(BQ) Part 2 book The immune system presents the following contents: Preventing infection at mucosal surfaces, immunological memory and vaccination, coevolution of innate and adaptive immunity, failures of the body’s defenses, transplantation of tissues and organs, disruption of healthy tissue by the adaptive immune response, cancer and its interactions with the immune system.
267 Chapter 10 Preventing Infection at Mucosal Surfaces Most infectious diseases suffered by humans are caused by pathogens much smaller than a human cell For these microbes, the human body constitutes a vast resource-rich environment in which to live and reproduce In facing such threats, the body deploys a variety of defense mechanisms that have accumulated over hundreds of millions of years of invertebrate and vertebrate evolution In considering mechanisms of innate immunity in Chapters and and of adaptive immunity in Chapters 4–11, we principally used the example of a bacterial pathogen that enters the body through a skin wound, causing an innate immune response in the infected tissue that then leads to an adaptive immune response in the draining lymph node The merits of this example are that it is simple and involves a tissue for which we have all observed the effects of wounds, infection, and inflammation Until recently, these were the only responses studied by most immunologists, who usually administered their experimental antigens by subcutaneous injection But in the real world, only a fraction of human infections are caused by pathogens that enter the body’s tissues by passage through the skin Many more infections, including all of those caused by viruses, make their entry by passage through one of the mucosal surfaces Although the immune response to infection of mucosal tissue has strategies and principles in common with those directed at infections of skin and connective tissue, there are important differences, both in the cells and molecules involved, as well as the ways in which they are used Appreciation of the extent of these differences has led to the concept that the human immune system actually consists of two semi-autonomous parts: the systemic immune system, which defends against pathogens penetrating the skin, and the mucosal immune system, which defends against pathogens breaching mucosal surfaces This chapter focuses on mucosal immunity and how it differs from systemic immunity 10-1 The communication functions of mucosal surfaces render them vulnerable to infection Mucosal surfaces or the mucosae (singular mucosa) are found throughout much of the body, except the limbs, but they are predominantly out of sight Continually bathing the mucosae is a layer of the thick, viscous fluid called mucus, which is secreted by the mucosae and gives them their name Mucus contains glycoproteins, proteoglycans, peptides, and enzymes that protect the epithelial cells from damage and help to limit infection Mucosal epithelia line the gastrointestinal, respiratory, and urogenital tracts, and are also present in the exocrine glands associated with these organs: the pancreas, the conjunctivae and lachrymal glands of the eye, the salivary glands, and the mammary 268 Chapter 10: Preventing Infection at Mucosal Surfaces Mucosal tissues of the human body lachrymal gland salivary gland mammary gland gastrointestinal tract kidney conjunctiva oral cavity sinus trachea esophagus respiratory tract lungs stomach pancreas intestine urogenital tract uterus bladder vagina Figure 10.1 Distribution of mucosal tissues This diagram of a woman shows the mucosal tissues The mammary glands are a mucosal tissue only after pregnancy, when the breast is lactating Red, gastrointestinal tract; blue, respiratory tract; green, urinary tract; yellow, genital tract; orange, secretory glands glands of the lactating breast (Figure 10.1) These tissues are all sites of comi10.01/10.01 munication, where material and information are IS4 passed between the body and its environment Because of their physiological functions of gas exchange (lungs), food absorption (gut), sensory activity (eyes, nose, mouth, and throat), and reproduction (uterus, vagina, and breast), the mucosal surfaces are by necessity dynamic, thin, permeable barriers to the interior of the body These properties make the mucosal tissues particularly vulnerable to subversion and breach by pathogens This fragility, combined with the vital functions of mucosae, has driven the evolution of specialized mechanisms for their defense The combined area of a person’s mucosal surfaces is vastly greater than that of the skin: the small intestine alone has a surface area 200 times that of the skin Reflecting this difference, three-quarters of the body’s lymphocytes and plasma cells are to be found in secondary lymphoid tissues serving mucosal surfaces A similar proportion of all the antibodies made by the body is secreted at mucosal services as the dimeric form of IgA, also known as secretory IgA or SIgA (see Chapter 9) A distinctive feature of the gut mucosa is its constant contact with the large populations of commensal microorganisms that inhabit the lumen of the gut and constitute the gut microbiota Other major contents of the gut are the proteins, carbohydrates, lipids, and nucleic acids derived from the plants and animals that contribute to our diet In this situation, the major challenge is to make immune responses that eliminate pathogenic microorganisms and restrict the growth and location of commensal microorganisms, but not interfere with our food and nutrition As most research on mucosal immunity has been on the gut, this will provide our principal example of a mucosal tissue, but first we will examine the constituents and properties of the mucus Preventing infection at mucosal surfaces 10-2 Mucins are gigantic glycoproteins that endow the mucus with the properties to protect epithelial surfaces In every mucosal tissue, a layer of epithelial cells joined by tight junctions separates the outside environment from the inside of the body The epithelial layer provides a formidable barrier that prevents commensal and pathogenic organisms from gaining access to the internal issues Adding to this defense is the mucus, which prevents microorganisms and other environmental material, such as smoke and smog particles, from gaining access to the epithelium The molecular basis for the viscosity and protective properties of mucus is a family of glycoproteins called mucins that are secreted by the epithelium These proteins are huge, their polypeptide chains reaching lengths of more than 10,000 amino acids, but they are constructed from simple sequence motifs repeated many times over The motifs are rich in serine and threonine residues that are glycosylated with short, negatively charged glycans This carbohydrate comprises more than 70% of the weight of the mucin glycoprotein The extensive glycosylation forces the mucin polypeptides into extended conformations Globular domains at the ends of the polypeptides contain cysteine residues that make disulfide bonds between the stretched-out polypeptides, forming polymers and molecular networks that reach sizes greater than million daltons (1 MDa) (Figure 10.2) The intertwining of these gigantic proteins is what makes mucus viscous, so that it physically impedes the movement of microorganisms and particles The extensive glycosylation of mucins causes mucus to be heavily hydrated and thus able to protect epithelial surfaces by retaining water and preventing dehydration A major constituent of the mucin glycans is sialic acid, which gives mucins a polyanionic surface Through this they can bind the positively charged soluble effector molecules of innate immunity, such as defensins and other antimicrobial peptides, and of adaptive immunity, notably secretory IgA Bacteria negotiating their way through mucus can thus be trapped by IgA and killed by defensins Mucosal epithelia are dynamic tissues in which the epithelial cell layer turns over every 2 days or so, and mucus with its content of microorganisms is continuously being expelled from the body The viscoelastic properties of mucus vary with the mucosal tissue and its state of health or disease This is achieved by varying the mucin polypeptides that are incorporated into the mucus and the extent of their cross-linking In the human genome, seven genes encode secreted mucin polypeptides and are expressed in different mucosal tissues; an additional 13 genes encode mucin molecules that are membrane glycoproteins (Figure 10.3) These are expressed on the surface of epithelial cells and are not cross-linked like the secreted mucins Although not so well characterized as the secretory mucins, these membrane mucins are believed to form a mucus-like environment at the epithelial cell surface that has similar protective properties Because they are so much bigger than other components of the plasma membrane, the membrane mucins stand out from the cell surface, giving them the potential to trap and kill approaching microorganisms before they can interact with other components at the surface 10-3 Commensal microorganisms assist the gut in digesting food and maintaining health The gastrointestinal tract extends from the mouth to the anus and is about 9 meters in length in an adult human being (Figure 10.4) Its physiological purpose is to take in food and process it into nutrients that are absorbed by the body and into waste that is eliminated from the body Alimentation means giving nourishment; hence the older alternative name of alimentary canal for the Secreted polymeric mucin molecule N-terminal globular domain sugars one mucin polypeptide C-terminal globular domain Figure 10.2 The structure of mucins gives mucus its characteristic protective properties Mucins secreted by goblet cells are long polypeptides densely arrayed with short carbohydrates IS4 n10.100/10.02 attached to serine and threonine residues Through cysteine residues in the globular domains at the N- and C-termini, the mucin polypeptides become cross-linked into the gigantic extended polymeric networks that form the mucus This unusual structure gives mucus its viscosity, which lubricates mucosal surfaces and prevents the approach of commensal and pathogenic microorganisms The free cysteine residues of the mucin polypeptides are used to form covalent bonds with molecules of secreted IgA and defensins The former are used to bind microorganisms approaching a mucosal surface; the latter are used to kill them 269 270 Chapter 10: Preventing Infection at Mucosal Surfaces Mucin polypeptide Gene location (chromosome) Mode of action Tissues where expressed MUC2 11 Secreted Small intestine, colon MUC5A 11 Secreted Airways, stomach MUC5B 11 Secreted Airways, salivary glands MUC6 11 Secreted Stomach, small intestine, gall bladder MUC8 12 Secreted Airways MUC19 12 Secreted Salivary glands, trachea MUC7 Secreted Salivary glands MUC9 Secreted and membrane-bound Fallopian tubes MUC1 Membrane-bound Breast, pancreas MUC16 19 Membrane-bound Ovarian epithelium MUC20 Membrane-bound Placenta, colon, lung, prostate MUC4 Membrane-bound Airways, colon MUC3A Membrane-bound Small intestine, gall bladder, colon MUC3B Membrane-bound Small intestine, gall bladder, colon MUC17 Membrane-bound Stomach, small intestine, colon MUC11 Membrane-bound Colon, airwaves, reproductive tract MUC12 Membrane-bound Colon, pancreas, prostate, uterus MUC13 Membrane-bound Trachea, small intestine, colon MUC15 11 Membrane-bound Airways, small intestine, prostate, colon MUC18 Membrane-bound Lung, breast Figure 10.3 Mucosal tissues differ in the mucins they produce In the human genome are genes encoding 20 mucin polypeptides Six of these encode secreted mucins, 12 encode membrane-bound mucins and encodes both secreted and membrane-bound mucins Shown are the mucosal tissues in which the mucins are expressed and the chromosomal location of their genes mouth gastrointestinal tract Segments of the gastrointestinal tract serve different specialized functions and are populated to different extents by commensal IS4 n10.101/10.03 bacteria In the mouth, food is physically broken down by chewing in an environment populated by more than 750 species of bacteria In the stomach, acid and enzymes are used to chemically degrade the masticated food in an environment that is relatively unfriendly for microbes Here, the main function of the mucus is to protect and buffer the epithelium from the corrosive effects of hydrochloric acid secreted by the stomach Enzymatic degradation continues the digestive process in the small intestine (the duodenum, jejunum, and ileum), which is the major site for the absorption of nutrients In the large intestine (the colon), waste is stored, compacted, and periodically eliminated The cecum is a pouch-like structure that connects the small and large intestines As food travels along the gastrointestinal tract and becomes increasingly degraded, it passes through environments with increasing numbers of resident bacteria Starting in the stomach at 1000 bacteria per milliliter of gut contents, numbers increase to 105 to 108 per milliliter in the small intestine and esophagus stomach large intestine small intestine cecum appendix rectum anus Figure 10.4 The human gastrointestinal tract IS4 i10.02/10.04 Preventing infection at mucosal surfaces Synthesize essential metabolites vitamin K Cofactor for synthesis of clotting factors in the liver Break down plant fibers in food Inactivate toxic substances in food or made by pathogens Prevent pathogens from benefiting from the resources of the human gut Interact with epithelium to trigger development of secondary lymphoid tissue Degradation of toxins into harmless components that can be used by human cells Limitation of pathogen species to small numbers that are not harmful Establishment of the gutassociated lymphoid tissue short-chain fatty acids Release of small molecules that can be used in metabolism and biosynthesis reach 1012 per milliliter in the colon Digestion is a highly dynamic process in which the flow from stomach to anus is driven by peristalsis in the intestines The growth of the populations of resident commensal organisms is equally dynamic, and to contain this population at a manageable size, vast numbers of commensals are forced out of the human body each day Commensal microorganisms have co-evolved with their human hosts in a n10.102/10.05 symbiotic relationship, which benefits the hostIS4 in various ways (Figure 10.5) Bacteria provide metabolic building blocks that are essential for human health but cannot be made by human cells One example is the menaquinone precursors used to make vitamin K, a cofactor in the synthesis of blood-clotting factors Bacteria also increase the efficiency with which humans digest certain foods, by providing enzymes that convert plant fibers, which are indigestible by human enzymes, into energy-rich metabolites Other microbial enzymes render toxic substances present in food or secreted by pathogens into innocuous derivatives The presence of large, healthy populations of commensal microorganisms also prevents the emergence and proliferation of pathogenic variants by depriving them of food and space In fact, the normal development of the gut lymphoid tissues depends on the presence of a healthy gut microbiota, compelling evidence for the symbiotic co-evolution of commensal species and the human immune system Most bacterial infections of gut tissue are caused by commensals, but relatively few bacterial groups are involved Many potential pathogens belong to the facultatively anaerobic, Gram-negative phylum Proteobacteria, which includes Salmonella, Shigella, Helicobacter, and Escherichia Pathogenic variants of these normally harmless bacteria arise as new genetic variants acquire properties called virulence factors that enable them to leave the gut lumen, breach the gut epithelium, and invade the underlying lamina propria A common childhood viral infection of the epithelial lining of the small intestine is caused by rotavirus, a double-stranded RNA virus The infection causes an acute diarrhea, during which large numbers of stable and infectious virus particles are shed in the feces Worldwide, 500,000 children die each year from rotavirus infection In addition to bacteria and viruses, a spectrum of parasitic diseases are caused by helminth worms, as well as protozoans and other microorganisms that inhabit the gastrointestinal tract Figure 10.5 Five ways in which the commensal gut microbiota benefit their human hosts 271 272 Chapter 10: Preventing Infection at Mucosal Surfaces 10-4 The gastrointestinal tract is invested with distinctive secondary lymphoid tissues To provide prompt defense against infection, secondary lymphoid tissues and immune-system cells are spread throughout the gut and other mucosal tissues The gut-associated lymphoid tissues (GALT) comprise two functionally distinct compartments The lymphoid tissue directly beneath the mucosal epithelium is called the inductive