Immunology_Janeway

Immunology_Janeway. Fig. 10.28 Dimeric IgA is the major class of antibody present in the lumen of the gut. IgA is synthesized by plasma cells in the lamina propria and transported into the lumen of the gut through epithelial cells at the base of the crypts. Dimeric IgA binds to the layer of mucus overlying the gut epithelium and acts as an antigen-specific barrier to pathogens and toxins in the gut lumen The structure of a molecule of FcRn (blue) is shown bound to one chain of the Fc portion of IgG (red), at the interface of the Cγ2 and Cγ3 domains, with the Cγ2 region at the top. The β2-microglobulin component of the FcRn is green. The dark-blue structure attached to the Fc portion of IgG is a carbohydrate chain, reflecting glycosylation. FcRn transports IgG molecules across the placenta in humans and also across the gut in rats and mice. It also has a role in maintaining the levels of IgG in adults. Although only one molecule of FcRn is shown binding to the Fc portion, it is thought that it takes two


Immunology_Janeway

Immunology_Janeway. across the gut in rats and mice. It also has a role in maintaining the levels of IgG in adults. Although only one molecule of FcRn is shown binding to the Fc portion, it is thought that it takes two molecules of FcRn to capture one molecule of IgG. Courtesy of


Immunology_Janeway

Immunology_Janeway. Fig. 10.29 The neonatal Fc receptor (FcRn) binds to the Fc portion of IgG. P. Björkman. 10-17 The neonatal Fc receptor carries IgG across the placenta and prevents IgG excretion from the body.


Immunology_Janeway

Immunology_Janeway. Newborn infants are especially vulnerable to infection, having had no previous exposure to the microbes in the environment they enter at birth. IgA antibodies are secreted in breast milk and are transferred to the gut of the newborn infant, where they provide protection from newly encountered bacteria until the infant can synthesize its own protective antibody. IgA is not the only protective antibody that a mother passes on to her baby. Maternal IgG is transported across the placenta directly into the bloodstream of the fetus during intrauterine life; human babies at birth have as high levels of plasma IgG as their mothers, and with the same range of antigen specificities. The selective transport of IgG from mother to fetus is due to an IgG transport protein in the placenta, FcRn (neonatal Fc receptor), which is closely related in structure to MHC class I molecules. Despite this similarity, FcRn binds IgG quite differently from the binding of peptide to MHC class I molecules, because


Immunology_Janeway

Immunology_Janeway. Fc receptor), which is closely related in structure to MHC class I molecules. Despite this similarity, FcRn binds IgG quite differently from the binding of peptide to MHC class I molecules, because its peptide-binding groove is occluded. It binds to the Fc portion of IgG molecules (Fig. 10.29). Two molecules of FcRn bind one molecule of IgG, bearing it across the placenta. Maternal IgG is ingested by the newborn animal from its mother’s milk and colostrum, the protein-rich fluid secreted by the early postnatal mammary gland. In this case, FcRn transports the IgG from the lumen of the neonatal gut into the blood and tissues. Interestingly, FcRn is also found in adults in the gut and liver and on endothelial cells. Its function in adults is to maintain the levels of IgG in plasma, which it does by binding antibody, endocytosing it, and recycling it to the blood, thus preventing its excretion from the body.


Immunology_Janeway

Immunology_Janeway. By means of these specialized transport systems, mammals are supplied from birth with antibodies against pathogens common in their environments. As they mature and make their own antibodies of all isotypes, these are distributed selectively to different sites in the body (Fig. 10.30). Thus, throughout life, class switching and the distribution of antibody classes throughout the body provide effective protection against infection in extracellular spaces. 10-18 High-affinity IgG and IgA antibodies can neutralize toxins and block the infectivity of viruses and bacteria.


Immunology_Janeway

Immunology_Janeway. Pathogens can cause damage to a host by producing toxins or by infecting cells directly, and antibodies can protect by blocking both of these actions. Many bacteria cause disease by secreting toxins that damage or disrupt the function of the host’s cells (Fig. 10.31). To affect cells, many toxins consist of separate domains for exerting toxicity and for binding to specific cell-surface receptors by which they enter cells. Antibodies that bind a toxin’s receptor-binding site can prevent cell entry and protect cells from attack (Fig. 10.32). Antibodies that act in this way to neutralize toxins are referred to as neutralizing antibodies. Most toxins are active at nanomolar concentrations: a single molecule of diphtheria toxin can kill a cell. To neutralize toxins, therefore, antibodies must be able to diffuse into the tissues and bind the toxin rapidly and with high affinity. The ability of IgG antibodies to diffuse easily throughout the


Immunology_Janeway

Immunology_Janeway. Fig. 10.30 Immunoglobulin classes are selectively distributed in the body. IgG and IgM predominate in blood (shown here for simplicity by IgM and IgG in the heart), whereas IgG and monomeric IgA are the major antibodies in extracellular fluid within the body. Dimeric IgA predominates in secretions across epithelia, including breast milk. The fetus receives IgG from the mother by transplacental transport. IgE is found mainly associated with mast cells just beneath epithelial surfaces (especially of the respiratory tract, gastrointestinal tract, and skin). The brain is normally devoid of immunoglobulin.


Immunology_Janeway

Immunology_Janeway. Fig. 10.31 Many common diseases are caused by bacterial toxins. The toxins shown here are all exotoxins—proteins secreted by the bacteria. High-affinity IgG and IgA antibodies protect against these toxins. Bacteria also have nonsecreted endotoxins, such as lipopolysaccharide, which are released when the bacterium dies and may also mediate pathogenesis of disease. Host responses to exotoxins are more complex because the innate immune system has receptors for some endotoxins, such as TLR-4 (see Chapter 3). extracellular fluid, and their high affinity for antigen once affinity maturation has taken place, make them the principal antibodies that neutralize toxins in tissues. High-affinity IgA antibodies similarly neutralize toxins at the mucosal surfaces of the body. Dissociation of toxin releases its active chain, which poisons cell Antibody protects cell by blocking binding of toxin Toxin binds to cellular receptors Endocytosis of toxin:receptor complexes


Immunology_Janeway

Immunology_Janeway. Dissociation of toxin releases its active chain, which poisons cell Antibody protects cell by blocking binding of toxin Toxin binds to cellular receptors Endocytosis of toxin:receptor complexes Fig. 10.32 Neutralization of toxins by IgG antibodies protects molecule binds a cell-surface receptor, which enables the molecule cells from damage. The damaging effects of many bacteria are to be internalized. Another part of the toxin molecule then enters the due to the toxins they produce (see Fig. 10.31). These toxins are cytoplasm and poisons the cell. Antibodies that inhibit toxin binding usually composed of several distinct moieties. One part of the toxin can prevent, or neutralize, these effects.


Immunology_Janeway

Immunology_Janeway. Diphtheria and tetanus toxins are two bacterial toxins in which the toxic and receptor-binding functions are on separate protein chains. It is therefore possible to immunize individuals, usually as infants, with modified toxin molecules in which the toxic chain has been denatured. These modified toxins, called toxoids, lack toxic activity but retain the receptor-binding site. Thus, immunization with the toxoid induces neutralizing antibodies that protect against the native toxin.


Immunology_Janeway

Immunology_Janeway. Some insect or animal venoms are so toxic that a single exposure can cause severe tissue damage or death. For these the adaptive immune response is too slow to be protective. Exposure to these venoms is a rare event, and protective vaccines have not been developed for use in humans. Instead, neutralizing antibodies are generated by immunizing other species, such as horses, with insect and snake venoms to produce anti-venom antibodies, or antivenins. The antivenins are injected into exposed individuals to protect them against the toxic effects of the venom. Transfer of antibodies in this way is known as passive immunization (see Appendix I, Section A-30).


