the nomenclature of such as COVID-19 have highlighted the importance of immunology, important general properties of all 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 Control of tissue Repair of damaged tissues regeneration and scarring Cell injury and Immune responses are the cause pathologic inflammation of allergic, autoimmune, and other inflammatory diseases, and for some of the harmful consequences of infections Recognition of and injury Immune responses are barriers to to tissue grafts and newly transplantation and gene therapy introduced proteins Fig. 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. immune responses, and the cells and tissues that are the increased risk for serious, often life-threatening in- principal components of the immune system. In fections. Conversely, stimulating immune responses particular, the following questions are addressed: against microbes through vaccination is the most What types of immune responses protect individuals effective method for protecting individuals against in- from infections? fections; this approach has led to the worldwide eradi- What are the important characteristics of immunity, cation of smallpox, the only disease that has been and what mechanisms are responsible for these eliminated from civilization by human intervention characteristics? (Fig. 1.2). The inﬂuenza pandemic of 1918, the How are the cells and tissues of the immune system appearance of acquired immunodeﬁciency syndrome organized to ﬁnd and respond to microbes in ways (AIDS) in the 1980s, and COVID-19 in 2019 have that lead to their elimination? tragically emphasized the importance of the immune The basic principles introduced here set the stage for system for defending individuals against infection. more detailed discussions of immune responses in later These newly emerged pathogens caused widespread chapters. A Glossary of the important terms used in this infections mainly because populations had not been book is provided near the end of the book. previously exposed to them and were hence not im- mune. Pandemics generally subside when a large frac- tion of the population develops immunity (called herd INFECTIONS AND IMMUNITY immunity) as a result of vaccination or by natural The most important physiologic function of the im- infection. In the case of human immunodeﬁciency virus mune system is to prevent and eradicate infections. (HIV)/AIDS, there is no herd immunity or effective Individuals with defective immune responses are at vaccine, and control of the infection in many parts of CHAPTER 1 Introduction to the Immune System 3 Disease Maximum number Number of of cases (year) cases in 2019 Diptheria 206,939 (1921) 2 Measles 894,134 (1941) 1,192 Mumps 152,209 (1968) 3,780 Pertussis 265,269 (1934) 18,617 Polio 21,269 (1952) 0 (paralytic) Rubella 57,686 (1969) 6 Tetanus 1,560 (1923) 26 Hemophilus ~20,000 (1984) 18 influenza type B Hepatitis B 26,611 (1985) 3,563 Average daily deaths per 100,000 people who tested positive: Unvaccinated Vaccinated Covid-19 1.3 0.1 Fig. 1.2 Effectiveness of vaccination for some common infectious diseases in the United States. Many infectious diseases for which effective vaccines have been developed have been virtually eradicated in the United States and other developed countries. Vaccines against SARS-CoV-2 have dramatically reduced the risks for developing a severe case of COVID-19. The COVID-19 death rate data are from a 6-month period in 2021. (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 ed. New York, NY: Churchill Living- stone, 1995; and Nationally Notiﬁable Infectious Diseases and Conditions, United States: 2018 Annual Tables.) the world relied on the development of effective anti- Chapter 2). The inﬂammation in these diseases is viral drugs. usually chronic (prolonged) because the inciting anti- gens cannot be eliminated, resulting in damage to normal tissues. Some of the most successful treatments IMMUNOLOGIC DISORDERS for such chronic inﬂammatory diseases are speciﬁcally The immune system reacts against potentially harmful targeted to components of the immune response. For infectious pathogens and cancers, but it does not nor- instance, current therapy for autoimmune diseases, mally respond to self molecules or harmless foreign such as rheumatoid arthritis and psoriasis, and for antigens. (The basis of this nonreactivity is discussed in allergic diseases, such as asthma, rely on therapeutic later chapters.) In some genetically predisposed in- blockade of molecules called cytokines that are dividuals, the immune system mounts damaging re- responsible for many of the harmful effects of immune actions against self structures causing autoimmune responses. Sometimes, protective immune responses to diseases, or against common environmental substances infections may lead to tissue damage and organ causing allergies. These disorders are characterized by dysfunction. For instance, in COVID-19, a signiﬁcant reactions of host cells, called inﬂammation (see part of the morbidity is the result of inﬂammatory 4 CHAPTER 1 Introduction to the Immune System responses to the virus, not the damage caused by the different classes of lymphocytes, and the enhanced re- virus itself. sponses seen upon repeat exposures to the same microbe (the phenomenon of immunologic memory, STAGES OF HOST DEFENSE: INNATE AND discussed later). The adaptive immune response takes a few days to develop, and innate immunity provides ADAPTIVE IMMUNITY defense in this critical early window after infection. Defense against infections is provided by the early Innate immunity is phylogenetically older, and the reactions of innate immunity and the later, more more specialized adaptive immune system evolved later. powerful, reactions of adaptive immunity (Fig. 1.3). In innate immunity, the ﬁrst lines of defense are the Innate immunity, also called natural immunity or epithelial barriers of the skin and mucosal tissues, native immunity, is always present in healthy in- antimicrobial substances produced by the epithelial dividuals (hence the term innate), prepared to block the barrier cells, and other cells located within or under the entry of microbes and to rapidly eliminate microbes epithelium, all of which function to block the entry of that do succeed in entering host tissues. Adaptive im- microbes. If microbes do breach epithelia and enter the munity, also called speciﬁc immunity or acquired im- tissues or circulation, several other components of the munity, requires proliferation and differentiation of innate immune system defend against them, including lymphocytes in response to microbes before it can phagocytes and plasma proteins such as the