compartment, because this is where interactions between antigen, dendritic cells, and lymphocytes induce adaptive immune responses The underlying connective tissue, called the lamina propria, comprises the effector compartment, because this is where effector cells, including plasma cells, effector T cells, macrophages, mast cells, and eosinophils reside Although not technically a part of the gut-associated lymphoid tissue, the mesenteric lymph nodes, the largest lymph nodes in the body, are dedicated to defending the gut They form a chain within the mesentery, the membrane of connective tissue that holds the gut in place Although the gut-associated lymphoid tissues come in a variety of sizes and forms, the microanatomy and organization of their inductive compartments into B-cell and T-cell zones are generally similar to those of other secondary lymphoid tissues The secondary lymphoid tissues within the gut mucosa continuously sample and monitor the contents of the gut lumen, allowing adaptive immune responses to be quickly made against the gut microbiota and implemented locally before any prospective pathogen can invade the gut tissue In contrast, a mesenteric lymph node can respond to infection only after the pathogen has invaded gut tissue and is then brought to the node in the draining lymph This latter mechanism is like that used to respond to infections in the rest of the body, where adaptive immune responses are made in secondary lymphoid organs that are often distant from the site of infection At the back of the mouth and guarding the entrance to the gut and the airways are the palatine tonsils, adenoids, and lingual tonsils These large aggregates of secondary lymphoid tissue are covered by a layer of squamous epithelium and form a ring known as Waldeyer’s ring (Figure 10.6) In early childhood, when pathogens are being experienced for the first time and the mouth provides a conduit for all manner of extraneous material that is not food, the tonsils and adenoids can become painfully swollen because of recurrent infection In the not-so-distant past, this condition was routinely treated by surgically removing the lymphoid organs, a procedure causing loss of immune capacity as reflected in the poorer secretory IgA response of such children, including the author of this book, to oral polio vaccination The small intestine is the major site of nutrient absorption, and its surface is deeply folded into finger-like projections called villi (singular villus), which greatly increase the surface area available for absorption It is the part of the gut most heavily invested with lymphoid tissue Characteristic secondary lymphoid organs of the small intestine are the Peyer’s patches, which integrate into the intestinal wall and have a distinctive appearance, forming dome-like aggregates of lymphocytes that bulge into the intestinal lumen (Figure 10.7) The patches vary in size and contain between and 200 B-cell follicles with germinal centers, interspersed with T-cell areas that also include dendritic cells The small intestine also contains numerous isolated lymphoid follicles, each composed of a single follicle and consisting mostly of B cells Isolated lymphoid follicles, but not Peyer’s patches, are also a feature of the large intestine A distinctive secondary lymphoid organ of the large intestine is the appendix (see Figure 10.2) It consists of a blind-ended tube about 10 cm in length and 0.5 cm in diameter that is attached to the cecum It is packed with lymphoid follicles, and appendicitis results when it is overrun by infection The only treatment for appendicitis is surgical removal of the appendix, to prevent it from bursting and causing life-threatening peritonitis—infection of the peritoneum, the membrane lining the abdominal cavity The tonsils and adenoids form a ring of lymphoid tissues, Waldeyer’s ring, around the entrance of the gut and airway adenoid palatine tonsil lingual tonsil tongue Figure 10.6 A ring of lymphoid organs guards the entrance to the gastrointestinal and respiratory tracts Lymphoid tissues are shown in blue The adenoids lie at either side of the base of the nose, and the palatine tonsils lie atIS4 either side of the palate at i10.03/10.06 the back of the oral cavity The lingual tonsils are on the base of the tongue Preventing infection at mucosal surfaces Organized lymphoid tissue and single lymphoid follicles are present in the gut wall Villi Peyer’s patch dome villi Gut lumen villus epithelium T-cell area Peyer’s patch M cell crypt Lamina propria GC follicle-associated epithelium isolated lymphoid follicle lymphatic to mesenteric lymph node Figure 10.7 Gut-associated lymphoid tissues and lymphocytes The diagram shows the structure of the mucosa of the small intestine It consists of finger-like processes (villi) covered by a layer of thin epithelial cells (red) that are specialized for the uptake and further breakdown of already partly degraded food coming from the stomach The tissue layer under the epithelium is the lamina propria, colored pale yellow in this and other figures in this chapter Lymphatics arising in the lamina propria drain to the mesenteric lymph nodes, which are not shown on this diagram (the direction of lymph flow is indicated by arrows) Peyer’sIS4 patches are secondary lymphoid i10.04/10.07 organs that underlie the gut epithelium and consist of a T-cell area (blue), B-cell follicles (yellow), and a ‘dome’ area (striped blue and yellow) immediately under the epithelium that is populated by B cells, T cells, and dendritic cells Antigen enters a Peyer’s patch from the gut via the M cells Peyer’s patches have no afferent lymphatics, but they are a source of efferent lymphatics that connect with the lymphatics carrying lymph to the mesenteric lymph node Also found in the gut wall are isolated lymphoid follicles consisting mainly of B cells The light micrograph is of a section of gut epithelium and shows villi and a Peyer’s patch The T-cell area and a germinal center (GC) are indicated Anatomical changes Enlarged cecum Longer small intestine Underdeveloped mesenteric lymph nodes Underdeveloped Peyer’s patches Fewer isolated lymphoid follicles Smaller spleen Immunological effects Reduction in secretory IgA and serum immunoglobulin Reduction in systemic T-cell numbers and in their activation Reduced cytotoxicity of CD8 T cells During early childhood, the human body and its immune system grow and mature in the context of the body’s microbiota and the common pathogens in the environment Like most other parts of the body, if the immune system is not used regularly it becomes impaired This is well illustrated by laboratory mice that are born and raised under ‘germ-free’ (gnotobiotic) conditions In comparison with control mice that have a normal gut microbiota, the gnotobiotic mice have stunted immune systems—with smaller secondary lymphoid tissues, lower levels of serum immunoglobulin, and a generally reduced capacity to make immune responses (Figure 10.8) 10-5 Inflammation of mucosal tissues is associated with causation not cure of disease The systemic immune response to infection in non-mucosal tissues involves the activation of tissue macrophages, which by secreting inflammatory Impaired lymphocyte homing to inflammatory sites Reduced numbers of lymphocytes in mucosal tissues Impaired responses of TH17 CD4 T cells Reduced ability of neutrophils to kill bacteria Figure 10.8 In the absence of a microbiota, the immune system develops abnormally Listed here are the differences distinguishing mice born and raised under sterile conditions from those raised under nonsterile conditions IS4 n10.103/10.08 The former have no microbiota, the latter have normal gut microbiota 273 274 Chapter 10: Preventing Infection at Mucosal Surfaces cytokines create a state of inflammation in the infected tissue Neutrophils, NK cells, and other effector cells of innate immunity are recruited from the blood to the infected tissue, and dendritic cells migrate out of the infected tissue to the draining secondary lymphoid tissue to initiate adaptive immunity Emerging from the adaptive immune response are effector T cells and pathogen-specific antibodies that travel to the infected tissue, where they work in conjunction with innate immunity to eliminate the pathogen and terminate the infection Afterward, in the recovery phase, inflammation and immunity are suppressed, the damaged tissue is repaired, and both pathogens and effector cells of the immune system become excluded from the