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Immunology_Janeway. dendritic cells. 366 9-14 Cell-adhesion molecules mediate the initial interaction of naive T cells with antigen- presenting cells. 367 the clonal expansion and differentiation of naive T cells. 368 9-16 CD28-dependent co-stimulation of activated T cells induces expression of interleukin-2 and the high-affinity IL-2 receptor. 368 9-17 Additional co-stimulatory pathways are involved in T-cell activation. 369 9-18 Proliferating T cells differentiate into effector T cells that do not require co-stimulation to act. 370 9-19 CD8 T cells can be activated in different ways to become cytotoxic effector cells. 372 9-20 CD4 T cells differentiate into several subsets of functionally different effector cells. 372 9-21 Cytokines induce the differentiation of naive CD4


Immunology_Janeway

Immunology_Janeway. T cells down distinct effector pathways. 375 9-22 CD4 T-cell subsets can cross-regulate each other’s differentiation through the cytokines they produce. 377 9-23 Regulatory CD4 T cells are involved in controlling adaptive immune responses. 379 Summary. 380 General properties of effector T cells and their cytokines. 380 9-24 Effector T-cell interactions with target cells are molecules. 381 T cells and their targets to regulate signaling and to direct the release of effector molecules. 381 9-26 The effector functions of T cells are determined by the array of effector molecules that they produce. 383 9-27 Cytokines can act locally or at a distance. 383 9-28 T cells express several TNF-family cytokines as trimeric proteins that are usually associated with the cell surface. 386 Summary. 386


Immunology_Janeway

Immunology_Janeway. Summary. 386 T-cell-mediated cytotoxicity. 387 9-29 Cytotoxic T cells induce target cells to undergo pathways of apoptosis. 387 9-30 The intrinsic pathway of apoptosis is mediated by the release of cytochrome c from mitochondria. 389 9-31 Cytotoxic effector proteins that trigger apoptosis are contained in the granules of CD8 cytotoxic T cells. 390 9-32 Cytotoxic T cells are selective serial killers of targets expressing a specific antigen. 9-33 Cytotoxic T cells also act by releasing cytokines. 392 Summary. 392 Summary to Chapter 9. Questions. 393 References. 395 B-cell activation by antigen and helper T cells.


Immunology_Janeway

Immunology_Janeway. 10-1 Activation of B cells by antigen involves signals from the B-cell receptor and either TFH cells or microbial antigens. 400 10-2 Linked recognition of antigen by T cells and B cells promotes robust antibody responses. 402 the boundaries between B-cell and T-cell areas in secondary lymphoid tissues. 403 activate B cells, which in turn promote TFH-cell development. 406 10-5 Activated B cells differentiate into antibody-secreting plasmablasts and plasma cells. 406 10-6 The second phase of a primary B-cell immune follicles and proliferate to form germinal centers. 408 hypermutation, and cells with mutations that improve affinity for antigen are selected. 410 10-8 Positive selection of germinal center B cells involves contact with TFH cells and CD40 signaling. 412 in B cells. 413 contribute to somatic hypermutation following initiation by AID. 414 10-11 AID initiates class switching to allow the same assembled VH exon to be associated with different


Immunology_Janeway

Immunology_Janeway. CH genes in the course of an immune response. 415 10-12 Cytokines made by TFH cells direct the choice of responses. 418 10-13 B cells that survive the germinal center reaction memory cells. 419 10-14 Some antigens do not require T-cell help to induce B-cell responses. Summary. 421 The distributions and functions of immunoglobulin classes. 422 10-15 Antibodies of different classes operate in distinct places and have distinct effector functions. 10-16 Polymeric immunoglobulin receptor binds to the Fc regions of IgA and IgM and transports them across epithelial barriers.


Immunology_Janeway

Immunology_Janeway. 10-17 The neonatal Fc receptor carries IgG across the placenta and prevents IgG excretion from the body. 426 12-6 Priming of lymphocytes in one mucosal tissue may 13-4 SCID can also be due to defects in the purine induce protective immunity at other mucosal salvage pathway. 538 surfaces. 502 12-7 Distinct populations of dendritic cells control can result in SCID. 538 mucosal immune responses. 503 can cause severe immunodeficiency. 539 roles in mucosal immune responses. 505 12-9 Antigen-presenting cells in the intestinal mucosa development result in severe immunodeficiencies. 539 acquire antigen by a variety of routes. 505 12-10 Secretory IgA is the class of antibody associated in antibody production that cause an inability to with the mucosal immune system. 506 clear extracellular bacteria and some viruses. 541 12-11 T-independent processes can contribute to IgA 13-9 Immune deficiencies can be caused by defects in production in some species. 509


Immunology_Janeway

Immunology_Janeway. B-cell or T-cell activation and function that lead to abnormal antibody responses. 543 12-12 IgA deficiency is relatively common in humans but may be compensated for by secretory IgM. 509 13-10 Normal pathways for host defense against different infectious agents are pinpointed by genetic deficiencies 12-13 The intestinal lamina propria contains antigen of cytokine pathways central to type 1/TH1 and typeexperienced T cells and populations of unusual 3/TH17 responses. 546 innate lymphoid cells. 510 13-11 Inherited defects in the cytolytic pathway of 12-14 The intestinal epithelium is a unique compartment of the immune system. 511 proliferation and inflammatory responses to viral Summary. 514 infections. 548


Immunology_Janeway

Immunology_Janeway. The mucosal response to infection and regulation 13-12 X-linked lymphoproliferative syndrome is associated with fatal infection by Epstein–Barr virus and with the of mucosal immune responses. 514 development of lymphomas. 550 12-15 Enteric pathogens cause a local inflammatory response and the development of protective 13-13 Immunodeficiency is caused by inherited defects immunity. 515 in the development of dendritic cells. 551 regulatory proteins cause defective humoral immune function and tissue damage. 552 when innate defenses have been breached. 518 12-17 Effector T-cell responses in the intestine protect the function of the epithelium. 518 bacterial infections. 553 12-18 The mucosal immune system must maintain 13-16 Mutations in the molecular regulators of inflammation tolerance to harmless foreign antigens. 519 can cause uncontrolled inflammatory responses that 12-19 The normal intestine contains large quantities of result in ‘autoinflammatory disease.’ 556 bacteria that are


Immunology_Janeway

Immunology_Janeway. harmless foreign antigens. 519 can cause uncontrolled inflammatory responses that 12-19 The normal intestine contains large quantities of result in ‘autoinflammatory disease.’ 556 bacteria that are required for health. 520 therapy can be useful to correct genetic defects. 557 microbiota while preventing inflammation without 13-18 Noninherited, secondary immunodeficiencies are compromising the ability to react to invaders. 521 major predisposing causes of infection and death. 558 12-21 The intestinal microbiota plays a major role in


Immunology_Janeway

Immunology_Janeway. Summary. 559 shaping intestinal and systemic immune function. 522 12-22 Full immune responses to commensal bacteria Evasion and subversion of immune defenses. 560 provoke intestinal disease. 524 13-19 Extracellular bacterial pathogens have evolved different strategies to avoid detection by pattern Summary. 525 recognition receptors and destruction by antibody, Summary to Chapter 12. 525 complement, and antimicrobial peptides. 560 Questions. 526 13-20 Intracellular bacterial pathogens can evade the immune system by seeking shelter within phagocytes. 563 References. 527 13-21 Immune evasion is also practiced by protozoan parasites. 565 13-22 RNA viruses use different mechanisms of antigenic variation to keep a step ahead of the adaptive immune system. 566 Chapter 13 Failures of Host Defense Mechanisms 533 13-23 DNA viruses use multiple mechanisms to subvert NK-cell and CTL responses. 568


Immunology_Janeway

Immunology_Janeway. Chapter 13 Failures of Host Defense Mechanisms 533 13-23 DNA viruses use multiple mechanisms to subvert NK-cell and CTL responses. 568 Immunodeficiency diseases. 533 13-1 A history of repeated infections suggests a replicate until immunity wanes. 571 diagnosis of immunodeficiency. 534 Summary. 573 13-2 Primary immunodeficiency diseases are caused by inherited gene defects. 534 Acquired immune deficiency syndrome. 573 13-25 HIV is a retrovirus that establishes a chronic combined immunodeficiencies. 535 infection that slowly progresses to AIDS. 574 Fighting infectious diseases with vaccination. 729 A-14 Immunoblotting (Western blotting). A-15 Use of antibodies in the isolation and or material from killed organisms. 730 characterization of multiprotein complexes by mass spectrometry. 764 16-21 Most effective vaccines generate antibodies that prevent the damage caused by toxins or that


Immunology_Janeway

Immunology_Janeway. A-16 Isolation of peripheral blood lymphocytes by density- neutralize the pathogen and stop infection. 731 gradient fractionation. 766 A-17 Isolation of lymphocytes from tissues other than protection while being safe and inexpensive. 732 blood. 766 16-23 Live-attenuated viral vaccines are usually more A-18 Flow cytometry and FACS analysis. 767 by the use of recombinant DNA technology. 732 magnetic beads. 770 A-20 Isolation of homogeneous T-cell lines. 770 A-21 Limiting-dilution culture. 771 creating genetically attenuated parasites (GAPs). 734 A-22 ELISPOT assay. 773 16-25 The route of vaccination is an important A-23 Identification of functional subsets of T cells based determinant of success. 735 on cytokine production or transcription factor 16-26 Bordetella pertussis vaccination illustrates the expression. 773 importance of the perceived safety of a vaccine. 736


Immunology_Janeway

Immunology_Janeway. A-24 Identification of T-cell receptor specificity using peptide:MHC 16-27 Conjugate vaccines have been developed as a tetramers. 776 result of linked recognition between T and B cells. 737 A-25 Biosensor assays for measuring the rates of association and dissociation of antigen receptors immunity, but they require adjuvants and must for their ligands. 777 be targeted to the appropriate cells and cell A-26 Assays of lymphocyte proliferation. 778 compartment to be effective. 738 A-27 Measurements of apoptosis. 779 16-29 Adjuvants are important for enhancing the immunogenicity of vaccines, but few are approved A-28 Assays for cytotoxic T cells. 780 for use in humans. 739 A-29 Assays for CD4 T cells. 782 A-30 Transfer of protective immunity. 782 vaccination. 740 A-31 Adoptive transfer of lymphocytes. 783 A-32 Hematopoietic stem-cell transfers. 784 useful in controlling existing chronic infections. 741 A-33 In vivo administration of antibodies. 785 Summary. 742