Immunology_Janeway

Immunology_Janeway. Animal viruses infect cells by binding to a particular cell-surface receptor. These are often cell-type-specific proteins that determine which cells a virus can infect, or its tropism. Many antibodies that neutralize viruses do so by directly blocking the binding of virus to surface receptors (Fig. 10.33). The hemagglutinin of influenza virus, for example, binds to terminal sialic acid residues on the carbohydrates of glycoproteins present on epithelial cells of the respiratory tract. It is known as hemagglutinin because it recognizes and binds to similar sialic acid residues on chicken red blood cells and agglutinates these red blood cells. Antibodies against the hemagglutinin can prevent infection by the influenza virus. Such antibodies are called virus-neutralizing antibodies, and, as with the neutralization of toxins, high-affinity IgA and IgG antibodies are particularly important. However, antibodies can also neutralize viruses by interfering with the fusion mechanisms used to


Immunology_Janeway

Immunology_Janeway. with the neutralization of toxins, high-affinity IgA and IgG antibodies are particularly important. However, antibodies can also neutralize viruses by interfering with the fusion mechanisms used to enter the cell’s cytoplasm after binding to surface receptors.


Immunology_Janeway

Immunology_Janeway. Many bacteria have cell-surface molecules called adhesins that enable them to bind to the surface of host cells. This adherence is crucial to the ability of these bacteria to cause disease, whether they subsequently enter the cell, as do Salmonella species, or remain attached to the cell surface as extracellular pathogens (Fig. 10.34). Neisseria gonorrhoeae, the causative agent of the sexually transmitted disease gonorrhea, has a cell-surface protein known as pilin that enables the bacterium to adhere to the epithelial cells of the urinary and reproductive tracts and is essential to its infectivity. Antibodies against pilin can inhibit this adhesive reaction and prevent infection.


Immunology_Janeway

Immunology_Janeway. IgA antibodies secreted onto the mucosal surfaces of the intestinal, respiratory, and reproductive tracts are particularly important in inhibiting the colonization of these surfaces by pathogens and in preventing infection of the epithelial cells. Adhesion of bacteria to cells within tissues can also contribute to pathogenesis, and IgG antibodies against adhesins protect tissues from damage in much the same way as IgA antibodies protect mucosal surfaces.


Immunology_Janeway

Immunology_Janeway. Fig. 10.33 Viral infection of cells can be blocked by neutralizing antibodies. For a virus to multiply within a cell, it must introduce its genes into the cell. The first step in entry is usually the binding of the virus to a receptor on the cell surface. For enveloped viruses, as shown in the figure, entry into the cytoplasm requires fusion of the viral envelope and the cell membrane. For some viruses this fusion event takes place on the cell surface (not shown); for others it can occur only within the more acidic environment of endosomes, as shown here. Non-enveloped viruses must also bind to receptors on cell surfaces, but they enter the cytoplasm by disrupting endosomes. Antibodies bound to viral surface proteins neutralize the virus, inhibiting either its initial binding to the cell or its subsequent entry. 10-19 Antibody:antigen complexes activate the classical pathway of complement by binding to C1q.


Immunology_Janeway

Immunology_Janeway. 10-19 Antibody:antigen complexes activate the classical pathway of complement by binding to C1q. Chapter 2 introduced the complement system as an essential component of innate immunity. Complement activation can proceed in the absence of antibody via the lectin pathway through the actions of mannose-binding lectin (MBL) and ficolins. But complement is also an important effector of antibody responses via the classical pathway. The different pathways of complement activation converge to coat pathogen surfaces or antigen:antibody complexes with covalently attached complement fragment C3b, which acts as an opsonin to promote uptake and removal by phagocytes. In addition, the terminal complement components can form a membrane-attack complex that damages some bacteria.


Immunology_Janeway

Immunology_Janeway. In the classical pathway, complement activation is triggered by C1, a complex of C1q and the serine proteases C1r and C1s (see Section 2-7). Complement activation is initiated when antibodies that are attached to the surface of a pathogen then bind to C1 via C1q (Fig. 10.35). C1q can be bound by either Fig. 10.34 Antibodies can prevent the attachment of bacteria to cell surfaces. Many bacterial infections require an interaction between the bacterium and a cell-surface receptor. This is particularly true for infections of mucosal surfaces. The attachment process involves very specific molecular interactions between bacterial adhesins and their receptors on host cells; antibodies against bacterial adhesins can block such infections.


Immunology_Janeway

Immunology_Janeway. Fig. 10.35 The classical pathway of complement activation is initiated by the binding of C1q to antibody on a pathogen surface. When a molecule of IgM binds several identical epitopes on a pathogen surface, it is bent into the ‘staple’ conformation, which allows the globular heads of C1q to bind to the Fc regions of IgM (left panels). Multiple molecules of IgG bound on the surface of a pathogen allow the binding of a single molecule of C1q to two or more Fc regions (right panels). In both cases, the binding of C1q to the Fc regions induces a conformational change that activates the associated C1r, which becomes an active enzyme that cleaves the pro-enzyme C1s, generating a serine protease that initiates the classical complement cascade (see Chapter 2). Fig. 10.36 The two conformations of IgM. The left panel shows the planar conformation of soluble IgM; the right panel shows the ‘staple’ conformation of IgM bound to a bacterial flagellum. Photographs (×760,000) courtesy of K.H. Roux.


Immunology_Janeway

Immunology_Janeway. IgM or IgG antibodies, but, because of the structural requirements of binding to C1q, neither of these antibody classes can activate complement in solution; the complement reactions are initiated only when the antibodies are already bound to multiple sites on a cell surface, normally that of a pathogen.


Immunology_Janeway

Immunology_Janeway. Each globular head of a C1q molecule can bind to one Fc region, and binding of two or more heads activates the C1 complex. In plasma, the pentameric IgM molecule has a planar conformation that does not bind C1q (Fig. 10.36, left panel); however, binding to the surface of a pathogen deforms the IgM pen-tamer so that it looks like a staple (see Fig. 10.36, right panel), and this distortion exposes binding sites for the C1q heads. As mentioned in Section 10-15, IgM hexamers can also form but comprise less than 5% of total serum IgM. Hexameric IgM activates complement about 20 times more efficiently than its pentameric form, possibly because C1q is also a hexamer. The in vivo role of IgM hexamers in protecting against infections has not been fully established, and it has even been suggested that IgM hexamers are too reactive and may be harmful.


Immunology_Janeway

Immunology_Janeway. Although C1q binds with low affinity to some subclasses of IgG in solution, the binding energy required for C1q activation is achieved only when a single molecule of C1q can bind two or more IgG molecules that are held within 30–40 nm of each other as a result of binding antigen. This requires that multiple molecules of IgG be bound to a single pathogen or to an antigen in solution. For this reason, IgM is much more efficient than IgG in activating complement. The binding of C1q to a single bound IgM molecule, or to two or more bound IgG molecules (see Fig. 10.35), leads to activation of the protease activity of C1r, triggering the complement cascade. 10-20 Complement receptors and Fc receptors both contribute to removal of immune complexes from the circulation.


Immunology_Janeway

Immunology_Janeway. Fc receptors confer the distinct effector functions to the various antibody isotypes by interacting with their Fc regions. One such function is the clearance from the circulation of antigen:antibody complexes (immune complexes), which can include toxins, or debris from dead host cells and microorganisms, bound by neutralizing antibodies. Immune complexes can be cleared by the binding of the antibody’s Fc region to Fc receptors expressed on various phagocytic cells in tissues. This clearance is also helped by complement activation (described in the last section), which occurs when the Fc region activates C1q. The deposition of C4b and C3b onto the immune complex aids clearance by binding to complement receptor 1 (CR1) on the surface of erythrocytes (see Section 2-13 for a description of the different types of complement receptors). The erythrocytes transport the bound complexes of antigen, antibody, and complement to the liver and spleen. Here, macrophages bearing CR1 and Fc


Immunology_Janeway

Immunology_Janeway. CR1 on the erythrocyte surface has an important role in the clearance of immune complexes from the circulation. Immune complexes bind to CR1 on erythrocytes, which transport them to the liver and spleen, where they are removed by macrophages expressing receptors for both Fc and bound complement components. receptors remove the complexes from the erythrocyte surface without destroying the cell, and then degrade the complexes (Fig. 10.37). Even larger aggregates of particulate antigen, such as bacteria, viruses, and cell debris, can be coated with complement, picked up by erythrocytes, and transported to the spleen for destruction.