now healthy tissue In effect, short violent episodes of localized and intense inflammation are the price paid to quash the sporadic infections of non-mucosal tissues (Figure 10.9, upper panels) Healthy tissue protected by systemic immunity Surface wound introduces bacteria that activate macrophages to make inflammatory cytokines Cytokines released by macrophages produce an inflammatory immune response Infection is terminated, leaving a damaged and distorted tissue for repair Repaired and healthy tissue Effector B cells and T cells that are highly specific for the invading bacteria colonize the infected area Infection is terminated with either minor tissue damage or no need for repair blood clot Skin bacteria cytokines Dermis Blood capillary Healthy tissue protected by mucosal immunity Bacteria gain access to lamina propria by endocytosis, activate macrophages but not cause inflammation Local effector cells respond to limit infection, dendritic cells travel to mesenteric lymph node to activate adaptive immunity Mucus Lamina propria draining lymph Figure 10.9 The systemic and mucosal immune systems use different strategies for coping with infections Compared here are the immune responses made to infecting bacteria by the systemic immune system (upper panels) and the mucosal immune system (lower panels) As the systemic immune system cannot anticipate infection, it is necessary for macrophages to be activated by the invading bacteria and then to secrete cytokines that recruit effector cells to the infected tissue This creates a state of inflammation in which the bacteria are killed, but at a cost to the structural integrity of the tissue Infection is followed by an extensive for repair and recovery of the damaged tissue (upper panels) In contrast, IS4period n10.104/10.09 the mucosal immune system anticipates potential infections by continually making adaptive immune responses against the gut microbiota, which places secretory IgA in the gut lumen and the lamina propria, and effector cells in the lamina propria and the epithelium When bacteria invade the gut tissue, effector molecules and cells are ready and waiting to contain the infection In the absence of inflammation, a further adaptive immune response to the invading organism is made in the draining mesenteric lymphoid which augments that in the local lymphoid tissue Little damage is done to the tissue, and repair occurs as part of the normal process by which gut epithelial cells are frequently turned over and replaced (lower panels) Preventing infection at mucosal surfaces In contrast to non-mucosal tissues, which interact only occasionally with the microbial world, the mucosal tissues have close and continuous contact with numerous and diverse commensal microorganisms, all of which are a potential source of pathogens For the gut, any significant breach of the epithelial layer could lead to a massive influx of bacteria and infection of the type that occurs in peritonitis (see Section 10-4) To avoid this, the mucosal immune system adopts two complementary strategies First, rather than being reactive like systemic immunity, the mucosal immune response is proactive and is constantly making adaptive immune responses against the microorganisms populating the gut The result is that healthy gut tissue is populated with effector T cells and B cells that stand guard and are poised to respond to any invader from the gut lumen (Figure 10.9, lower panels) The advantage of a proactive strategy is that infections can be stopped earlier and with greater force than is possible in non-mucosal tissues The second strategy of the mucosal immune system is to be sparing in the activation of inflammation, because the molecular and cellular weapons of the inflammatory response inevitably cause damage to the tissues where they work, which for mucosal tissues, and particularly the gut, is more likely to exacerbate the infection than clear it up Inflammation in the gut is the cause of a variety of chronic human diseases Of several strategies used to prevent inflammation in mucosal tissues, one is the use of regulatory T cells (CD4 Treg) to turn off inflammatory T cells IL-10 is a cytokine secreted by Treg that suppresses inflammation by turning off the synthesis of inflammatory cytokines Rare immunodeficient patients who lack a functional receptor for IL-10 suffer from a chronic inflammatory disease of the gut mucosa that resembles the more prevalent Crohn’s disease and is mediated by inflammatory TH1 and TH17 subsets of CD4 T cells Another inflammatory condition, celiac disease, is caused by an immune response in the gut lymphoid tissue that damages the intestinal epithelium and reduces the capacity of those affected to absorb nutrients from their food This condition can arrest the growth and development of children, and in adults causes unpleasant symptoms including diarrhea and stomach pains and general ill health Celiac disease is caused by an adaptive immune response to the proteins of gluten, a major component of grains such as wheat, barley, and rye, which are dietary staples for some human populations Proving this causeand-effect relationship, the symptoms of celiac disease disappear when patients adopt a strict gluten-free diet, but quickly come back if they consume gluten again In healthy gut tissue a compromise is made between the competing demands of nutrition and defense In celiac patients the truce is broken when a staple food is mistakenly perceived as a dangerous pathogen, which ‘infects’ the gut with every square meal The qualitatively different responses of the mucosal and systemic immune systems to microorganisms correlates with their developmental origin During fetal development, the mesenteric lymph nodes and Peyer’s patches differentiate independently of the spleen and the lymph nodes that supply systemic immunity The distinctive development of the secondary lymphoid tissues of mucosal and systemic immunity occurs under the guidance of different sets of chemokines and receptors for cytokines in the tumor necrosis factor (TNF) family The differences between the gut-associated lymphoid tissues and the systemic lymphoid organs are thus imprinted early on in life 10-6 Intestinal epithelial cells contribute to innate immune responses in the gut Intestinal epithelial cells are very active in the uptake of nutrients and other materials from the gut lumen They also have Toll-like receptors on their apical and basolateral surfaces, for example TLR5, which recognizes flagellin, the Celiac disease 275 276 Chapter 10: Preventing Infection at Mucosal Surfaces Figure 10.10 Epithelial cells contribute to the defense of mucosal tissue As well as providing a barrier between the gut tissue and the contents of the gut lumen, the epithelial cells are also first responders to invading microorganisms Epithelial cell receptors detect the invader and initiate the innate immune response by secreting cytokines and chemokines that recruit neutrophils and monocytes from the blood protein from which bacterial flagella are constructed Toll-like receptors on the apical surface allow the cells to sense bacteria that overcome the defenses of the mucus and reach the epithelium; those on the basolateral surface sense invading bacteria that penetrate the epithelium The cytoplasm of epithelial cells contains NOD1 and NOD2 receptors, which detect components of bacterial cell walls (see Section 3-5) Signals generated from NOD and Toll-like receptors lead to activation of NFκB and formation of the inflammasome by NOD-like receptor P3 (NLRP3) These events lead to the production and secretion of antimicrobial peptides, chemokines, and cytokines such as IL-1 and IL-6 by the epithelial cells (Figure 10.10) The defensins kill the bacteria, whereas the chemokines attract neutrophils (via the chemokine CXCL8), monocytes (via CCL3), eosinophils (via CCL4), T cells (via CCL5), and immature dendritic cells (via CCL20) from the blood Bacteria are recognized by TLRs on cell surface or in intracellular vesicles Bacteria or their products entering the cytosol are recognized by NOD1 and NOD2 TLR NODs IκB NFκB In this way, epithelial cells respond to incipient infection with a quick and localized inflammatory response that is usually sufficient to eliminate the infection without causing lasting damage If not, then an adaptive immune response is initiated in the draining mesenteric lymph node Because gut epithelial cells turn over every 2 days, their inflammatory responses are tightly