Immunology_Janeway

Immunology_Janeway. A-32 Hematopoietic stem-cell transfers. 784 useful in controlling existing chronic infections. 741 A-33 In vivo administration of antibodies. 785 Summary. 742 A-34 Transgenic mice. 786 Summary to Chapter 16. 742 A-35 Gene knockout by targeted disruption. 786 Questions. 743 A-36 Knockdown of gene expression by References. 744 RNA interference (RNAi). 790 Appendix I The Immunologist's Toolbox 749 A-1. Immunization. 749 A-2 Antibody responses. 752 A-3 Affinity chromatography. 753 A-4 Radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), and competitive inhibition assay. 753 A-5 Hemagglutination and blood typing. 755 A-6 Coombs tests and the detection of rhesus incompatibility. 756 A-7 Monoclonal antibodies. 757 A-8 Phage display libraries for antibody V-region production. 758 A-9 Generation of human monoclonal antibodies from vaccinated individuals. 759 A-10 Microscopy and imaging using fluorescent dyes. 760 A-11 Immunoelectron microscopy. 761


Immunology_Janeway

Immunology_Janeway. A-9 Generation of human monoclonal antibodies from vaccinated individuals. 759 A-10 Microscopy and imaging using fluorescent dyes. 760 A-11 Immunoelectron microscopy. 761 A-12 Immunohistochemistry. 762 A-13 Immunoprecipitation and co-immunoprecipitation. 762 Immunology is the study of the body’s defense against infection. We are continually exposed to microorganisms, many of which cause disease, and yet become ill only rarely. How does the body defend itself? When infection does occur, how does the body eliminate the invader and cure itself? And why do we develop long-lasting immunity to many infectious diseases encountered once and overcome? These are the questions addressed by immunology, which we study to understand our body’s defenses against infection at the cellular and molecular levels.


Immunology_Janeway

Immunology_Janeway. The beginning of immunology as a science is usually attributed to Edward Jenner for his work in the late 18th century (Fig. 1.1). The notion of immunity— that surviving a disease confers greater protection against it later—was known since ancient Greece. Variolation—the inhalation or transfer into superficial skin wounds of material from smallpox pustules—had been practiced since at least the 1400s in the Middle East and China as a form of protection against that disease and was known to Jenner. Jenner had observed that the relatively mild disease of cowpox, or vaccinia, seemed to confer protection against the often fatal disease of smallpox, and in 1796, he demonstrated that inoculation with cowpox protected the recipient against smallpox. His scientific proof relied on the deliberate exposure of the inoculated individual to infectious smallpox material two months after inoculation. This scientific test was his original contribution.


Immunology_Janeway

Immunology_Janeway. Jenner called the procedure vaccination. This term is still used to describe the inoculation of healthy individuals with weakened or attenuated strains of disease-causing agents in order to provide protection from disease. Although Jenner’s bold experiment was successful, it took almost two centuries for smallpox vaccination to become universal. This advance enabled the World Health Organization to announce in 1979 that smallpox had been eradicated (Fig. 1.2), arguably the greatest triumph of modern medicine. Jenner’s strategy of vaccination was extended in the late 19th century by the discoveries of many great microbiologists. Robert Koch proved that infectious diseases are caused by specific microorganisms. In the 1880s, Louis Pasteur the origins of vertebrate immune cells. Principles of innate immunity. Principles of adaptive immunity. the effector mechanisms of immunity.


Immunology_Janeway

Immunology_Janeway. Principles of adaptive immunity. the effector mechanisms of immunity. Fig. 1.1 Edward Jenner. Portrait by John raphael Smith. reproduced courtesy of yale university, Harvey Cushing/John Hay Whitney medical library. Number of countries with one or more cases Fig. 1.2 The eradication of smallpox by vaccination. After a period of 3 years in which no cases of smallpox were recorded, the World Health organization was able to announce in 1979 that smallpox had been eradicated, and vaccination stopped (upper panel). A few laboratory stocks have been retained, however, and some fear that these are a source from which the virus might reemerge. Ali maow maalin (lower panel) contracted and survived the last case of smallpox in Somalia in 1977. Photograph courtesy of dr. Jason Weisfeld. devised a vaccine against cholera in chickens, and developed a rabies vaccine that proved to be a spectacular success upon its first trial in a boy bitten by a rabid dog.


Immunology_Janeway

Immunology_Janeway. devised a vaccine against cholera in chickens, and developed a rabies vaccine that proved to be a spectacular success upon its first trial in a boy bitten by a rabid dog. These practical triumphs led to a search for vaccination’s mechanism of protection and to the development of the science of immunology. In the early 1890s, Emil von Behring and Shibasaburo Kitasato discovered that the serum of animals immune to diphtheria or tetanus contained a specific ‘antitoxic activity’ that could confer short-lived protection against the effects of diphtheria or tetanus toxins in people. This activity was later determined to be due to the proteins we now call antibodies, which bind specifically to the toxins and neutralize their activity. That these antibodies might have a crucial role in immunity was reinforced by Jules Bordet’s discovery in 1899 of complement, a component of serum that acts in conjunction with antibodies to destroy pathogenic bacteria.


Immunology_Janeway

Immunology_Janeway. A specific response against infection by potential pathogens, such as the production of antibodies against a particular pathogen, is known as adaptive immunity, because it develops during the lifetime of an individual as an adaptation to infection with that pathogen. Adaptive immunity is distinguished from innate immunity, which was already known at the time von Behring was developing serum therapy for diphtheria chiefly through the work of the great Russian immunologist Elie Metchnikoff, who discovered that many microorganisms could be engulfed and digested by phagocytic cells, which thus provide defenses against infection that are nonspecific. Whereas these cells— which Metchnikoff called 'macrophages'—are always present and ready to act, adaptive immunity requires time to develop but is highly specific.


Immunology_Janeway

Immunology_Janeway. It was soon clear that specific antibodies could be induced against a vast range of substances, called antigens because they could stimulate antibody generation. Paul Ehrlich advanced the development of an antiserum as a treatment for diphtheria and developed methods to standardize therapeutic serums. Today the term antigen refers to any substance recognized by the adaptive immune system. Typically antigens are common proteins, glycoproteins, and polysaccharides of pathogens, but they can include a much wider range of chemical structures, for example, metals such as nickel, drugs such as penicillin, and organic chemicals such as the urushiol (a mix of pentadecylcatechols) in the leaves of poison ivy. Metchnikoff and Ehrlich shared the 1908 Nobel Prize for their respective work on immunity.


Immunology_Janeway

Immunology_Janeway. This chapter introduces the principles of innate and adaptive immunity, the cells of the immune system, the tissues in which they develop, and the tissues through which they circulate. We then outline the specialized functions of the different types of cells by which they eliminate infection. The origins of vertebrate immune cells.


Immunology_Janeway

Immunology_Janeway. The origins of vertebrate immune cells. The body is protected from infectious agents, their toxins, and the damage they cause by a variety of effector cells and molecules that together make up the immune system. Both innate and adaptive immune responses depend upon the activities of white blood cells or leukocytes. Most cells of the immune system arise from the bone marrow, where many of them develop and mature. But some, particularly certain tissue-resident macrophage populations (for example, the microglia of the central nervous system), originate from the yolk sack or fetal liver during embryonic development. They seed tissues before birth and are maintained throughout life as independent, self-renewing populations. Once mature, immune cells reside within peripheral tissues, circulate in the bloodstream, or circulate in a specialized system of vessels called Principles of innate immunity.


Immunology_Janeway

Immunology_Janeway. Principles of innate immunity. the lymphatic system. The lymphatic system drains extracellular fluid and immune cells from tissues and transports them as lymph that is eventually emptied back into the blood system. All the cellular elements of blood, including the red blood cells that transport oxygen, the platelets that trigger blood clotting in damaged tissues, and the white blood cells of the immune system, ultimately derive from the hematopoietic stem cells (HSCs) of the bone marrow. Because these can give rise to all the different types of blood cells, they are often known as pluripotent hematopoietic stem cells. The hematopoietic stem cells give rise to cells of more limited developmental potential, which are the immediate progenitors of red blood cells, platelets, and the two main categories of white blood cells, the lymphoid and myeloid lineages. The different types of blood cells and their lineage relationships are summarized in Fig. 1.3. Principles of innate immunity.


Immunology_Janeway

Immunology_Janeway. Principles of innate immunity. In this part of the chapter we will outline the principles of innate immunity and describe the molecules and cells that provide continuous defense against invasion by pathogens. Although the white blood cells known as lymphocytes possess the most powerful ability to recognize and target pathogenic microorganisms, they need the participation of the innate immune system to initiate and mount their offensive. Indeed, the adaptive immune response and innate immunity use many of the same destructive mechanisms to eliminate invading microorganisms. 1-1 Commensal organisms cause little host damage while pathogens damage host tissues by a variety of mechanisms.


Immunology_Janeway

Immunology_Janeway. We recognize four broad categories of disease-causing microorganisms, or pathogens: viruses, bacteria and archaea, fungi, and the unicellular and multicellular eukaryotic organisms collectively termed parasites (Fig. 1.4). These microorganisms vary tremendously in size and in how they damage host tissues. The smallest are viruses, which range from five to a few hundred nanometers in size and are obligate intracellular pathogens. Viruses can directly kills cells by inducing lysis during their replication. Somewhat larger are intracellular bacteria and mycobacteria. These can kill cells directly or damage cells by producing toxins. Many single-celled intracellular parasites, such as members of the Plasmodium genus that cause malaria, also directly kill infected cells. Pathogenic bacteria and fungi growing in extracellular spaces can induce shock and sepsis by releasing toxins into the blood or tissues. The largest pathogens—parasitic worms, or helminths—are too large to infect host


Immunology_Janeway

Immunology_Janeway. and fungi growing in extracellular spaces can induce shock and sepsis by releasing toxins into the blood or tissues. The largest pathogens—parasitic worms, or helminths—are too large to infect host cells but can injure tissues by forming cysts that induce damaging cellular responses in the tissues into which the worms migrate.


