Immunology_Janeway

Immunology_Janeway. 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 bottom left shows a transverse section of white pulp of human diagram show enlargements of a transverse section (bottom center) spleen immunostained for mature B cells. Both follicle and PAlS are and longitudinal section (bottom right) of white pulp. Surrounding surrounded by the perifollicular zone. the follicular arteriole emerges the central arteriole is the periarteriolar lymphoid sheath (PAlS), in the PAlS (arrowhead at bottom), traverses the follicle, goes made up of t cells. lymphocytes and antigen-loaded dendritic through the marginal zone, and opens into the perifollicular zone cells come together here. the follicles consist mainly of B cells; (upper arrowheads). Co, follicular B-cell corona; gC, germinal center; in secondary follicles, a germinal center is surrounded by a B-cell


Immunology_Janeway

Immunology_Janeway. come together here. the follicles consist mainly of B cells; (upper arrowheads). Co, follicular B-cell corona; gC, germinal center; in secondary follicles, a germinal center is surrounded by a B-cell mZ, marginal zone; rP, red pulp; arrowheads, central arteriole. corona. the follicles are surrounded by a so-called marginal zone Photograph courtesy of n. m. milicevic.


Immunology_Janeway

Immunology_Janeway. areas of white pulp. The sheath of lymphocytes around an arteriole is called the periarteriolar lymphoid sheath (PALS) and contains mainly T cells. Lymphoid follicles occur at intervals along it, and these contain mainly B cells. An area called the marginal zone surrounds the follicle; it has few T cells, is rich in macrophages, and has a resident, noncirculating population of B cells known as marginal zone B cells. These B cells are poised to rapidly produce antibodies that have low affinity to bacterial capsular polysaccharides. These antibodies, which are discussed in Chapter 8, provide some degree of protection before the adaptive immune response is fully activated. Blood-borne microbes, soluble antigens, and antigen:antibody complexes are filtered from the blood by macrophages and immature dendritic cells within the marginal zone. Like the migration of immature dendritic cells from peripheral tissues to the T-cell areas of lymph nodes, dendritic cells in the marginal zones in the


Immunology_Janeway

Immunology_Janeway. dendritic cells within the marginal zone. Like the migration of immature dendritic cells from peripheral tissues to the T-cell areas of lymph nodes, dendritic cells in the marginal zones in the spleen migrate to the T-cell areas after taking up antigen and becoming activated; here they are able to present the antigens they carry to T cells.


Immunology_Janeway

Immunology_Janeway. villusgerminal center T cells follicle-associated epithelium subepithelial dome follicle efferent lymphatics Peyer’s patches are covered by an epithelial layer containing specialized cells called M cells, which have characteristic membrane ruf˜es M cell a dome TDA GC epithelium M cell b c


Immunology_Janeway

Immunology_Janeway. Fig. 1.24 Organization of a Peyer’s patch in the gut mucosa. As the diagram on the left shows, a Peyer’s patch contains numerous B-cell follicles with germinal centers. the areas between follicles are occupied by t cells and are therefore called the t-cell dependent areas. the layer between the surface epithelium and the follicles is known as the subepithelial dome, and is rich in dendritic cells, t cells, and B cells. Peyer’s patches have no afferent lymphatics, and the antigen enters directly from the gut across a specialized epithelium made up of so-called microfold (m) cells. Although this tissue looks very different from other lymphoid organs, the basic divisions are maintained. As in the lymph nodes, lymphocytes enter Peyer’s patches from the blood across the walls of high endothelial venules (not shown), and leave via the efferent lymphatic. the light micrograph in panel a shows a section through a Peyer’s patch in the gut wall of a mouse. the Peyer’s patch can be seen lying


Immunology_Janeway

Immunology_Janeway. venules (not shown), and leave via the efferent lymphatic. the light micrograph in panel a shows a section through a Peyer’s patch in the gut wall of a mouse. the Peyer’s patch can be seen lying beneath the epithelial tissues. gC, germinal center; tdA, t-cell dependent area. Panel b, a scanning electron micrograph of the follicle-associated epithelium boxed in panel a, shows the m cells, which lack the microvilli and the mucus layer present on normal epithelial cells. each m cell appears as a sunken area on the epithelial surface. Panel c, a higher-magnification view of the boxed area in panel b, shows the characteristic ruffled surface of an m cell. m cells are the portal of entry for many pathogens and other particles. Panel a, hematoxylin and eosin stain, magnification ×100; panel b, ×5000; panel c, ×23,000.


Immunology_Janeway

Immunology_Janeway. 1-17 Mucosal surfaces have specialized immune structures that orchestrate responses to environmental microbial encounters.


Immunology_Janeway

Immunology_Janeway. Most pathogens enter the body through mucosal surfaces, and these are also exposed to a vast load of other potential antigens from the air, food, and the natural microbial flora of the body. Mucosal surfaces are protected by an extensive system of lymphoid tissues known generally as the mucosal immune system or mucosa-associated lymphoid tissues (MALT). Collectively, the mucosal immune system is estimated to contain as many lymphocytes as all the rest of the body, and they form a specialized set of cells obeying somewhat different rules of recirculation from those in the other peripheral lymphoid organs. The gut-associated lymphoid tissues (GALT) include the tonsils, adenoids, appendix, and specialized structures in the small intestine called Peyer’s patches, and they collect antigen from the epithelial surfaces of the gastrointestinal tract. In Peyer’s patches, which are the most important and highly organized of these tissues, the antigen is collected by specialized epithelial cells


Immunology_Janeway

Immunology_Janeway. the epithelial surfaces of the gastrointestinal tract. In Peyer’s patches, which are the most important and highly organized of these tissues, the antigen is collected by specialized epithelial cells called microfold or M cells (Fig. 1.24). The lymphocytes form a follicle consisting of a large central dome of B lymphocytes surrounded by smaller numbers of T lymphocytes. Dendritic cells resident within the Peyer’s patch present the antigen to T lymphocytes. Lymphocytes enter Peyer’s patches from the blood and leave through efferent lymphatics. Effector lymphocytes generated in Peyer’s patches travel through the lymphatic system and into the bloodstream, from where they are disseminated back into mucosal tissues to carry out their effector actions.


Immunology_Janeway

Immunology_Janeway. Similar but more diffuse aggregates of lymphocytes are present in the respiratory tract and other mucosa: nasal-associated lymphoid tissue (NALT) and bronchus-associated lymphoid tissue (BALT) are present in the respiratory tract. Like the Peyer’s patches, these mucosal lymphoid tissues are also overlaid by M cells, through which inhaled microbes and antigens that become trapped in the mucous covering of the respiratory tract can pass. The mucosal immune system is discussed in Chapter 12.


Immunology_Janeway

Immunology_Janeway. Although very different in appearance, the lymph nodes, spleen, and mucosa-associated lymphoid tissues all share the same basic architecture. They all operate on the same principle, trapping antigens and antigen-presenting cells from sites of infection in order to present antigen to migratory small lymphocytes, thus inducing adaptive immune responses. The peripheral lymphoid tissues also provide sustaining signals to lymphocytes that do not encounter their specific antigen immediately, so that they survive and continue to recirculate. Because they are involved in initiating adaptive immune responses, the peripheral lymphoid tissues are not static structures but vary quite markedly, Principles of adaptive immunity.


Immunology_Janeway

Immunology_Janeway. Because they are involved in initiating adaptive immune responses, the peripheral lymphoid tissues are not static structures but vary quite markedly, Principles of adaptive immunity. depending on whether or not infection is present. The diffuse mucosal lymphoid tissues may appear in response to infection and then disappear, whereas the architecture of the organized tissues changes in a more defined way during an infection. For example, the B-cell follicles of the lymph nodes expand as B lymphocytes proliferate to form germinal centers (see Fig. 1.22), and the entire lymph node enlarges, a phenomenon familiarly known as swollen glands.


Immunology_Janeway

Immunology_Janeway. Finally, specialized populations of lymphocytes and innate lymphoid cells can be found distributed throughout particular sites in the body rather than being found in organized lymphoid tissues. Such sites include the liver and the lamina propria of the gut, as well as the base of the epithelial lining of the gut, reproductive epithelia, and, in mice but not in humans, the epidermis. These lymphocyte populations seem to have an important role in protecting these tissues from infection, and are described further in Chapters 8 and 12. 1-18 Lymphocytes activated by antigen proliferate in the peripheral lymphoid organs, generating effector cells and immunological memory.


Immunology_Janeway

Immunology_Janeway. 1-18 Lymphocytes activated by antigen proliferate in the peripheral lymphoid organs, generating effector cells and immunological memory. The great diversity of lymphocyte receptor repertoire means that there will usually be some lymphocytes bearing a receptor for any given foreign antigen. Recent experiments suggest this number to be perhaps a few hundred per mouse, certainly not enough to mount a response against a pathogen. To generate sufficient antigen-specific effector lymphocytes to fight an infection, a lymphocyte with an appropriate receptor specificity is activated first to proliferate. Only when a large clone of identical cells has been produced do these finally differentiate into effector cells, a process that requires 4 to 5 days. This means that the adaptive immune response to a pathogen occurs several days after the initial infection has occurred and been detected by the innate immune system.


Immunology_Janeway

Immunology_Janeway. On recognizing its specific antigen on an activated antigen-presenting cell, a naive lymphocyte stops migrating, the volume of the nucleus and cytoplasm increases, and new mRNAs and new proteins are synthesized. Within a few hours, the cell looks completely different and is known as a lymphoblast. Dividing lymphoblasts are able to duplicate themselves two to four times every 24 hours for 3–5 days, so that a single naive lymphocyte can produce a clone of around 1000 daughter cells of identical specificity. These then differentiate into effector cells. In the case of B cells, the differentiated effector cells are the plasma cells, which secrete antibody. In the case of T cells, the effector cells are either cytotoxic T cells, which are able to destroy infected cells, or helper T cells, which activate other cells of the immune system (see Section 1-8).


Immunology_Janeway

Immunology_Janeway. Effector lymphocytes do not recirculate like naive lymphocytes. Some effector T cells detect sites of infection and migrate into them from the blood; others stay in the lymphoid tissues to activate B cells. Some antibody-secreting plasma cells remain in the peripheral lymphoid organs, but most plasma cells generated in the lymph nodes and spleen will migrate to the bone marrow and take up residence there, secreting large amounts of antibodies into the blood system. Effector cells generated in the mucosal immune system generally stay within the mucosal tissues. Most lymphocytes generated by clonal expansion in an immune response will eventually die. However, a significant number of activated antigen-specific B cells and T cells persist after antigen has been eliminated. These cells are known as memory cells and form the basis of immunological memory. They can be reactivated much more quickly than naive lymphocytes, which ensures a more rapid and effective response on a second encounter


Immunology_Janeway

Immunology_Janeway. as memory cells and form the basis of immunological memory. They can be reactivated much more quickly than naive lymphocytes, which ensures a more rapid and effective response on a second encounter with a pathogen and thereby usually provides lasting protective immunity.