controlled and will only persist in the presence of infection 10-7 Intestinal macrophages eliminate pathogens without creating a state of inflammation In gut-associated lymphoid tissues the lamina propria is populated with intestinal macrophages that provide a first line of defense against microbial invasion Although intestinal macrophages are proficient at phagocytosis and the elimination of microorganisms and apoptotic dying cells, they cannot perform other functions that characterize blood monocytes and macrophages present in non-mucosal tissues These functions are those associated with the initiation and maintenance of a state of inflammation (Figure 10.11) Intestinal macrophages not respond to infection by secreting inflammatory cytokines Neither they give a respiratory burst in response to inflammatory cytokines made by other cells Although intestinal macrophages express MHC class II molecules, they lack B7 co-stimulators and also the capacity to make the cytokines needed to activate and expand naive T cells: IL-1, IL-10, IL-12, IL-21, IL-22, and IL-23 In short, the intestinal macrophage is not a professional antigen-presenting cell and cannot initiate adaptive immune responses Neither are intestinal macrophages the instigators of inflammation like their counterparts in non-mucosal tissues, but they can fully perform their role of recognizing microorganisms and killing them in an environment free of inflammation Because of these qualities, some immunologists describe the intestinal macrophages as ‘inflammation-anergic’ macrophages Intestinal macrophages live only for a few months, so their population is constantly being replenished through the recruitment of monocytes from the blood These then differentiate into intestinal macrophages in the lamina propria When the monocytes arrive at the intestines, they have all the inflammatory properties associated with macrophages in non-mucosal tissues Under the influence of transforming growth factor (TGF)-β and other cytokines made TLR-5 TLRs, NOD1, and NOD2 activate NFκB, inducing the epithelial cell to express inflammatory cytokines, chemokines, and other mediators These recruit and activate neutrophils and monocytes IS4 n10.105/10.10 I:12 Index transmission, 388–389 type (HIV-1), 387, Fig. 13.22 type (HIV-2), 387 vaccine, 322–323, 396, Fig. 11.26 virions, 389, Fig. 13.21 Human leukocyte antigens see HLA Human papillomaviruses (HPV), 519–520 oncogenicity, 513, Fig. 17.4 proteins, 519–520, Fig. 17.16 vaccination, 518–519, Fig. 11.15 vaccines, 520, Fig. 11.25, Fig. 17.17 Human T-cell leukemia virus type (HTLV-1), 512, Fig. 17.4 Humoral immunity, 18, 231–264 polarized TH2 response, 214 Humors, 18 H-Y antigens, 464, Fig. 15.38 Hybridomas, 88, 154–155, Fig. 4.12 Hydrocortisone, 447, 448, Fig. 15.16 Hydrogen peroxide, 60, Fig. 3.17 Hydroxymethyl-but-2-enyl-pyrophosphate (HMBPP), 350, Fig. 12.24, Fig. 12.25 Hygiene hypothesis, 406, Fig. 14.8 Hyper-IgD syndrome, Fig. 16.41 Hyper-IgM syndrome, 102, Fig. 13.10 absence of germinal centers, 243–244, Fig. 9.14 X-linked, 380–381 Hypersensitivity reactions, 401–403, Fig. 14.2 allergy, transplant rejection and autoimmunity compared, 504, Fig. 16.42 allogeneic transplantation, 433–440 common causes, Fig. 14.1 type I, 401–402, 403, Fig. 14.2 see also Allergic disease, IgE-mediated type II, 402, 403, Fig. 14.2 autoimmune diseases, 475, Fig. 16.1 hyperacute graft rejection, 436–437, Fig. 15.4 incompatible blood transfusions, 435 type III, 402, 403, Fig. 14.2 autoimmune diseases, 475, 476, Fig. 16.1 chronic graft rejection, 443–444 serum sickness, 450–451, Fig. 15.22 type IV, 402–403, Fig. 14.2 autoimmune diseases, 475, 476–477, Fig. 16.1 transplant recipients, 438–439, 441, 461 Hyperthyroidism, 482 Hypervariable regions (HVs) see also Complementarity-determining regions antibodies, 85–86, Fig. 4.8 T-cell receptors, 114–115, Fig. 5.2 Hypoglycemia, autoimmune, 483, Fig. 16.1, Fig. 16.12 Hypohydrotic ectodermal dysplasia and immunodeficiency, X-linked, 53, Fig. 3.8, Fig. 13.10 Hypothyroidism, 484 I Ibritumomab, 529, Fig. 17.27 iC3, 32–33, Fig. 2.6 iC3b, 34, Fig. 2.9 B-cell activation, 233 macrophage interactions, 36 production, 233, Fig. 9.2 ICAM-1 B cell–helper TFH cell interaction, 238, Fig. 9.8 effector T-cell interactions, 219 naive T-cell homing, 205, Fig. 8.6 neutrophil recruitment, 57–58, Fig. 3.13 peripheral supramolecular activation complex, 208, Fig. 8.9 ICAM-2, 57–58, 205 ICAM-3, 205 ICOS (inducible T-cell co-stimulator), 214 Ig see Immunoglobulin(s) IgA, 83, 103–104 dimeric (secretory), 104, 268, Fig. 4.31 binding by mucins, 269 breast milk, 250, 287, Fig. 9.21 commensal bacteria-specific, 278–279, 285 effector functions, 246–247 mucosal secretions, 282, 283 neutralizing toxins and venoms, 253– 255 poly-Ig receptor, 247, Fig. 9.18 preventing pathogen entry to cells, 251, 252–253, Fig. 9.23, Fig. 9.24 protection at mucosal surfaces, 283– 285, Fig. 10.19, Fig. 10.20 transcytosis, 247, Fig. 9.18 effector functions, 103–104, Fig. 4.30 evasion by staphylococcal superantigenlike proteins, 374–375, Fig. 13.9 isotype switching to, 243, 283, 285, Fig. 9.13 monomeric, 103 effector function, 246 Fc receptor, 262–263, Fig. 9.37 secretory component (secretory piece), 247, Fig. 9.18 selective deficiency, 286–288, Fig. 10.23, Fig. 10.24, Fig. 13.10 structure, 84, Fig. 4.5 subclasses, 103, 285–286, Fig. 4.29 IgA1, 285–286 differential expression, 285–286, Fig. 10.22 hinge region, 285, Fig. 10.21 physical properties, Fig. 4.29 IgA2, 285–286 differential expression, 285–286, Fig. 10.22 hinge region, 285, Fig. 10.21 physical properties, Fig. 4.29 Igα, 97, 156, Fig. 4.23 pre-B-cell receptor, Fig. 6.7 regulation of expression, 152, 158, Fig. 6.12 signal transduction, 232, Fig. 9.1 Igβ, 97, 156, Fig. 4.23 pre-B-cell receptor, 153, Fig. 6.7 regulation of expression, 158, Fig. 6.12 signal transduction, 232, Fig. 9.1 IgD, 83 anergic B cells, 166, Fig. 6.19 biased use of λ light chains, 156 effector function, 104, Fig. 4.30 expression by maturing B cells, 164, 167 isotype switching from, 101–102, Fig. 4.28 mature naive B cells, 96, Fig. 4.22 membrane-bound form, 97–98 physical properties, Fig. 4.29 secreted antibodies, 98–99 structure, 84, Fig. 4.5 IgE, 83, 104, 406–410 effector functions, 104, 247–250, Fig. 4.30 Fc receptors, 248, 262, 407–409, Fig. 9.37 high affinity see FcεRI low-affinity see FcεRII important characteristics, 406–407 intestinal helminth infections, 289, Fig. 10.27 isotype switching to, 243, 404–406, Fig. 9.13, Fig. 14.5 mast-cell activation, 248, 249–250, 407, Fig. 9.19, Fig. 14.11 mediated allergic disease, 250, 402, 416– 428 monoclonal antibody targeting, 90, 409– 410, Fig. 14.14 parasite-specific responses, 248–250, 404, Fig. 9.20 physical properties, Fig. 4.29 somatic hypermutation levels, 405, Fig. 14.6 structure, 84, Fig. 4.5 transfer from mother to child, 419, Fig. 14.26 transport across mucosae, 283 IgG, 83, 104–105 complement activation, 257–258, Fig. 9.31 conformational flexibility, 104–105, Fig. 4.32 domains, 84, Fig. 4.6 effector functions, 104–107, 246, Fig. 4.30 Fc receptors, 258–262, Fig. 9.35, Fig. 9.37 FcRn receptor, 246, Fig. 9.17 hinge region, 83, Fig. 4.2, Fig. 4.4 infants, 250–251, Fig. 9.22 isotype switching to, 243, Fig. 9.13 negative regulation of naive B cells, Fig. 11.5 neutralizing function, 253–255, Fig. 9.26 proteolytic cleavage, 83, Fig. 4.3 structure, 82–84, Fig. 4.2, Fig. 4.5 subclasses, 103, Fig. 4.29 effector functions, 105–107, Fig. 4.30, Fig. 4.34 FcγRI binding, 259, Fig. 9.33 hinge region structures, 105–106, Fig. 4.33 IgE-mediated allergies, 405–406, Fig. 14.6 isotype switching to, 243, 405, Fig. 9.13, Fig. 14.5 transfer from mother to fetus, 250, Fig. 9.21 transport to mucosal secretions, 283, Fig. 10.18 type II hypersensitivity reactions, 402, Fig. 14.2 vs IgE, 406–407 IgG1, 105–106, Fig. 4.29 effector functions, 105–106, Fig. 4.30, Fig. 4.34 FcγRI binding, 259, Fig. 9.33 immune complex formation, 405–406, Fig. 14.7 isotype switching to, 101, 405, Fig. 4.28 structure, Fig. 4.33 IgG2, 105–106, Fig. 4.29 deficiency, 106, Fig. 13.10 effector functions, 105–106, Fig. 4.30, Fig. 4.34 Fc receptor, 261 isotype switching to, 405 structure, Fig. 4.33 IgG3, 106, Fig. 4.29 deficiency, 106 Index effector functions, 106, Fig. 4.30, Fig. 4.34 FcγRI binding, 259, Fig. 9.33 isotype switching to, 404–405 structure, 106, Fig. 4.33 IgG4, 106–107, Fig. 4.29 allergen-specific, 427 effector functions, 106–107, Fig. 4.30, Fig. 4.34 functionally monovalent, 106–107, Fig. 4.35 immune