Immunology_Janeway

Immunology_Janeway. Complement-coated immune complexes that are not removed from the circulation tend to deposit in the basement membranes of small blood vessels, most notably those of the renal glomerulus, where the blood is filtered to form urine. Immune complexes that pass through the basement membrane of the glomerulus bind to CR1 present on the renal podocytes, cells that lie beneath the basement membrane. The functional significance of these receptors in the kidney is unknown; however, they have an important role in the pathology of some autoimmune diseases. In the autoimmune disease systemic lupus erythematosus (SLE) (see Section 15-16), excessive levels of circulating immune complexes lead to their deposition in large amounts on the podocytes, damaging the glomerulus; kidney failure is the principal danger in this disease. The strongest genetic risk factor for SLE is C1q deficiency, although this is very rare. Mutations in complement receptors 2 and 3 and the Fc receptor FcγRIIIa are also


Immunology_Janeway

Immunology_Janeway. danger in this disease. The strongest genetic risk factor for SLE is C1q deficiency, although this is very rare. Mutations in complement receptors 2 and 3 and the Fc receptor FcγRIIIa are also associated with increased susceptibility to develop lupus, implying the involvement of both complement receptors and FcR pathways in clearing immune complexes.


Immunology_Janeway

Immunology_Janeway. Antigen:antibody complexes can also be a cause of pathology in patients with deficiencies in the early components of complement (C1, C2, and C4). These deficiencies result in the classical complement pathway not being activated properly, and immune complexes not being cleared effectively because they do not become tagged with complement. These patients also suffer tissue damage as a result of immune-complex deposition, especially in the kidneys. Summary.


Immunology_Janeway

Immunology_Janeway. The T-cell-dependent antibody response begins with IgM secretion but quickly progresses to the production of additional antibody classes. Each class is specialized both in its localization in the body and in the functions it can perform. IgM antibodies are found mainly in blood; they are pentameric in structure. IgM is specialized to activate complement efficiently upon binding antigen and to compensate for the low affinity of a typical IgM antigen-binding site. IgG antibodies are usually of higher affinity and are found in blood and in extracellular fluid, where they can neutralize toxins, viruses, and bacteria, opsonize them for phagocytosis, and activate the complement system. IgA antibodies are synthesized as monomers, which enter blood and extracellular fluids, or they are secreted as dimeric molecules by plasma cells in the lamina propria of various mucosal tissues. IgA dimers are selectively transported across the epithelial layer into sites such as the lumen of the gut, where


Immunology_Janeway

Immunology_Janeway. dimeric molecules by plasma cells in the lamina propria of various mucosal tissues. IgA dimers are selectively transported across the epithelial layer into sites such as the lumen of the gut, where they neutralize toxins and viruses and block the entry of bacteria across the intestinal epithelium. Most IgE antibody is bound to the surface of mast cells that reside mainly just below the body surface; antigen binding to this IgE triggers local defense reactions. Antibodies can defend the body against extracellular pathogens and their toxic products in several ways. The simplest is by direct interactions with pathogens or their products, for example, by binding to the active sites of toxins and neutralizing them or by blocking their ability to bind to host cells through specific receptors. When antibodies of the appropriate isotype bind to antigens, they can activate the classical pathway of complement, which leads


Immunology_Janeway

Immunology_Janeway. Fig. 10.37 Erythrocyte CR1 helps to clear immune complexes from the circulation. Small antigen:antibody complexes form in the circulation FcRIn the spleen and liver, phagocytic cells remove the immune complexes from the erythrocyte surface Complement receptor CR1 on erythrocytes binds the immune complexes via bound C3b CR1 to the elimination of the pathogen by the various mechanisms described in Chapter 2. Soluble immune complexes of antigen and antibody also fix complement and are cleared from the circulation via complement receptors on red blood cells. The destruction of antibody-coated pathogens via Fc receptors.


Immunology_Janeway

Immunology_Janeway. The neutralization of toxins, viruses, or bacteria by high-affinity antibodies can protect against infection but does not, on its own, solve the problem of how to remove the pathogens and their products from the body. Moreover, many pathogens cannot be neutralized by antibody and must be destroyed by other means. Many pathogen-specific antibodies do not bind to neutralizing targets on pathogen surfaces and thus need to be linked to other effector mechanisms to play their part in host defense. We have already seen how the binding of antibody to antigen can activate complement. Another important defense mechanism is the activation of a variety of accessory effector cells bearing receptors called Fc receptors because they are specific for the Fc portion of antibodies. These receptors facilitate the phagocytosis of antibody-bound extracellular pathogens by macrophages, dendritic cells, and neutrophils. Other, nonphagocytic cells of the immune system—NK cells, eosinophils, basophils, and


Immunology_Janeway

Immunology_Janeway. the phagocytosis of antibody-bound extracellular pathogens by macrophages, dendritic cells, and neutrophils. Other, nonphagocytic cells of the immune system—NK cells, eosinophils, basophils, and mast cells (see Fig. 1.8)—are triggered to secrete stored mediators when their Fc receptors are engaged by antibody-coated pathogens. These mechanisms maximize the effectiveness of all antibodies regardless of where they bind.


Immunology_Janeway

Immunology_Janeway. 10-21 The Fc receptors of accessory cells are signaling receptors specific for immunoglobulins of different classes. The Fc receptors are a family of cell-surface molecules that bind the Fc portion of immunoglobulins. Each member of the Fc family recognizes immunoglobulin of one or a few closely related heavy-chain isotypes through a recognition domain on the α chain of the Fc receptor. Most Fc receptors are themselves members of the immunoglobulin gene superfamily. Different cell types bear different sets of Fc receptors, and the isotype of the antibody thus determines which types of cells will be engaged in a given response. The different Fc receptors, the cells that express them, and their specificities for different antibody classes are shown in Fig. 10.38.


Immunology_Janeway

Immunology_Janeway. Most Fc receptors function as part of a multisubunit complex. Only the α chain is required for antibody recognition; the other chains are required for transport of the receptor to the cell surface and for signal transduction when an Fc region is bound. Some Fcγ receptors, the Fcα receptor I, and the high-affinity receptor for IgE (FcεRI) all use a γ chain for signaling. This chain, which is closely related to the ζ chain of the T-cell receptor complex (see Section 7-7), associates noncovalently with the Fc-binding α chain. The human FcγRII-A is a single-chain receptor in which the cytoplasmic domain of the α chain replaces the function of the γ chain. FcγRII-B1 and FcγRII-B2 are also single-chain receptors, but function as inhibitory receptors because they contain an ITIM that engages the inositol 5ʹ-phosphatase SHIP (see Section 7-25). The most prominent function of Fc receptors is the activation of accessory cells to attack pathogens, but they also contribute in other ways to immune


Immunology_Janeway

Immunology_Janeway. inositol 5ʹ-phosphatase SHIP (see Section 7-25). The most prominent function of Fc receptors is the activation of accessory cells to attack pathogens, but they also contribute in other ways to immune responses. For example, FcγRII-B receptors negatively regulate the activities of B cells, mast cells, macrophages, and neutrophils by adjusting the threshold at which immune complexes will activate these cells. Fc receptors expressed by dendritic cells enable them to ingest antigen:antibody complexes efficiently and thus process these antigens and present their peptides to T cells.


Immunology_Janeway

Immunology_Janeway. ReceptorFc˜RI Fc°RI (CD89) Cell type Binding Structure Macrophages Neutrophils Eosinophils IgG1 108 M–1 2 × 106 M–1 2 × 106 M–1 1) IgG1=IgG3 2) IgG4 3) IgG2 Order of afÿnity Macrophages Neutrophils Eosinophils Platelets Langerhans cells Macrophages Neutrophils Eosinophils B cells Mast cells IgG1 IgG1 IgG1 ITIM ITIM IgG1=IgG3 IgA1=IgA2 NK cells Eosinophils Macrophages Neutrophils Mast cells IgG1 Mast cells Basophils IgE IgA1, IgA2 IgA, IgM Fc˛RII-A (CD32) Fc˛RIII (CD16) Fc˛RI (CD64) Fc˛RII-B2 (CD32) Fc˛RII-B1 (CD32) or Effect of ligation Uptake Stimulation Activation of respiratory burst Induction of killing Uptake Granule release (eosinophils) Uptake Inhibition of stimulation No uptake Inhibition of stimulation Induction of killing (NK cells) Uptake Induction of killing UptakeSecretion of granules Macrophages Eosinophils† Neutrophils Macrophages B cells Eosinophils B cells ˜ ° 72 kDa ° 40 kDa ˜-like domain ° 50–70 kDa ˜or ˝ Fc°/˝RFc˜RII (CD23) ° 45 kDa ˙ 33 kDa ˜ 9 kDa ˜ 9 kDa ° 55–75