Immunology_Janeway

Immunology_Janeway. Fig. 1.25 The course of a typical antibody response. the first encounter with an antigen produces a primary response. Antigen A introduced at time zero encounters little specific antibody in the serum. After a lag phase (light blue), antibody against antigen A (dark blue) appears; its concentration rises to a plateau and then gradually declines, typical of a primary response. When the serum is tested for antibody against another antigen, B (yellow), there is little preset. When the animal is later challenged with a mixture of antigens A and B, a very rapid and intense antibody secondary response to A occurs, illustrating immunological memory. this is the main reason for giving booster injections after an initial vaccination. note that the response to B resembles the primary response to A, as this is the first encounter with antigen B.


Immunology_Janeway

Immunology_Janeway. The characteristics of immunological memory are readily observed by comparing an individual’s antibody response to a first or primary immunization with the response to a secondary or booster immunization with the same antigen. As shown in Fig. 1.25, the secondary antibody response occurs after a shorter lag phase and achieves a markedly higher level than in the primary response. During the secondary responses, antibodies can also acquire higher affinity, or strength of binding, for the antigen due to a process called affinity maturation, which takes place in the specialized germinal centers within B-cell follicles (see Section 1-16). Importantly, helper T cells are required for the process of affinity maturation, but T-cell receptors do not undergo affinity maturation. Compared with naive T cells, memory T cells show a lower threshold for activation, but as a result of changes in the responsiveness of the cell and not because of changes in the receptor. We describe the mechanisms of


Immunology_Janeway

Immunology_Janeway. T cells, memory T cells show a lower threshold for activation, but as a result of changes in the responsiveness of the cell and not because of changes in the receptor. We describe the mechanisms of affinity maturation in Chapters 5 and 10.


Immunology_Janeway

Immunology_Janeway. The cellular basis of immunological memory is the clonal expansion and clonal differentiation of cells that have a specific attraction for the eliciting antigen, and the memory is therefore entirely antigen-specific. It is immunological memory that enables successful vaccination and prevents reinfection with pathogens that have been repelled successfully by an adaptive immune response. In Chapter 11, we will return to immunological memory, which is perhaps the most important biological consequence of adaptive immunity. Summary.


Immunology_Janeway

Immunology_Janeway. Summary. While the innate immune system relies on invariant pattern recognition receptors to detect common microbial structures or the damage they cause, the adaptive immune system relies on a repertoire of antigen receptors to recognize structures that are specific to individual pathogens. This feature provides adaptive immunity with greater sensitivity and specificity. The clonal expansion of antigen-reactive lymphocytes also confers the property of immunological memory, which enhances protection against reinfection by the same pathogen. Adaptive immunity relies on two major types of lymphocytes. B cells mature in the bone marrow and are the source of circulating antibodies. T cells mature in the thymus and recognize peptides from pathogens presented by MHC the effector mechanisms of immunity.


Immunology_Janeway

Immunology_Janeway. molecules on infected cells or antigen-presenting cells. An adaptive response involves the selection and amplification of clones of lymphocytes bearing receptors that recognize the foreign antigen. This clonal selection provides the theoretical framework for understanding all the key features of an adaptive immune response. Each lymphocyte carries cell-surface receptors of a single antigen specificity. These receptors are generated by the random recombination of variable receptor gene segments and the pairing of distinct variable protein chains: heavy and light chains in immunoglobulins, or the two chains of T-cell receptors. The large antigen-receptor repertoire of lymphocytes can recognize virtually any antigen. Adaptive immunity is initiated when an innate immune response fails to eliminate a new infection and activated antigen-presenting cells—typically dendritic cells that bear antigens from pathogens and co-stimulatory receptors—migrate to the draining lymphoid tissues.


Immunology_Janeway

Immunology_Janeway. Immune responses are initiated in several peripheral lymphoid tissues. The spleen serves as a filter for blood-borne infections. Lymph nodes draining various tissues and the mucosal and gut-associated lymphoid tissues (MALT and GALT) are organized into specific zones where T and B cells can be activated efficiently by antigen-presenting cells or helper T cells. When a recirculating lymphocyte encounters its corresponding antigen in these peripheral lymphoid tissues, it proliferates, and its clonal progeny differentiate into effector T and B lymphocytes that can eliminate the infectious agent. A subset of these proliferating lymphocytes differentiates into memory cells, ready to respond rapidly to the same pathogen if it is encountered again. The details of these processes of recognition, development, and differentiation form the main material of the central three parts of this book. The effector mechanisms of immunity.


Immunology_Janeway

Immunology_Janeway. For activated innate and adaptive immune cells to destroy pathogens, they must employ an appropriate effector mechanism suited to each infecting agent. The different types of pathogens noted in Fig. 1.26 have different lifestyles and require different responses for both their recognition and their destruction. Perhaps it is not surprising, then, that defenses against different pathogen types are organized into effector modules suited for these different lifestyles. In this sense, an effector module is a collection of cell-mediated and humoral mechanisms, both innate and adaptive, that act together to achieve elimination of a particular category of pathogen. For example, defense against extracellular pathogens can involve both phagocytic cells and B cells, which recognize extracellular antigens and become plasma cells that secrete antibody into the extracellular environment. Defense against intracellular pathogens involves T cells that can detect peptides generated inside the infected


Immunology_Janeway

Immunology_Janeway. and become plasma cells that secrete antibody into the extracellular environment. Defense against intracellular pathogens involves T cells that can detect peptides generated inside the infected cell. Some effector T cells directly kill cells infected with intracellular pathogens such as viruses. Moreover, activated T cells differentiate into three major subsets of helper T cells, which produce different patterns of cytokines. These three subsets, discussed below, generally specialize in promoting defenses against pathogens having three major lifestyles: they can defend against intracellular infection, destroy extracellular bacteria and fungi, or provide barrier immunity directed at parasites. T cells also promote defense against extracellular pathogens by helping B cells make antibody.


Immunology_Janeway

Immunology_Janeway. Most of the other effector mechanisms used by an adaptive immune response to dispose of pathogens are the same as those of innate immunity and involve cells such as macrophages and neutrophils, and proteins such as complement. Indeed, it seems likely that the vertebrate adaptive immune response evolved by the addition of specific recognition properties to innate defense mechanisms already existing in invertebrates. This is supported by recent findings that the innate lymphoid cells—the ILCs—show similar patterns of differentiation into different cytokine-producing subsets to those of T cells. We begin this section by outlining the effector actions of antibodies, which depend almost entirely on recruiting cells and molecules of the innate immune system. 1-19 Innate immune responses can select from several effector modules to protect against different types of pathogens.


Immunology_Janeway

Immunology_Janeway. As we mentioned in Section 1-7, the innate immune system contains several types of cells—NK cells and ILCs—that have similarities to lymphocytes, particularly T cells. NK cells lack the antigen-specific receptors of T cells, but can exhibit the cytotoxic capacity of T cells and produce some of the cytokines that effector T cells produce. ILCs develop from the same progenitor cells in the bone marrow as NK cells, and they also lack antigen-specific receptors. Very recent discoveries indicate that ILCs actually comprise several closely related lineages that differ in the specific cytokines that they will produce when activated. Remarkably, there is a striking similarity between the patterns of cytokines produced by ILC subsets and helper T-cell subsets, as mentioned above. It appears that subsets of ILCs are the innate homologs of their helper T-cell counterparts, and NK cells are the innate homolog of cytotoxic T cells.


Immunology_Janeway

Immunology_Janeway. As mentioned in Section 1-6, there are a large number of cytokines with different functions (see Appendix III). A convenient way to organize the effects of cytokines is by the effector module that each cytokine promotes. Some cytokines tend to promote immunity to intracellular pathogens. One such cytokine is interferon-γ, which acts both by activating phagocytes to more efficiently kill intracellular pathogens and by inducing target tissues to resist intracellular pathogens. This is called type 1 immunity. IFN-γ is produced by some but not all subsets of innate and adaptive lymphocytes, and the subset of ILC making IFN-γ is called ILC1. Other ILC subsets produce cytokines favoring effector modules called type 2 and type 3, which coordinate defense against parasitic and extracellular pathogens, respectively. The modular nature of immune effector functions will be encountered frequently throughout this book. One principle seems to be that activated sensor cells from either the innate or


Immunology_Janeway

Immunology_Janeway. respectively. The modular nature of immune effector functions will be encountered frequently throughout this book. One principle seems to be that activated sensor cells from either the innate or the adaptive immune system can activate different subsets of innate or adaptive lymphocytes that are specialized for amplifying particular effector modules that are directed against different categories of pathogens (Fig. 1.27).


Immunology_Janeway

Immunology_Janeway. the effector mechanisms of immunity. Fig. 1.27 Innate and adaptive lymphocyte cells share a variety of functions. the different effector modules are served by both innate and adaptive immune mechanisms. For each of the four major types of innate lymphocytes, there is a corresponding type of t cell with generally similar functional characteristics. each set of innate lymphocyte and t cell exert an effector activity that is broadly directed at a distinct category of pathogen. 1-20 Antibodies protect against extracellular pathogens and their toxic products. Antibodies are found in plasma—the fluid component of blood—and in extracellular fluids. Because body fluids were once known as humors, immunity mediated by antibodies is known as humoral immunity.


Immunology_Janeway

Immunology_Janeway. Antibodies are found in plasma—the fluid component of blood—and in extracellular fluids. Because body fluids were once known as humors, immunity mediated by antibodies is known as humoral immunity. Antibodies are Y-shaped molecules with two identical antigen-binding sites and one constant, or Fc, region. As mentioned in Section 1-9, there are five forms of the constant region of an antibody, known as the antibody classes or isotypes. The constant region determines an antibody’s functional properties—how it will engage with the effector mechanisms that dispose of antigen once it is recognized. Each class carries out its particular function by engaging a distinct set of effector mechanisms. We describe the antibody classes and their actions in Chapters 5 and 10.


Immunology_Janeway

Immunology_Janeway. The first and most direct way in which antibodies can protect against pathogens or their products is by binding to them and thereby blocking their access to cells that they might infect or destroy (Fig. 1.28, left panels). This is known as neutralization and is important for protection against viruses, which become prevented from entering cells and replicating, and against bacterial toxin and is the form of immunity elicited by most vaccines.