complex formation, 405–406, Fig. 14.7 isotype switching to, 405 structure, Fig. 4.33 therapeutic use, 107 IgM, 83 anergic B cells, 166, Fig. 6.19 cell-surface (monomeric), 97–98, Fig. 4.24 cross-linking, B-cell activation, 232, Fig. 9.1 maturing B cells, 164, 165, 167 structure, 101, Fig. 4.27 synthesis, 108, 156, Fig. 4.36, Fig. 6.10 timing of expression, 151, Fig. 6.4 complement activation, 255–256, Fig. 9.28 developing B cells, 151, Fig. 6.10 DiGeorge syndrome, 234–235 domain structure, 84, Fig. 4.5 effector functions, 103, 246, Fig. 4.30 IgA-deficient individuals, 287, Fig. 10.24 isotype switching, 101–102, Fig. 4.28 naive B cells, 96, Fig. 4.22 physical properties, Fig. 4.29 secreted (pentameric), 282 poly-Ig receptor, 247 production, 98–100, 169, 238, Fig. 4.24, Fig. 9.9 protective function, 283–284, Fig. 10.19 structure, 101, Fig. 4.27 transport mechanism, 283 staple form, C1q binding, 255, Fig. 9.28 IκB, 52–53, 448, Fig. 3.7 Ikaros, 188, Fig. 7.14 IKK (inhibitor of κ kinase) γ subunit (IKKγ), inherited deficiency, 53, Fig. 3.8 NOD receptor signaling, 55, Fig. 3.10 TLR4 signaling, 52–53, Fig. 3.7 Immediate hypersensitivity see Hypersensitivity reactions, type I Immune-complex disease, 381 Immune complexes autoimmune diseases due to, Fig. 16.1 chronic graft rejection, 443, Fig. 15.11 complement activation, 257–258, Fig. 9.31 deposition in kidney, 258, Fig. 16.20 preventing hemolytic disease of newborn, 305–306, Fig. 11.11 regulation of naive B cells, 300–301, Fig. 11.5 removal from circulation, 258, Fig. 9.32 serum sickness, 451, Fig. 15.22 systemic lupus erythematosus (SLE), 258, 476, 487, Fig. 16.20 type III hypersensitivity reactions, 403, Fig. 14.2 Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), 478, Fig. 13.10 Immune response see also Adaptive immune response; Innate immune response evasion/manipulation by tumors, 518–519, Fig. 17.13, Fig. 17.14, Fig. 17.15 evasion/subversion by pathogens, 365–375 phases, 47, Fig. 3.1 primary see Primary immune response secondary see Secondary immune response Immune system, Immunity, Immunization, 1–2 see also Vaccination childhood schedule, Fig. 11.15 passive, 255, 380 Immunocompromised individuals cancer risk, 513–514 cytomegalovirus infections, 372 Immunodeficiency diseases, 24, 365 see also Acquired immune deficiency syndrome inherited see Inherited immunodeficiency diseases primary, 375 secondary, 375 Immunogenetics, 438 Immunoglobulin(s), 16–17, 81–109 antigen-binding site see Antibodies, antigen-binding site diversity, 81–109 mechanisms of generation, 91–107 structural basis, 82–88 vs T-cell receptors, 120, Fig. 5.9 domains, 83–85, Fig. 4.6, Fig. 4.7 Fc receptors, 246, 258–263 genes see Immunoglobulin gene(s) intravenous see Intravenous immunoglobulin isotype exclusion, 156–157 isotypes (classes), 82, 83, 103 see also IgA; IgD; IgE; IgG; IgM distribution in body, Fig. 9.21 effector functions, 103–107, 245–250, Fig. 4.30 physical properties, Fig. 4.29 structure, 83, Fig. 4.5 switching see Isotype switching transfer from mother to baby, 250, Fig. 9.21 membrane-bound form, 97–98, 99, Fig. 4.23, Fig. 4.24 proteolytic fragments, 83, Fig. 4.3 secreted form see Antibodies structure, 81–109, Fig. 4.2 vs T-cell receptors, 113–114, Fig. 5.1 synthesis and membrane binding, 97–98, Fig. 4.23 Immunoglobulin gene(s), 91–92 allelic exclusion, 96–97, 154–155, Fig. 6.8 chromosome locations, 91–92, Fig. 4.15 control of transcription, 159, Fig. 6.13 germline configuration, 91, Fig. 4.15, Fig. 6.4 rearrangements, 92–96, 108, Fig. 4.36 B-1 cells, 161–162 developing B cells, 150–151, Fig. 6.4 D to J, 95–96, Fig. 4.20 nonproductive and productive, 152–153, Fig. 6.6 recombination enzymes, 93–95, Fig. 4.19 regulation, 96–97, 157, 159, Fig. 6.13 summary, 162–163, Fig. 6.16 segments, 91–92, Fig. 4.15 somatic recombination, 92–95, Fig. 4.16 summary of changes, 108–109, Fig. 4.37 translocations in B-cell tumors, 160–161, Fig. 6.14 Immunoglobulin-like domains, 85 Fc receptors, 260 MHC molecules, 123, 124, Fig. 5.14 NK-cell receptors, 335, Fig. 12.2 T-cell receptors, 114, Fig. 5.1 Immunoglobulin superfamily, 85, Fig. 3.12 Immunological memory see Memory, immunological Immunological privilege, eye, 495 Immunological tolerance see Tolerance, immunological Immunology, Immunophilins, 450 Immunoproteasome, 127 Immunoreceptor tyrosine-based activation motifs (ITAMs) B-cell receptor, 232, Fig. 9.1 Fc receptors, 259 T-cell receptor, 208, Fig. 8.10 Immunoreceptor tyrosine-based inhibitory motifs (ITIMs) Fc receptors, 261, Fig. 9.37 NK-cell receptors, 334 Immunosuppressive drugs, 210 autoimmune disease, 483 mechanisms of action, Fig. 15.30 organ transplant recipients, 441, 445–454, 457–458 side-effects, 446 Immunosurveillance, cancer, 514–515 Immunotoxins, 529, Fig. 17.28 Indigenous American populations, HLA diversity, 142, Fig. 5.39 Inducible T-cell co-stimulator (ICOS), 214 Infants see also Newborn babies dietary gluten exposure, 501 protective antibodies, 250–251, 287, Fig. 9.22 Infections causing cancer, 512–513, Fig. 17.4 effector T-cell responses, 218–219 establishment, 20 extracellular see Extracellular pathogens initiation of T-cell activation, 200–201, Fig. 8.1 intracellular see Intracellular pathogens mucosal vs systemic immune responses, 273–275, Fig. 10.9 opportunistic, AIDS, 395–396, Fig. 13.31 persistent, 369–371, Fig. 13.5 recovery from, 23 triggering autoimmune disease, 492–494, Fig. 16.31 Infectious diseases, 1, Fig. 1.4 with available vaccines, Fig. 11.25 chronic, vaccines against, 322–323 organisms causing see Pathogens protective immunity, 296–297, Fig. 11.1 selecting for MHC diversity, 140–143, Fig. 5.37 Infectious mononucleosis, 370 Inflammasome, 55–56, Fig. 3.11 Inflammation, 9, Fig. 1.7 airway, allergic asthma, 424, Fig. 14.35, Fig. 14.36 I:13 I:14 Index allergic reactions, 412 cancer-induced, 514 complement-mediated, 40, Fig. 2.15 IgE-mediated, 249 induction by macrophages, 53–54, Fig. 3.9 mucosal immune system, 273–275, 276– 277, Fig. 10.9 rheumatoid arthritis, 490, Fig. 16.25 role of NFκB, 52–53, Fig. 3.7 suppressive effects of corticosteroids, 448, Fig. 15.18 systemic effects, 62–63, Fig. 3.20 transplanted organs and recipients, 440– 441, Fig. 15.7 viral infections, 71–72, Fig. 3.32 Inflammatory cells, Inflammatory cytokines see Cytokines, inflammatory Inflammatory mediators eosinophils, 414, Fig. 14.20 mast cells, 249, 411–413, Fig. 14.16 parasitic infections, 250 Infliximab, 490–491, Fig. 16.26 Influenza, 4, 11 deaths, 23 epidemics, 367 H1N1 pandemic, 318–319, Fig. 11.23 immune response, 11, 370 immunization schedule, Fig. 11.15 pandemics, 367–368 vaccines, 318–319, Fig. 11.25 Influenza virus evasion of immune response, 366–368, Fig. 13.2, Fig. 13.3 extracellular and intracellular forms, 30–31 hemagglutinin see Hemagglutinin, influenza immunological memory, 306–307, Fig. 11.12 morphology, Fig. 1.3 neutralizing antibodies, 251–252, Fig. 9.23 Inherited immunodeficiency diseases, 375– 386, Fig. 13.10 antibody deficiencies, 379–381, Fig. 13.12 complement deficiencies, 381–382, Fig. 13.13 genetics, 377 IFN-γ receptor mutations, 378–379, Fig. 13.11 phagocyte defects, 382–383, Fig. 13.15 specific disease susceptibilities, 385–386 T-cell defects, 178–179, 380–381, 383–385, Fig. 13.16 Inhibitor of κB see IκB Inhibitor of κB kinase see IKK Innate immune response, 8–9 effector mechanisms, 8, Fig. 1.6 failure to contain infection, 10, 12, 77, Fig. 3.41 immediate, 29–44, Fig. 3.1 importance, 12, Fig. 1.10 induced, 47–78, Fig. 3.1 inflammation, 9, Fig. 1.7 pathogen recognition mechanisms, vs adaptive immunity, 10, Fig. 1.8 Innate immunity, 2, autoinflammatory diseases, 502–503 cellular receptors, 47–49, Fig. 3.2 coevolution with adaptive immunity, 329–361, Fig. 12.1 immediate defenses, 29–44 importance, 12 induced defenses, 47–78 Insects, venomous, 422 Insulin, 495, 496 Insulin-dependent diabetes mellitus (IDDM) see Diabetes, type Insulin receptor autoantibodies, 483, Fig. 16.12 Insulitis, 496, Fig. 16.33 Integrins, 50, Fig. 3.12 effector T cells, 219, Fig. 8.19 mucosa-specific lymphocyte homing, 281, 282, Fig. 10.16 Interallelic conversion, 142, Fig. 5.38 Intercellular adhesion molecules see ICAM-1; ICAM-2; ICAM-3 Interferon(s), 68–71 coordinate gene regulation, 138 response, 70, Fig. 3.33, Fig. 3.34 type I, 68–69 functions, 70–71, Fig. 3.34 induction of synthesis, 69, 75, Fig. 3.32, Fig. 3.33, Fig. 3.39 NK-cell activation, 71, 74, Fig. 3.34, Fig. 3.38 plasmacytoid dendritic cells, 71 therapeutic use, 71 type II, 76 Interferon-α (IFN-α) functions, 