comple- provide effective defense (i.e., it adapts to the presence ment system. In addition to providing early defense of microbial invaders). The potency of adaptive im- against infections, innate immune responses are mune responses is because of the tremendous increase required to initiate adaptive immune responses against in the number of microbe-speciﬁc lymphocytes in the infectious agents. The cells and molecules of innate response to infection, the highly specialized functions of immunity recognize a limited number of molecular 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 Fig. 1.3 Principal components of innate and adaptive immunity. The components of innate immunity provide the initial defense against infections. Some of these (e.g., epithelial barriers) prevent infections, and others (e.g., phagocytes, natural killer [NK] cells, 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 extracellular microbes, and T lymphocytes eradicate intracellular microbes. The kinetics of the innate and adaptive immune responses are approximations and may vary in different infections. CHAPTER 1 Introduction to the Immune System 5 structures shared by classes of microbes. The compo- speciﬁcally recognized by lymphocytes or antibodies is nents and mechanisms of innate immunity are dis- called an antigen. cussed in detail in Chapter 2; the remainder of this chapter is an introduction to adaptive immunity. Division of Labor: Types of Adaptive Immunity The adaptive immune response is mediated by There are two types of adaptive immunity, called lymphocytes with highly diverse and variable re- humoral immunity and cell-mediated immunity, ceptors for foreign substances and the products of mediated by different cells and molecules, that pro- these cells, such as antibodies and other proteins. vide defense against microbes in different locations Adaptive immune responses are critical for defense (Fig. 1.4). Extracellular microbes (which survive outside against infectious pathogens that may have evolved to host cells and are readily destroyed when they are resist innate immunity. The lymphocytes of adaptive ingested by phagocytes) are combated by antibodies. immunity express receptors that speciﬁcally recognize a Microbes that have evolved to survive inside host cells, wide variety of molecules produced by microbes, as well either in phagocytic vesicles or in the cytosol, are as noninfectious molecules. Any molecule that is eradicated by the actions of T lymphocytes. Humoral Cell-mediated immunity immunity Microbe Intracellular microbes Extracellular Phagocytosed (e.g., viruses) microbes microbes in replicating within macrophage infected cell Responding lymphocytes Helper Cytotoxic B lymphocyte T lymphocyte T lymphocyte Cytokines Secreted antibody Effector mechanism Activated Killed infected cell Antibodies macrophage prevent Functions infections Cytokine- CTLs kill and activated infected cells eliminate phagocytes and eliminate extracellular kill ingested reservoirs microbes microbes of infection Fig. 1.4 Types of adaptive immunity. In humoral immunity, B lymphocytes secrete antibodies that eliminate extracellular microbes. In cell-mediated immunity, some T lymphocytes secrete soluble proteins called cyto- kines that recruit and activate phagocytes to destroy ingested microbes, and other T lymphocytes kill infected cells. CTLs, Cytotoxic T lymphocytes. 6 CHAPTER 1 Introduction to the Immune System Humoral immunity is mediated by proteins called infection and develops resistance to later infection by antibodies, which are produced by cells called B lym- that microbe. Such an individual is said to be immune phocytes. Secreted antibodies enter the circulation, to that microbe, in contrast with an individual who has extracellular tissue ﬂuids, and lumens of mucosal organs not previously been exposed to that microbe’s antigens such as the gastrointestinal and respiratory tracts. Anti- and is said to be naive for that microbe. bodies defend against microbes present in these loca- In passive immunity, a naive individual receives an- tions by preventing them from infecting tissue cells tibodies from another individual already immune to and by neutralizing toxins made by the microbes. Anti- an infection or protective antibodies that are pro- bodies also enhance the uptake of extracellular microbes duced in laboratories. The recipient acquires the into phagocytes, resulting in the killing of the pathogens. ability to combat the infection, but only for as long In addition, antibodies are transported through the as the transferred antibodies last. Passive immunity placenta into the fetal circulation and protect the fetus is therefore useful for rapidly conferring immunity and newborn from infections. even before the individual is able to mount an active Defense against microbes that have entered host cells response, but it does not induce long-lived resistance is called cell-mediated immunity because it is medi- to the infection. The only physiologic example of ated by cells that are called T lymphocytes. Many passive immunity is seen in newborns, whose im- intracellular microbes can live and replicate inside mune systems are not mature enough to respond infected cells, including phagocytes. Although anti- to many pathogens but who are protected against in- bodies can prevent such microbes from infecting tis- fections by acquiring antibodies during fetal life from sue cells, they are not effective after the microbes their mothers through the placenta and in the have entered the cells. Cell-mediated immunity is neonatal period from breast milk. Clinically, passive especially important to defend against these intracel- immunity is useful for treating some immunodeﬁ- lular organisms. As we discuss later, there are two ciency diseases with antibodies pooled from multiple major classes of T lymphocytes. Cytokine- donors and for emergency treatment of some viral producing helper T lymphocytes activate phagocytes infections, such as SARS-CoV-2, and snakebites us- to destroy microbes that have been ingested and live ing serum from immunized donors. Recently, some within intracellular vesicles of these phagocytes. viral infections, including SARS-CoV-2, have been Cytotoxic T lymphocytes kill any type of host cells treated by administering antibodies puriﬁed from (including nonphagocytic cells) that harbor infec- infected individuals or monoclonal antibodies pro- tious microbes, such as viruses in the cytoplasm. duced in the laboratory. Antibodies designed to Some helper T lymphocytes also promote defense recognize tumors are now widely used for passive against extracellular microbes by recruiting large immunotherapy of cancers. Passive