Immunology_Janeway

Immunology_Janeway. For bacteria, however, binding by antibodies is not sufficient to stop their replication. In this case, the function of the antibody is to enable a phagocytic cell such as a macrophage or a neutrophil to ingest and destroy the bacterium. Many bacteria evade the innate immune system because they have an outer coat that is not recognized by the pattern recognition receptors of phagocytes. However, antigens in the coat can be recognized by antibodies, and phagocytes have receptors, called Fc receptors, that bind the constant region and facilitate phagocytosis of the bacterium (see Fig. 1.28, center panels). The coating of pathogens and foreign particles in this way is known as opsonization.


Immunology_Janeway

Immunology_Janeway. The third function of antibodies is complement activation. In Section 1-2 we briefly mentioned Bordet’s discovery of complement as a serum factor that ‘complements’ the activities of antibodies. Complement can be activated by microbial surfaces even without the help of antibodies, which leads to the covalent deposition of certain complement proteins onto the bacterial surface. But when an antibody binds first to the bacterial surface, its constant region provides a platform that is much more efficient in complement activation than the left panels show antibodies binding to and neutralizing a bacterial toxin, thus preventing it from interacting with host cells and causing pathology. unbound toxin can react with receptors on the host cell, whereas the toxin:antibody complex cannot. Antibodies also neutralize complete virus particles and bacterial cells by binding and inactivating them. the antigen:antibody complex is eventually scavenged and degraded by macrophages. Antibodies coating


Immunology_Janeway

Immunology_Janeway. also neutralize complete virus particles and bacterial cells by binding and inactivating them. the antigen:antibody complex is eventually scavenged and degraded by macrophages. Antibodies coating an antigen render it recognizable as foreign by phagocytes (macrophages and neutrophils), which then ingest and destroy it; this is called opsonization. the center panels show opsonization and phagocytosis of a bacterial cell. Antibody first binds to antigens (red) on the bacterial cell through the variable regions. then the antibody’s Fc region binds to Fc receptors (yellow) expressed by macrophages and other phagocytes, facilitating phagocytosis. the right panels show activation of the complement system by antibodies coating a bacterial cell. Bound antibodies form a platform that activates the first protein in the complement system, which deposits complement proteins (blue) on the surface of the bacterium. this can lead in some cases to formation of a pore that lyses the bacterium directly.


Immunology_Janeway

Immunology_Janeway. protein in the complement system, which deposits complement proteins (blue) on the surface of the bacterium. this can lead in some cases to formation of a pore that lyses the bacterium directly. more generally, complement proteins on the bacterium can be recognized by complement receptors on phagocytes; this stimulates the phagocytes to ingest and destroy the bacterium. thus, antibodies target pathogens and their toxic products for disposal by phagocytes.


Immunology_Janeway

Immunology_Janeway. microbial activation alone. Thus, once antibodies are produced, complement activation against a pathogen can be substantially increased.


Immunology_Janeway

Immunology_Janeway. Certain complement components that are deposited on the bacterial surface can directly lyse the membranes of some bacteria, and this is important in a few bacterial infections (see Fig. 1.28, right panels). The major function of complement, however, is to enable phagocytes to engulf and destroy bacteria that the phagocytes would not otherwise recognize. Most phagocytes express receptors that bind certain complement proteins; called complement receptors, these receptors bind to the complement proteins deposited onto the bacterial surface and thus facilitate bacterial phagocytosis. Certain other complement proteins also enhance the phagocytes’ bactericidal capacity. The end result is that all pathogens and free molecules bound by antibody are eventually delivered to phagocytes for ingestion, degradation, and removal from the body (see Fig. 1.28, bottom panels). The complement system and the phagocytes that antibodies recruit are not themselves antigen-specific; they depend upon antibody


Immunology_Janeway

Immunology_Janeway. degradation, and removal from the body (see Fig. 1.28, bottom panels). The complement system and the phagocytes that antibodies recruit are not themselves antigen-specific; they depend upon antibody molecules to mark the particles as foreign.


Immunology_Janeway

Immunology_Janeway. the effector mechanisms of immunity. 1-21 T cells orchestrate cell-mediated immunity and regulate B-cell responses to most antigens. Some bacteria and parasites, and all viruses, replicate inside cells, where they cannot be detected by antibodies, which access only the blood and extracellular space. The destruction of intracellular invaders is the function of the T lymphocytes, which are responsible for the cell-mediated immune responses of adaptive immunity. But T lymphocytes participate in responses to a wide variety of pathogens, including extracellular organisms, and so must exert a wide variety of effector activities.


Immunology_Janeway

Immunology_Janeway. T lymphocytes, of which there are several types, develop in the thymus. They are characterized by the type of T-cell receptors they express and by the expression of certain markers. The two main classes of T cells express either a cell-surface protein called CD8 or another called CD4. These are not just random markers, but are important for a T cell’s function, because they help to determine the interactions between the T cell and other cells. Recall from Section 1-10 that T cells detect peptides derived from foreign antigens that are displayed by MHC molecules on a cell’s surface. CD8 and CD4 function in antigen recognition by recognizing different regions of MHC molecules and by being involved in the signaling of the T-cell receptor that is engaged with its antigen. Thus, CD4 and CD8 are known as co-receptors and they provide a functional difference between CD8 and CD4 T cells,


Immunology_Janeway

Immunology_Janeway. Importantly, there are two main types of MHC molecules, called MHC class I and MHC class II. These have slightly different structures, but both have an elongated groove on the outer surface that can bind a peptide (Fig. 1.29). The peptide becomes trapped in this groove during the synthesis and assembly of the MHC molecule inside the cell, and the peptide:MHC complex is then transported to the cell surface and displayed to T cells (Fig. 1.30). Because CD8 recognizes a region of the MHC class I protein while CD4 recognizes a region of MHC class II protein, the two co-receptors functionally distinguish T cells. Therefore, CD8 T cells selectively recognize peptides that are bound to MHC class I molecules, while CD4 T cells recognize peptides presented by MHC class II.


Immunology_Janeway

Immunology_Janeway. The most direct action of T cells is cytotoxicity. Cytotoxic T cells are effector T cells that act against cells infected with viruses. Antigens derived from the virus multiplying inside the infected cell are displayed on the cell’s surface, where they are recognized by the antigen receptors of cytotoxic T cells. These T cells can then control the infection by directly killing the infected cell before viral replication is complete and new viruses are released (Fig. 1.31). Cytotoxic T cells carry CD8, and so recognize antigen presented by MHC class I molecules. Because MHC class I molecules are expressed on most cells of the body, they serve as an important mechanism to defend against viral infections.


Immunology_Janeway

Immunology_Janeway. Fig. 1.29 MHC molecules on the cell surface display peptide fragments of antigens. mHC molecules are membrane proteins whose outer extracellular domains form a cleft in which a peptide fragment is bound. these fragments are derived from proteins degraded inside the cell and include both self and foreign protein antigens. the peptides are bound by the newly synthesized mHC molecule before it reaches the cell surface. there are two kinds of mHC molecules, mHC class I and mHC class II; they have related but distinct structures and functions. Although not shown here for simplicity, both mHC class I and mHC class II molecules are trimers of two protein chains and the bound self or nonself peptide. Bound peptides transported by MHC class I to the cell surface Viral proteins synthesized in cytosol endoplasmic reticulumcytosol Peptide fragments of viral proteins bound by MHC class I in ER cytosol nucleus Virus infects cell


Immunology_Janeway

Immunology_Janeway. Fig. 1.30 MHC class I molecules present antigen derived from proteins in the cytosol. In cells infected with viruses, viral proteins are synthesized in the cytosol. Peptide fragments of viral proteins are transported into the endoplasmic reticulum (er), where they are bound by mHC class I molecules, which then deliver the peptides to the cell surface.


Immunology_Janeway

Immunology_Janeway. Fig. 1.31 Mechanism of host defense against intracellular infection by viruses. Cells infected by viruses are recognized by specialized t cells called cytotoxic t cells, which kill the infected cells directly. the killing mechanism involves the activation of enzymes known as caspases, which contain cysteine in their active site and cleave target proteins at aspartic acid. the caspases in turn activate a cytosolic nuclease that cleaves host and viral dnA in the infected cell. Panel a is a transmission electron micrograph showing the plasma membrane of a cultured CHo cell (the Chinese hamster ovary cell line) infected with influenza virus. many virus particles can be seen budding from the cell surface. Some of these have been labeled with a monoclonal antibody that is specific for a viral protein and is coupled to gold particles, which appear as the solid black dots in the micrograph. Panel b is a transmission electron micrograph of a virus-infected cell (V) surrounded by cytotoxic


Immunology_Janeway

Immunology_Janeway. protein and is coupled to gold particles, which appear as the solid black dots in the micrograph. Panel b is a transmission electron micrograph of a virus-infected cell (V) surrounded by cytotoxic t lymphocytes. note the close apposition of the membranes of the virus-infected cell and the t cell (t) in the upper left corner of the micrograph, and the clustering of the cytoplasmic organelles in the t cell between its nucleus and the point of contact with the infected cell. Panel a courtesy of m. Bui and


Immunology_Janeway

Immunology_Janeway. A. Helenius; panel b courtesy of n. rooney. MHC class I molecules bearing viral peptides are recognized by CD8-bearing cytotoxic T cells, which then kill the infected cell (Fig. 1.32).


Immunology_Janeway

Immunology_Janeway. CD4 T cells recognize antigen presented by MHC class II proteins, which are expressed by the predominant antigen-presenting cells of the immune system: dendritic cells, macrophages, and B cells (Fig. 1.33). Thus CD4 T cells tend to recognize antigens taken up by phagocytosis from the extracellular environment. CD4 T cells are the helper T cells mentioned earlier in the chapter. They develop into a variety of different effector subsets, called TH1 (for T helper type 1), TH2, TH17, and so on, and they produce cytokines in patterns similar to the subsets of ILCs mentioned earlier that activate effector modules protective against different pathogens. These subsets act primarily at sites of infection or injury in peripheral tissues. In the lymphoid tissues, a subset of CD4 T cells, called the T follicular helper (TFH) cell, interacts with B cells to regulate antibody production during the immune response. The various T helper subsets are described later, in Chapter 9.