70–71, Fig. 3.34 induction of synthesis, 75, Fig. 3.34, Fig. 3.39 NK-cell activation, 71, 74, Fig. 3.38 Interferon-β (IFN-β) functions, 70–71, Fig. 3.34 induction of synthesis, 69, 75, Fig. 3.33, Fig. 3.39 NK-cell activation, 71, 74, Fig. 3.38 therapy in multiple sclerosis, 477 Interferon-γ (IFN-γ), 76 celiac disease and, 501 control of HLA-DM/HLA-DO balance, 131 control of isotype switching, 243, Fig. 9.13 coordinate gene regulation, 138 intestinal helminth infections, 289, Fig. 10.27 macrophage activation, 224–225, Fig. 8.27 multiple sclerosis, 476 production by NK cells, 76, Fig. 3.40 proteasome modification, 126–127 T cells expressing, 223, Fig. 11.7 TH1 development, 213, Fig. 8.14 Interferon-γ (IFN-γ) receptors, 378, Fig. 13.11 deficiency, 378–379, 385 dominant and recessive mutations, 378– 379, Fig. 13.11 intracellular infections, 386, Fig. 13.18 Interferon-response factor (IRF3), 69, Fig. 3.32, Fig. 3.33 NK-cell activation, 75, Fig. 3.39 Interferon-response factor (IRF7), 70–71, Fig. 3.34 NK-cell activation, 75, Fig. 3.39 Interleukin-1 (IL-1), 55 Interleukin-1β (IL-1β), 53, Fig. 3.9 amplification of production, 55–56, Fig. 3.11 autoinflammatory syndromes and, 503 induction of inflammation, 53–54 precursor protein (proIL-1β), 55–56, Fig. 3.11 systemic effects, 62–63, Fig. 3.20 Interleukin-1 receptor antagonist (IL-1RA), 56 deficiency, Fig. 16.41 Interleukin-2 (IL-2) activated T cells, 209–210, Fig. 8.12 CD8 T-cell differentiation, 216, Fig. 8.17 Interleukin-2 (IL-2) receptors activated T cells, 210, Fig. 8.12 α chain see CD25 CD8 T cells, 216, Fig. 8.17 monoclonal antibody inhibiting, 452–453, Fig. 15.24, Fig. 15.30 Interleukin-3 (IL-3), intestinal helminth infections, 289, Fig. 10.27 Interleukin-4 (IL-4) control of isotype switching, 243, Fig. 9.13 gene polymorphism, 418, Fig. 14.25 inhibition of macrophage activation, 225 memory B-cell development, 244, Fig. 9.15 secretion by basophils, 415 sensitization to inhaled allergens, Fig. 14.23 TH2 development, 213, Fig. 8.14 Interleukin-4 (IL-4) receptor, gene polymorphism, 418, Fig. 14.25 Interleukin-5 (IL-5) B-cell differentiation, 238 control of isotype switching, Fig. 9.13 intestinal helminth infections, 289, Fig. 10.27 monoclonal antibodies, 428 regulation of eosinophils, 414, 415 Interleukin-6 (IL-6), 53, 54, Fig. 3.9 B-cell effects, 238, 239 systemic effects, 62–63, Fig. 3.20 TFH cell development, 214 Interleukin-7 (IL-7) B-cell development, 152, Fig. 6.5 T-cell development, 180 Interleukin-7 (IL-7) receptor B cells, Fig. 6.5, Fig. 6.12 memory T cells, 300, 303, 305 thymocytes, 180, Fig. 7.5 Interleukin-9 (IL-9), intestinal helminth infections, 289, Fig. 10.27 Interleukin-10 (IL-10) B-1 cell survival, 162 deficiency, 275 gut dendritic cells, 278 inhibition of macrophage activation, 225 plasma cell development, 244, Fig. 9.15 Interleukin-12 (IL-12) NK cell activation, 54, 75–76, Fig. 3.40 NKT cell activation, 357, Fig. 12.32 production by macrophages, 53, Fig. 3.9 TH1 development, 213, Fig. 8.14 Interleukin-12 (IL-12) receptors, 75–76 deficiency, 385–386 Interleukin-13 (IL-13) inhibition of macrophage activation, 225 intestinal helminth infections, 289, Fig. 10.27 secretion by basophils, 415 Interleukin-15 (IL-15) germinal center formation, 239 NK-cell activation, 76, Fig. 3.40 Interleukin-15 (IL-15) receptors, memory T cell survival, 300 Index Interleukin-16 (IL-16), 214 Interleukin-17 (IL-17), 213–214 Interleukin-21 (IL-21), 214 Interleukin-33 (IL-33), 289 Interleukins, 220 Intestinal epithelial cells (enterocytes), 277 see also Intraepithelial lymphocytes; M cells destruction in celiac disease, 498, 500, Fig. 16.36 innate immune responses, 276–277, Fig. 10.10 response to helminth infections, 289 Intestine see Large intestine; Small intestine Intracellular compartments, 125–126, Fig. 5.17 Intracellular pathogens, 30–31, Fig. 2.2 antigen presentation, 122–123 antigen processing, 126–128, 134, Fig. 5.19, Fig. 5.27 cytotoxic CD8 T-cell responses, 222–224 innate and adaptive immune response, 385–386, Fig. 13.18 interferon response, 68–71 susceptibility to infection, 385–386 Intraepithelial lymphocytes (IEL), 282, Fig. 10.17 Intraepithelial pockets, 278, Fig. 10.13 Intravenous immunoglobulin (IVIG) autoimmune disease, 489–490, Fig. 16.22, Fig. 16.23 inherited immunodeficiencies, 90, 160, 379–380 Invariant chain, 130, Fig. 5.23 gene locus, 138 IPEX, 478, Fig. 13.10 Ipilimumab, 521–522, Fig. 17.19, Fig. 17.27 IRAK4, 52, Fig. 3.7 Ischemia, donor organs, 440–441 Islets of Langerhans, 496, Fig. 16.33 Isograft, 439 Isopentyl pyrophosphate (IPP), 350, Fig. 12.24 Isotype switching, 101–102, Fig. 4.28 B-cell zone of lymph node, 239–241, Fig. 9.11 regulation by cytokines, 243–244, Fig. 9.13 ITAMs see Immunoreceptor tyrosine-based activation motifs ITIM see Immunoreceptor tyrosine-based inhibitory motifs J Jak1, 70, 378, Fig. 13.11 Jak2, 378, Fig. 13.11 Jak3, 384 deficiency, Fig. 13.16 Janus kinases (JAKs), 221, Fig. 8.22 J chain, Fig. 4.27, Fig. 4.31 Jenner, Edward, 1–2, 308, 309 J gene segments see Joining gene segments Joining (J) gene segments immunoglobulins, 92, Fig. 4.15, Fig. 4.17 recombination signal sequences (RSSs), 93, Fig. 4.18 somatic recombination, 92–95, Fig. 4.16 T-cell receptors, 115, Fig. 5.3, Fig. 5.8 T-cell vs B-cell receptors, Fig. 5.9 Jun, 209 Junctional diversity immunoglobulins, 95–96, Fig. 4.20 T-cell receptors, 115, 119 T-cell vs B-cell receptors, Fig. 5.9 Juvenile rheumatoid arthritis, HLA association, Fig. 16.9 K Kaposi’s sarcoma, 396, Fig. 17.4 κ light chains, immunoglobulin, 83 gene locus, 91–92, Fig. 4.15 gene rearrangements, 151, 155–156, Fig. 6.9 gene segments, 93, Fig. 4.17 utilization by B cells, 156 Kidney glomerular basement membrane autoantibodies, 475–476, Fig. 16.3 immune complex deposition, 258, Fig. 16.20 Kidney transplantation see also Organ transplantation acute rejection, Fig. 15.8, Fig. 15.9 anti-T-cell antibody therapy, 90, 450, Fig. 15.21 baseline inflammatory state, 440–441, Fig. 15.7 cadaveric donors, 445 cancer risk after, 513–514 chronic rejection, 443 combined with hematopoietic cell transplant, 467 HLA matching, 445, Fig. 15.14 hyperacute rejection, 436–437, Fig. 15.4 immunosuppressive drugs, 445–446 live organ donors, 441, 445 mechanism of graft rejection, 143 supply of donor organs, 454, Fig. 15.26 syngeneic, 439 transfer of tumors, 515 Killer-cell immunoglobulin-like receptors (KIR), 335–336 see also specific KIRs cancer therapy targeting, 525 gene organization, 339–340, Fig. 12.12 haplotypes gene-content variation, 340–341, Fig. 12.14 pregnancy complications and, 344–345, Fig. 12.18 ligand-binding sites, 335, Fig. 12.7 ligands or epitopes of HLA class I, 335–336, Fig. 12.8 NK-cell education, 336, 337–339, Fig. 12.9, Fig. 12.10 polymorphisms and HIV progression, 336, 393, Fig. 13.26 and human disease, 336, 340, 377 similarities to Ly49 receptors, 340, Fig. 12.13 variegated gene expression, 336 Kinin system, 40 KIR see Killer-cell immunoglobulin-like receptors KIR2DL1, 335, 336, Fig. 12.2 placental formation, 344, Fig. 12.17 KIR2DL2/3, 335, 336, Fig. 12.2 NK-cell education, 337–339, Fig. 12.11 placental formation, 344, Fig. 12.17 KIR2DL4, 335, 336, Fig. 12.2 placental formation, 344, Fig. 12.17 KIR2DS1, 335, 336, Fig. 12.2 KIR2DS2, senescent T cells, 502 KIR3DL1, 335, 336, Fig. 12.2 KIR3DL2, 335, 336, Fig. 12.2 Kit B-cell development, 152, Fig. 6.5, Fig. 6.12 T-cell development, Fig. 7.14 Klebsiella pneumoniae, 314–315 Kostmann syndrome, Fig. 15.32 Kupffer cells, 36, 131–132 L Lactoferrin, 60 λ5, 153–154, Fig. 6.7 inherited defects, 154, Fig. 13.10 regulation of expression, 158, Fig. 6.12 λ light chains, immunoglobulin, 83 gene locus, 92, Fig. 4.15 gene rearrangements, 151, 155–156, Fig. 6.9 gene segments, 93, Fig. 4.17 utilization by human B cells, 156 Lamina propria, 272, Fig. 10.7 effector lymphocytes, 281, 283, Fig. 10.16 IgA production, 247, Fig. 9.18 macrophages, 276–277 Langerhans cell histiocytosis, Fig. 14.19 Langerhans cells, Fig. 8.1 Large granular lymphocytes, 16 Large intestine, lymphoid tissues, 272 Latent infections, 370–371, Fig. 13.5 Lck expression in developing T cells, 188, Fig. 7.14 pre-T-cell receptor signaling, 184 role in TCR signaling, 192, 208, Fig. 8.10 Leader peptide (L), genes, 92, Fig. 4.15 Lectin-like domains, NK-cell receptors, 333, Fig. 12.2 Lectins, 50 Leishmania, macrophage receptors, 50 Lenalidomide, 524 Lentiviruses, 388 Leprosy lepromatous/tuberculoid macrophage activation, 225 polarized TH1 response, 215, Fig. 8.15, Fig. 8.16 T-cell responses