immunity by numbers of phagocytes to sites of infection, and transfer of T cells between genetically nonidentical the phagocytes ingest and destroy the microbes. people is not possible because transferred cells will The speciﬁcities of B and T lymphocytes differ in be rejected. important respects. Most T cells recognize only peptide fragments of protein antigens presented on cell surfaces and thus sense the presence of intracellular microbes, PROPERTIES OF ADAPTIVE IMMUNE whereas B cells and antibodies are able to recognize many different types of molecules, including proteins, RESPONSES carbohydrates, nucleic acids, and lipids of extracellular Several properties of adaptive immune responses are microbes. These and other differences are discussed in crucial for the effectiveness of these responses in more detail later. combating infections (Fig. 1.5). Immunity may be induced in an individual by infection or vaccination (active immunity) or conferred Specificity and Diversity on an individual by transfer of antibodies from an The adaptive immune system is capable of dis- actively immunized individual (passive immunity). tinguishing millions of different antigens or por- In active immunity, an individual exposed to the anti- tions of antigens, a feature that is referred to as gens of a microbe mounts a response to eradicate the speciﬁcity. It ensures that when an individual is CHAPTER 1 Introduction to the Immune System 7 Feature Functional significance rise to a large number of cells capable of eliminating the microbes. The marked proliferative expansion of the clone Specificity Ensures that immune of lymphocytes speciﬁc for any antigen upon exposure to responses combat the pathogens (or tumors) that are that antigen is called clonal expansion. encountered Memory Diversity Enables the immune system to respond to a large The adaptive immune system mounts faster, larger, variety of antigens and more effective responses to repeated exposure to Leads to enhanced responses the same antigen. This feature of adaptive immune Memory responses implies that the immune system remembers to repeated exposures to the same antigens every encounter with antigen, and this property of Nonreactivity Prevents injury to the adaptive immunity is therefore called immunologic to self host during responses to memory. The response to the ﬁrst exposure to antigen, foreign antigens called the primary immune response, is initiated by Fig. 1.5 Properties of adaptive immune responses. This table lymphocytes called naive lymphocytes that are seeing summarizes the important properties of adaptive immune re- antigen for the ﬁrst time (Fig. 1.7). The term naive refers sponses and how each feature contributes to host defense to these cells being immunologically inexperienced, not against microbes. having previously responded to the antigen. Subsequent infected by a microbe, the response is directed against encounters with the same antigen lead to responses that microbe and not, wastefully, against others that called secondary immune responses that usually are are not infecting the individual. Each lymphocyte ex- larger, more rapid and better able to eliminate the an- presses a single antigen receptor and can therefore tigen than primary responses. Secondary responses are recognize and respond to only one antigen. Because the generated by the activation of memory lymphocytes, immune system has to be able to react to a vast which are long-lived cells that were induced during the number of antigens from all the possible infectious primary immune response. Immunologic memory op- pathogens, the total collection of lymphocyte speciﬁc- timizes the ability of the immune system to combat ities, sometimes called the lymphocyte repertoire, is persistent and recurrent infections, because each expo- extremely diverse. In an adult, there are about 0.5 to sure to a microbe generates more memory cells and 1 1012 B and T lymphocytes, consisting of millions activates previously generated memory cells. Immuno- of clones (each clone made up of cells derived from logic memory is one mechanism by which vaccines one lymphocyte), and all the cells of one clone express confer long-lasting protection against infections. identical antigen receptors, which are different from the receptors of all other clones. We now know the Nonreactivity to Self molecular basis for the generation of this remarkable The immune system is able to react against an enor- diversity of lymphocytes (see Chapter 4). The clonal mous number and variety of microbes and other selection hypothesis, formulated in the 1950s, correctly foreign antigens, but it normally does not react against predicted that clones of lymphocytes speciﬁc for the host’s own potentially antigenic substances, so- different antigens develop before an encounter with called self antigens. This unresponsiveness to self is these antigens, and each antigen elicits an immune called immunologic tolerance, referring to the ability response by selecting and activating the lymphocytes of of the immune system to coexist with (tolerate) a speciﬁc clone (Fig. 1.6). potentially antigenic self molecules, cells, and tissues. The diversity of the lymphocyte repertoire also means Failure of self-tolerance is the fundamental abnormality that before exposure to any one antigen, very few cells, in autoimmune diseases. perhaps as few as 1 in 100,000 or 1 in 1,000,000 lympho- cytes, are speciﬁc for that antigen. Thus, the total number Other Features of Adaptive Immunity of lymphocytes that can recognize and react against any Adaptive immune responses have other characteristics one antigen ranges from approximately 1000 to 10,000 that are important for their functions. cells. To mount an effective defense against rapidly Immune responses are specialized, and different re- proliferating microbes, these few lymphocytes have to give sponses are designed to defend best against different 8 CHAPTER 1 Introduction to the Immune System Lymphocyte precursor Lymphocyte Mature clones with lymphocytes 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 Fig. 1.6 Clonal selection. Mature lymphocytes with receptors for antigens develop before encountering the antigens. A clone refers to a population of lymphocytes with identical antigen receptors and therefore spec- iﬁcities; 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 lymphocytes. kinds of microbes and at different sites of infections. classiﬁed into two groups: myeloid cells and lymphoid For example, there are several classes of secreted an- cells (lymphocytes) (Fig. 1.8). Myeloid cells consist tibodies, each of which performs a different set of mainly of phagocytes (neutrophils