Immunology_Janeway

Immunology_Janeway. For example, the TH1 subset of CD4 T cells helps to control certain bacteria that take up residence in membrane-enclosed vesicles inside macrophages. They produce the same cytokine as ILC1 cells, IFN-γ, which activates macrophages to increase their intracellular killing power and destroy these bacteria. Important infections that are controlled by this function are tuberculosis and leprosy, which are caused by the bacteria Mycobacterium tuberculosis and M. leprae, respectively. Mycobacteria survive intracellularly because they prevent the vesicles they occupy from fusing with lysosomes, which contain a variety of degradative enzymes and antimicrobial substances (Fig. 1.34). However, on its surface, the infected macrophage presents mycobacteriaderived antigens that can be recognized by activated antigen-specific TH1 cells, which in turn secrete particular cytokines that induce the macrophage to the effector mechanisms of immunity.


Immunology_Janeway

Immunology_Janeway. Fig. 1.33 CD4 T cells recognize antigen presented by MHC class II molecules. on recognition of their specific antigen on infected macrophages, tH1 cells activate the macrophage, leading to the destruction of the intracellular bacteria (top panel). When t follicular helper (tFH) cells recognize antigen on B cells (bottom panel), they activate these cells to proliferate and differentiate into antibody-producing plasma cells (not shown). overcome the block on vesicle fusion. TH2 and TH17 subsets produce cytokines that are specialized for promoting responses against parasites or extracellular bacteria and fungi, respectively. CD4 T cells, and their specialized subsets, play a pervasive role in adaptive immunity, and we will be returning to them many times in this book, including in Chapters 8, 9, 11 and 12. 1-22 Inherited and acquired defects in the immune system result in increased susceptibility to infection.


Immunology_Janeway

Immunology_Janeway. We tend to take for granted the ability of our immune systems to free our bodies of infection and prevent its recurrence. In some people, however, parts of the immune system fail. In the most severe of these immunodeficiency diseases, adaptive immunity is completely absent, and death occurs in infancy from overwhelming infection unless heroic measures are taken. Other less catastrophic failures lead to recurrent infections with particular types of pathogens, depending on the particular deficiency. Much has been learned about the functions of the different components of the human immune system through the study of these immunodeficiencies, many of which are caused by inherited genetic defects. Because understanding the features of immunodeficiencies requires a detailed knowledge of normal immune mechanisms, we have postponed discussion of most of these diseases until Chapter 13, where they can be considered together.


Immunology_Janeway

Immunology_Janeway. More than 30 years ago, a devastating form of immunodeficiency appeared, the acquired immune deficiency syndrome, or AIDS, which is caused by an infectious agent, the human immunodeficiency viruses HIV-1 and HIV-2. This disease destroys T cells, dendritic cells, and macrophages bearing CD4, leading to infections caused by intracellular bacteria and other pathogens


Immunology_Janeway

Immunology_Janeway. Fig. 1.34 Mechanism of host defense against intracellular infection by mycobacteria. mycobacteria are engulfed by macrophages but resist being destroyed by preventing the intracellular vesicles in which they reside from fusing with lysosomes containing bactericidal agents. thus the bacteria are protected from being killed. In resting macrophages, mycobacteria persist and replicate in these vesicles. When the phagocyte is recognized and activated by a tH1 cell, however, the phagocytic vesicles fuse with lysosomes, and the bacteria can be killed. macrophage activation is controlled by tH1 cells, both to avoid tissue damage and to save energy. the light micrographs (bottom row) show resting (left) and activated (right) macrophages infected with mycobacteria. the cells have been stained with an acid-fast red dye to reveal mycobacteria. these are prominent as red-staining rods in the resting macrophages but have been eliminated from the activated macrophages. Photographs courtesy of g.


Immunology_Janeway

Immunology_Janeway. an acid-fast red dye to reveal mycobacteria. these are prominent as red-staining rods in the resting macrophages but have been eliminated from the activated macrophages. Photographs courtesy of g. Kaplan.


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Immunology_Janeway. Fig. 1.35 Immune responses can be beneficial or harmful, depending on the nature of the antigen. Beneficial responses are shown in white, harmful responses in red shaded boxes. Where the response is beneficial, its absence is harmful. normally controlled by such cells. These infections are the major cause of death from this increasingly prevalent immunodeficiency disease, which is discussed fully in Chapter 13 together with the inherited immunodeficiencies. 1-23 Understanding adaptive immune responses is important for the control of allergies, autoimmune disease, and the rejection of transplanted organs.


Immunology_Janeway

Immunology_Janeway. The main function of our immune system is to protect the human host from infectious agents. However, many medically important diseases are associated with a normal immune response directed against an inappropriate antigen, often in the absence of infectious disease. Immune responses directed at noninfectious antigens occur in allergy, in which the antigen is an innocuous foreign substance; in autoimmune disease, in which the response is to a self antigen; and in graft rejection, in which the antigen is borne by a transplanted foreign cell (discussed in Chapter 15). The major antigens provoking graft rejection are, in fact, the MHC molecules, as each of these is present in many different versions in the human population—that is, they are highly polymorphic—and most unrelated people differ in the set of MHC molecules they express, a property commonly known as their ‘tissue type.’ The MHC was originally recognized by the work of Peter Goren in the 1930s as a gene locus in mice, the H-2


Immunology_Janeway

Immunology_Janeway. in the set of MHC molecules they express, a property commonly known as their ‘tissue type.’ The MHC was originally recognized by the work of Peter Goren in the 1930s as a gene locus in mice, the H-2 locus, that controlled the acceptance or rejection of transplanted tumors, and later by George Snell, who examined their role in tissue transplantation by developing mouse strains differing only at these histocompatibility loci. The human MHC molecules were first discovered during the Second World War, when attempts were made to use skin grafts from donors to repair badly burned pilots and bomb victims. The patients rejected the grafts, which were recognized by their immune systems as being ‘foreign.’ What we call a successful immune response or a failure, and whether the response is considered harmful or beneficial to the host, depends not on the response itself but rather on the nature of the antigen and the circumstances in which the response occurs (Fig. 1.35). Snell was awarded the


Immunology_Janeway

Immunology_Janeway. harmful or beneficial to the host, depends not on the response itself but rather on the nature of the antigen and the circumstances in which the response occurs (Fig. 1.35). Snell was awarded the 1980 Nobel Prize for his work on MHC, together with Baruj Benacerraf and Jean Dausset.


Immunology_Janeway

Immunology_Janeway. Allergic diseases, which include asthma, are an increasingly common cause of disability in the developed world. Autoimmunity is also now recognized as the cause of many important diseases. An autoimmune response directed against pancreatic β cells is the leading cause of diabetes in the young. In allergies and autoimmune diseases, the powerful protective mechanisms of the adaptive immune response cause serious damage to the patient. Immune responses to harmless antigens, to body tissues, or to organ grafts are, like all other immune responses, highly specific. At present, the usual way to treat these responses is with immunosuppressive drugs, which inhibit all the effector mechanisms of immunity.


Immunology_Janeway

Immunology_Janeway. immune responses, desirable and undesirable alike. If it were possible to suppress only those lymphocyte clones responsible for the unwanted response, the disease could be cured or the grafted organ protected without impeding protective immune responses. At present, antigen-specific immunoregulation is outside the reach of clinical treatment. But as we shall see in Chapter 16, many new drugs have been developed recently that offer more selective immune suppression to control autoimmune and other unwanted immune responses. Among these, therapies using highly specific monoclonal antibodies were made possible by Georges Köhler and César Milstein, who shared the 1984 Nobel Prize for the discovery of their production. We shall discuss the present state of understanding of allergies, autoimmune disease, graft rejection, and immunosuppressive drugs and monoclonal antibodies in Chapters 14–16, and we shall see in Chapter 15 how the mechanisms of immune regulation are beginning to emerge from


Immunology_Janeway

Immunology_Janeway. disease, graft rejection, and immunosuppressive drugs and monoclonal antibodies in Chapters 14–16, and we shall see in Chapter 15 how the mechanisms of immune regulation are beginning to emerge from a better understanding of the functional subsets of lymphocytes and the cytokines that control them.


Immunology_Janeway

Immunology_Janeway. 1-24 Vaccination is the most effective means of controlling infectious diseases. The deliberate stimulation of an immune response by immunization, or vaccination, has achieved many successes in the two centuries since Jenner’s pioneering experiment. Mass immunization programs have led to the virtual eradication of several diseases that used to be associated with significant morbidity (illness) and mortality (Fig. 1.36). Immunization is considered so safe 100 10 1.0 0.1 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 vaccine inactivated vaccine oral vaccine vaccine measles SSPE 40 30 20 10 0 1940 1950 1960 1970 1980 1990 600 500 400 300 200 100 0 1960 1965 1970 1975 1980 1985 1990 Reported cases per 100,000 population Reported cases per 100,000 population Reported cases per 100,000 population Reported SSPE cases in USA 60 50 40 30 20 10 0 DiphtheriaPolioMeasles


Immunology_Janeway

Immunology_Janeway. Fig. 1.36 Successful vaccination campaigns. diphtheria, polio, and measles and their consequences have been virtually eliminated in the united States, as shown in these three graphs. SSPe stands for subacute sclerosing panencephalitis, a brain disease that is a late consequence of measles infection in a few patients. When measles was prevented, SSPe disappeared 15–20 years later. However, because these diseases have not been eradicated worldwide, immunization must be maintained in a very high percentage of the population to prevent their reappearance.


Immunology_Janeway

Immunology_Janeway. and so important that most states in the United States require children to be immunized against up to seven common childhood diseases. Impressive as these accomplishments are, there are still many diseases for which we lack effective vaccines. And even where vaccines for diseases such as measles can be used effectively in developed countries, technical and economic problems can prevent their widespread use in developing countries, where mortality from these diseases is still high. The tools of modern immunology and molecular biology are being applied to develop new vaccines and improve old ones, and we discuss these advances in Chapter 16. The prospect of controlling these important diseases is tremendously exciting. The guarantee of good health is a critical step toward population control and economic development. At a cost of pennies per person, great hardship and suffering can be alleviated.


Immunology_Janeway

Immunology_Janeway. Many serious pathogens have resisted efforts to develop vaccines against them, often because they can evade or subvert the protective mechanisms of an adaptive immune response. We examine some of the evasive strategies used by successful pathogens in Chapter 13. The conquest of many of the world’s leading diseases, including malaria and diarrheal diseases (the leading killers of children) as well as the more recent threat from AIDS, depends on a better understanding of the pathogens that cause them and their interactions with the cells of the immune system. Summary.