Immunology_Janeway

Immunology_Janeway. Not all microbes are pathogens. Many tissues, especially the skin, oral mucosa, conjunctiva, and gastrointestinal tract, are constantly colonized by microbial communities—called the microbiome—that consist of archaea, bacteria, and fungi but cause no damage to the host. These are also called commensal microorganisms, since they can have a symbiotic relationship with the host. Indeed, some commensal organisms perform important functions, as in the case of the bacteria that aid in cellulose digestion in the stomachs of ruminants. The difference between commensal organisms and pathogens lies in whether they induce damage. Even enormous numbers of microbes in the intestinal microbiome normally cause no damage and are confined within the intestinal lumen by a protective layer of mucus, whereas pathogenic bacteria can penetrate this barrier, injure intestinal epithelial cells, and spread into the underlying tissues.


Immunology_Janeway

Immunology_Janeway. Fig. 1.3 All the cellular elements of the blood, including the cells of the immune system, arise from pluripotent hematopoietic stem cells in the bone marrow. these pluripotent cells divide to produce two types of stem cells. A common lymphoid progenitor gives rise to the lymphoid lineage (blue background) of white blood cells or leukocytes—the innate lymphoid cells (IlCs) and natural killer (nK) cells and the t and B lymphocytes. A common myeloid progenitor gives rise to the myeloid lineage (pink and yellow backgrounds), which comprises the rest of the leukocytes, the erythrocytes (red blood cells), and the megakaryocytes that produce platelets important in blood clotting. t and B lymphocytes are distinguished from the other leukocytes by having antigen receptors and from each other by their sites of differentiation—the thymus and bone marrow, respectively. After encounter with antigen, B cells differentiate into antibody-secreting plasma cells, while t cells differentiate into


Immunology_Janeway

Immunology_Janeway. by their sites of differentiation—the thymus and bone marrow, respectively. After encounter with antigen, B cells differentiate into antibody-secreting plasma cells, while t cells differentiate into effector t cells with a variety of functions. unlike t and B cells, IlCs and nK cells lack antigen specificity. the remaining leukocytes are the monocytes, the dendritic cells, and the neutrophils, eosinophils, and basophils. the last three of these circulate in the blood and are termed granulocytes, because of the cytoplasmic granules whose staining gives these cells a distinctive appearance in blood smears, or polymorphonuclear leukocytes, because of their irregularly shaped nuclei. Immature dendritic cells (yellow background) are phagocytic cells that enter the tissues; they mature after they have encountered a potential pathogen. the majority of dendritic cells are derived from the common myeloid progenitor cells, but some may also arise from the common lymphoid progenitor. monocytes


Immunology_Janeway

Immunology_Janeway. have encountered a potential pathogen. the majority of dendritic cells are derived from the common myeloid progenitor cells, but some may also arise from the common lymphoid progenitor. monocytes enter tissues, where they differentiate into phagocytic macrophages or dendritic cells. mast cells also enter tissues and complete their maturation there.


Immunology_Janeway

Immunology_Janeway. Principles of innate immunity. Viruses Intracellular bacteria Extracellular bacteria, Archaea, Protozoa Fungi Parasites Log scale of size in meters 10–7 10–6 10–5 10–4 10–3 10–2 (1 cm) Fig. 1.4 Pathogens vary greatly in size and lifestyle. Intracellular pathogens include viruses, such as herpes simplex (first panel), and various bacteria, such as Listeria monocytogenes (second panel). many bacteria, such as Staphylococcus aureus (third panel), or fungi, such as Aspergillus fumigates (fourth panel), tissues, as do some archaea and protozoa (third panel). many parasites, such as the nematode Strongyloides stercoralis (fifth panel), are large multicellular organisms that can move throughout the body in a complex life cycle. Second panel courtesy of dan Portnoy. Fifth panel courtesy of James lok. can grow in the extracellular spaces and directly invade through 1-2 Anatomic and chemical barriers are the first defense against pathogens.


Immunology_Janeway

Immunology_Janeway. The host can adopt three strategies to deal with the threat posed by microbes: avoidance, resistance, and tolerance. Avoidance mechanisms prevent exposure to microbes, and include both anatomic barriers and behavior modifications. If an infection is established, resistance is aimed at reducing or eliminating pathogens. To defend against the great variety of microbes, the immune system has numerous molecular and cellular functions, collectively called mediators, or effector mechanisms, suited to resist different categories of pathogens. Their description is a major aspect of this book. Finally, tolerance involves responses that enhance a tissue’s capacity to resist damage induced by microbes. This meaning of the term ‘tolerance’ has been used extensively in the context of disease susceptibility in plants rather than animal immunity. For example, increasing growth by activating dormant meristems, the undifferentiated cells that generate new parts of the plant, is a common tolerance


Immunology_Janeway

Immunology_Janeway. in plants rather than animal immunity. For example, increasing growth by activating dormant meristems, the undifferentiated cells that generate new parts of the plant, is a common tolerance mechanism in response to damage. This should be distinguished from the term immunological tolerance, which refers to mechanisms that prevent an immune response from being mounted against the host’s own tissues.


Immunology_Janeway

Immunology_Janeway. Anatomic and chemical barriers are the initial defenses against infection (Fig. 1.5). The skin and mucosal surfaces represent a kind of avoidance strategy that prevents exposure of internal tissues to microbes. At most anatomic barriers, additional resistance mechanisms further strengthen host defenses. For example, mucosal surfaces produce a variety of antimicrobial proteins that act as natural antibiotics to prevent microbes from entering the body.


Immunology_Janeway

Immunology_Janeway. If these barriers are breached or evaded, other components of the innate immune system can immediately come into play. We mentioned earlier the discovery by Jules Bordet of complement, which acts with antibodies to lyse bacteria. Complement is a group of around 30 different plasma proteins that act together and are one of the most important effector mechanisms in serum and interstitial tissues. Complement not only acts in conjunction with antibodies, but can also target foreign organisms in the absence of a specific antibody; thus it contributes to both innate and adaptive responses. We will examine anatomic barriers, the antimicrobial proteins, and complement in greater detail in Chapter 2.


Immunology_Janeway

Immunology_Janeway. the first is the anatomic barrier provided by the body’s epithelial surfaces. Second, various chemical and enzymatic systems, including complement, act as an immediate antimicrobial barrier near these epithelia. If epithelia are breached, nearby various innate lymphoid cells can coordinate a rapid cell-mediated defense. If the pathogen overcomes these barriers, the slower-acting defenses of the adaptive immune system are brought to bear. Target tissues Production of antimicrobial proteins Induction of intracellular antiviral proteins Killing of infected cells Mediators Cytokines, cytotoxicity In˜ammatory inducers Bacterial lipopolysaccharides, ATP, urate crystals Sensor cells Macrophages, neutrophils, dendritic cells Fig. 1.6 Cell-mediated immunity proceeds in a series of steps.


Immunology_Janeway

Immunology_Janeway. Fig. 1.6 Cell-mediated immunity proceeds in a series of steps. Inflammatory inducers are chemical structures that indicate the presence of invading microbes or the cellular damage produced by them. Sensor cells detect these inducers by expressing various innate recognition receptors, and in response produce a variety of mediators that act directly in defense or that further propagate the immune response. mediators include many cytokines, and they act on various target tissues, such as epithelial cells, to induce antimicrobial proteins and resist intracellular viral growth; or on other immune cells, such as IlCs that produce other cytokines that amplify the immune response. 1-3 The immune system is activated by inflammatory inducers that indicate the presence of pathogens or tissue damage.


Immunology_Janeway

Immunology_Janeway. A pathogen that breaches the host’s anatomic and chemical barriers will encounter the cellular defenses of innate immunity. Cellular immune responses are initiated when sensor cells detect inflammatory inducers (Fig. 1.6). Sensor cells include many cell types that detect inflammatory mediators through expression of many innate recognition receptors, which are encoded by a relatively small number of genes that remain constant over an individual’s lifetime. Inflammatory inducers that trigger these receptors include molecular components unique to bacteria or viruses, such as bacterial lipopolysaccharides, or molecules such as ATP, which is not normally found in the extracellular space. Triggering these receptors can activate innate immune cells to produce various mediators that either act directly to destroy invading microbes, or act on other cells to propagate the immune response. For example, macrophages can ingest microbes and produce toxic chemical mediators, such as degradative


Immunology_Janeway

Immunology_Janeway. directly to destroy invading microbes, or act on other cells to propagate the immune response. For example, macrophages can ingest microbes and produce toxic chemical mediators, such as degradative enzymes or reactive oxygen intermediates, to kill them. Dendritic cells may produce cytokine mediators, including many cytokines that activate target tissues, such as epithelial or other immune cells, to resist or kill invading microbes more efficiently. We will discuss these receptors and mediators briefly below and in much greater detail in Chapter 3.


Immunology_Janeway

Immunology_Janeway. Innate immune responses occur rapidly on exposure to an infectious organism (Fig. 1.7). In contrast, responses by the adaptive immune system take days rather than hours to develop. However, the adaptive immune system is capable of eliminating infections more efficiently because of exquisite specificity Fig. 1.7 Phases of the immune response.


Immunology_Janeway

Immunology_Janeway. Innate immune response Phases of the immune response Response Duration of response Typical time after infection to start of response Infammation, complement activation, phagocytosis, and destruction of pathogen Emigration of effector lymphocytes from peripheral lymphoid organs Interaction of T cells with B cells, formation of germinal centers. Formation of effector B cells (plasma cells) and memory B cells. Production of antibody Interaction between antigen-presenting dendritic cells and antigen-specifc T cells: recognition of antigen, adhesion, co-stimulation, T-cell proliferation and differentiation Adaptive immune response Activation of antigen-specifc B cells Formation of effector and memory T cells Immunological memory Elimination of pathogen by effector cells and antibody Maintenance of memory B cells and T cells and high serum or mucosal antibody levels. Protection against reinfection Minutes Days Hours Days Hours Days Weeks Days Weeks Days A few days Weeks A few days Weeks


Immunology_Janeway

Immunology_Janeway. of memory B cells and T cells and high serum or mucosal antibody levels. Protection against reinfection Minutes Days Hours Days Hours Days Weeks Days Weeks Days A few days Weeks A few days Weeks Days to weeks Can be lifelong


Immunology_Janeway

Immunology_Janeway. Principles of innate immunity. of antigen recognition by its lymphocytes. In contrast to a limited repertoire of receptors expressed by innate immune cells, lymphocytes express highly specialized antigen receptors that collectively possess a vast repertoire of specificity. This enables the adaptive immune system to respond to virtually any pathogen and effectively focus resources to eliminate pathogens that have evaded or overwhelmed innate immunity. But the adaptive immune system interacts with, and relies on, cells of the innate immune system for many of its functions. The next several sections will introduce the major components of the innate immune system and prepare us to consider adaptive immunity later in the chapter. 1-4 The myeloid lineage comprises most of the cells of the innate immune system.