and macrophages), functions, and there are several subsets of T cells, antigen-presenting cells (APCs) (e.g., dendritic cells), each of which combats infections in different ways. and mast cells. Several of these myeloid cells reside in All immune responses are self-limited and decline as tissues and serve as sentinels to detect the presence of the infection is eliminated, allowing the system to re- microbes and to initiate immune responses. Phagocytes turn to a resting state (homeostasis), prepared to and mast cells are described in Chapter 2. Here, we respond to another infection. describe lymphocytes and APCs, which serve key roles in adaptive immunity. CELLS OF THE ADAPTIVE IMMUNE SYSTEM Lymphocytes The cells of the immune system are mostly derived Lymphocytes are the only cells that produce clonally from progenitors in the bone marrow and are broadly distributed receptors speciﬁc for diverse antigens and Antigen X Antigen X + Plasma cells Antigen Y Anti-X B cell Anti-Y B cell Secondary Memory anti-X B cells Serum antibody titer Plasma response cell Plasma Memory cells B cells Memory Naive Primary Naive B cells B cell Primary B cells anti-X anti-Y response response 2 4 6 8 10 Weeks Fig. 1.7 Primary and secondary immune responses. The properties of memory and speciﬁcity can be demonstrated by repeated immunizations with deﬁned antigens in animal experiments. Antigens X and Y induce the production of different 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 immu- nization 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 immunization. Cell type Principal function(s) Lymphocytes: Specific recognition of antigens B lymphocytes; and generation of adaptive immune responses: T lymphocytes B lymphocytes: mediators of humoral immunity Lymphocyte T lymphocytes: mediators of cell-mediated immunity Myeloid cells: Neutrophils and Neutrophils; monocytes/macrophages: Macrophages; phagocytosis and killing of microbes Dendritic cells; Dendritic cells: antigen Mast cells Neutrophil presentation to T cells; initiation of T cell responses Mast cells: secretion of inflammatory mediators Monocyte Fig. 1.8 Principal cells of the adaptive immune system. Micrographs illustrate the morphology of some cells of each type. The major functions of these cell types are listed. 10 CHAPTER 1 Introduction to the Immune System are the key mediators of adaptive immunity. of surface molecules that can be identiﬁed using Although all lymphocytes are morphologically similar, monoclonal antibodies. The standard nomenclature for they are heterogeneous in lineage, function, and these proteins is the cluster of differentiation (CD) phenotype (Fig. 1.9). Different types of lymphocytes numeric designation, which is used to delineate surface (and other cells) may be distinguished by the expression proteins that deﬁne a particular cell type or stage of cell A Antigen recognition Effector functions Neutralization of microbe, B phagocytosis, lymphocyte complement Microbe activation Antibody Cytokines Activation of macrophages Inflammation Helper T lymphocyte Microbial antigen Activation of presented by antigen B lymphocytes presenting cell Cytotoxic T Killing of infected cell lymphocyte (CTL) Infected cell expressing microbial antigen Responding T lymphocyte Regulatory Regulatory T lymphocyte Suppression of other T lymphocyte lymphocytes Fig. 1.9 Classes of lymphocytes. A, Different classes of lymphocytes in the adaptive immune system recognize distinct types of antigens and differentiate into effector cells whose function is to eliminate the antigens. B lymphocytes recognize soluble or microbial surface antigens and differentiate into antibody- secreting cells called plasma cells. Both helper T cells and cytotoxic T lymphocytes recognize peptides derived from intracellular microbial proteins displayed on the cell surface by major histocompatibility complex (MHC) molecules, described in Chapter 3. Helper T cells recognize these peptides displayed on the surface of macrophages or other antigen-presenting cells, and secrete cytokines that stimulate different mechanisms of immunity and inﬂammation. Cytotoxic T lymphocytes recognize peptides displayed by any type of infected cell type (or tumor cell) and kill these cells. Regulatory T cells limit the activation of other lymphocytes, especially of T cells, and prevent autoimmunity. CHAPTER 1 Introduction to the Immune System 11 B Class Functions Antigen Selected Percentage of receptor and phenotype total lymphocytes* specificity markers αβ T Lymphocytes CD4+ B cell activation αβ heterodimers CD3+ Blood Lymph Spleen helper T (humoral Diverse specificities CD4– + node immunity) CD8 lymphocytes for peptide–class II 35–60 50–60 50–60 Macrophage MHC complexes activation (cell-mediated immunity) Stimulation of inflammation CD8+ Killing of cells αβ heterodimers CD3+ 15–40 15–20 10–15 – cytotoxic T infected with Diverse specificities CD4+ intracellular for peptide–class I CD8 lymphocytes microbes, MHC complexes tumor cells Regulatory Suppress αβ heterodimers CD3+ 0.5–2 5–10 5–10 T cells function of Specific for self CD4+ other T cells and some CD25+ (regulation foreign antigens FoxP3+ of immune (peptide–class II (most responses, MHC complexes) common) maintenance of self-tolerance) B Lymphocytes B cells Antibody Surface Ig Fc receptors Blood Lymph Spleen production Diverse specificities class II MHC node (humoral for many types CD19 immunity) CD20 5–20 20–25 40–45 of molecules Fig. 1.9 B, The table summarizes the major properties of the lymphocytes of the adaptive immune system. Not included are gd T cells, natural killer cells and other innate lymphoid cells, which are discussed in Chapter 2. *The percentages are approximations, based on data from human peripheral blood and mouse lymphoid organs. Ig, Immunoglobulin; MHC, major histocompatibility complex. differentiation and that are recognized by a set (cluster) express membrane-bound antibodies that serve as the of antibodies. (A list of CD molecules mentioned in the receptors that recognize antigens and initiate the pro- book is provided in Appendix I.) cess of activation of the cells. Soluble antigens and an- As alluded to earlier, B lymphocytes are the only tigens on the surface of microbes and other cells may cells capable of producing antibodies; therefore, they are bind to these B lymphocyte antigen receptors, resulting the cells that mediate humoral immunity. B cells in the proliferation and differentiation of the antigen- 12 CHAPTER 1 Introduction to the Immune System speciﬁc B cells. This leads to the secretion of soluble (generated) are called the generative (also called central forms of antibodies with the same antigen