Immunology_Janeway

Immunology_Janeway. granules Macrophages Eosinophils† Neutrophils Macrophages B cells Eosinophils B cells ˜ ° 72 kDa ° 40 kDa ˜-like domain ° 50–70 kDa ˜or ˝ Fc°/˝RFc˜RII (CD23) ° 45 kDa ˙ 33 kDa ˜ 9 kDa ˜ 9 kDa ° 55–75 kDa ° 70 kDa N lectin domain trimer Degranulation IgE 1) IgG1 2) IgG3=IgG2* 3) IgG4 1) IgG1=IgG3 2) IgG4 3) IgG2 2 × 106 M–1 1) IgG1=IgG3 2) IgG4 3) IgG2 1) IgM 2) IgA 5 × 105 M–1 3 × 109 M–12–7 × 107 M–1 (trimer) 2–7 × 106 M–1 (monomer) 1010 M–1 107 M–1


Immunology_Janeway

Immunology_Janeway. Fig. 10.38 Distinct receptors for the Fc region of the glycosylphosphatidylinositol membrane anchor without γ chains, different immunoglobulin classes are expressed on different whereas in NK cells it is a transmembrane molecule associated with accessory cells. The subunit structure and binding properties of γ chains. The FcγRII-B1 differs from the FcγRII-B2 by the presence these receptors and the cell types expressing them are shown. All of an additional exon in the intracellular region (indicated by yellow are immunoglobulin superfamily members except FcεRII, which triangle). This exon prevents the FcγRII-B1 from being internalized is a lectin and can form trimers. The exact chain composition after cross-linking. The binding affinities are taken from data on of any receptor can vary from one cell type to another. For human receptors. *Only some allotypes of FcγRII-A bind IgG2. †In example, FcγRIII in neutrophils is expressed as a molecule with a eosinophils, the molecular weight of


Immunology_Janeway

Immunology_Janeway. one cell type to another. For human receptors. *Only some allotypes of FcγRII-A bind IgG2. †In example, FcγRIII in neutrophils is expressed as a molecule with a eosinophils, the molecular weight of the CD89α chain is 70–100 kDa.


Immunology_Janeway

Immunology_Janeway. Antibody-coated viruses that enter the cytoplasm are cleared by a system that employs a novel class of Fc receptor called TRIM21 (tripartite motif-containing 21) that is expressed by a variety of immune and nonimmune cell types. TRIM21 is a cytosolic IgG receptor that has a higher affinity for IgG than any other Fc receptor, and it also has E3 ligase activity. When a virus that has bound IgG enters the cytoplasm, TRIM21 attaches to the antibody and uses its E3 ligase activity to ubiquitinate viral proteins. This leads to proteasomal degradation of virions in the cytosol before translation of virally encoded genes can occur. 10-22 Fc receptors on phagocytes are activated by antibodies bound to the surface of pathogens and enable the phagocytes to ingest and destroy pathogens.


Immunology_Janeway

Immunology_Janeway. 10-22 Fc receptors on phagocytes are activated by antibodies bound to the surface of pathogens and enable the phagocytes to ingest and destroy pathogens. The most important Fc-bearing cells in humoral immune responses are the phagocytic cells of the monocytic and myelocytic lineages, particularly macrophages and neutrophils. Many bacteria are directly recognized, ingested, and destroyed by phagocytes, and these bacteria are not pathogenic in normal individuals. However, some bacterial pathogens have polysaccharide capsules, a large structure that lies outside the bacterial cell membrane and resists direct engulfment by phagocytes. Such pathogens become susceptible to phagocytosis only when they are coated with antibodies and complement that engage the Fcγ or Fcα receptors and the complement receptor CR1 on phagocytic cells, triggering bacterial uptake (Fig. 10.39). The stimulation


Immunology_Janeway

Immunology_Janeway. Macrophage membranes fuse, creating a membrane-enclosed vesicle, the phagosome Lysosomes fuse with these vesicles, delivering enzymes that degrade the bacterium When C3b binds to CR1 and antibody binds to Fc receptor, bacteria are phagocytosed Bacterium is coated with complement and IgG antibody FcreceptorsC3bbacteriummacrophagelysosomeCR1


Immunology_Janeway

Immunology_Janeway. Fig. 10.39 Fc and complement receptors on phagocytes trigger the uptake and degradation of antibody-coated bacteria. Many bacteria resist phagocytosis by macrophages and neutrophils. Antibodies bound to these bacteria, however, enable the bacteria to be ingested and degraded through the interaction of the multiple Fc domains arrayed on the bacterial surface with Fc receptors on the phagocyte surface. Antibody coating also induces activation of the complement system and the binding of complement components to the bacterial surface. These can interact with complement receptors (for example, CR1) on the phagocyte. Fc receptors and complement receptors synergize in inducing phagocytosis. Bacteria coated with IgG antibody and complement are therefore more readily ingested than those coated with IgG alone. Binding of Fc and complement receptors signals the phagocyte to increase the rate of phagocytosis, to fuse lysosomes with phagosomes, and to increase its bactericidal activity.


Immunology_Janeway

Immunology_Janeway. No activation of macrophage, no destruction of bacterium Activation of macrophage, leading to phagocytosis and destruction of bacterium Free immunoglobulin does not cross-link Fc receptors Aggregation of immunoglobulin on bacterial surface allows cross-linking of Fc receptors Fc receptors macrophage bacterium of phagocytosis by complement-coated antigens binding to complement receptors is particularly important early in the immune response, before isotype-switched antibodies have been made. Capsular polysaccharides belong to the TI-2 class of thymus-independent antigens, and can therefore stimulate the early production of IgM antibodies, which are very effective at activating the complement system. IgM binding to encapsulated bacteria thus triggers the opsonization of these bacteria by complement and their prompt ingestion and destruction by phagocytes bearing complement receptors. Recently, Fcα/μR was discovered as a receptor that binds both IgA and IgM. Fcα/μR is expressed primarily


Immunology_Janeway

Immunology_Janeway. and their prompt ingestion and destruction by phagocytes bearing complement receptors. Recently, Fcα/μR was discovered as a receptor that binds both IgA and IgM. Fcα/μR is expressed primarily on macrophages and B cells in the lamina propria of the intestine and in germinal centers. It is thought to have a role in the endocytosis of IgM antibody complexed with bacteria such as Staphylococcus aureus.


Immunology_Janeway

Immunology_Janeway. Phagocyte activation can initiate an inflammatory response that causes tissue damage, and so Fc receptors on phagocytes must be able to distinguish antibody molecules bound to a pathogen from the much larger number of free antibody molecules that are not bound to anything. This distinction is made possible by the aggregation of antibodies that occurs when they bind to multimeric antigens or to multivalent particulate antigens such as viruses and bacteria. Individual Fc receptors on a cell surface bind monomers of free antibody with low affinity, but when presented with an antibody-coated particle, the simultaneous binding by multiple Fc receptors results in binding of high avidity, and this is the principal mechanism by which bound antibodies are distinguished from free immunoglobulin (Fig. 10.40). The result is that Fc receptors enable cells to detect pathogens via the antibody molecules bound to them. Fc receptors therefore give phagocytic cells that lack intrinsic specificity the


Immunology_Janeway

Immunology_Janeway. 10.40). The result is that Fc receptors enable cells to detect pathogens via the antibody molecules bound to them. Fc receptors therefore give phagocytic cells that lack intrinsic specificity the ability to identify and remove specific pathogens and their products from the extracellular spaces.


Immunology_Janeway

Immunology_Janeway. Fig. 10.40 Bound antibody is distinguishable from free immunoglobulin by its state of aggregation. Free immunoglobulin molecules bind most Fc receptors with very low affinity and cannot cross-link Fc receptors. Antigen-bound immunoglobulin, however, binds to Fc receptors with high avidity because several antibody molecules that are bound to the same surface bind to multiple Fc receptors on the surface of the accessory cell. This Fc receptor cross-linking sends a signal to activate the cell bearing it. With Fc receptors that have ITIMs, the result is inhibition.