Immunology_Janeway

Immunology_Janeway. The responses to infection can be organized into several effector modules that target the various types of pathogen lifestyles. Innate sensor cells that detect infection generate mediators that activate innate lymphoid cells (ILCs) and T cells, which amplify the immune response and also activate various effector modules. Innate lymphoid cells include subsets that produce different cytokines and activate distinct effector modules. T cells fall into two major classes that are based on the expression of the co-receptors CD8 and CD4; these T cells recognize antigen presented by MHC class I or MHC class II proteins, respectively. These subsets of T cells, like their ILC counterparts, also promote the actions of distinct effector modules. NK cells and CD8 T cells can exert cytotoxic activity to target intracellular infections such as viruses. Other subsets of innate lymphoid and helper T cells can secrete mediators that activate other effector functions, ones that target intracellular


Immunology_Janeway

Immunology_Janeway. to target intracellular infections such as viruses. Other subsets of innate lymphoid and helper T cells can secrete mediators that activate other effector functions, ones that target intracellular bacteria, extracellular bacteria and fungi, and parasites. T cells also provide signals that help regulate B cells and stimulate them to produce antibodies. Specific antibodies mediate the clearance and elimination of soluble toxins and extracellular pathogens. They interact not only with the toxins or the antigens on microbes, but also with the Fc region of specific receptors that are expressed by many types of phagocytes. Phagocytes also express receptors for complement proteins that are deposited on microbial surfaces, particularly in the presence of antibody.


Immunology_Janeway

Immunology_Janeway. Failures of immunity can be caused by genetic defects or by infections that target important components of the immune system. Misdirected immune responses can damage host tissues, as in autoimmune diseases or allergy, or lead to the failure of transplanted organs. While vaccination is still the greatest tool of immunology to fight diseases, modern approaches have added new tools, such as monoclonal antibodies, that have become progressively more important in the clinic over the past two decades. Summary to Chapter 1. The immune system defends the host against infection. Innate immunity serves as a first line of defense but lacks the ability to recognize certain pathogens and Questions.


Immunology_Janeway

Immunology_Janeway. to provide the specific protective immunity that prevents reinfection. Adaptive immunity is based on clonal selection from a repertoire of lymphocytes bearing highly diverse antigen-specific receptors that enable the immune system to recognize any foreign antigen. In the adaptive immune response, antigen-specific lymphocytes proliferate and differentiate into clones of effector lymphocytes that eliminate the pathogen. Figure1.7 summarizes the phases of the immune response and their approximate timings. Host defense requires different recognition systems and a wide variety of effector mechanisms to seek out and destroy the wide variety of pathogens in their various habitats within the body and at its external and internal surfaces. Not only can the adaptive immune response eliminate a pathogen, but, in the process, it also generates increased numbers of differentiated memory lymphocytes through clonal selection, and this allows a more rapid and effective response upon reinfection. The


Immunology_Janeway

Immunology_Janeway. but, in the process, it also generates increased numbers of differentiated memory lymphocytes through clonal selection, and this allows a more rapid and effective response upon reinfection. The regulation of immune responses, whether to suppress them when unwanted or to stimulate them in the prevention of infectious disease, is the major medical goal of research in immunology.


Immunology_Janeway

Immunology_Janeway. Questions. 1.1 Multiple Choice: Which of the following examples can be considered an illustration of vaccination? A. Inoculating an individual with cowpox in order to protect that individual against smallpox B. Administering the serum of animals immune to diphtheria to protect against the effect of diphtheria toxin in an exposed individual C. A bacterial infection that results in complement activation and destruction of the pathogen D. An individual that becomes ill with chickenpox, but does not develop it again due to the development of immunologic memory 1.2 Multiple Choice: Which of the following is an appropriate definition for immunological memory? A. the mechanism by which an organism prevents the development of an immune response against the host’s own tissues B. the mechanism by which an organism prevents exposure to microbes


Immunology_Janeway

Immunology_Janeway. A. the mechanism by which an organism prevents the development of an immune response against the host’s own tissues B. the mechanism by which an organism prevents exposure to microbes C. the persistence of pathogen-specific antibodies and lymphocytes after the original infection has been eliminated so that reinfection can be prevented D. the process of reducing or eliminating a pathogen 1.3 True or False: toll-like receptors (tlrs) recognize intracellular bacteria, while nod-like receptors (nlrs) recognize extracellular bacteria. 1.4 Matching: Classify the following as lymphoid or myeloid in origin: A. eosinophils B. B cells C. neutrophils D. nK cells E. mast cells F. macrophages


Immunology_Janeway

Immunology_Janeway. 1.4 Matching: Classify the following as lymphoid or myeloid in origin: A. eosinophils B. B cells C. neutrophils D. nK cells E. mast cells F. macrophages G. red blood cells 1.5 Multiple Choice: the immunologist’s ‘dirty little secret’ involves the addition of microbial constituents in order to stimulate a strong immune response against the desired protein antigen of interest. Which of the following is not a receptor or receptor family that can recognize microbial products in order to achieve a potent immune response? A. toll-like receptors (tlrs) B. t-cell antigen receptor (tCr) C. nod-like receptors (nlrs) D. Pattern recognition receptors (Prrs) 1.6 True or False: Hematopoietic stem cells can develop into any cell type in the body. 1.7 Matching: match each of the following terms to the numbered phrase that describes it best: A. Allergy __ 1. Immunological response to an antigen present on a transplanted foreign cell


Immunology_Janeway

Immunology_Janeway. 1.7 Matching: match each of the following terms to the numbered phrase that describes it best: A. Allergy __ 1. Immunological response to an antigen present on a transplanted foreign cell B. Immunological 2. Immunological response tolerance __ to an antigen that is an innocuous foreign substance C. Autoimmune 3. Immunological process disease __ that prevents an immune response to self antigens D. graft rejection __ 4. Immunological response to a self antigen 1.8 Multiple Choice: Which of the following processes is not a mechanism of maintaining immunologic tolerance? A. Clonal deletion B. Anergy C. Clonal expansion D. Suppression of self-reactive lymphocytes 1.9 Matching: Classify each of the following as a central/ primary or peripheral/secondary lymphoid organ: A. Bone marrow B. lymph node C. Spleen D. thymus E. Appendix 1.10 Matching: match the following region, structure, or subcompartments with the numbered organ they are present in: A. lymph node __ B. Spleen __


Immunology_Janeway

Immunology_Janeway. B. lymph node C. Spleen D. thymus E. Appendix 1.10 Matching: match the following region, structure, or subcompartments with the numbered organ they are present in: A. lymph node __ B. Spleen __ C. mucosa of the small intestine __ 1. 2. 3. 1.11 Multiple Choice: Which of the following events do not occur during inflammation? A. Cytokine secretion B. Chemokine secretion C. recruitment of innate immune cells D. Constriction of blood vessels 1.12 Fill-in-the-Blanks: ___________ t cells are able to kill infected cells, while ________ t cells activate other cells of the immune system. 1.13 True or False: Both t-cell and B-cell receptors undergo the process of affinity maturation in order to acquire progressively higher affinity for an antigen during an immune response. 1.14 True or False: each lymphocyte carries cell-surface receptors with multiple antigen specificity.


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Immunology_Janeway. 1.14 True or False: each lymphocyte carries cell-surface receptors with multiple antigen specificity. 1.15 Multiple Choice: Which cell type forms an important link between the innate immune response and the adaptive immune response? A. dendritic cell B. neutrophil C. B cell D. Innate lymphoid cell (IlC) 1.16 Multiple Choice: Which of the following options is not a mechanism by which an antibody can protect against a pathogen? A. neutralization B. Co-stimulation of t cells C. opsonization D. Complement activation/deposition 1.17 True or False: tH2 cells do not possess mHC class I molecules. General references. Burnet, F.M.: The Clonal Selection Theory of Acquired Immunity. London: Cambridge University Press, 1959. Gowans, J.L.: The lymphocyte—a disgraceful gap in medical knowledge. Immunol. Today 1996, 17:288–291. Landsteiner, K.: The Specificity of Serological Reactions, 3rd ed. Boston: Harvard University Press, 1964.


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Immunology_Janeway. Landsteiner, K.: The Specificity of Serological Reactions, 3rd ed. Boston: Harvard University Press, 1964. Metchnikoff, É.: Immunity in the Infectious Diseases, 1st ed. New York: Macmillan Press, 1905. Silverstein, A.M.: History of Immunology, 1st ed. London: Academic Press, 1989. Alberts, B., Johnson, A., Lewis, J., Morgan, D., Raff, M., Roberts, K., and Walter, P.: Molecular Biology of the Cell, 6th ed. New York: Garland Science, 2015. Berg, J.M., Stryer, L., and Tymoczko, J.L.: Biochemistry, 5th ed. New York: W.H. Freeman, 2002. Geha, R.S., and Notarangelo, L.D.: Case Studies in Immunology: A Clinical Companion, 7th ed. New York: Garland Science, 2016. Harper, D.R.: Viruses: Biology, Applications, Control. New York: Garland Science, 2012. Kaufmann, S.E., Sher, A., and Ahmed, R. (eds): Immunology of Infectious Diseases. Washington, DC: ASM Press, 2001.


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Immunology_Janeway. Kaufmann, S.E., Sher, A., and Ahmed, R. (eds): Immunology of Infectious Diseases. Washington, DC: ASM Press, 2001. Lodish, H., Berk, A., Kaiser, C.A., Krieger, M., Scott, M.P., Bretscher, A., Ploegh, H., and Matsudaira, P.: Molecular Cell Biology, 6th ed. New York: W.H. Freeman, 2008. Lydyard, P., Cole, M., Holton, J., Irving, W., Porakishvili, N., Venkatesan, P., and Ward, K.: Case Studies in Infectious Disease. New York: Garland Science, 2009. Mims, C., Nash, A., and Stephen, J.: Mims’ Pathogenesis of Infectious Disease, 5th ed. London: Academic Press, 2001. Ryan, K.J. (ed): Medical Microbiology, 3rd ed. East Norwalk, CT: Appleton-Lange, 1994. Advanced textbooks in immunology, compendia, etc. Lachmann, P.J., Peters, D.K., Rosen, F.S., and Walport, M.J. (eds): Clinical Aspects of Immunology, 5th ed. Oxford: Blackwell Scientific Publications, 1993. Mak, T.W., and Saunders, M.E.: The Immune Response: Basic and Clinical Principles. Burlington: Elsevier/Academic Press, 2006.