speciﬁcity as or primary) lymphoid organs. Mature lymphocytes the membrane receptors. leave the generative lymphoid organs and enter the T lymphocytes are responsible for cell-mediated circulation and secondary (peripheral) lymphoid or- immunity. The antigen receptors of most T lympho- gans, which are the major site of immune responses cytes recognize only peptide fragments of protein an- where lymphocytes encounter antigens and are tigens that are bound to specialized peptide display activated. molecules, called major histocompatibility complex When naive lymphocytes recognize microbial an- (MHC) molecules, on the surface of other cells, called tigens and also receive additional signals induced by antigen-presenting cells (see Chapter 3). Among T microbes, the antigen-speciﬁc lymphocytes prolifer- lymphocytes, CD4þ T cells are called helper T cells ate and then differentiate into effector cells and because they help B lymphocytes to produce antibodies memory cells (Fig. 1.11). and help phagocytes to destroy ingested microbes. Naive lymphocytes express receptors for antigens CD8þ T lymphocytes are called cytotoxic T lympho- but do not perform the functions that are required cytes (CTLs) because they kill cells harboring microbes. to eliminate antigens. These cells circulate between Some CD4þ T cells belong to a special subset that and temporarily reside in secondary lymphoid or- functions to prevent or limit immune responses; these gans, where they are positioned to respond to anti- are called regulatory T lymphocytes. gens. If they are not activated by antigen, after All lymphocytes arise from common lymphoid several months up to a few years, naive lymphocytes progenitor cells in the bone marrow (Fig. 1.10). B die by the process of apoptosis and are replaced by lymphocytes mature in the bone marrow, and T new cells that have developed in the generative lymphocytes mature in an organ called the thymus. lymphoid organs. The differentiation of naive lym- These sites in which mature lymphocytes are produced phocytes into effector cells and memory cells is Generative Blood, Secondary lymphoid lymph (peripheral) organs lymphoid organs Immature Naive Bone B lymphocytes B lymphocytes Lymph Common marrow nodes lymphoid B precursor lymphocyte lineage Recirculation Spleen T lymphocyte lineage Naive Mucosal and T lymphocytes cutaneous Naive T lymphocytes lymphoid Bone Marrow tissues Thymus Fig. 1.10 Maturation and tissue distribution of lymphocytes. Lymphocytes develop from precursors in the generative lymphoid organs (bone marrow and thymus). Mature lymphocytes enter the secondary (peripheral) lymphoid organs, where they respond 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). CHAPTER 1 Introduction to the Immune System 13 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 Activated or Naive cell effector lymphocyte Memory lymphocyte T lymphocytes Migration Preferentially Preferentially to Heterogenous: different to secondary inflamed tissues subsets to lymphoid organs, lymphoid organs mucosa and other 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 Fig. 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 differ- entiate 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 lymphocytes 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 initiated by antigen recognition, thus ensuring that Thymic output the immune response that develops is speciﬁc for the antigen that is encountered. 100 Effector lymphocytes are the differentiated progeny of naive cells that have the ability to produce mole- 80 Naive T cells % Blood T cells cules that function to eliminate antigens. The Memory T cells effector cells in the B lymphocyte lineage are 60 antibody-secreting cells called plasma cells. Plasma 40 cells develop from B cells in response to antigenic stimulation in the secondary lymphoid organs, 20 where they may stay and produce antibodies. Small numbers of antibody-secreting cells are also found 0 0 10 20 30 40 50 60 70 80 in the blood; these are called plasmablasts. These Age (Years) often migrate to the bone marrow, where they Fig. 1.12 Change in proportions of naive and memory T cells mature into long-lived plasma cells and continue with age. The proportions of naive and memory T cells are to produce antibody for years after the infection is based on data from multiple healthy individuals. The estimate of eradicated, providing immediate protection in case thymic output is an approximation. (Courtesy Dr. Donna L. the infection recurs. Farber, Columbia University College of Physicians and Sur- Effector CD4þ T cells (helper T cells) produce geons, New York, NY.) proteins called cytokines that activate B cells, macrophages, and other cell types, thereby medi- ating the helper function of this lineage. The they rapidly respond by becoming effector cells that properties of cytokines are listed in Appendix II and initiate secondary immune responses. The signals will be discussed in later chapters. Effector CD8þ that generate and maintain memory cells are not T cells (CTLs) have the machinery to kill infected well understood but include cytokines. host cells. The development and functions of these effector cells are also discussed in later chapters. Antigen-Presenting Cells Effector T lymphocytes are short-lived and die as The common portals of entry for microbesdthe skin the antigen is eliminated. and gastrointestinal, respiratory, and genitourinary Memory cells, also generated from the progeny of tractsdcontain specialized cells located at the antigen-stimulated lymphocytes, can survive for epithelial barriers that capture antigens, transport long periods in the absence of antigen. Therefore, them to secondary lymphoid organs, and display the frequency of memory cells increases with age, pre- (present) them to lymphocytes. These are the ﬁrst sumably because exposure to microbes throughout steps in the development of adaptive immune responses one’s life has generated memory cells speciﬁc for against antigens. This function of antigen capture and those microbes. In fact, memory cells make up less presentation is best understood for dendritic cells, the than 5% of peripheral blood T cells in a newborn most specialized APCs in the immune system. The role but 50% or more in an adult (Fig. 1.12). As individ- of dendritic cells in presenting antigens to T lympho- uals age, the gradual accumulation of memory cells cytes and initiating cell-mediated immune responses is compensates for the reduced output of new, naive described in Chapter 3. T cells from the thymus, which involutes after puberty B lymphocytes may directly recognize the antigens (see Chapter 4). Memory cells are functionally inac- of microbes (either released or on the surface of the tive; they do not perform effector functions unless microbes), and macrophages and dendritic cells in stimulated by antigen. When memory cells encounter secondary lymphoid organs may also capture antigens the same antigen that induced their development, and display them to B cells. CHAPTER 1 Introduction to the Immune System 15 microbes that enter at any site in the body, then TISSUES OF THE IMMUNE SYSTEM respond to these microbes and eliminate them. The The tissues of the immune system consist of the anatomic organization of secondary lymphoid organs generative lymphoid organs, in which T and B lym- enables APCs to concentrate antigens in these organs phocytes mature and become competent to respond to and lymphocytes to locate and respond to the antigens. antigens, and the secondary lymphoid organs, in which Furthermore, different types of lymphocytes often need adaptive immune responses to microbes are initiated to communicate with each other to generate effective (see Fig. 1.10). Most of the lymphocytes in a healthy immune responses. For example, within secondary human are found in lymphoid organs and other tissues lymphoid organs, helper T cells speciﬁc for a protein (Fig. 1.13). However, as we discuss later, lymphocytes antigen interact with and help B lymphocytes speciﬁc are unique among the cells of the body because of their for the same antigen, resulting in antibody production. ability to recirculate, repeatedly traveling via the blood An important function of lymphoid organs is to bring to secondary lymphoid organs and other tissues. The together these rare T and B cells speciﬁc for the same generative lymphoid organs are described in Chapter 4, antigen after stimulation by that antigen. when we discuss the process of lymphocyte maturation. The major secondary lymphoid organs share many The following section highlights some of the features of characteristics but also have some unique features. secondary lymphoid organs that are important for Lymph nodes are encapsulated nodular aggregates of adaptive immunity. lymphoid tissues located along lymphatic channels throughout the body (Fig. 1.14). Fluid constantly leaks out of small blood vessels in all epithelia and Secondary (Peripheral) Lymphoid Organs and connective tissues and most parenchymal organs. Tissues This ﬂuid, called lymph, is drained by lymphatic ves- The secondary lymphoid organs and tissues, which sels from the tissues to the lymph nodes and eventu- consist of lymph nodes, the spleen, and the mucosal ally back into the blood circulation. Therefore, the and cutaneous immune systems, are organized in a lymph contains a mixture of substances absorbed way that promotes the development of adaptive im- from epithelia and tissues. As the lymph passes mune responses. T and B lymphocytes must locate through lymph nodes, APCs in the nodes are able to sample the antigens of microbes that may enter through epithelia into tissues. In addition, dendritic cells pick up antigens of microbes from epithelia Tissue Number of and other tissues and transport these antigens to the lymphocytes x 109 lymph nodes. The net result of these processes of an- tigen capture and transport is that the antigens of mi- Spleen 70 crobes entering through epithelia or colonizing tissues Lymph nodes 190 become concentrated in draining lymph nodes. The spleen is a highly vascularized abdominal organ Bone marrow 50 that serves the same role in immune responses to Blood 10 blood-borne antigens as that of lymph nodes in re- sponses to lymph-borne antigens (Fig. 1.15). Blood Skin 20 entering the spleen ﬂows through a network of chan- nels (sinusoids). Blood-borne antigens are captured Intestines 50 and concentrated by dendritic cells and macrophages Liver 10 in the spleen. The spleen contains abundant phago- cytes that line the sinusoids, which ingest and Lungs 30 destroy microbes in the blood. These macrophages Fig. 1.13 Distribution of lymphocytes in lymphoid organs and also ingest and destroy old red blood cells. other tissues. Approximate numbers of lymphocytes in The cutaneous and mucosal immune systems are different organs of healthy adults are shown. specialized collections of lymphoid tissues and 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 Red pulp Germinal T cell center of zone lymphoid Capsule follicle Germinal Medulla center Vein Medullary White pulp sinus Artery Efferent lymphatic vessel Periarteriolar Lymphocytes lymphoid sheath B Lymphoid follicles Parafollicular (B cell zone) with cortex (T cell zone) germinal centers Fig. 1.15 Morphology of the spleen. A, Schematic diagram shows a splenic arteriole surrounded by the periarteriolar lymphoid sheath (PALS) and attached follicles. The PALS and lymphoid follicles together constitute the white pulp. The mar- ginal zone with its sinus is the indistinct boundary between the white pulp and the red pulp. B, Light micrograph of a section of spleen shows an arteriole with the PALS and a follicle with a prominent germinal center. These are surrounded by the red pulp, which is rich in vascular sinusoids. APCs located in and under the epithelia of the skin and the gastrointestinal and respiratory tracts, respectively. Although most of the immune cells in these tissues are diffusely scattered beneath the epithelial barriers, there are discrete collections of Fig. 1.14 Morphology of lymph nodes. A, Schematic diagram lymphocytes and APCs organized in a similar way shows the structural organization of a lymph node. B, Light as in lymph nodes. For example, tonsils in the phar- micrograph shows a cross section of a lymph node illustrating the T cell and B cell zones. The B cell zones contain numerous ynx and Peyer’s patches in the intestine are two follicles in the cortex, some of which contain lightly stained anatomically deﬁned mucosal lymphoid tissues central areas (germinal centers). (Courtesy Robert Oghami, MD, (Fig. 1.16). The immune system of the skin contains PhD, and Kaushik Sridhar, Department of Pathology, University most of the cells of innate and adaptive immunity, of California San Francisco, San Francisco, CA.) but without any anatomically deﬁned structures CHAPTER 1 Introduction to the Immune System 17 A Commensal Villus bacteria Intraepithelial lymphocytes Intestinal Intestinal M cell lumen epithelia cell Mucus Goblet cell Dendritic Tuft cell cell Peyer’s Crypt patch Mucosal epithelium Afferent IgA Lymphatic lymphatic Plasma drainage cell Follicle Lamina Dendritic B cell propria cell Innate T cell Antimicrobial Mast cell lymphoid peptides Paneth cells Macrophage cell B Mucosal epithelium Lamina propria Mesenteric Peyer's lymph node patch Fig. 