Immunology_Janeway

Immunology_Janeway. Phagocytosis is greatly enhanced by interactions between the molecules coating an opsonized microorganism and receptors on the phagocyte surface. When an antibody-coated pathogen binds to Fcγ receptors, for example, the cell surface of the phagocyte extends around the surface of the pathogen through successive binding of the Fcγ receptors to the antibody Fc regions bound to the pathogen. This is an active process that is triggered by the stimulation of the Fcγ receptors. Phagocytosis leads to enclosure of the pathogen (or particle) in an acidified cytoplasmic vesicle—the phagosome. This then fuses with one or more lysosomes to generate a phagolysosome; lysosomal enzymes are released into the vesicle interior, where they destroy the bacterium (see Fig. 10.39). The process of intracellular killing by phagocytes was described in more detail in Chapter 3.


Immunology_Janeway

Immunology_Janeway. Some particles are too large for a phagocyte to ingest; parasitic worms are one example. In this case the phagocyte attaches to the surface of the antibody-coated parasite via its Fcγ, Fcα, or Fcε receptors, and the contents of the secretory granules or lysosomes of the phagocyte are released by exocytosis. The contents are discharged directly onto the surface of the parasite and damage it. Thus, stimulation of Fcγ and Fcα receptors can trigger either the internalization of external particles by phagocytosis or the externalization of internal vesicles by exocytosis. The principal leukocytes involved in the destruction of bacteria are macrophages and neutrophils, whereas large parasites such as helminths are usually attacked by eosinophils (Fig. 10.41), nonphagocytic cells that can bind antibody-coated parasites via several different Fc receptors, including the low-affinity Fcε receptor for IgE, CD23 (see Fig. 10.38). Cross-linking of these receptors by antibody-coated surfaces


Immunology_Janeway

Immunology_Janeway. bind antibody-coated parasites via several different Fc receptors, including the low-affinity Fcε receptor for IgE, CD23 (see Fig. 10.38). Cross-linking of these receptors by antibody-coated surfaces activates the eosinophil to release its granule contents, which include proteins toxic to parasites (see Fig. 14.10). Cross-linking by antigen of IgE bound to the high-affinity FcεRI on mast cells and basophils also results in exocytosis of their granule contents, as we describe below.


Immunology_Janeway

Immunology_Janeway. 10-23 Fc receptors activate NK cells to destroy antibody-coated targets.


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Immunology_Janeway. Virus-infected cells are usually destroyed by T cells that recognize virus-derived peptides bound to cell-surface MHC molecules. Cells infected by some viruses also signal the presence of intracellular infection by expressing on their surface proteins, such as viral envelope proteins, that can be recognized by antibodies originally produced against the virus particle. Host cells with antibodies bound to them can be killed by a specialized non-T, non-B cell of the lymphoid lineage called a natural killer cell (NK cell), which we met in Chapter 3. NK cells are large cells with prominent intracellular granules and make up a small fraction of peripheral blood lymphocytes. Although belonging to the lymphoid lineage, NK cells express a limited repertoire of invariant receptors recognizing a range of ligands that are induced on abnormal cells, such as those infected with viruses; NK cells are considered to be part of innate immunity (see Section 3-25). On recognition of a ligand, the NK cell


Immunology_Janeway

Immunology_Janeway. of ligands that are induced on abnormal cells, such as those infected with viruses; NK cells are considered to be part of innate immunity (see Section 3-25). On recognition of a ligand, the NK cell kills the target cell directly without the need for antibody. Although first discovered for their ability to kill some tumor cells, NK cells play an important role in innate immunity in the early stages of virus infection.


Immunology_Janeway

Immunology_Janeway. As well as this innate function, NK cells can recognize and destroy antibody-coated target cells in a process called antibody-dependent cell-mediated cytotoxicity (ADCC). This is triggered when antibody bound to the surface of a cell interacts with Fc receptors on the NK cell (Fig. 10.42). NK cells express the receptor FcγRIII (CD16), which recognizes the IgG1 and IgG3 subclasses. The killing mechanism is analogous to that of cytotoxic T cells, involving the release of cytoplasmic granules containing perforin and granzymes (see Section 9-31). ADCC has been shown to have a role in the defense against Fig. 10.41 Eosinophils attacking a schistosome larva in the presence of serum from an infected patient.


Immunology_Janeway

Immunology_Janeway. Fig. 10.41 Eosinophils attacking a schistosome larva in the presence of serum from an infected patient. Large parasites, such as worms, cannot be ingested by phagocytes; however, when the worm is coated with antibody, eosinophils can attack it through binding via their Fc receptors for IgG and IgA. Similar attacks on large targets can be mounted by other Fc receptor-bearing cells. These cells release the toxic contents of their granules directly onto the target, a process known as exocytosis. Photograph courtesy of A. Butterworth.


Immunology_Janeway

Immunology_Janeway. Fig. 10.42 Antibody-coated target cells can be killed by cells encounter cells coated with IgG antibody, they rapidly kill the NK cells in antibody-dependent cell-mediated cytotoxicity target cell. ADCC is only one way in which NK cells can contribute to (ADCC). NK cells (see Chapter 3) are large granular non-T, non-B host defense. lymphoid cells that have FcγRIII (CD16) on their surface. When these infection by viruses, and represents another mechanism by which antibodies can direct an antigen-specific attack by an effector cell that itself lacks specificity for antigen. 10-24 Mast cells and basophils bind IgE antibody via the high-affinity Fcε receptor.


Immunology_Janeway

Immunology_Janeway. 10-24 Mast cells and basophils bind IgE antibody via the high-affinity Fcε receptor. When pathogens cross epithelial barriers and establish a local focus of infection, the host must mobilize its defenses and direct them to the site of pathogen growth. One way in which this is achieved is to activate the cells known as mast cells. Mast cells are large cells containing distinctive cytoplasmic granules that contain a mixture of chemical mediators, including histamine, that act rapidly to make local blood vessels more permeable. Mast cells have a distinctive appearance after staining with the dye toluidine blue that makes them readily identifiable in tissues (see Fig. 1.8). They are found in particularly high concentrations in vascularized connective tissues just beneath epithelial surfaces, including the submucosal tissues of the gastrointestinal and respiratory tracts and the dermis of the skin.


Immunology_Janeway

Immunology_Janeway. Mast cells have Fc receptors specific for IgE (FcεRI) and IgG (FcγRIII), and can be activated to release their granules and to secrete lipid inflammatory mediators and cytokines via antibody bound to these receptors. Most Fc receptors bind stably to the Fc regions of antibodies only when the antibodies have themselves bound antigen, and cross-linking of multiple Fc receptors is needed for strong binding. In contrast, FcεRI binds IgE antibody monomers with a very high affinity—approximately 1010 M–1. Thus, even at the low levels of circulating IgE present in normal individuals, a substantial portion of the total IgE is bound to the FcεRI on mast cells in tissues and on circulating basophils.


Immunology_Janeway

Immunology_Janeway. Although mast cells are usually stably associated with bound IgE, this on its own does not activate them, nor will the binding of monomeric antigen to the IgE. Mast-cell activation occurs only when the bound IgE is cross-linked by multivalent antigens. This signal activates the mast cell to release the contents of its granules, which occurs in seconds (Fig. 10.43), to synthesize and release lipid mediators such as prostaglandin D2 and leukotriene C4, and to secrete cytokines such as TNF-α, thereby initiating a local inflammatory response. Degranulation also releases stored histamine, which increases local blood flow and vascular permeability; this quickly leads to an accumulation Resting mast cell has granules that contain histamine and other infammatory mediators Multivalent antigen cross-links bound IgE antibody, causing release of granule contents Fc˜RI IgE antibody Resting mast cell Activated mast cell


Immunology_Janeway

Immunology_Janeway. Fig. 10.43 IgE antibody cross-linking on mast-cell surfaces leads to a rapid release of inflammatory mediators. Mast cells are large cells found in connective tissue and can be distinguished by their secretory granules, which contain many inflammatory mediators. They bind stably to monomeric IgE antibodies through the very high-affinity receptor FcεRI. Antigen cross-linking of the bound IgE antibody molecules triggers rapid degranulation, releasing inflammatory mediators into the surrounding tissue. These mediators trigger local inflammation, which recruits cells and proteins required for host defense to sites of infection. These cells are also triggered during allergic reactions when allergens bind to IgE on mast cells. Photographs courtesy of A.M. Dvorak.