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Immunology_Janeway. Mak, T.W., and Saunders, M.E.: The Immune Response: Basic and Clinical Principles. Burlington: Elsevier/Academic Press, 2006. Mak, T.W., and Simard, J.J.L.: Handbook of Immune Response Genes. New York: Plenum Press, 1998. Paul, W.E. (ed): Fundamental Immunology, 7th ed. New York: Lippincott Williams & Wilkins, 2012. Roitt, I.M., and Delves, P.J. (eds): Encyclopedia of Immunology, 2nd ed. (4 vols.). London and San Diego: Academic Press, 1998. Innate Immunity: The First Lines of Defense


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Immunology_Janeway. Innate Immunity: The First Lines of Defense As introduced in Chapter 1, most microbial invaders can be detected and destroyed within minutes or hours by the body’s defense mechanisms of innate immunity, which do not rely on expansion of antigen-specific lymphocytes. The innate immune system uses a limited number of secreted proteins and cell-associated receptors to detect infection and to distinguish between pathogens and host tissues. These are called innate receptors because they are inborn; they are encoded by genes directly inherited from an individual’s parents, and do not need to be generated by the gene rearrangements used to assemble antigen receptors of lymphocytes described in Section 1-11. The importance of innate immunity is illustrated by several immunodeficiencies that result when it is impaired, discussed in Chapter 13, which increase susceptibility to infection even in the presence of an intact adaptive immune system.


Immunology_Janeway

Immunology_Janeway. As we saw in Fig. 1.5, an infection starts when a pathogen breaches one of the host’s anatomic barriers. Some innate immune mechanisms start acting immediately (Fig. 2.1). These immediate defenses include several classes of preformed soluble molecules that are present in extracellular fluid, blood, and epithelial secretions and that can either kill the pathogen or weaken its effect. Antimicrobial enzymes such as lysozyme begin to digest bacterial cell walls; antimicrobial peptides such as the defensins lyse bacterial cell membranes directly; and a system of plasma proteins known as the complement system targets pathogens both for lysis and for phagocytosis by cells of the innate immune system such as macrophages. If these fail, innate immune cells become activated by pattern recognition receptors (PRRs) that detect molecules called pathogen-associated molecular patterns (PAMPs) (see Section 1-5) that are typical of microbes. The activated innate cells can engage various effector


Immunology_Janeway

Immunology_Janeway. receptors (PRRs) that detect molecules called pathogen-associated molecular patterns (PAMPs) (see Section 1-5) that are typical of microbes. The activated innate cells can engage various effector mechanisms to eliminate the infection. By themselves, neither the soluble nor the cellular components of innate immunity generate long-term protective immunological memory. Only if an infectious organism breaches these first two lines of defense will mechanisms be engaged to induce an adaptive immune response—the third phase of the response to a pathogen. This leads to the expansion of antigen-specific lymphocytes that target the pathogen specifically and to the formation of memory cells that provide long-lasting specific immunity.


Immunology_Janeway

Immunology_Janeway. Fig. 2.1 The response to an initial infection occurs in three phases. These are the innate phase, the early induced innate response, and the adaptive immune response. The first two phases rely on the recognition of pathogens by germline-encoded receptors of the innate immune system, whereas adaptive immunity uses variable antigen-specific receptors that are produced as a result of gene segment rearrangements. Adaptive immunity occurs late, because the rare B cells and T cells specific for the invading pathogen must first undergo clonal expansion before they differentiate into effector cells that migrate to the site of infection and clear the infection. The effector mechanisms that remove the infectious agent are similar or identical in each phase. Anatomic barriers and initial chemical defenses. The complement system and innate immunity.


Immunology_Janeway

Immunology_Janeway. Anatomic barriers and initial chemical defenses. The complement system and innate immunity. Clonal expansion and differentiation to effector cells Removal of infectious agent Recognition by naive B and T cells Adaptive immune response (late: >96 hours) Transport of antigen to lymphoid organs Recognition of PAMPs. Activation of effector cells and infammation Removal of infectious agent Early induced innate response (early: 4–96 hours) Recruitment of effector cells FAIL Recognition by preformed nonspecifc and broadly specifc effectors Removal of infectious agent Infection FAIL Containment by an anatomic barrier Prevention of infection Pathogen FAIL


Immunology_Janeway

Immunology_Janeway. This chapter considers the first phase of the innate immune response. We first describe the anatomic barriers that protect the host against infection and examine the immediate innate defenses provided by various secreted soluble proteins. The anatomic barriers are fixed defenses against infection and consist of the epithelia that line the internal and external surfaces of the body along with the phagocytes residing beneath all epithelial surfaces. These phagocytes act directly by engulfing and digesting invading microorganisms. Epithelia are also protected by many kinds of chemical defenses, including antimicrobial enzymes and peptides. Next we describe the complement system, which directly kills some microorganisms and interacts with others to promote their removal by phagocytic cells. The complement system together with other soluble circulating defensive proteins is sometimes referred to as humoral innate immunity, from the old word ‘humor’ for body fluids. If these early defenses


Immunology_Janeway

Immunology_Janeway. complement system together with other soluble circulating defensive proteins is sometimes referred to as humoral innate immunity, from the old word ‘humor’ for body fluids. If these early defenses fail, the phagocytes at the site of infection help recruit new cells and circulating effector molecules, a process called inflammation, which we will discuss in Chapter 3.


Immunology_Janeway

Immunology_Janeway. Anatomic barriers and initial chemical defenses.


Immunology_Janeway

Immunology_Janeway. Microorganisms that cause disease in humans and animals enter the body at different sites and produce disease symptoms by a variety of mechanisms. Microorganisms that cause disease and produce damage, or pathology, to tissues are referred to as pathogenic microorganisms, or simply pathogens. As innate immunity eliminates most microorganisms that may occasionally cross an anatomic barrier, pathogens are microorganisms that have evolved ways of overcoming the body’s innate defenses more effectively than other microorganisms. Once infection is established, both innate and adaptive immune responses are typically required to eliminate pathogens from the body. Even in these cases, the innate immune system performs a valuable function by reducing pathogen numbers during the time needed for the adaptive immune system to gear up for action. In the first part of this chapter we briefly describe the different types of pathogens and their invasive strategies, and then examine the immediate innate


Immunology_Janeway

Immunology_Janeway. immune system to gear up for action. In the first part of this chapter we briefly describe the different types of pathogens and their invasive strategies, and then examine the immediate innate defenses that, in most cases, prevent microorganisms from establishing an infection.


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Immunology_Janeway. 2-1 Infectious diseases are caused by diverse living agents that replicate in their hosts. The agents that cause disease fall into five groups: viruses, bacteria, fungi, protozoa, and helminths (worms). Protozoa and worms are usually grouped together as parasites, and are the subject of the discipline of parasitology, whereas viruses, bacteria, and fungi are the subject of microbiology. Fig. 2.2 lists some examples of the different classes of microorganisms and parasites, and the diseases they cause. The characteristic features of each pathogen are its mode of transmission, its mechanism of replication, its mechanism of pathogenesis—the means by which it causes disease—and the response it elicits from the host. The distinct pathogen habitats and life cycles mean that a range of different innate and adaptive immune mechanisms have to be deployed for pathogen destruction.


Immunology_Janeway

Immunology_Janeway. Infectious agents can grow in all body compartments, as shown schematically in Fig. 2.3. We saw in Chapter 1 that two major compartments can be defined—extracellular and intracellular. Both innate and adaptive immune responses have different ways of dealing with pathogens found in these two Anatomic barriers and initial chemical defenses.


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Immunology_Janeway. Physical contact Trichophyton Bacillus anthracis Clostridium tetani Francisella tularensis Athlete’s foot Mosquito bites (Aedes aegypti) Deer tick bites Mosquito bites (Anopheles) Flavivirus Borrelia burgdorferi Plasmodium spp. Yellow fever Lyme disease Malaria Minor skin abrasions Puncture wounds Handling infected animals Cutaneous anthrax Tetanus Tularemia Route of entry Mode of transmission Pathogen Disease External epithelia Mucosal surfaces Routes of infection for pathogens Mouth and respiratory tract Contaminated water or food Sexual transmission/ infected blood Sexual transmission Neisseria meningitidis Bacillus anthracis Meningococcal meningitis Inhalation anthrax Fungus Virus Bacterium (spirochete) Protozoan Gram-positive bacterium Gram-positive bacterium Gram-negative bacterium Type of pathogen Hepatitis B virus Hepatitis B Hepadnavirus Neisseria gonorrhoeae Gonorrhea Gram-negative bacterium Human immunodefciency virus (HIV) Acquired immunodefciency syndrome (AIDS)


Immunology_Janeway

Immunology_Janeway. Type of pathogen Hepatitis B virus Hepatitis B Hepadnavirus Neisseria gonorrhoeae Gonorrhea Gram-negative bacterium Human immunodefciency virus (HIV) Acquired immunodefciency syndrome (AIDS) Retrovirus Gram-negative bacterium Gram-positive bacterium Wounds and abrasions Insect bites Gastrointestinal tract Reproductive tract and other routes External surface Resident microbiota Candida albicans Candidiasis, thrush Opportunistic infections Fungus Resident lung microbiota Pneumocystis jirovecii Pneumonia Fungus Measles virus Measles Paramyxovirus Infuenza virus Infuenza Orthomyxovirus Varicella-zoster Chickenpox Herpesvirus Epstein–Barr virus Mononucleosis Herpesvirus Streptococcus pyogenes Tonsillitis Gram-positive bacterium Haemophilus infuenzae Pneumonia, meningitis Gram-negative bacterium Rotavirus Diarrhea Rotavirus Hepatitis A Jaundice Picornavirus Salmonella enteritidis, Food poisoning Gram-negative bacteriumS. typhimurium Vibrio cholerae Cholera Gram-negative bacterium Inhalation


Immunology_Janeway

Immunology_Janeway. Rotavirus Diarrhea Rotavirus Hepatitis A Jaundice Picornavirus Salmonella enteritidis, Food poisoning Gram-negative bacteriumS. typhimurium Vibrio cholerae Cholera Gram-negative bacterium Inhalation or ingestion of infective material (e.g., saliva droplets) Salmonella typhi Trichuris trichiura Typhoid fever Trichuriasis Gram-negative bacterium Helminth Treponema pallidum Syphilis Bacterium (spirochete) Spores


Immunology_Janeway

Immunology_Janeway. Fig. 2.2 A variety of microorganisms can cause disease. Pathogenic organisms are of five main types: viruses, bacteria, fungi, protozoa, and worms. Some well-known pathogens are listed. Virtually all pathogens have an extracellular phase in which they are vulnerable to the circulating molecules and cells of innate immunity and to the antibodies of the adaptive immune response. All these clear the microorganism mainly by promoting its uptake and destruction by the phagocytes of the immune system. Intracellular phases of pathogens such as viruses are not accessible to these mechanisms; instead, the infected cell is attacked by the NK cells of innate immunity or by the cytotoxic T cells of adaptive immunity. Activation of macrophages as a result of NK-cell or T-cell activity can induce the macrophage to kill pathogens that are living inside macrophage vesicles.