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 provides 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 intestine. 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). (Fig. 1.17). At any time, at least a quarter of the immune systems is that they are able to respond to body’s lymphocytes are in the mucosal tissues and pathogens but do not react to the enormous skin (reﬂecting the large size of these tissues) (see numbers of usually harmless commensal microbes Fig. 1.13), and many of these are memory cells. Cuta- present at the epithelial barriers. This is accom- neous and mucosal lymphoid tissues are sites of im- plished by several mechanisms, including the action mune responses to antigens that breach epithelia. A of regulatory T cells and other signals that suppress remarkable property of the cutaneous and mucosal rather than activate lymphocytes. 18 CHAPTER 1 Introduction to the Immune System Commensal and pathogenic microbes Epidermis Keratinocytes Epidermal Langerhans cell Intrepithelial lymphocyte Basal keratinocytes Plasma cell Dermis Postcapillary Lymphatic venule Mast cell vessel Macrophage T lymphocyte Drainage to regional lymph node Dermal dendritic cell Fig. 1.17 Cutaneous immune system. The major components of the cutaneous immune system shown in this schematic diagram include keratinocytes, Langerhans cells, and intraepithelial lymphocytes, all located in the epidermis, and T lymphocytes, dendritic cells, and macrophages, located in the dermis. Within the secondary lymphoid organs, T lym- The anatomic organization of secondary lymphoid phocytes and B lymphocytes are segregated into organs is tightly regulated to allow immune responses different anatomic regions (Fig. 1.18). In lymph nodes, to develop after stimulation by antigens. B lymphocytes the B cells are concentrated in discrete structures, called are attracted to and retained in the follicles because of follicles, located around the periphery, or cortex, of the action of a class of cytokines called chemokines each node. If the B cells in a follicle have recently (chemoattractant cytokines; chemokines and other cy- responded to a protein antigen and received signals tokines are discussed in more detail in later chapters). from helper T cells, this follicle may contain a central FDCs in the follicles secrete a particular chemokine for lightly staining region called a germinal center. The which naive B cells express a receptor, called CXCR5. germinal center has an important role in the production The chemokine that binds to CXCR5 attracts B cells of highly effective antibodies and is described in from the blood into the follicles of lymphoid organs. Chapter 7. The T lymphocytes are concentrated outside Similarly, T cells are segregated in the paracortex of but adjacent to the follicles, in the paracortex. APCs lymph nodes and the periarteriolar lymphoid sheaths of colocalize with the classes of lymphocytes to which they the spleen because naive T lymphocytes express a re- present antigensd dendritic cells with T lymphocytes ceptor, called CCR7, which recognizes chemokines that in the parafollicular cortex and a type of cell called are produced in these regions of the lymph nodes and follicular dendritic cells (FDCs; see Chapter 7) with B spleen. When the lymphocytes are activated by anti- cells in the follicles. In the spleen, T lymphocytes are gens, they alter their expression of chemokine receptors. concentrated in periarteriolar lymphoid sheaths sur- As a result, the antigen-activated B cells and T cells rounding small arterioles, and B cells reside in the migrate toward each other and meet at the edge of follicles. follicles, where helper T cells interact with and help B CHAPTER 1 Introduction to the Immune System 19 A B Dendritic cell High Naive endothelial B cell B cell–specific venule chemokine T cell zone Afferent (parafollicular lymphatic cortex) vessel B cell zone (lymphoid B cell follicle) zone T cell zone Naive B cell T cell Artery T cell and dendritic cell–specific chemokine T cell Fig. 1.18 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 only one or the other 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 cellerich 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 incubated with antibodies speciﬁc for T or B cells coupled to ﬂuo- rochromes 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). (B, Courtesy Drs. Kathryn Pape and Jennifer Walter, University of Minnesota Medical School, Minneapolis, MN.) cells to differentiate into antibody-secreting plasma cells they were generated and migrate into lymphoid follicles, (see Chapter 7). Thus, these lymphocyte populations where they help B cells to make high-afﬁnity antibodies. are kept apart from each other until it is useful for them to interact, after exposure to an antigen. This is an Lymphocyte Recirculation and Migration into excellent example of how the structure of lymphoid Tissues organs ensures that the cells that have recognized and Naive lymphocytes constantly recirculate between the responded to an antigen interact and communicate blood and secondary lymphoid organs, where they with one another when necessary. may be activated by antigens to become effector cells, Many of the effector T cells exit the node through and effector lymphocytes migrate from lymphoid efferent lymphatic vessels and leave the spleen through tissues to sites of infection, where microbes are veins. These activated lymphocytes end up in the cir- eliminated (Fig. 1.19). Thus, these lymphocytes with culation and can go to distant sites of infection. Some different histories of antigen exposure selectively activated T cells remain in the lymphoid organ where migrate to the sites where they can perform their 20 CHAPTER 1 Introduction to the Immune System Lymph node Peripheral tissue Chemokines High endothelial Peripheral venule Blood blood vessel Artery vessel Effector or Efferent memory T cell lymphatic vessel Naive T cell Fig. 1.19 Migration of T lymphocytes. Naive T lymphocytes migrate from the blood through high endothelial 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 Chapter 5. different functions. Migration of effector lymphocytes In that location they can ﬁnd antigens that are to sites of infection is most relevant for T cells because brought to the lymph nodes by dendritic cells or in effector T cells have to locate and eliminate microbes at free form through lymphatic vessels that drain these sites. By contrast, B cellederived plasma cells do epithelia and parenchymal organs. not need to migrate to sites of infection; instead, they Within the lymph node paracortex, naive T cells secrete antibodies, and the antibodies enter and circu- move