Immunology_Janeway

Immunology_Janeway. of fluid and blood proteins, including antibodies, in the surrounding tissue. Shortly afterward there is an influx of blood-borne cells such as neutrophils and, later, monocytes, eosinophils, and effector lymphocytes. This influx can last from a few minutes to a few hours and produces an inflammatory response at the site of infection. Thus, mast cells are part of the front-line host defenses against pathogens that enter the body across epithelial barriers. They are also of medical importance because of their involvement in IgE-mediated allergic responses, which are discussed in Chapter 14. In allergic responses, mast cells are activated in the way described above by exposure to normally innocuous antigens (allergens), such as pollen, to which the individual has previously mounted a sensitizing immune response that produces allergen-specific IgE. 10-25 IgE-mediated activation of accessory cells has an important role in resistance to parasite infection.


Immunology_Janeway

Immunology_Janeway. Mast cells are thought to serve at least three important functions in host defense. First, their location near body surfaces allows them to recruit both pathogen-specific elements, such as antigen-specific lymphocytes, and nonspecific effector elements, such as neutrophils, macrophages, basophils, and eosinophils, to sites where infectious agents are most likely to enter the internal milieu. Second, the inflammation they cause increases the flow of lymph from sites of antigen deposition to the regional lymph nodes, where naive lymphocytes are first activated. Third, the ability of mast-cell products to trigger muscular contraction can contribute to the physical expulsion of pathogens from the lungs or the gut. Mast cells respond rapidly to the binding of antigen to surface-bound IgE antibodies, and their activation leads to the initiation of an inflammatory response and the recruitment and activation of basophils and eosinophils, which contribute further to the inflammatory response


Immunology_Janeway

Immunology_Janeway. and their activation leads to the initiation of an inflammatory response and the recruitment and activation of basophils and eosinophils, which contribute further to the inflammatory response (see Chapter 14). There is increasing evidence that such IgE-mediated responses are crucial to defense against parasite infestation.


Immunology_Janeway

Immunology_Janeway. A role for mast cells in the clearance of parasites is suggested by the accumulation of mast cells in the intestine, known as mastocytosis, that accompanies helminth infection, and by observations in W/WV mutant mice, which have a profound mast-cell deficiency caused by a mutation in the gene c-kit. These mutant mice show impaired clearance of the intestinal nematodes Trichinella spiralis and Strongyloides species. Clearance of Strongyloides is even more impaired in W/WV mice that lack IL-3 and so also fail to produce basophils. Thus, both mast cells and basophils seem to contribute to defense against these helminth parasites.


Immunology_Janeway

Immunology_Janeway. Other evidence points to the importance of IgE antibodies and eosinophils in the defense against parasites. Infection with certain types of multicellular parasites, particularly helminths, is strongly associated with the production of IgE antibodies and the presence of abnormally large numbers of eosinophils (eosinophilia) in blood and tissues. Furthermore, experiments in mice show that depletion of eosinophils by polyclonal anti-eosinophil antisera increases the severity of infection with the parasitic helminth Schistosoma mansoni. Eosinophils seem to be directly responsible for helminth destruction; examination of infected tissues shows degranulated eosinophils adhering to helminths, and experiments in vitro have shown that eosinophils can kill S. mansoni in the presence of anti-schistosome IgG or IgA antibodies (see Fig. 10.41).


Immunology_Janeway

Immunology_Janeway. The role of IgE, mast cells, basophils, and eosinophils can also be seen in resistance to the feeding of blood-sucking ixodid ticks. Skin at the site of a tick bite has degranulated mast cells and an accumulation of degranulated basophils and eosinophils, an indicator of recent activation. Subsequent resistance to feeding by these ticks develops after the first exposure, suggesting a specific immunological mechanism. Mice deficient in mast cells show no such acquired resistance to ticks, and in guinea pigs the depletion of either basophils or eosinophils by specific polyclonal antibodies also reduces resistance to tick feeding. Finally, experiments in mice showed that resistance to ticks is mediated by specific IgE antibody. Thus, many clinical studies and experiments support a role for this system of IgE bound to the high-affinity FcεRI in host resistance to pathogens that enter across epithelia or exoparasites such as ticks that breach it. Summary.


Immunology_Janeway

Immunology_Janeway. Antibody-coated pathogens are recognized by effector cells through Fc receptors that bind to an array of constant regions (Fc portions) provided by the pathogen-bound antibodies. Binding activates the cell and triggers destruction of the pathogen, through either phagocytosis, granule release, or both. Fc receptors comprise a family of proteins, each of which recognizes immunoglobulins of particular isotypes. Fc receptors on macrophages and neutrophils recognize the constant regions of IgG or IgA antibodies bound to a pathogen and trigger the engulfment and destruction of such bacteria. Binding to the Fc receptor also induces the production of microbicidal agents in the intracellular vesicles of the phagocyte. Eosinophils are important in the elimination of parasites too large to be engulfed; they bear Fc receptors specific for the constant region of IgG, as well as receptors for IgE; aggregation of these receptors triggers the release of toxic substances onto the surface of the


Immunology_Janeway

Immunology_Janeway. engulfed; they bear Fc receptors specific for the constant region of IgG, as well as receptors for IgE; aggregation of these receptors triggers the release of toxic substances onto the surface of the parasite. NK cells, tissue mast cells, and blood basophils also release their granule contents when their Fc receptors are engaged. The high-affinity receptor for IgE is expressed constitutively by mast cells and basophils. It differs from other Fc receptors in that it can bind free monomeric antibody, thus enabling an immediate response to pathogens at their site of first entry into the tissues. When IgE bound to the surface of a mast cell is aggregated by binding to antigen, it triggers the release of histamine and many other mediators that increase the blood flow to sites of infection; it thereby recruits antibodies and effector cells to these sites. Mast cells are found principally below epithelial surfaces of the skin and beneath the basement membrane of the digestive and respiratory


Immunology_Janeway

Immunology_Janeway. recruits antibodies and effector cells to these sites. Mast cells are found principally below epithelial surfaces of the skin and beneath the basement membrane of the digestive and respiratory tracts. Their activation by innocuous substances is responsible for many of the symptoms of acute allergic reactions, as will be described in Chapter 14.


Immunology_Janeway

Summary to Chapter 10.

Immunology_Janeway. Summary to Chapter 10.


Immunology_Janeway

Immunology_Janeway. The humoral immune response to infection involves the production of antibody by plasma cells derived from B lymphocytes, the binding of this antibody to the pathogen, and the elimination of the pathogen by phagocytic cells and molecules of the humoral immune system. The production of antibody usually requires the action of helper T cells specific for a peptide fragment of the antigen recognized by the B cell, a phenomenon called linked recognition. An activated B cell first moves to the T-zone–B-zone boundary in secondary lymphoid tissues, where it may encounter its cognate T cell and begin to proliferate. Some B cells become plasmablasts, while others move to the germinal center, where somatic hypermutation and class switch recombination take place. B cells that bind antigen with the highest affinity are selected for survival and further differentiation, leading to affinity maturation of the antibody response. Cytokines made by helper T cells direct class switching, leading to the


Immunology_Janeway

Immunology_Janeway. affinity are selected for survival and further differentiation, leading to affinity maturation of the antibody response. Cytokines made by helper T cells direct class switching, leading to the production of antibody of various classes that can be distributed to various body compartments.


Immunology_Janeway

Immunology_Janeway. IgM antibodies are produced early in an infection by conventional B cells and are also made in the absence of infection by subsets of nonconventional B cells in particular locations (as natural antibodies). IgM has a major role in protecting against infection in the bloodstream, whereas isotypes secreted later in an adaptive immune response, such as IgG, diffuse into the tissues. Antigens that have highly repeating antigenic determinants and that contain mitogens— called TI antigens—can elicit IgM and some IgG independently of T-cell help, and this provides an early protective immune response. Multimeric IgA is produced in the lamina propria and is transported across epithelial surfaces, whereas IgE is made in small amounts and binds avidly to receptors on the surface of basophils and mast cells.