Immunology_Janeway

Immunology_Janeway. 1-4 The myeloid lineage comprises most of the cells of the innate immune system. The common myeloid progenitor (CMP) is the precursor of the macrophages, granulocytes (the collective term for the white blood cells called neutrophils, eosinophils, and basophils), mast cells, and dendritic cells of the innate immune system. Macrophages, granulocytes, and dendritic cells make up the three types of phagocytes in the immune system. The CMP also generates megakaryocytes and red blood cells, which we will not be concerned with here. The cells of the myeloid lineage are shown in Fig. 1.8.


Immunology_Janeway

Immunology_Janeway. Macrophages are resident in almost all tissues. Many tissue-resident macrophages arise during embryonic development, but some macrophages that arise in the adult animal from the bone marrow are the mature form of monocytes, which circulate in the blood and continually migrate into tissues, where they differentiate. Macrophages are relatively long-lived cells and perform several different functions throughout the innate immune response and the subsequent adaptive immune response. One is to engulf and kill invading microorganisms. This phagocytic function provides a first defense in innate immunity. Macrophages also dispose of pathogens and infected cells targeted by an adaptive immune response. Both monocytes and macrophages are phagocytic, but most infections occur in the tissues, and so it is primarily macrophages that perform this important protective function. An additional and crucial role of macrophages is to orchestrate immune responses: they help induce inflammation, which, as


Immunology_Janeway

Immunology_Janeway. it is primarily macrophages that perform this important protective function. An additional and crucial role of macrophages is to orchestrate immune responses: they help induce inflammation, which, as we shall see, is a prerequisite to a successful immune response, and they produce many inflammatory mediators that activate other immune-system cells and recruit them into an immune response.


Immunology_Janeway

Immunology_Janeway. Local inflammation and the phagocytosis of invading bacteria can also be triggered by the activation of complement. Bacterial surfaces can activate the complement system, inducing a cascade of proteolytic reactions that coat the microbes with fragments of specific proteins of the complement system.


Immunology_Janeway

Immunology_Janeway. Fig. 1.8 Myeloid cells in innate and adaptive immunity. In the rest of the book, these cells will be represented in the schematic form shown on the left. A photomicrograph of each cell type is shown on the right. macrophages and neutrophils are primarily phagocytic cells that engulf pathogens and destroy them in intracellular vesicles, a function they perform in both innate and adaptive immune responses. dendritic cells are phagocytic when they are immature and can take up pathogens; after maturing, they function as specialized cells that present pathogen antigens to t lymphocytes in a form they can recognize, thus activating t lymphocytes and initiating adaptive immune responses. macrophages can also present antigens to t lymphocytes and can activate them. the other myeloid cells are primarily secretory cells that release the contents of their prominent granules upon activation via antibody during an adaptive immune response. eosinophils are thought to be involved in attacking large


Immunology_Janeway

Immunology_Janeway. secretory cells that release the contents of their prominent granules upon activation via antibody during an adaptive immune response. eosinophils are thought to be involved in attacking large antibody-coated parasites such as worms; basophils are also thought to be involved in anti-parasite immunity. mast cells are tissue cells that trigger a local inflammatory response to antigen by releasing substances that act on local blood vessels. mast cells, eosinophils, and basophils are also important in allergic responses. Photographs courtesy of n. rooney, r. Steinman, and d. Friend.


Immunology_Janeway

Immunology_Janeway. MOVIE 1.1 Microbes coated in this way are recognized by specific complement receptors on macrophages and neutrophils, taken up by phagocytosis, and destroyed. In addition to their specialized role in the immune system, macrophages act as general scavenger cells in the body, clearing it of dead cells and cell debris.


Immunology_Janeway

Immunology_Janeway. The granulocytes are named for the densely staining granules in their cytoplasm; they are also called polymorphonuclear leukocytes because of their oddly shaped nuclei. The three types of granulocytes—neutrophils, eosinophils, and basophils— are distinguished by the different staining properties of their granules, which serve distinct functions. Granulocytes are all relatively short-lived, surviving for only a few days. They mature in the bone marrow, and their production increases during immune responses, when they migrate to sites of infection or inflammation. The phagocytic neutrophils are the most numerous and important cells in innate immune responses: they take up a variety of microorganisms by phagocytosis and efficiently destroy them in intracellular vesicles by using degradative enzymes and other antimicrobial substances stored in their cytoplasmic granules. Hereditary deficiencies in neutrophil function open the way to overwhelming bacterial infection, which is fatal if


Immunology_Janeway

Immunology_Janeway. enzymes and other antimicrobial substances stored in their cytoplasmic granules. Hereditary deficiencies in neutrophil function open the way to overwhelming bacterial infection, which is fatal if untreated. Their role is discussed further in Chapter 3.


Immunology_Janeway

Immunology_Janeway. Eosinophils and basophils are less abundant than neutrophils, but like neutrophils, they have granules containing a variety of enzymes and toxic proteins, which are released when these cells are activated. Eosinophils and basophils are thought to be important chiefly in defense against parasites, which are too large to be ingested by macrophages or neutrophils. They can also contribute to allergic inflammatory reactions, in which their effects are damaging rather than protective. Mast cells begin development in the bone marrow, but migrate as immature precursors that mature in peripheral tissues, especially skin, intestines, and airway mucosa. Their granules contain many inflammatory mediators, such as histamine and various proteases, which play a role in protecting the internal surfaces from pathogens, including parasitic worms. We cover eosinophils, basophils, and mast cells and their role in allergic inflammation further in Chapters 10 and 14.


Immunology_Janeway

Immunology_Janeway. Dendritic cells were discovered in the 1970s by Ralph Steinman, for which he received half the 2011 Nobel Prize. These cells form the third class of phagocytic cells of the immune system and include several related lineages whose distinct functions are still being clarified. Most dendritic cells have elaborate membranous processes, like the dendrites of nerve cells. Immature dendritic cells migrate through the bloodstream from the bone marrow to enter tissues. They take up particulate matter by phagocytosis and also continually ingest large amounts of the extracellular fluid and its contents by a process known as macropinocytosis. They degrade the pathogens that they take up, but their main role in the immune system is not the clearance of microorganisms. Instead, dendritic cells are a major class of sensor cells whose encounter with pathogens triggers them to produce mediators that activate other immune cells. Dendritic cells were discovered because of their role in activating a


Immunology_Janeway

Immunology_Janeway. a major class of sensor cells whose encounter with pathogens triggers them to produce mediators that activate other immune cells. Dendritic cells were discovered because of their role in activating a particular class of lymphocytes—T lymphocytes—of the adaptive immune system, and we will return to this activity when we discuss T-cell activation in Section 1-15. But dendritic cells and the mediators they produce also play a critical role in controlling responses of cells of the innate immune system.


Immunology_Janeway

Immunology_Janeway. 1-5 Sensor cells express pattern recognition receptors that provide an initial discrimination between self and nonself. Long before the mechanisms of innate recognition were discovered, it was recognized that purified antigens such as proteins often did not evoke an immune response in an experimental immunization—that is, they were not Principles of innate immunity. immunogenic. Rather, the induction of strong immune responses against purified proteins required the inclusion of microbial constituents, such as killed bacteria or bacterial extracts, famously called the immunologist’s ‘dirty little secret’ by Charles Janeway (see Appendix I, Sections A-1–A-4). This additional material was termed an adjuvant, because it helped intensify the response to the immunizing antigen (adjuvare is Latin for ‘to help’). We know now that adjuvants are needed, at least in part, to activate innate receptors on various types of sensor cells to help activate T cells in the absence of an infection.


Immunology_Janeway

Immunology_Janeway. Macrophages, neutrophils, and dendritic cells are important classes of sensor cells that detect infection and initiate immune responses by producing inflammatory mediators, although other cells, even cells of the adaptive immune system, can serve in this function. As mentioned in Section 1-3, these cells express a limited number of invariant innate recognition receptors as a means of detecting pathogens or the damage induced by them. Also called pattern recognition receptors (PRRs), they recognize simple molecules and regular patterns of molecular structure known as pathogen-associated molecular patterns (PAMPs) that are part of many microorganisms but not of the host body’s own cells. Such structures include mannose-rich oligosaccharides, peptidoglycans, and lipopolysaccharides of the bacterial cell wall, as well as unmethylated CpG DNA common to many pathogens. All of these microbial elements have been conserved during evolution, making them excellent targets for recognition because


Immunology_Janeway

Immunology_Janeway. cell wall, as well as unmethylated CpG DNA common to many pathogens. All of these microbial elements have been conserved during evolution, making them excellent targets for recognition because they do not change (Fig. 1.9). Some PRRs are transmembrane proteins, such as the Toll-like receptors (TLRs) that detect PAMPs derived from extracellular bacteria or bacteria taken into vesicular pathways by phagocytosis. The role of the Toll receptor in immunity was discovered first in Drosophila melanogaster by Jules Hoffman, and later extended to homologous TLRs in mice by Janeway and Bruce Beutler. Hoffman and Beutler shared the remaining half of the 2011 Nobel Prize (see Section 1-4) for their work in the activation of innate immunity. Other PRRs are cytoplasmic proteins, such as the NOD-like receptors (NLRs) that sense intracellular bacterial invasion. Yet other cytoplasmic receptors detect viral infection based on differences in the structures and locations of the host mRNA and virally


Immunology_Janeway

Immunology_Janeway. receptors (NLRs) that sense intracellular bacterial invasion. Yet other cytoplasmic receptors detect viral infection based on differences in the structures and locations of the host mRNA and virally derived RNA species, and between host and microbial DNA. Some receptors expressed by sensor cells detect cellular damage induced by pathogens, rather than the pathogens themselves. Much of our knowledge of innate recognition has emerged only within the past 15 years and is still an active area of discovery. We describe these innate recognition systems further in Chapter 3, and how adjuvants are used as a component of vaccines in Chapter 16.


Immunology_Janeway

Immunology_Janeway. 1-6 Sensor cells induce an inflammatory response by producing mediators such as chemokines and cytokines. Activation of PRRs on sensor cells such as macrophages and neutrophils can directly induce effector functions in these cells, such as the phagocytosis and degradation of bacteria they encounter. But sensor cells serve to amplify the immune response by the production of inflammatory mediators. Two important categories of inflammatory mediators are the secreted proteins called cytokines and chemokines, which act in a manner similar to hormones to convey important signals to other immune cells.