around rapidly along specialized connective late in the blood. These antibodies bind pathogens or tissue ﬁbers, scanning the surfaces of dendritic cells, toxins in the blood, or in tissues into which the anti- located on these ﬁbers, for antigens. If a T cell specif- bodies enter. Plasma cells in mucosal organs secrete ically recognizes an antigen on a dendritic cell, that antibodies that enter the lumens of these organs, where T cell forms stable conjugates with the dendritic they bind to and combat ingested and inhaled microbes. cell and is activated. Such an encounter between The migration of different lymphocyte populations an antigen and a speciﬁc lymphocyte is likely to has distinct features and is controlled by different be a rare and random event, but most T cells in molecular interactions. the body circulate through some lymph nodes at Naive T lymphocytes that have matured in the least once a day. As mentioned earlier and thymus and entered the circulation migrate into described further in Chapter 3, the likelihood of lymph nodes by binding to adhesion molecules and the correct T cell ﬁnding its antigen is increased chemokines on the endothelial lining of specialized in secondary lymphoid organs, particularly lymph postcapillary venules, called high endothelial ve- nodes, because microbial antigens are concentrated nules (HEVs), located in the parafollicular cortex. in the same regions of these organs through which The process of lymphocyte migration out of blood naive T cells circulate. Thus, T cells ﬁnd the antigen vessels is discussed in Chapter 5. Once outside the they can recognize, and these T cells are activated HEV, the T cells remain in the paracortex because to proliferate and differentiate. Naive cells that they are attracted to chemokines produced there. have not encountered speciﬁc antigens leave the CHAPTER 1 Introduction to the Immune System 21 lymph nodes through lymphatic vessels and reenter Lymphocytes are the cells of adaptive immunity and the circulation. are the only cells with clonally distributed receptors Many of the effector cells that are generated upon speciﬁc for different antigens. T cell activation leave the lymph node by lymphatics, Adaptive immunity consists of humoral immunity, enter the circulation, and then preferentially migrate in which antibodies neutralize and eliminate extracel- into infected tissues. Effector T cell migration selec- lular microbes and toxins, and cell-mediated tively occurs at infection sites because the local immunity, in which T lymphocytes eradicate intra- innate response to the microbes induces expression cellular microbes. of chemokines and endothelial adhesion molecules Adaptive immune responses consist of sequential on postcapillary venules (see Chapter 5). Once in phases: antigen recognition by lymphocytes, activa- the infected tissue, T lymphocytes perform their tion of the lymphocytes to proliferate and to differ- function of eradicating the microbes. entiate into effector and memory cells, elimination B lymphocytes that recognize and respond to antigen of the microbes, decline of the immune response, in lymph node follicles differentiate into antibody- and long-lived memory. secreting plasma cells, many of which migrate to Different populations of lymphocytes serve distinct the bone marrow or mucosal tissues (see Chapter 7). functions and may be distinguished by the surface Memory T cells consist of different populations (see expression of particular membrane molecules. Chapter 6); some cells recirculate through lymph B lymphocytes are the only cells that produce an- nodes, where they can mount secondary responses tibodies. B lymphocytes express membrane anti- to captured antigens, and other cells migrate to sites bodies that recognize antigens, and the progeny of infection, where they can respond rapidly to elim- of activated B cells, called plasma cells, secrete inate the infection. Yet other memory cells perma- the antibodies that neutralize and eliminate the nently reside in epithelial tissues, such as mucosal antigen. tissues and the skin. T lymphocytes recognize peptide fragments of pro- We know less about lymphocyte circulation through tein antigens displayed on other cells. Helper T lym- the spleen or other lymphoid tissues. The spleen does phocytes produce cytokines that activate phagocytes not contain HEVs, but the general pattern of naive to destroy ingested microbes, recruit leukocytes, and lymphocyte migration through this organ is probably activate B lymphocytes to produce antibodies. Cyto- similar to migration through lymph nodes. toxic T lymphocytes (CTLs) kill infected cells harboring microbes in the cytoplasm. Antigen-presenting cells (APCs) capture antigens of SUMMARY microbes that enter through epithelia, concentrate these antigens in lymphoid organs, and display the The physiologic function of the immune system is to antigens for recognition by T cells. protect individuals from infections and cancers. Lymphocytes and APCs are organized in secondary Innate immunity is the early line of defense, medi- (peripheral) lymphoid organs, where immune re- ated by cells and molecules that are always present sponses are initiated and develop. and ready to eliminate infectious microbes. Naive lymphocytes circulate through secondary Adaptive immunity is mediated by lymphocytes lymphoid organs, where they may encounter foreign stimulated by microbial antigens, which leads to antigens. Effector T lymphocytes migrate to periph- the proliferation and differentiation of the lympho- eral sites of infection, where they function to elimi- cytes and the generation of effector cells, which elim- nate infectious microbes. Plasma cells remain in inate microbes, and memory cells, which respond lymphoid organs and the bone marrow, where they more effectively against each successive exposure to secrete antibodies that enter the circulation and a microbe. ﬁnd and eliminate microbes. 22 CHAPTER 1 Introduction to the Immune System REVIEW QUESTIONS 1. What are the major differences between innate and 5. Where are T and B lymphocytes located in lymph adaptive immunity? nodes, and how is their anatomic separation 2. What are the two types of adaptive immunity, and maintained? what types of microbes do these adaptive immune 6. How do naive and effector T lymphocytes differ in responses combat? their patterns of migration? 3. What are the principal classes of lymphocytes, and how do they differ in function? Answers to and discussion of the Review Questions 4. What are the important differences among naive, may be found on p. 322. effector, and memory T and B lymphocytes?

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