Immunology_Janeway

Immunology_Janeway. Antibodies that bind with high affinity to critical sites on toxins, viruses, and bacteria can neutralize them. However, pathogens and their products are destroyed and removed from the body largely through uptake into phagocytes and degradation inside these cells. Antibodies that coat pathogens bind to Fc receptors on phagocytes, which are thereby triggered to engulf and destroy the pathogen. Binding of antibody C regions to Fc receptors on other cells leads to the exocytosis of stored mediators; this is particularly important in parasite infections, in which Fcε-expressing mast cells are triggered by the binding of antigen to IgE antibody to release inflammatory mediators directly onto parasite surfaces. Antibodies can also initiate the destruction of pathogens by activating the complement system. Complement components can opsonize pathogens for uptake by phagocytes, and recruit phagocytes to sites of infection. Receptors for complement components and Fc receptors often synergize in


Immunology_Janeway

Immunology_Janeway. system. Complement components can opsonize pathogens for uptake by phagocytes, and recruit phagocytes to sites of infection. Receptors for complement components and Fc receptors often synergize in activating the uptake and destruction of pathogens and immune complexes. Thus, the humoral immune response is targeted to the infecting pathogen through the production of specific antibody; however, the effector actions of that antibody are determined by its heavy-chain isotype.


Immunology_Janeway

Immunology_Janeway. Questions. 10.1 Multiple Choice: Which of the following is not an antibody effector function? A. Opsonization B. Neutralization C. Complement activation D. Linked recognition E. NK-cell cytotoxicity F. Mast-cell degranulation 10.2 Short Answer: The Haemophilus influenzae type b (Hib) vaccine was initially composed only of the polysaccharide capsule of the organism, but this failed to mount potent antibody responses. Directly conjugating the Hib polysaccharide to a tetanus or diphtheria toxoid, however, yielded very potent antibody responses to Hib, and is the current vaccine formulation. Indicate which immunological phenomenon is taken advantage of by conjugating the Hib capsule-derived polysaccharide to a toxoid, and how it works to elicit a potent antibody response.


Immunology_Janeway

Immunology_Janeway. 10.3 Matching: During T-dependent antibody responses, numerous receptor/ligand interactions and cytokine signaling events occur between TFH cells and activated B cells. For the following list of surface receptors/ligands and cytokines, indicate whether they are produced by T cells (T), B cells (B), both (TB), or neither (N) in this context. A. IL-21 B. ICOSL C. CD40L D. CD30L E. Peptide:MHC II F. CCL21 G. SLAM 10.4 Matching: Match the human disease to the associated genetic defect. A. X-linked i. Translesion polymerase lymphoproliferative disorder Polη B. Hyper IgM type 2 ii. ATM (a DNA-PKcsimmunodeficiency family kinase) C. Xeroderma pigmentosum iii. SLAM-associated protein (SAP) D. Ataxia telangiectasia iv. Activation-induced cytidine deaminase (AID) 10.5 Matching: Indicate whether the following properties apply to IgA, IgD, IgE, IgG, and/or IgM. A. First produced during humoral response B. Monomeric (predominantly) C. Dimeric (predominantly)


Immunology_Janeway

Immunology_Janeway. A. First produced during humoral response B. Monomeric (predominantly) C. Dimeric (predominantly) D. Pentameric (predominantly) E. Contains a J chain F. Capable of eliciting complement deposition G. Most abundant in mucosal surfaces and secretions H. Low-affinity I. Bound onto mast cells J. Binds to polymeric immunoglobulin receptor (pIgR) K. Binds the neonatal Fc receptor (FcRn) 10.6 Short Answer: How is TRIM21, a novel class of Fc receptor, different from other Fc receptors? 10.7 Multiple Choice: Which of the following functions is not elicited by antibody binding to Fcγ receptors? A. Antibody-dependent cell-mediated cytotoxicity (ADCC) via NK cells B. Phagocytosis by neutrophils C. Mast-cell degranulation D. Downregulation of B-cell activity E. Ingestion of immune complexes by dendritic cells 10.8 Multiple Choice: Which of the following is a false statement?


Immunology_Janeway

Immunology_Janeway. C. Mast-cell degranulation D. Downregulation of B-cell activity E. Ingestion of immune complexes by dendritic cells 10.8 Multiple Choice: Which of the following is a false statement? A. Naive B-cell survival in follicles is dependent on BAFF, which signals through BAFF-R, TACI, and BCMA to induce Bcl-2 expression. B. Subcapsular sinuses of lymph nodes and marginal sinuses of the spleen are functionally similar areas filled with specialized macrophages that retain but do not digest antigens. C. ICOS signaling in T cells is essential for their completion of TFH differentiation and expression of the transcription factors Bcl-6 and c-Maf. D. Both plasmablasts and plasma cells express B7 co-stimulatory molecules, MHC class II molecules, and high levels of B-cell receptors. E. TFH cells determine the choice of isotype for class switching in T-dependent antibody responses.


Immunology_Janeway

Immunology_Janeway. E. TFH cells determine the choice of isotype for class switching in T-dependent antibody responses. 10.9 True or False: Germinal centers contain a light and a dark zone. In the light zone, B cells proliferate extensively and are called centroblasts. They are maintained there by CXCL12–CXCR4 chemokine signaling and undergo somatic hypermutation leading to affinity maturation and class switching. In the dark zone, B cells cease proliferation and are called centrocytes. Here, they are maintained by CXCL13–CXCR5 chemokine signaling, express higher levels of B-cell receptor, and interact extensively with TFH cells. 10.10 Multiple Choice: Choose the correct statement: A. R-loops are structures formed during somatic hypermutation that promote accessibility of the immunoglobulin V regions to AID. B. APE1 removes deaminated cytosine to create an abasic residue that results in the random insertion of a base during the next round of DNA replication.


Immunology_Janeway

Immunology_Janeway. B. APE1 removes deaminated cytosine to create an abasic residue that results in the random insertion of a base during the next round of DNA replication. C. Frameshift mutations during class switch recombination do not occur because switch regions lie in introns. D. The error-prone MSH2/6 polymerase repairs DNA lesions and causes mutations that promote somatic hypermutation. 10.11Fill-in-the-Blanks: Fc receptors diversify the effector functions of the distinct antibody isotypes. Most Fc receptors can bind the Fc regions of antibodies with _________ affinity. In contrast, FcεRI binds with ________ affinity. Multivalent antigen-bound IgE can bind _________ in mast cells and cause release of lipid mediators such as _________ and _________. Mast cells also degranulate in response to cross-linking of the FC receptor-bound IgE, which causes release of __________, and as a consequence local blood flow and __________ are increased, initiating an inflammatory response. General references.


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Immunology_Janeway. General references. Batista, F.D., and Harwood, N.E.: The who, how and where of antigen presentation to B cells. Nat. Rev. Immunol. 2009, 9:15–27. Nimmerjahn, F., and Ravetch, J.V.: Fcγ receptors as regulators of immune responses. Nat. Rev. Immunol. 2008, 8:34–47. Rajewsky, K.: Clonal selection and learning in the antibody system. Nature 1996, 381:751–758. Section references. 10-1 Activation of B cells by antigen involves signals from the B-cell receptor and either TFH cells or microbial antigens. Crotty, S.: T follicular helper cell differentiation, function, and roles in disease. Immunity 2014, 41:529–542. Maglione, P.J., Simchoni, N., Black, S., Radigan, L., Overbey, J.R., Bagiella, E., Bussel, J.B., Bossuyt, X., Casanova, J.L., Meyts, I., et al.: IRAK-4and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens. Blood 2014, 124:3561–3571. Pasare, C., and Medzhitov, R.: Control of B-cell responses by Toll-like receptors. Nature 2005, 438:364–368.


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Immunology_Janeway. Pasare, C., and Medzhitov, R.: Control of B-cell responses by Toll-like receptors. Nature 2005, 438:364–368. Vijayanand, P., Seumois, G., Simpson, L.J., Abdul-Wajid, S., Baumjohann, D., Panduro, M., Huang, X., Interlandi, J., Djuretic, I.M., Brown, D.R., et al.: Interleukin-4 production by follicular helper T cells requires the conserved Il4 enhancer hypersensitivity site V. Immunity 2012, 36:175–187. 10-2 Linked recognition of antigen by T cells and B cells promotes robust antibody responses. Barrington, R.A., Zhang, M., Zhong, X., Jonsson, H., Holodick, N., Cherukuri, A., Pierce, S.K., Rothstein, T.L., and Carroll, M.C.: CD21/CD19 coreceptor signaling promotes B cell survival during primary immune responses. J. Immunol. 2005, 175:2859–2867.