Immunology_Janeway

Immunology_Janeway. ‘Cytokine’ is a term for any protein secreted by immune cells that affects the behavior of nearby cells bearing appropriate receptors. There are more than 60 different cytokines; some are produced by many different cell types; others, by only a few specific cell types. Some cytokines influence many types of cells, while others influence only a few, through the expression pattern of each cytokine’s specific receptor. The response that a cytokine induces in a target cell is typically related to amplifying an effector mechanism of the target cell, as illustrated in the next section.


Immunology_Janeway

Immunology_Janeway. macrophages express a variety of receptors, each of which is able to recognize specific components of microbes. Some, like the mannose and glucan receptors and the scavenger receptor, bind cell-wall carbohydrates of bacteria, yeast, and fungi. the toll-like receptors (tlrs) are an important family of pattern recognition receptors present on macrophages, dendritic cells, and other immune cells. tlrs recognize different microbial components; for example, a heterodimer of tlr-1 and tlr-2 binds certain lipopeptides from pathogens such as gram-positive bacteria, while tlr-4 binds both lipopolysaccharides from gram-negative and lipoteichoic acids from gram-positive bacteria.


Immunology_Janeway

Immunology_Janeway. Fig. 1.10 Infection triggers an inflammatory response. macrophages encountering bacteria or other types of microorganisms in tissues are triggered to release cytokines (left panel) that increase the permeability of blood vessels, allowing fluid and proteins to pass into the tissues (center panel). macrophages also produce chemokines, which direct the migration of neutrophils to the site of infection. the stickiness of the endothelial cells of the blood vessel wall is also changed, so that circulating cells of the immune system adhere to the wall and are able to crawl through it; first neutrophils and then monocytes are shown entering the tissue from a blood vessel (right panel). the accumulation of fluid and cells at the site of infection causes the redness, swelling, heat, and pain known collectively as inflammation. neutrophils and macrophages are the principal inflammatory cells. later in an immune response, activated lymphocytes can also contribute to inflammation.


Immunology_Janeway

Immunology_Janeway. Vasodilation and increased vascular permeability cause redness, heat, and swelling fuids protein neutrophil Infammatory cells migrate into tissue, releasing infammatory mediators that cause pain monocyte Instead of presenting all the cytokines together all at once, we introduce each cytokine as it arises during our description of cellular and functional responses. We list the cytokines, their producer and target cells, and their general functions in Appendix III.


Immunology_Janeway

Immunology_Janeway. Chemokines are a specialized subgroup of secreted proteins that act as chemoattractants, attracting cells bearing chemokine receptors, such as neutrophils and monocytes, out of the bloodstream and into infected tissue (Fig. 1.10). Beyond this role, chemokines also help organize the various cells in lymphoid tissues into discrete regions where specialized responses can take place. There are on the order of 50 different chemokines, which are all related structurally but fall into two major classes. Appendix IV lists the chemokines, their target cells, and their general functions. We will discuss chemokines as the need arises during our descriptions of particular cellular immune processes.


Immunology_Janeway

Immunology_Janeway. The cytokines and chemokines released by activated macrophages act to recruit cells from the blood into infected tissues, a process, known as inflammation, that helps to destroy the pathogen. Inflammation increases the flow of lymph, which carries microbes or cells bearing their antigens from the infected tissue to nearby lymphoid tissues, where the adaptive immune response is initiated. Once adaptive immunity has been generated, inflammation also recruits these effector components to the site of infection.


Immunology_Janeway

Immunology_Janeway. Inflammation is described clinically by the Latin words calor, dolor, rubor, and tumor, meaning heat, pain, redness, and swelling. Each of these features reflects an effect of cytokines or other inflammatory mediators on the local blood vessels. Heat, redness, and swelling result from the dilation and increased permeability of blood vessels during inflammation, leading to increased local blood flow and leakage of fluid and blood proteins into the tissues. Cytokines and complement fragments have important effects on the endothelium that lines blood vessels; the endothelial cells themselves also produce cytokines in response to infection. These alter the adhesive properties of the endothelial cells and cause circulating leukocytes to stick to the endothelial cells and migrate between them into the site of infection, to which they are attracted by chemokines. The migration of cells into the tissue and their local actions account for the pain.


Immunology_Janeway

Immunology_Janeway. The main cell types seen in the initial phase of an inflammatory response are macrophages and neutrophils, the latter being recruited into the inflamed, infected tissue in large numbers. Macrophages and neutrophils are thus also known as inflammatory cells. The influx of neutrophils is followed a short time later by the increased entry of monocytes, which rapidly differentiate into macrophages, thus reinforcing and sustaining the innate immune response. Later, if the inflammation continues, eosinophils also migrate into inflamed tissues and contribute to the destruction of the invading microorganisms. Principles of adaptive immunity. 1-7 Innate lymphocytes and natural killer cells are effector cells that share similarities with lymphoid lineages of the adaptive immune system.


Immunology_Janeway

Immunology_Janeway. The common lymphoid progenitor (CLP) in the bone marrow gives rise both to antigen-specific lymphocytes of the adaptive immune system and to several innate lineages that lack antigen-specific receptors. Although the B and T lymphocytes of the adaptive immune system were recognized in the 1960s, the natural killer (NK) cells (Fig. 1.11) of the innate immune system were not discovered until the 1970s. NK cells are large lymphocyte-like cells with a distinctive granular cytoplasm that were identified because of their ability to recognize and kill certain tumor cells and cells infected with herpesviruses. Initially, the distinction between these cells and T lymphocytes was unclear, but we now recognize that NK cells are a distinct lineage of cells that arise from the CLP in the bone marrow. They lack the antigen-specific receptors of the adaptive immune system cells, but express members of various families of innate receptors that can respond to cellular stress and to infections by very


Immunology_Janeway

Immunology_Janeway. They lack the antigen-specific receptors of the adaptive immune system cells, but express members of various families of innate receptors that can respond to cellular stress and to infections by very specific viruses. NK cells play an important role in the early innate response to viral infections, before the adaptive immune response has developed.


Immunology_Janeway

Immunology_Janeway. More recently, additional lineages of cells related to NK cells have been identified. Collectively, these cells are called innate lymphoid cells (ILCs). Arising from the CLP, ILCs reside in peripheral tissues, such as the intestine, where they function as the sources of mediators of inflammatory responses. The functions of NK cells and ILC cells are discussed in Chapter 3. Summary.


Immunology_Janeway

Immunology_Janeway. Strategies of avoidance, resistance, and tolerance represent different ways to deal with pathogens. Anatomic barriers and various chemical barriers such as complement and antimicrobial proteins may be considered a primitive form of avoidance, and they are the first line of defense against entry of both commensal organisms and pathogens into host tissues. If these barriers are breached, the vertebrate immune response becomes largely focused on resistance. Inflammatory inducers, which may be either chemical structures unique to microbes (PAMPs) or the chemical signals of tissue damage, act on receptors expressed by sensor cells to inform the immune system of infection. Sensor cells are typically innate immune cells such as macrophages or dendritic cells. Sensor cells can either directly respond with effector activity or produce inflammatory mediators, typically cytokines and chemokines that act on other immune cells, such as the innate NK cells and ILCs. These cells then are recruited


Immunology_Janeway

Immunology_Janeway. with effector activity or produce inflammatory mediators, typically cytokines and chemokines that act on other immune cells, such as the innate NK cells and ILCs. These cells then are recruited into target tissues to provide specific types of immune-response effector activities, such as cell killing or production of cytokines that have direct antiviral activity, all aimed to reduce or eliminate infection by pathogens. Responses by mediators in target tissues can induce several types of inflammatory cells that are specially suited for eliminating viruses, intracellular bacteria, extracellular pathogens, or parasites.


Immunology_Janeway

Immunology_Janeway. Principles of adaptive immunity. these are large, granular, lymphoid-like cells with important functions in innate immunity, especially against intracellular infections, being able to kill other cells. unlike lymphocytes, they lack antigen-specific receptors. Photograph courtesy of B. Smith. We come now to the components of adaptive immunity, the antigen-specific lymphocytes. Unless indicated otherwise, we shall use the term lymphocyte to refer only to the antigen-specific lymphocytes. Lymphocytes allow responses against a vast array of antigens from various pathogens encountered during a person’s lifetime and confer the important feature of immunological memory. Lymphocytes make this possible through the highly variable antigen receptors


Immunology_Janeway

Immunology_Janeway. Fig. 1.12 Lymphocytes are mostly small and inactive cells. the left panel shows a light micrograph of a small lymphocyte in which the nucleus has been stained purple by hematoxylin and eosin dye, surrounded by red blood cells (which have no nuclei). note the darker purple patches of condensed chromatin of the lymphocyte nucleus, indicating little transcriptional activity and the relative absence of cytoplasm. the right panel shows a transmission electron micrograph of a small lymphocyte. Again, note the evidence of functional inactivity: the condensed chromatin, the scanty cytoplasm, and the absence of rough endoplasmic reticulum. Photographs courtesy of n. rooney.


Immunology_Janeway

Immunology_Janeway. on their surface, by which they recognize and bind antigens. Each lymphocyte matures bearing a unique variant of a prototype antigen receptor, so that the population of lymphocytes expresses a huge repertoire of receptors that are highly diverse in their antigen-binding sites. Among the billion or so lymphocytes circulating in the body at any one time there will always be some that can recognize a given foreign antigen. A unique feature of the adaptive immune system is that it is capable of generating immunological memory, so that having been exposed once to an infectious agent, a person will make an immediate and stronger response against any subsequent exposure to it; that is, the individual will have protective immunity against it. Finding ways of generating long-lasting immunity to pathogens that do not naturally provoke it is one of the greatest challenges facing immunologists today.


Immunology_Janeway

Immunology_Janeway. 1-8 The interaction of antigens with antigen receptors induces lymphocytes to acquire effector and memory activity. There are two major types of lymphocytes in the vertebrate immune system, the B lymphocytes (B cells) and T lymphocytes (T cells). These express distinct types of antigen receptors and have quite different roles in the immune system, as was discovered in the 1960s. Most lymphocytes circulating in the body appear as rather unimpressive small cells with few cytoplasmic organelles and a condensed, inactive-appearing nuclear chromatin (Fig. 1.12). Lymphocytes manifest little functional activity until they encounter a specific antigen that interacts with an antigen receptor on their cell surface. Lymphocytes that have not yet been activated by antigen are known as naive lymphocytes; those that have met their antigen, become activated, and have differentiated further into fully functional lymphocytes are known as effector lymphocytes.