Immunology_Janeway

Immunology_Janeway. compartments. Many bacterial pathogens live and replicate in extracellular spaces, either within tissues or on the surface of the epithelia that line body cavities. Extracellular bacteria are usually susceptible to killing by phagocytes, an important arm of the innate immune system, but some pathogens, such as Staphylococcus and Streptococcus species, are protected by a polysaccharide capsule that resists engulfment. This can be overcome to some extent by the help of another component of innate immunity—complement—which renders the bacteria more susceptible to phagocytosis. In the adaptive immune response, bacteria are rendered more susceptible to phagocytosis by a combination of antibodies and complement.


Immunology_Janeway

Immunology_Janeway. Infectious diseases differ in their symptoms and outcome depending on where the causal pathogen replicates within the body—the intracellular or the extracellular compartment—and what damage it does to the tissues (Fig. 2.4). Pathogens that live intracellularly frequently cause disease by damaging or killing the cells they infect. Obligate intracellular pathogens, such as viruses, must invade host cells to replicate. Facultative intracellular pathogens, such as mycobacteria, can replicate either intracellularly or outside the cell. Two strategies of innate immunity defend against intracellular pathogens. One is to destroy pathogens before they infect cells. To this end, innate immunity includes soluble defenses such as antimicrobial peptides, as well as phagocytic cells that can engulf and destroy pathogens before they become intracellular. Alternatively, the innate immune system can recognize and kill cells infected by some pathogens. This is the role of the natural killer cells (NK


Immunology_Janeway

Immunology_Janeway. destroy pathogens before they become intracellular. Alternatively, the innate immune system can recognize and kill cells infected by some pathogens. This is the role of the natural killer cells (NK cells), which are instrumental in keeping certain viral infections in check before cytotoxic T cells of the adaptive immune system become functional. Intracellular pathogens can be subdivided further into those that replicate freely in the cell, such as viruses and certain bacteria (for example, Chlamydia, Rickettsia, and Listeria), and those that replicate inside intracellular vesicles, such as mycobacteria. Pathogens that live inside macrophage vesicles may become more susceptible to being killed after activation of the macrophage as a result of NK-cell or T-cell actions (see Fig. 2.3).


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Immunology_Janeway. Many of the most dangerous extracellular bacterial pathogens cause disease by releasing protein toxins; these secreted toxins are called exotoxins (see Fig. 2.4). The innate immune system has little defense against such toxins, Anatomic barriers and initial chemical defenses.


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Immunology_Janeway. Anatomic barriers and initial chemical defenses. Direct mechanisms of tissue damage by pathogens Direct cytopathic effect Variola Varicella-zoster Hepatitis B virus Polio virus Measles virus Infuenza virus Herpes simplex virus Human herpes virus 8 (HHV8) Smallpox Chickenpox, shingles Hepatitis Poliomyelitis Measles, subacute sclerosing panencephalitis Infuenza Cold Kaposi's sarcoma sores Exotoxin production Streptococcus pyogenes Staphylococcus aureus Corynebacterium diphtheriae Clostridium tetani Vibrio cholerae Tonsillitis, scarlet fever Boils, toxic shock syndrome, food poisoning Diphtheria Tetanus Cholera Endotoxin Escherichia coli Haemophilus infuenzae Salmonella typhi Shigella Pseudomonas aeruginosa Yersinia pestis Gram-negative sepsis Meningitis, pneumonia Typhoid fever Bacillarydysentery Wound infection Plague


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Immunology_Janeway. Fig. 2.4 Pathogens can damage tissues in a variety of different ways. The mechanisms of damage, representative infectious agents, and the common names of the diseases associated with each are shown. Exotoxins are released by microorganisms and act at the surface of host cells, for example, by binding to receptors. Endotoxins, which are intrinsic components of microbial structure, trigger phagocytes to release cytokines that produce local or systemic symptoms. Many pathogens are cytopathic, directly damaging the cells they infect. Finally, an adaptive immune response to the pathogen can generate antigen:antibody complexes that activate neutrophils and macrophages, antibodies that can cross-react with host tissues, or T cells that kill infected cells. All of these have some potential to damage the host’s tissues. In addition, neutrophils, the most abundant cells early in infection, release many proteins and small-molecule inflammatory mediators that both control infection and cause


Immunology_Janeway

Immunology_Janeway. damage the host’s tissues. In addition, neutrophils, the most abundant cells early in infection, release many proteins and small-molecule inflammatory mediators that both control infection and cause tissue damage.


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Immunology_Janeway. and highly specific antibodies produced by the adaptive immune system are required to neutralize their action (see Fig. 1.28). The damage caused by a particular infectious agent also depends on where it grows; Streptococcus pneumoniae in the lung causes pneumonia, for example, whereas in the blood it causes a potentially fatal systemic illness, pneumococcal sepsis. In contrast, nonsecreted constituents of bacterial structure that trigger phagocytes to release cytokines with local and systemic effects are called endotoxins. An endotoxin of major medical importance is the lipopolysaccharide (LPS) of the outer cell membrane of Gram-negative bacteria, such as Salmonella. Many of the clinical symptoms of infection by such bacteria—including fever, pain, rash, hemorrhage, septic shock—are due largely to LPS.


Immunology_Janeway

Immunology_Janeway. Most pathogenic microorganisms can overcome innate immune responses and continue to grow, making us ill. An adaptive immune response is required to eliminate them and to prevent subsequent reinfection. Certain pathogens are never entirely eliminated by the immune system, and persist in the body for years. But most pathogens are not universally lethal. Those that have lived for thousands of years in the human population are highly evolved to exploit their human hosts; they cannot alter their pathogenicity without upsetting the compromise they have achieved with the human immune system. Rapidly killing every host it infects is no better for the long-term survival of a pathogen than being wiped out by the immune response before the microbe has had time to infect someone else. In short, we have adapted to live with many microbes, and they with us. Nevertheless, the recent concern about highly pathogenic strains of avian influenza and the episode in 2002–2003 of SARS (severe acute


Immunology_Janeway

Immunology_Janeway. we have adapted to live with many microbes, and they with us. Nevertheless, the recent concern about highly pathogenic strains of avian influenza and the episode in 2002–2003 of SARS (severe acute respiratory syndrome), a severe pneumonia in humans that is caused by a coronavirus from bats, remind us that new and deadly infections can transfer from animal reservoirs to humans. Such transmission appears responsible for the Ebola virus epidemic in West Africa in 2014–2015. These are known as zoonotic infections—and we must be on the alert at all times for the emergence of new pathogens and new threats to health. The human immunodeficiency virus that causes AIDS (discussed in Chapter 13) serves as a warning that we remain constantly vulnerable.


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Immunology_Janeway. 2-2 Epithelial surfaces of the body provide the first barrier against infection. Our body surfaces are defended by epithelia, which impose a physical barrier between the internal milieu and the external world that contains pathogens. Epithelia comprise the skin and the linings of the body’s tubular structures— the respiratory, urogenital, and gastrointestinal tracts. Epithelia in these locations are specialized for their particular functions and possess unique innate defense strategies against the microbes they typically encounter (Fig. 2.5 and Fig. 2.6).


Immunology_Janeway

Immunology_Janeway. Epithelial cells are held together by tight junctions, which effectively form a seal against the external environment. The internal epithelia are known as mucosal epithelia because they secrete a viscous fluid called mucus, which contains many glycoproteins called mucins. Mucus has a number of protective functions. Microorganisms coated in mucus may be prevented from adhering to the epithelium, and in the respiratory tract, microorganisms can be expelled in the outward flow of mucus driven by the beating of cilia on the mucosal epithelium (Fig. 2.7). The importance of mucus flow in clearing infection is illustrated by people with the inherited disease cystic fibrosis, in which the mucus becomes abnormally thick and dehydrated due to defects in a gene, CFTR, encoding a chloride channel in the epithelium. Such individuals frequently develop lung infections caused by bacteria that colonize the epithelial surface but do not cross it (see Fig. 2.7). In the gut, peristalsis is an important


Immunology_Janeway

Immunology_Janeway. the epithelium. Such individuals frequently develop lung infections caused by bacteria that colonize the epithelial surface but do not cross it (see Fig. 2.7). In the gut, peristalsis is an important mechanism for keeping both food and infectious agents moving through the body. Failure of peristalsis is typically accompanied by the overgrowth of pathogenic bacteria within the lumen of the gut.


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Immunology_Janeway. Fig. 2.5 Many barriers prevent pathogens from crossing epithelia and colonizing tissues. Surface epithelia provide mechanical, chemical, and microbiological barriers to infection. Skin Gut Lungs Eyes/nose/oral cavity Mechanical Epithelial cells joined by tight junctions Longitudinal fow of air or fuid Longitudinal fow of air or fuid Normal microbiota Movement of mucus by cilia Fatty acids Low pH Pulmonary surfactant Enzymes (pepsin) Enzymes in tears and saliva (lysozyme) Microbiological Chemical ˜-defensins Lamellar bodies Cathelicidin Histatins ˜-defensins °-defensins Cathelicidin Tears Nasal cilia °-defensins (cryptdins) RegIII (lecticidins) Cathelicidin Anatomic barriers and initial chemical defenses.


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Immunology_Janeway. Fig. 2.6 Epithelia form specialized physical and chemical barriers that provide innate defenses in different locations. Top panel: the epidermis has multiple layers of keratinocytes in different stages of differentiation arising from the basal layer of stem cells. Differentiated keratinocytes in the stratum spinosum produce β-defensins and cathelicidins, which are incorporated into secretory organelles called lamellar bodies (yellow) and secreted into the intercellular space to form a waterproof lipid layer (the stratum corneum) containing antimicrobial activity. Center panel: in the lung, the airways are lined by ciliated epithelium. Beating of the cilia moves a continuous stream of mucus (green) secreted by goblet cells outward, trapping and ejecting potential pathogens. Type II pneumocytes in the lung alveoli (not shown) also produce and secrete antimicrobial defensins. Bottom panel: in the intestine, Paneth cells—specialized cells deep in the epithelial crypts— produce several


Immunology_Janeway

Immunology_Janeway. in the lung alveoli (not shown) also produce and secrete antimicrobial defensins. Bottom panel: in the intestine, Paneth cells—specialized cells deep in the epithelial crypts— produce several kinds of antimicrobial proteins: α-defensins (cryptdins) and the antimicrobial lectin RegIII.