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Immunology_Janeway. Eskola, J., Peltola, H., Takala, A.K., Kayhty, H., Hakulinen, M., Karanko, V., Kela, E., Rekola, P., Ronnberg, P.R., Samuelson, J.S., et al.: Efficacy of Haemophilus influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine in infancy. N.Engl. J. Med. 1987, 317:717–722. Kalled, S.L.: Impact of the BAFF/BR3 axis on B cell survival, germinal center maintenance and antibody production. Semin. Immunol. 2006, 18:290–296. Mackay, F., and Browning, J.L.: BAFF: a fundamental survival factor for B cells. Nat. Rev. Immunol. 2002, 2:465–475. Mackay, F., and Schneider, P.: Cracking the BAFF code. Nat. Rev. Immunol. 2009, 9:491–502. MacLennan, I.C.M., Gulbranson-Judge, A., Toellner, K.M., Casamayor-Palleja, M., Chan, E., Sze, D.M.Y., Luther, S.A., and Orbea, H.A.: The changing preference of T and B cells for partners as T-dependent antibody responses develop. Immunol. Rev. 1997, 156:53–66.


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Immunology_Janeway. Chan, E., Sze, D.M.Y., Luther, S.A., and Orbea, H.A.: The changing preference of T and B cells for partners as T-dependent antibody responses develop. Immunol. Rev. 1997, 156:53–66. McHeyzer-Williams, L.J., Malherbe, L.P., and McHeyzer-Williams, M.G.: Helper T cell-regulated B cell immunity. Curr. Top. Microbiol. Immunol. 2006, 311:59–83. Nitschke, L.: The role of CD22 and other inhibitory co-receptors in B-cell activation. Curr. Opin. Immunol. 2005, 17:290–297. Rickert, R.C.: Regulation of B lymphocyte activation by complement C3 and the B cell coreceptor complex. Curr. Opin. Immunol. 2005, 17:237–243. Teichmann, L.L., Kashgarian, M., Weaver, C.T., Roers, A., Müller, W., and Shlomchik, M.J.: B cell-derived IL-10 does not regulate spontaneous systemic autoimmunity in MRL.Fas(lpr) mice. J. Immunol. 2012, 188:678–685. 10-3 B cells that encounter their antigens migrate toward the boundaries between B-cell and T-cell areas in secondary lymphoid tissues.


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Immunology_Janeway. 10-3 B cells that encounter their antigens migrate toward the boundaries between B-cell and T-cell areas in secondary lymphoid tissues. Cinamon, G., Zachariah, M.A., Lam, O.M., Foss, F.W., Jr., and Cyster, J.G.: Follicular shuttling of marginal zone B cells facilitates antigen transport. Nat. Immunol. 2008, 9:54–62. Fang, Y., Xu, C., Fu, Y.X., Holers, V.M., and Molina, H.: Expression of complement receptors 1 and 2 on follicular dendritic cells is necessary for the generation of a strong antigen-specific IgG response. J. Immunol. 1998, 160:5273–5279. Okada, T., and Cyster, J.G.: B cell migration and interactions in the early phase of antibody responses. Curr. Opin. Immunol. 2006, 18:278–285. Phan, T.G., Gray, E.E., and Cyster, J.G.: The microanatomy of B cell activation. Curr. Opin. Immunol. 2009, 21:258–265. 10-4 T cells express surface molecules and cytokines that activate B cells, which in turn promote TFH-cell development.


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Immunology_Janeway. 10-4 T cells express surface molecules and cytokines that activate B cells, which in turn promote TFH-cell development. Choi, Y.S., Kageyama, R., Eto, D., Escobar, T.C., Johnston, R.J., Monticelli, L., Lao, C., and Crotty, S.: ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity 2011, 34:932–946. Gaspal, F.M., Kim, M.Y., McConnell, F.M., Raykundalia, C., Bekiaris, V., and Lane, P.J.: Mice deficient in OX40 and CD30 signals lack memory antibody responses because of deficient CD4 T cell memory. J. Immunol. 2005, 174:3891–3896. Iannacone, M., Moseman, E.A., Tonti, E., Bosurgi, L., Junt, T., Henrickson, S.E., Whelan, S.P., Guidotti, L.G., and von Andrian, U.H.: Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus. Nature 2010, 465:1079–1083.


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Immunology_Janeway. Yoshinaga, S.K., Whoriskey, J.S., Khare, S.D., Sarmiento, U., Guo, J., Horan, T., Shih, G., Zhang, M., Coccia, M.A., Kohno, T., et al.: T-cell co-stimulation through B7RP-1 and ICOS. Nature 1999, 402:827–832. 10-5 Activated B cells differentiate into antibody-secreting plasmablasts and plasma cells. Moser, K., Tokoyoda, K., Radbruch, A., MacLennan, I., and Manz, R.A.: Stromal niches, plasma cell differentiation and survival. Curr. Opin. Immunol. 2006, 18:265–270. Pelletier, N., McHeyzer-Williams, L.J., Wong, K.A., Urich, E., Fazilleau, N., and McHeyzer-Williams, M.G.: Plasma cells negatively regulate the follicular helper T cell program. Nat. Immunol. 2010, 11:1110–1118. Radbruch, A., Muehlinghaus, G., Luger, E.O., Inamine, A., Smith, K.G., Dorner, T., and Hiepe, F.: Competence and competition: the challenge of becoming a long-lived plasma cell. Nat. Rev. Immunol. 2006, 6:741–750.


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Immunology_Janeway

Immunology_Janeway. Throughout this book we have examined the separate ways in which the innate and the adaptive immune responses protect against invading pathogens. In this chapter, we consider how the cells and molecules of the immune system work as an integrated defense system to eliminate or control different types of infectious agents, and also how the adaptive immune system provides long-lasting protective immunity. In Chapters 2 and 3, we saw how innate immunity is brought into play in the earliest phases of an infection and is probably sufficient to prevent colonization of the body by most of the microorganisms encountered in the environment. We also introduced innate lymphoid cells (ILCs), which, although lacking antigen-specific receptors, share overlapping developmental and functional features with effector CD4 T-cell subsets and cytotoxic CD8 T cells and act early during infection to generate distinct types of immune responses that target specific types of pathogens. Unlike naive T and B


Immunology_Janeway

Immunology_Janeway. with effector CD4 T-cell subsets and cytotoxic CD8 T cells and act early during infection to generate distinct types of immune responses that target specific types of pathogens. Unlike naive T and B cells, ILCs reside in barrier tissues, such as the intestinal and respiratory mucosae, where they are poised to respond rapidly to pathogens to impair or eliminate their spread.


Immunology_Janeway

Immunology_Janeway. However, most pathogens have developed strategies to evade innate immune defenses and establish a focus of infection. In these circumstances, the innate immune response sets the scene for the induction of an adaptive immune response, which is orchestrated by signals that emanate from innate sensor cells and is coordinated with innate effector cells to bring about pathogen clearance. In the primary immune response, which occurs against a pathogen encountered for the first time, ILCs respond to innate sensor cells to mount a rapid response over the first few hours to days of pathogen invasion. Concurrent with this response, clonal expansion and differentiation of naive lymphocytes into effector T cells and antibody-secreting B cells is initiated and guided by innate sensor cells and ILCs. However, the adaptive response requires several days to weeks to fully mature, largely due to the rarity of antigen-specific precursor cells. Following expansion and differentiation in the secondary


Immunology_Janeway

Immunology_Janeway. However, the adaptive response requires several days to weeks to fully mature, largely due to the rarity of antigen-specific precursor cells. Following expansion and differentiation in the secondary lymphoid tissues, effector T cells migrate to sites of infection and, along with pathogen-specific antibodies, enhance the effector functions of innate immune cells, and, in most cases, effectively target the pathogen for elimination (Fig. 11.1).


Immunology_Janeway

Immunology_Janeway. 4. Memory phase 3. Effector phase 1. Establishment of infection 2. Inductive phase Level of microorganism Threshold level of antigen to activate adaptive immune response Duration of infection Integration of innate and adaptive immunity in response to specific types of pathogens. Effector T cells augment the effector functions of innate immune cells. Immunological memory.