Immunology_Janeway

Immunology_Janeway. B cells and T cells are distinguished by the structure of the antigen receptor that they express. The B-cell antigen receptor, or B-cell receptor (BCR), is formed by the same genes that encode antibodies, a class of proteins also known as immunoglobulins (Ig) (Fig. 1.13). Thus, the antigen receptor of B lymphocytes is also known as membrane immunoglobulin (mIg) or surface immunoglobulin (sIg). The T-cell antigen receptor, or T-cell receptor (TCR), is related to the immunoglobulins but is quite distinct in its structure and recognition properties. After antigen binds to a B-cell antigen receptor, or B-cell receptor (BCR), the B cell will proliferate and differentiate into plasma cells. These are the effector form of B lymphocytes, and they secrete antibodies that have the same antigen specificity as the plasma cell’s B-cell receptor. Thus the antigen that activates a given B cell becomes the target of the antibodies produced by that B cell’s progeny. Principles of adaptive immunity.


Immunology_Janeway

Immunology_Janeway. Fig. 1.13 Schematic structure of antigen receptors. upper panel: an antibody molecule, which is secreted by activated B cells as an antigen-binding effector molecule. A membrane-bound version of this molecule acts as the B-cell antigen receptor (not shown). An antibody is composed of two identical heavy chains (green) and two identical light chains (yellow). each chain has a constant part (shaded blue) and a variable part (shaded red). each arm of the antibody molecule is formed by a light chain and a heavy chain, with the variable parts of the two chains coming together to create a variable region that contains the antigen-binding site. the stem is formed from the constant parts of the heavy chains and takes a limited number of forms. this constant region is involved in the elimination of the bound antigen. lower panel: a t-cell antigen receptor. this is also composed of two chains, an α chain (yellow) and a β chain (green), each of which has a variable and a constant part. As with


Immunology_Janeway

Immunology_Janeway. of the bound antigen. lower panel: a t-cell antigen receptor. this is also composed of two chains, an α chain (yellow) and a β chain (green), each of which has a variable and a constant part. As with the antibody molecule, the variable parts of the two chains create a variable region, which forms the antigen-binding site. the t-cell receptor is not produced in a secreted form.


Immunology_Janeway

Immunology_Janeway. When a T cell first encounters an antigen that its receptor can bind, it proliferates and differentiates into one of several different functional types of effector T lymphocytes. When effector T cells subsequently detect antigen, they can manifest three broad classes of activity. Cytotoxic T cells kill other cells that are infected with viruses or other intracellular pathogens bearing the antigen. Helper T cells provide signals, often in the form of specific cytokines that activate the functions of other cells, such as B-cell production of antibody and macrophage killing of engulfed pathogens. Regulatory T cells suppress the activity of other lymphocytes and help to limit the possible damage of immune responses. We discuss the detailed functions of cytotoxic, helper, and regulatory T cells in Chapters 9, 11, 12, and 15.


Immunology_Janeway

Immunology_Janeway. Some of the B cells and T cells activated by antigen will differentiate into memory cells, the lymphocytes that are responsible for the long-lasting immunity that can follow exposure to disease or vaccination. Memory cells will readily differentiate into effector cells on a second exposure to their specific antigen. Immunological memory is described in Chapter 11. 1-9 Antibodies and T-cell receptors are composed of constant and variable regions that provide distinct functions.


Immunology_Janeway

Immunology_Janeway. 1-9 Antibodies and T-cell receptors are composed of constant and variable regions that provide distinct functions. Antibodies were studied by traditional biochemical techniques long before recombinant DNA technology allowed the study of the membrane-bound forms of the antigen receptors on B and T cells. These early studies found that antibody molecules are composed of two distinct regions. One is a constant region, also called the fragment crystallizable region, or Fc region, which takes one of only four or five biochemically distinguishable forms (see Fig. 1.13). The variable region, by contrast, can be composed of a vast number of different amino acid sequences that allow antibodies to recognize an equally vast variety of antigens. It was the uniformity of the Fc region relative to the variable region that allowed its early analysis by X-ray crystallography by Gerald Edelman and Rodney Porter, who shared the 1972 Nobel Prize for their work on the structure of antibodies.


Immunology_Janeway

Immunology_Janeway. The antibody molecule is composed of two identical heavy chains and two identical light chains. Heavy and light chains each have variable and constant regions. The variable regions of a heavy chain and a light chain combine to form an antigen-binding site that determines the antigen-binding specificity of the antibody. Thus, both heavy and light chains contribute to the antigen-binding specificity of the antibody molecule. Also, each antibody has two identical variable regions, and so has two identical antigen-binding sites. The constant region determines the effector function of the antibody, that is, how the antibody will interact with various immune cells to dispose of antigen once it is bound. Fig. 1.14 Antigens are the molecules recognized by the immune response, while epitopes are sites within antigens to which antigen receptors bind.


Immunology_Janeway

Immunology_Janeway. Fig. 1.14 Antigens are the molecules recognized by the immune response, while epitopes are sites within antigens to which antigen receptors bind. Antigens can be complex macromolecules such as proteins, as shown in yellow. most antigens are larger than the sites on the antibody or antigen receptor to which they bind, and the actual portion of the antigen that is bound is known as the antigenic determinant, or epitope, for that receptor. large antigens such as proteins can contain more than one epitope (indicated in red and blue) and thus may bind different antibodies (shown here in the same color as the epitopes they bind). Antibodies generally recognize epitopes on the surface of the antigen.


Immunology_Janeway

Immunology_Janeway. Fig. 1.15 T-cell receptors bind a complex of an antigen fragment and a self molecule. unlike most antibodies, t-cell receptors can recognize epitopes that are buried within antigens (first panel). these antigens must first be degraded by proteases (second panel) and the peptide epitope delivered to a self molecule, called an mHC molecule (third panel). It is in this form, as a complex of peptide and mHC molecule, that antigens are recognized by t-cell receptors (tCrs; fourth panel).


Immunology_Janeway

Immunology_Janeway. The T-cell receptor shows many similarities to the B-cell receptor and antibody (see Fig. 1.13). It is composed of two chains, the TCR αand β chains, that are roughly equal in size and which span the T-cell membrane. Like antibody, each TCR chain has a variable region and a constant region, and the combination of the αand β-chain variable regions creates a single site for binding antigen. The structures of both antibodies and T-cell receptors are described in detail in Chapter 4, and functional properties of antibody constant regions are discussed in Chapters 5 and 10. 1-10 Antibodies and T-cell receptors recognize antigens by fundamentally different mechanisms.


Immunology_Janeway

Immunology_Janeway. 1-10 Antibodies and T-cell receptors recognize antigens by fundamentally different mechanisms. In principle, almost any chemical structure can be recognized as an antigen by the adaptive immune system, but the usual antigens encountered in an infection are the proteins, glycoproteins, and polysaccharides of pathogens. An individual antigen receptor or antibody recognizes a small portion of the antigen’s molecular structure, and the part recognized is known as an antigenic determinant or epitope (Fig. 1.14). Typically, proteins and glycoproteins have many different epitopes that can be recognized by different antigen receptors. Antibodies and B-cell receptors directly recognize the epitopes of native antigen in the serum or the extracellular spaces. It is possible for different antibodies to simultaneously recognize an antigen by its different epitopes; such simultaneous recognition increases the efficiency of clearing or neutralizing the antigen.


Immunology_Janeway

Immunology_Janeway. Whereas antibodies can recognize nearly any type of chemical structure, T-cell receptors usually recognize protein antigens and do so very differently from antibodies. The T-cell receptor recognizes a peptide epitope derived from a partially degraded protein, but only if the peptide is bound to specialized cell-surface glycoproteins called MHC molecules (Fig. 1.15). The members of this large family of cell-surface glycoproteins are encoded in a cluster of genes called the major histocompatibility complex (MHC). The antigens recognized by T cells can be derived from proteins arising from intracellular pathogens, such as a virus, or from extracellular pathogens. A further difference from the antibody molecule is that there is no secreted form of the T-cell receptor; the T-cell receptor functions solely to signal to the T cell that it has bound its antigen, and the subsequent immunological effects depend on the actions of the T cells themselves. We will further describe how epitopes from


Immunology_Janeway

Immunology_Janeway. solely to signal to the T cell that it has bound its antigen, and the subsequent immunological effects depend on the actions of the T cells themselves. We will further describe how epitopes from antigens are placed on MHC proteins in Chapter 6 and how T cells carry out their subsequent functions in Chapter 9.


Immunology_Janeway

Immunology_Janeway. TCRMHCmoleculeMHCmoleculeepitopepeptideThe epitopes recognized by T-cell receptors are often buried The antigen must ÿrst be broken down into peptide fragments The epitope peptide binds to a self molecule, an MHC molecule The T-cell receptor binds to a complex of MHC molecule and epitope peptide Principles of adaptive immunity. 1-11 Antigen-receptor genes are assembled by somatic gene rearrangements of incomplete receptor gene segments.


Immunology_Janeway

Immunology_Janeway. The innate immune system detects inflammatory stimuli by means of a relatively limited number of sensors, such as the TLR and NOD proteins, numbering fewer than 100 different types of proteins. Antigen-specific receptors of adaptive immunity provide a seemingly infinite range of specificities, and yet are encoded by a finite number of genes. The basis for this extraordinary range of specificity was discovered in 1976 by Susumu Tonegawa, for which he was awarded the 1987 Nobel Prize. Immunoglobulin variable regions are inherited as sets of gene segments, each encoding a part of the variable region of one of the immunoglobulin polypeptide chains. During B-cell development in the bone marrow, these gene segments are irreversibly joined by a process of DNA recombination to form a stretch of DNA encoding a complete variable region. A similar process of antigen-receptor gene rearrangement takes place for the T-cell receptor genes during development of T cells in the thymus.


Immunology_Janeway

Immunology_Janeway. Just a few hundred different gene segments can combine in different ways to generate thousands of different receptor chains. This combinatorial diversity allows a small amount of genetic material to encode a truly staggering diversity of receptors. During this recombination process, the random addition or subtraction of nucleotides at the junctions of the gene segments creates additional diversity known as junctional diversity. Diversity is amplified further by the fact that each antigen receptor has two different variable chains, each encoded by distinct sets of gene segments. We will describe the gene rearrangement process that assembles complete antigen receptors from gene segments in Chapter 5. 1-12 Lymphocytes activated by antigen give rise to clones of antigen-specific effector cells that mediate adaptive immunity.