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Immunology_Janeway. Most healthy epithelial surfaces are also associated with a large population of normally nonpathogenic bacteria, known as commensal bacteria or the microbiota, that help keep pathogens at bay. The microbiota can also make antimicrobial substances, such as the lactic acid produced by vaginal lactobacilli, some strains of which also produce antimicrobial peptides (bacteriocins). Commensal microorganisms also induce responses that help to strengthen the barrier functions of epithelia by stimulating the epithelial cells to produce Lung of patient with cystic fbrosis Ciliated respiratory epithelium is covered by a layer of mucus Mucus Cilia Epithelium Fig. 2.7 Ciliated respiratory epithelium propels the overlying mucus layer for clearance of environmental microbes.


Immunology_Janeway

Immunology_Janeway. Fig. 2.7 Ciliated respiratory epithelium propels the overlying mucus layer for clearance of environmental microbes. Top panel: The ciliated respiratory epithelium in the airways of the lung is covered by a layer of mucus. The cilia propel the mucus outward and help prevent colonization of the airways by bacteria. Bottom panel: Section of a lung from a patient with cystic fibrosis. The dehydrated mucus layer impairs the ability of cilia to propel it, leading to frequent bacterial colonization and resulting inflammation of the airway. Courtesy of J. Ritter.


Immunology_Janeway

Immunology_Janeway. antimicrobial peptides. When commensal microorganisms are killed by antibiotic treatment, pathogens frequently replace them and cause disease (see Fig. 12.20). Under some circumstances commensal microbes themselves can cause disease if their growth is not kept in check or if the immune system is compromised. In Chapter 12, we will further discuss how commensal microorganisms play an important role in the setting of normal immunity, particularly in the intestine; and in Chapter 15, we will see how these normally nonpathogenic organisms can cause disease in the context of inherited immunodeficiencies. 2-3 Infectious agents must overcome innate host defenses to establish a focus of infection.


Immunology_Janeway

Immunology_Janeway. 2-3 Infectious agents must overcome innate host defenses to establish a focus of infection. Our bodies are constantly exposed to microorganisms present in our environment, including infectious agents that have been shed by other individuals. Contact with these microorganisms may occur through external or internal epithelial surfaces. In order to establish an infection, a microorganism must first invade the body by binding to or crossing an epithelium (Fig. 2.8). With the epithelial damage that is common due to wounds, burns, or loss of the integrity of the body’s internal epithelia, infection is a major cause of mortality and morbidity. The body rapidly repairs damaged epithelial surfaces, but even without epithelial damage, pathogens may establish infection by specifically adhering to and colonizing epithelial surfaces, using the attachment to avoid being dislodged by the flow of air or fluid across the surface.


Immunology_Janeway

Immunology_Janeway. Disease occurs when a microorganism succeeds in evading or overwhelming innate host defenses to establish a local site of infection, and then replicates there to allow its further transmission within our bodies. The epithelium lining the respiratory tract provides a route of entry into tissues for airborne microorganisms, and the lining of the gastrointestinal tract does the same for microorganisms ingested in food and water. The intestinal pathogens Salmonella typhi, which causes typhoid fever, and Vibrio cholerae, which causes cholera, are spread through fecally contaminated food and water, respectively. Insect bites and wounds allow microorganisms to penetrate the skin, and direct contact between individuals offers opportunities for infection through the skin, the gut, and the reproductive tract (see Fig. 2.2).


Immunology_Janeway

Immunology_Janeway. In spite of this exposure, infectious disease is fortunately quite infrequent. Most of the microorganisms that succeed in crossing an epithelial surface are efficiently removed by innate immune mechanisms that function in the underlying tissues, preventing infection from becoming established. It is difficult to know how many infections are repelled in this way, because they cause no symptoms and pass undetected. In general, pathogenic microorganisms are distinguished from the mass of microorganisms in the environment by having special adaptations that evade the immune system. In some cases, such as the fungal disease athlete’s foot, the initial infection remains local and does not cause significant pathology. In other cases, such as tetanus, the bacterium (Clostridium tetani in this case) secretes a powerful neurotoxin, and the infection causes serious illness as it spreads through the lymphatics or the bloodstream, invades and destroys tissues, and disrupts the body’s workings.


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Immunology_Janeway. The spread of a pathogen is often initially countered by an inflammatory response that recruits more effector cells and molecules of the innate immune system out of the blood and into the tissues, while inducing clotting in small blood vessels further downstream so that the microbe cannot spread through the circulation (see Fig. 2.8). The cellular responses of innate immunity act over several days. During this time, the adaptive immune response may also begin if antigens derived from the pathogen are delivered to local lymphoid tissues Anatomic barriers and initial chemical defenses.


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Immunology_Janeway. Anatomic barriers and initial chemical defenses. Fig. 2.8 An infection and the response to it can be divided from becoming established. If not, it helps to contain the infection into a series of stages. These are illustrated here for an infectious and also delivers the infectious agent, carried in lymph and inside microorganism entering through a wound in the skin. The infectious dendritic cells, to local lymph nodes. This initiates the adaptive agent must first adhere to the epithelial cells and then cross the immune response and eventual clearance of the infection. epithelium. A local immune response may prevent the infection by dendritic cells (see Section 1-15). While an innate immune response may eliminate some infections, an adaptive immune response can target particular strains and variants of pathogens and protect the host against reinfection by using either effector T cells or antibodies to generate immunological memory.


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Immunology_Janeway. 2-4 Epithelial cells and phagocytes produce several kinds of antimicrobial proteins.


Immunology_Janeway

Immunology_Janeway. Our surface epithelia are more than mere physical barriers to infection; they also produce a wide variety of chemical substances that are microbicidal or that inhibit microbial growth. For example, the acid pH of the stomach and the digestive enzymes, bile salts, fatty acids, and lysolipids present in the upper gastrointestinal tract create a substantial chemical barrier to infection (see Fig. 2.5). One important group of antimicrobial proteins comprises enzymes that attack chemical features specific to bacterial cell walls. Such antibacterial enzymes include lysozyme and secretory phospholipase A2, which are secreted in tears and saliva and by phagocytes. Lysozyme is a glycosidase that breaks a specific chemical bond in the peptidoglycan component of the bacterial cell wall. Peptidoglycan is an alternating polymer of N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc), strengthened by cross-linking peptide bridges (Fig. 2.9). Lysozyme selectively cleaves the β-(1,4)


Immunology_Janeway

Immunology_Janeway. is an alternating polymer of N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc), strengthened by cross-linking peptide bridges (Fig. 2.9). Lysozyme selectively cleaves the β-(1,4) linkage between these two sugars and is more effective in acting against Gram-positive bacteria, in which the peptidoglycan cell wall is exposed, than against Gram-negative bacteria, which have an outer layer of LPS covering the peptidoglycan layer. Lysozyme is also produced by Paneth cells, specialized epithelial cells in the base of the crypts in the small intestine that secrete many antimicrobial proteins into the gut (see Fig. 2.6). Paneth cells also produce secretory phospholipase A2, a highly basic enzyme that can enter the bacterial cell wall to access and hydrolyze phospholipids in the cell membrane, killing the bacteria.


Immunology_Janeway

Immunology_Janeway. The second group of antimicrobial agents secreted by epithelial cells and phagocytes is the antimicrobial peptides. These represent one of the most ancient forms of defense against infection. Epithelial cells secrete these peptides into the fluids bathing the mucosal surface, whereas phagocytes secrete them in tissues. Three important classes of antimicrobial peptides in mammals are defensins, cathelicidins, and histatins.


Immunology_Janeway

Immunology_Janeway. Defensins are an ancient, evolutionarily conserved class of antimicrobial peptides made by many eukaryotic organisms, including mammals, insects, and plants (Fig. 2.10). They are short cationic peptides of around 30–40 amino acids that usually have three disulfide bonds stabilizing a common amphipathic structure—a positively charged region separated from a hydrophobic region. Defensins act within minutes to disrupt the cell membranes of bacteria and fungi, as well as the membrane envelopes of some viruses. The mechanism is thought to involve insertion of the hydrophobic region into the membrane bilayer and the formation of a pore that makes the membrane leaky (see Fig. 2.10). Most multicellular organisms make many different defensins


Immunology_Janeway

Immunology_Janeway. Fig. 2.9 Lysozyme digests the cell walls of Gram-positive and Gram-negative bacteria. Upper panels: the peptidoglycan of bacterial cell walls is a polymer of alternating residues of β-(1,4)-linked N-acetylglucosamine (GlcNAc) (large turquoise hexagons) and N-acetylmuramic acid (MurNAc) (purple circles) that are cross-linked by peptide bridges (red bars) into a dense three-dimensional network. In Gram-positive bacteria (upper left panel), peptidoglycan forms the outer layer in which other molecules are embedded such as teichoic acid and the lipoteichoic acids that link the peptidoglycan layer to the bacterial cell membrane itself. In Gram-negative bacteria (upper right panel), a thin inner wall of peptidoglycan is covered by an outer lipid membrane that contains proteins and lipopolysaccharide (LPS). Lipopolysaccharide is composed of a lipid, lipid A (turquoise circles), to which is attached a polysaccharide core (small turquoise hexagons). Lysozyme (lower panels) cleaves β-(1,4)


Immunology_Janeway

Immunology_Janeway. (LPS). Lipopolysaccharide is composed of a lipid, lipid A (turquoise circles), to which is attached a polysaccharide core (small turquoise hexagons). Lysozyme (lower panels) cleaves β-(1,4) linkages between GlcNAc and MurNAc, creating a defect in the peptidoglycan layer and exposing the underlying cell membrane to other antimicrobial agents. Lysozyme is more effective against Gram-positive bacteria because of the relatively greater accessibility of the peptidoglycan.


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Immunology_Janeway. Anatomic barriers and initial chemical defenses. Fig. 2.10 Defensins are amphipathic peptides that disrupt the cell membranes of microbes. The structure of human β1-defensin is shown in the top panel. It is composed of a short segment of α helix (yellow) resting against three strands of antiparallel β sheet (green), generating an amphipathic peptide with charged and hydrophobic residues residing in separate regions. This general feature is shared by defensins from plants and insects and allows the defensins to interact with the charged surface of the cell membrane and become inserted in the lipid bilayer (center panel). Although the details are still unclear, a transition in the arrangement of the defensins in the membrane leads to the formation of pores and a loss of membrane integrity (bottom panel).


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Immunology_Janeway. —the plant Arabidopsis thaliana produces 13 and the fruitfly Drosophila melanogaster at least 15. Human Paneth cells make as many as 21 different defensins, many of which are encoded by a cluster of genes on chromosome 8.