Immunology_Janeway

Immunology_Janeway. There are two critical features of lymphocyte development that distinguish adaptive immunity from innate immunity. First, the process described above that assembles antigen receptors from incomplete gene segments is carried out in a manner that ensures that each developing lymphocyte expresses only one receptor specificity. Whereas the cells of the innate immune system express many different pattern recognition receptors and recognize features shared by many pathogens, the antigen-receptor expression of lymphocytes is ‘clonal,’ so that each mature lymphocyte differs from others in the specificity of its antigen receptor. Second, because the gene rearrangement process irreversibly changes the lymphocyte’s DNA, all its progeny inherit the same receptor specificity. Because this specificity is inherited by a cell’s progeny, the proliferation of an individual lymphocyte forms a clone of cells with identical antigen receptors.


Immunology_Janeway

Immunology_Janeway. There are lymphocytes of at least 108 different specificities in an individual human at any one time, comprising the lymphocyte receptor repertoire of the individual. These lymphocytes are continually undergoing a process similar to natural selection: only those lymphocytes that encounter an antigen to which their receptor binds will be activated to proliferate and differentiate into effector cells. This selective mechanism was first proposed in the 1950s by Macfarlane Burnet, who postulated the preexistence in the body of many different potential antibody-producing cells, each displaying on its surface a membrane-bound version of the antibody that served as a receptor for the antigen. On binding antigen, the cell is activated to divide and to produce many identical progeny, a process known as clonal expansion; this clone of identical cells can now secrete clonotypic antibodies with a specificity identical to that of the surface receptor that first triggered activation and clonal


Immunology_Janeway

Immunology_Janeway. known as clonal expansion; this clone of identical cells can now secrete clonotypic antibodies with a specificity identical to that of the surface receptor that first triggered activation and clonal expansion (Fig. 1.16). Burnet called this the clonal selection theory


Immunology_Janeway

Immunology_Janeway. A single progenitor cell gives rise to a large number of lymphocytes, each with a different speciÿcity Fig. 1.16 Clonal selection. each lymphoid progenitor gives rise to a large number of lymphocytes, each bearing a distinct antigen receptor. lymphocytes with receptors that bind ubiquitous self antigens are eliminated before they become fully mature, ensuring tolerance to such self antigens. When a foreign antigen (red dot) interacts with the receptor on a mature naive lymphocyte, that cell is activated and starts to divide. It gives rise to a clone of identical progeny, all of whose receptors bind the same antigen. Antigen specificity is thus maintained as the progeny proliferate and differentiate into effector cells. once antigen has been eliminated by these effector cells, the immune response ceases, although some lymphocytes are retained to mediate immunological memory. Each lymphocyte bears a single type of receptor with a unique speciÿcity


Immunology_Janeway

Immunology_Janeway. Each lymphocyte bears a single type of receptor with a unique speciÿcity Interaction between a foreign molecule and a lymphocyte receptor capable of binding that molecule with high afÿnity leads to lymphocyte activation The differentiated effector cells derived from an activated lymphocyte will bear receptors of identical speciÿcity to those of the parental cell from which that lymphocyte was derived Lymphocytes bearing receptors speciÿc for ubiquitous self molecules are deleted at an early stage in lymphoid cell development and are therefore absent from the repertoire of mature lymphocytes Fig. 1.17 The four basic principles of clonal selection. of antibody production; its four basic postulates are listed in Fig. 1.17. Clonal selection of lymphocytes is the single most important principle in adaptive immunity. 1-13 Lymphocytes with self-reactive receptors are normally eliminated during development or are functionally inactivated.


Immunology_Janeway

Immunology_Janeway. 1-13 Lymphocytes with self-reactive receptors are normally eliminated during development or are functionally inactivated. When Burnet formulated his theory, nothing was known of the antigen receptors or indeed the function of lymphocytes themselves. In the early 1960s, James Gowans discovered that removal of the small lymphocytes from rats resulted in the loss of all known adaptive immune responses, which were restored when the small lymphocytes were replaced. This led to the realization that lymphocytes must be the units of clonal selection, and their biology became the focus of the new field of cellular immunology.


Immunology_Janeway

Immunology_Janeway. Clonal selection of lymphocytes with diverse receptors elegantly explained adaptive immunity, but it raised one significant conceptual problem. With so many different antigen receptors being generated randomly during the lifetime of an individual, there is a possibility that some receptors might react against an individual’s own self antigens. How are lymphocytes prevented from recognizing native antigens on the tissues of the body and attacking them? Ray Owen had shown in the late 1940s that genetically different twin calves with a common placenta, and thus a shared placental blood circulation, were immunologically unresponsive, or tolerant, to one another’s tissues. Peter Medawar then showed in 1953 that exposure to foreign tissues during embryonic development caused mice to become immunologically tolerant to these tissues. Burnet proposed that developing lymphocytes that are potentially self-reactive are removed before they can mature, a process known as clonal deletion. Medawar


Immunology_Janeway

Immunology_Janeway. tolerant to these tissues. Burnet proposed that developing lymphocytes that are potentially self-reactive are removed before they can mature, a process known as clonal deletion. Medawar and Burnet shared the 1960 Nobel Prize for their work on tolerance. This process was demonstrated to occur experimentally in the late 1980s. Some lymphocytes that receive either too much or too little signal through their antigen receptor during development are eliminated by a form of cell suicide called apoptosis—derived from a Greek word meaning the falling of leaves from trees— or programmed cell death. Other types of mechanisms of immunological tolerance have been identified since then that rely on the induction of an inactive state, called anergy, as well as mechanisms of active suppression of self-reactive lymphocytes. Chapter 8 will describe lymphocyte development and tolerance mechanisms that shape the lymphocyte receptor repertoire. Chapters 14 and 15 will discuss how immune tolerance


Immunology_Janeway

Immunology_Janeway. self-reactive lymphocytes. Chapter 8 will describe lymphocyte development and tolerance mechanisms that shape the lymphocyte receptor repertoire. Chapters 14 and 15 will discuss how immune tolerance mechanisms can sometimes fail.


Immunology_Janeway

Immunology_Janeway. Principles of adaptive immunity. 1-14 Lymphocytes mature in the bone marrow or the thymus and then congregate in lymphoid tissues throughout the body.


Immunology_Janeway

Immunology_Janeway. Lymphocytes circulate in the blood and the lymph and are also found in large numbers in lymphoid tissues or lymphoid organs, which are organized aggregates of lymphocytes in a framework of nonlymphoid cells. Lymphoid organs can be divided broadly into the central or primary lymphoid organs, where lymphocytes are generated, and the peripheral or secondary lymphoid organs, where mature naive lymphocytes are maintained and adaptive immune responses are initiated. The central lymphoid organs are the bone marrow and the thymus, an organ in the upper chest. The peripheral lymphoid organs comprise the lymph nodes, the spleen, and the mucosal lymphoid tissues of the gut, the nasal and respiratory tract, the urogenital tract, and other mucosa. The locations of the main lymphoid tissues are shown schematically in Fig. 1.18; we describe the individual peripheral lymphoid organs in more detail later in the chapter. Lymph nodes are interconnected by a system of lymphatic vessels, which drain


Immunology_Janeway

Immunology_Janeway. schematically in Fig. 1.18; we describe the individual peripheral lymphoid organs in more detail later in the chapter. Lymph nodes are interconnected by a system of lymphatic vessels, which drain extracellular fluid from tissues, carry it through the lymph nodes, and deposit it back into the blood.


Immunology_Janeway

Immunology_Janeway. The progenitors that give rise to B and T lymphocytes originate in the bone marrow. B cells complete their development within the bone marrow. Although the ‘B’ in B lymphocytes originally stood for the bursa of Fabricius, a lymphoid organ in young chicks in which lymphocytes mature, it is a useful mnemonic for bone marrow. The immature precursors of T lymphocytes migrate to the thymus, from which they get their name, and complete their development there. Once they have completed maturation, both types of lymphocytes enter the bloodstream as mature naive lymphocytes and continuously circulate through the peripheral lymphoid tissues.


Immunology_Janeway

Immunology_Janeway. Fig. 1.18 The distribution of lymphoid tissues in the body. lymphocytes arise from stem cells in bone marrow and differentiate in the central lymphoid organs (yellow)—B cells in the bone marrow and t cells in the thymus. they migrate from these tissues and are carried in the bloodstream to the peripheral lymphoid organs (blue). these include lymph nodes, spleen, and lymphoid tissues associated with mucosa, such as the gut-associated tonsils, Peyer’s patches, and appendix. the peripheral lymphoid organs are the sites of lymphocyte activation by antigen, and lymphocytes recirculate between the blood and these organs until they encounter their specific antigen. lymphatics drain extracellular fluid from the peripheral tissues, through the lymph nodes, and into the thoracic duct, which empties into the left subclavian vein. this fluid, known as lymph, carries antigen taken up by dendritic cells and macrophages to the lymph nodes, as well as recirculating lymphocytes from the lymph nodes


Immunology_Janeway

Immunology_Janeway. into the left subclavian vein. this fluid, known as lymph, carries antigen taken up by dendritic cells and macrophages to the lymph nodes, as well as recirculating lymphocytes from the lymph nodes back into the blood. lymphoid tissue is also associated with other mucosa such as the bronchial linings (not shown).


Immunology_Janeway

Immunology_Janeway. Fig. 1.19 Dendritic cells initiate adaptive immune responses. Immature dendritic cells residing in a tissue take up pathogens and their antigens by macropinocytosis and by receptor-mediated endocytosis. they are stimulated by recognition of the presence of pathogens to migrate through the lymphatics to regional lymph nodes, where they arrive as fully mature nonphagocytic dendritic cells that express both antigen and the co-stimulatory molecules necessary to activate a naive t cell that recognizes the antigen. thus the dendritic cells stimulate lymphocyte proliferation and differentiation. MOVIE 1.1


Immunology_Janeway

Immunology_Janeway. MOVIE 1.1 Fig. 1.20 Dendritic cells form a key link between the innate immune system and the adaptive immune system. like the other cells of innate immunity, dendritic cells recognize pathogens via invariant cell-surface receptors for pathogen molecules and are activated by these stimuli early in an infection. dendritic cells in tissues are phagocytic; they are specialized to ingest a wide range of pathogens and to display their antigens at the dendritic cell surface in a form that can be recognized by t cells. 1-15 Adaptive immune responses are initiated by antigen and antigen-presenting cells in secondary lymphoid tissues.


Immunology_Janeway

Immunology_Janeway. Adaptive immune responses are initiated when B or T lymphocytes encounter antigens for which their receptors have specific reactivity, provided that there are appropriate inflammatory signals to support activation. For T cells, this activation occurs via encounters with dendritic cells that have picked up antigens at sites of infection and migrated to secondary lymphoid organs. Activation of the dendritic cells’ PRRs by PAMPs at the site of infection stimulates the dendritic cells in the tissues to engulf the pathogen and degrade it intracellularly. They also take up extracellular material, including virus particles and bacteria, by receptor-independent macropinocytosis. These processes lead to the display of peptide antigens on the MHC molecules of the dendritic cells, a display that activates the antigen receptors of lymphocytes. Activation of PRRs also triggers the dendritic cells to express cell-surface proteins called co-stimulatory molecules, which support the ability of the T


Immunology_Janeway

Immunology_Janeway. the antigen receptors of lymphocytes. Activation of PRRs also triggers the dendritic cells to express cell-surface proteins called co-stimulatory molecules, which support the ability of the T lymphocyte to proliferate and differentiate into its final, fully functional form (Fig. 1.19). For these reasons dendritic cells are also called antigen-presenting cells (APCs), and as such, they form a crucial link between the innate immune response and the adaptive immune response (Fig. 1.20). In certain situations, macrophages and B cells can also act as antigen-presenting cells, but dendritic cells are the cells that are specialized in initiating the adaptive immune response. Free antigens can also stimulate the antigen receptors of B cells, but most B cells require ‘help’ from activated helper T cells for optimal antibody responses. The activation of naive T lymphocytes is therefore an essential first stage in virtually all adaptive immune responses. Chapter 6 returns to dendritic cells to


Immunology_Janeway

Immunology_Janeway. T cells for optimal antibody responses. The activation of naive T lymphocytes is therefore an essential first stage in virtually all adaptive immune responses. Chapter 6 returns to dendritic cells to discuss how antigens are processed for presentation to T cells. Chapters 7 and 9 discuss co-stimulation and lymphocyte activation. Chapter 10 describes how T cells help in activating B cells.


Immunology_Janeway

Immunology_Janeway. Principles of adaptive immunity. naive lymphocytes recirculate constantly through peripheral lymphoid tissue, here illustrated as a popliteal lymph node—a lymph node situated behind the knee. In the case of an infection in the foot, this will be the draining lymph node, where lymphocytes may encounter their specific antigens and become activated. Both activated and nonactivated lymphocytes are returned to the bloodstream via the lymphatic system. 1-16 Lymphocytes encounter and respond to antigen in the peripheral lymphoid organs.


Immunology_Janeway

Immunology_Janeway. 1-16 Lymphocytes encounter and respond to antigen in the peripheral lymphoid organs. Antigen and lymphocytes eventually encounter each other in the peripheral lymphoid organs—the lymph nodes, spleen, and mucosal lymphoid tissues (see Fig. 1.18). Mature naive lymphocytes are continually recirculating through these tissues, to which pathogen antigens are carried from sites of infection, primarily by dendritic cells. The peripheral lymphoid organs are specialized to trap antigen-bearing dendritic cells and to facilitate the initiation of adaptive immune responses. Peripheral lymphoid tissues are composed of aggregations of lymphocytes in a framework of nonleukocyte stromal cells, which provide both the basic structural organization of the tissue and survival signals to help sustain the life of the lymphocytes. Besides lymphocytes, peripheral lymphoid organs also contain resident macrophages and dendritic cells.


Immunology_Janeway

Immunology_Janeway. When an infection occurs in a tissue such as the skin, free antigen and antigen-bearing dendritic cells travel from the site of infection through the afferent lymphatic vessels into the draining lymph nodes (Fig. 1.21)—peripheral lymphoid tissues where they activate antigen-specific lymphocytes. The activated lymphocytes then undergo a period of proliferation and differentiation, after which most leave the lymph nodes as effector cells via the efferent lymphatic vessel. This eventually returns them to the bloodstream (see Fig. 1.18), which then carries them to the tissues where they will act. This whole process takes about 4–6 days from the time that the antigen is recognized, which means that an adaptive immune response to an antigen that has not been encountered before does not become effective until about a week after infection (see Fig. 1.7). Naive lymphocytes that do not recognize their antigen also leave through the efferent lymphatic vessel and are returned to the blood, from


Immunology_Janeway

Immunology_Janeway. effective until about a week after infection (see Fig. 1.7). Naive lymphocytes that do not recognize their antigen also leave through the efferent lymphatic vessel and are returned to the blood, from which they continue to recirculate through lymphoid tissues until they recognize antigen or die.


Immunology_Janeway

Immunology_Janeway. The lymph nodes are highly organized lymphoid organs located at the points of convergence of vessels of the lymphatic system, which is the extensive system that collects extracellular fluid from the tissues and returns it to the blood (see Fig. 1.18). This extracellular fluid is produced continuously by filtration from the blood and is called lymph. Lymph flows away from the peripheral tissues under the pressure exerted by its continuous production, and is carried by lymphatic vessels, or lymphatics. One-way valves in the lymphatic vessels prevent a reverse flow, and the movements of one part of the body in relation to another are important in driving the lymph along.


Immunology_Janeway

Immunology_Janeway. As noted above, afferent lymphatic vessels drain fluid from the tissues and carry pathogens and antigen-bearing cells from infected tissues to the lymph nodes (Fig. 1.22). Free antigens simply diffuse through the extracellular fluid to the lymph node, while the dendritic cells actively migrate into the lymph node, attracted by chemokines. The same chemokines also attract lymphocytes from the blood, and these enter lymph nodes by squeezing through the walls of specialized blood vessels called high endothelial venules (HEV), named for their thicker, more rounded appearance relative to flatter endothelial cells in other locations. In the lymph nodes, B lymphocytes are localized in follicles, which make up the outer cortex of the lymph node, with T cells more Fig. 1.21 Circulating lymphocytes encounter antigen in peripheral lymphoid organs.


Immunology_Janeway

Immunology_Janeway. Fig. 1.21 Circulating lymphocytes encounter antigen in peripheral lymphoid organs. Lymphocytes and lymph return to blood via the thoracic duct Naive lymphocytes enter lymph nodes from blood infected peripheral tissue lymph node heart Antigens from sites of infection reach lymph nodes via lymphatics


Immunology_Janeway

Immunology_Janeway. Fig. 1.22 Organization of a lymph node. As shown at left in the diagram of a lymph node in longitudinal section, a lymph node consists of an outermost cortex and an inner medulla. the cortex is composed of an outer cortex of B cells organized into lymphoid follicles and of adjacent, or paracortical, areas made up mainly of t cells and dendritic cells. When an immune response is under way, some of the follicles—known as secondary lymphoid follicles— contain central areas of intense B-cell proliferation called germinal centers. these reactions are very dramatic, but eventually die out as germinal centers become senescent. lymph draining from the extracellular spaces of the body carries antigens in phagocytic dendritic cells and phagocytic macrophages from the tissues to the lymph node via the afferent lymphatics. these migrate directly from the sinuses into the cellular parts of the node. lymph leaves via the efferent lymphatics in the medulla. the medulla consists of strings of


Immunology_Janeway

Immunology_Janeway. via the afferent lymphatics. these migrate directly from the sinuses into the cellular parts of the node. lymph leaves via the efferent lymphatics in the medulla. the medulla consists of strings of macrophages and antibody-secreting plasma cells known as the medullary cords. naive lymphocytes enter the node from the bloodstream through specialized postcapillary venules (not shown) and leave with the lymph through the efferent lymphatic. the light micrograph (right) shows a transverse section through a lymph node, with prominent follicles containing germinal centers. magnification ×7. Photograph courtesy of n. rooney.


Immunology_Janeway

Immunology_Janeway. diffusely distributed in the surrounding paracortical areas, also referred to as the deep cortex or T-cell zones (see Fig. 1.22). Lymphocytes migrating from the blood into lymph nodes enter the paracortical areas first, and because they are attracted by the same chemokines, antigen-presenting dendritic cells and macrophages also become localized there. Free antigen diffusing through the lymph node can become trapped on these dendritic cells and macrophages. This juxtaposition of antigen, antigen-presenting cells, and naive T cells in the T-cell zone creates an ideal environment in which naive T cells can bind their specific antigen and thus become activated.


Immunology_Janeway

Immunology_Janeway. As noted earlier, activation of B cells usually requires not only antigen, which binds to the B-cell receptor, but also the cooperation of activated helper T cells, a type of effector T cell. The location of B cells and T cells within the lymph node is dynamically regulated by their state of activation. When they become activated, T cells and B cells both move to the border of the follicle and T-cell zone, where T cells can first provide their helper function to B cells. Some of the B-cell follicles include germinal centers, where activated B cells are undergoing intense proliferation and differentiation into plasma cells. These mechanisms are described in detail in Chapter 10.


Immunology_Janeway

Immunology_Janeway. In humans, the spleen is a fist-sized organ situated just behind the stomach (see Fig. 1.18). It has no direct connection with the lymphatic system; instead, it collects antigen from the blood and is involved in immune responses to blood-borne pathogens. Lymphocytes enter and leave the spleen via blood vessels. The spleen also collects and disposes of senescent red blood cells. Its organization is shown schematically in Fig. 1.23. The bulk of the spleen is composed of red pulp, which is the site of red blood cell disposal. The lymphocytes surround the arterioles running through the spleen, forming isolated Principles of adaptive immunity.


Immunology_Janeway

Immunology_Janeway. Fig. 1.23 Organization of the lymphoid tissues of the spleen. of lymphocytes. In each area of white pulp, blood carrying both the schematic at top left shows that the spleen consists of red pulp lymphocytes and antigen flows from a trabecular artery into a (pink areas), which is a site of red blood cell destruction, interspersed central arteriole. From this arteriole smaller blood vessels fan out, with the lymphoid white pulp. An enlargement of a small section eventually terminating in a specialized zone in the human spleen of a human spleen (top right) shows the arrangement of discrete called the perifollicular zone (PFZ), which surrounds each marginal areas of white pulp (yellow and blue) around central arterioles. zone. Cells and antigen then pass into the white pulp through open most of the white pulp is shown in transverse section, with two blood-filled spaces in the perifollicular zone. the light micrograph portions in longitudinal section. the two schematics below this at