to lipid antigens, 354–356 Leucine-rich repeat region (LRR), 51 Leukapheresis, 463 Leukemia, 510 see also Graft-versus-leukemia (GVL) effect acute lymphoblastic (ALL), 466, Fig. 6.23 acute myelogenous (AML), 466, 518–519 chronic lymphocytic (CLL), 162, Fig. 6.23, Fig. 17.27 chronic myelogenous, 517, Fig. 17.10 hematopoietic stem-cell transplant, 465– 466 pre-B-cell, Fig. 6.23 radiation-induced, 512 Leukocyte adhesion deficiency, 382, Fig. 13.15 Leukocyte-associated immunoglobulin-like receptors (LAIR), Fig. 12.12 Leukocyte immunoglobulin-like receptors (LILR), 339, Fig. 12.12 Leukocyte-receptor complex (LRC), 263, 339, 340, Fig. 12.12 Leukocytes (white blood cells), 12 adhesion to vascular endothelium, 57, Fig. 3.12 I:15 I:16 Index autoantibodies against, 475 in inflammation, numbers in blood, Fig. 1.14 origins and development, 12–16 Leukocytosis, 381 Leukotrienes, 412, Fig. 14.18 LFA-1 B cell–helper TFH cell interaction, 238, Fig. 9.8 effector T cells, 219, Fig. 8.18, Fig. 8.19 inherited defects, 382 naive T-cell homing, 205–206, Fig. 8.6 neutrophil recruitment, 57–58, Fig. 3.13 NK cells, 74, Fig. 12.2 peripheral supramolecular activation complex, 208, Fig. 8.9 LFA-3, T cell–dendritic cell adhesion, 205 Li–Fraumeni syndrome, 512 Light chains (L chains), 82–83, Fig. 4.2 biased use by B cells, 156 constant domain, 84, Fig. 4.6, Fig. 4.7 framework regions, 85–86, Fig. 4.8 gene loci, 91–92 gene rearrangements, 92–93, Fig. 4.16 B-cell precursors, 151, 155–157, Fig. 6.4, Fig. 6.9 self-reactive immature B cells, 165–166, Fig. 6.18 gene segments, 91–92, Fig. 4.15, Fig. 4.17 hypervariable regions (HV), 85–86, Fig. 4.8 isotypes, 83 κ see κ light chains λ see λ light chains surrogate, 153–154, Fig. 6.7 synthesis, 151, Fig. 6.4 variable domain (VL), 84, Fig. 4.6, Fig. 4.7 LILRB1, 339, Fig. 12.2 placental formation, 344, Fig. 12.17 Linkage disequilibrium, HLA allele associations, 479–480 Lipid antigens chemical structure, Fig. 12.27 presentation to γ:δ T cells, 352–353, Fig. 12.28, Fig. 12.32 presentation to NKT cells, 356–357 recognized by CD1-restricted α:β T cells, 354–356, Fig. 12.29 Lipid mediators eosinophils, Fig. 14.20 mast cells, 412, Fig. 14.16, Fig. 14.18 Lipid-transfer proteins, 355, 356 Lipoarabinomannan, Fig. 12.29 Lipomannan, Fig. 12.29 Lipopeptides, 50, Fig. 3.3, Fig. 3.29 Lipopolysaccharide (LPS) downstream signaling, 52–53, Fig. 3.7 macrophage receptors recognizing, 50, Fig. 3.3 neutrophil receptors, Fig. 3.15 receptor see CD14 recognition by TLR4, 51–52, Fig. 3.6, Fig. 3.29 Lipopolysaccharide-binding protein (LBP), Fig. 3.6 Lipoteichoic acid (LTA), Fig. 3.3, Fig. 3.29 5-Lipoxygenase, Fig. 14.25 Lirilumab, 525 Listeria monocytogenes, 371, Fig. 1.3 Liver transplantation factors affecting success, 457 organ donors, 441, 455, Fig. 15.26 LMP2, 138, Fig. 5.32 LMP7, 138, Fig. 5.32 LPS see Lipopolysaccharide L-selectin (CD62L) effector T cells, 219, Fig. 8.18 memory T cells, 303, 304, Fig. 11.7 mucosa-derived effector lymphocytes, 281 naive T-cell homing, 205, Fig. 8.6 Lung carcinoma, non-small cell, Fig. 17.10 Lung transplantation, Fig. 15.26 Lupus erythematosus, 476 see also Systemic lupus erythematosus Ly49 receptors, 340, Fig. 12.13 Lyme disease, chronic arthritis, Fig. 16.31 Lymph, 20 naive T cells, 203, Fig. 8.5 transport of pathogens, 21–22, Fig. 1.21 Lymphatics, 20 Lymphatic vessels, 20 afferent, 22, Fig. 1.22 efferent, 22, Fig. 1.22 Lymph nodes, 20, 21–23 activation of adaptive immunity, 22–23, Fig. 1.23 anatomy, Fig. 1.22 B-cell activation, 168–169, Fig. 6.22, Fig. 9.7 B-cell circulation, 167, Fig. 6.20 B-cell maturation, 167–168, Fig. 6.21 B-cell zone, 239–241 draining, 21, Fig. 1.21, Fig. 1.23 exit of T cells from, 206 mantle zone, 239–240, Fig. 9.11 medullary cords, 238–239, Fig. 9.9 migration of plasma cells to, 170 naive T-cell recirculation, 206, Fig. 8.5 swelling during infections, 22, 240 T-cell activation, 200–201, Fig. 8.1 T-cell zone (T-cell area), 203 activation of naive B cells, 236–237, Fig. 9.7 transport of pathogens to, 20–21, Fig. 1.21 Lymphoblasts, 169 Lymphocytes, 10 see also B cell(s); T cell(s) activation by pathogens, Fig. 1.21 antigen receptors, 17 cell-surface receptors, 10 circulating, populations, 71 effector see Effector cells gut-associated, 272 intraepithelial, 282, Fig. 10.17 large granular, 16 lymph nodes, 21–22, Fig. 1.22 mucosal lymphoid tissues, 25, Fig. 1.26 numbers in blood, Fig. 1.14 origins, 16 recirculation, 20, Fig. 1.20 recognition of pathogens, 10–11 selection by pathogens, 11, Fig. 1.9 small, 16, 20, Fig. 1.11, Fig. 1.20 spleen, 23, Fig. 1.24 thymus-dependent, 177 tissue locations, 19–20, Fig. 1.19 Lymphoid follicles, 22, Fig. 1.22 B-cell maturation, 167–168, Fig. 6.21 isolated, intestinal, 272, Fig. 10.7 primary, 167, Fig. 6.20 antigen capture and display, 235–236, Fig. 9.6 entry of immature B cells, 167, Fig. 6.21 germinal center formation, 239, Fig. 9.9 movement of B cells to, 239–240 secondary, 169, 239–240 spleen, Fig. 1.24 Lymphoid lineage cells, 16, Fig. 1.13 Lymphoid neogenesis, 484 Lymphoid organs, 19 Lymphoid progenitor cells, 16, 150, Fig. 1.13, Fig. 6.3 bone marrow stromal-cell interactions, Fig. 6.5 Lymphoid tissues, 19–20 primary (central), 19–20, 178, Fig. 1.19 secondary (peripheral) see Secondary lymphoid tissues tertiary (ectopic), 484–485, Fig. 16.16 Lymphokines, 220 Lymphoma, 510 see also Hodgkin’s disease; specific lymphomas diagnosis, 526–528 treatment, 528–529, Fig. 17.27 Lymphoproliferative syndrome, X-linked, 386 Lymphotoxin (LT), B cell–follicular dendritic cell interactions, 167–168 Lyn, B-cell receptor signaling, 232, 233, Fig. 9.1 Lysosomes antigen processing, 126 fusion with phagosome, 50, 60–61, Fig. 3.16 Lysozyme, neutrophils, 60 Paneth cells, 41, Fig. 2.18 M Mac-1 see CR3 α2-Macroglobulins, 40–41, Fig. 2.16 Macrophage receptor with collagenous structure (MARCO), 50, Fig. 3.3 Macrophages, 15, Fig. 1.11 activation, 224–225, Fig. 8.27 activity in lymph nodes, 22, Fig. 1.23 antigen processing, 129–130, 131, Fig. 5.22 cell-surface receptors, 49–51, Fig. 3.3 complement receptors, 36–37, Fig. 2.10 co-stimulatory molecules, 207 cytokines, Fig. 1.16 induction of synthesis, 51–53, Fig. 3.7 inflammatory effects, 53–54, Fig. 3.9 help from CD4 T cells, 122, Fig. 5.13 HIV infection, 389 induction of inflammation, 53–54, Fig. 3.9 inflammation-anergic, 276 inherited defects, 382–383, Fig. 13.15 intestinal, 276–277, Fig. 10.11 intracellular pathogens, 371 lipopolysaccharide recognition, 51–52, Fig. 3.6 lymph node, functions, 201–202 medullary sinus, 236 negative selection of T cells, 192, Fig. 7.18 NK-cell interactions, 75–76, Fig. 3.40 phagocytosis, 15, Fig. 1.16 as first line of cellular defense, 36–37 and pathogen degradation, 50, Fig. 3.4 receptors mediating, 49–50, Fig. 3.3 role of complement, 36–37, Fig. 2.10 responses to pathogens, 15, Fig. 1.16 signaling receptors, 50–51, Fig. 3.3 splenic, 23 subcapsular sinus, 236 Index thymic, 178, 182–183, Fig. 7.3, Fig. 7.8 tingible body, 241 TLR4 signaling pathways, 51–53, Fig. 3.7 Macropinocytosis, by dendritic cells, 202, Fig. 8.3 MAdCAM-1, 281, 282, Fig. 10.16 MAGEA1/MAGEA3 antigens, 520–521, Fig. 17.18 MAIT (mucosa-associated invariant T) cells, 354, 357–359, Fig. 12.34 Majeed syndrome, Fig. 16.41 Major basic protein, 415, Fig. 14.20 Major histocompatibility complex see MHC Malaria, 322–323, 369, Fig. 11.26 Malignant transformation, 511, 516, Fig. 17.3 Malignant tumors, 510, Fig. 17.1 see also Cancer MALT see Mucosa-associated lymphoid tissue Mannose-binding lectin (MBL), 63–66, Fig. 3.24 acute-phase response, Fig. 3.21 complement activation, 63–66, Fig. 3.25 inherited deficiency, 65–66, Fig. 13.10 structure, 63, Fig. 3.23 Mannose-binding lectin associated serine protease (MASP-1), 64, Fig. 3.23, Fig. 3.25 Mannose-binding lectin associated serine protease (MASP-2), 64–65, Fig. 3.23, Fig. 3.25 Mannose receptors, 50, Fig. 3.3 Mannosylated lipoarabinomannan, Fig. 3.3 Mannosyl-β-1-phosphomycoketide, Fig. 12.29 Mannuronic acid, Fig. 3.3 Mantle cell lymphoma, Fig. 6.23 Mantle zone, 239–240, Fig. 9.11 MARCO (macrophage receptor with collagenous structure), 50, Fig. 3.3 MART2, Fig. 17.10 MASP see Mannose-binding lectin associated serine protease Mast cells, 15–16, 410–413, Fig. 1.11 activation/degranulation, 411–412 IgE binding to FcεRI, 407, Fig. 14.11 IgE function, 248, 249–250, Fig. 9.19 localized allergic reactions, 420–421, Fig. 14.29 mediators released, 411–413, Fig. 14.16 recruitment of basophils, 415 connective tissue, 411 effector functions, 411, Fig. 14.16 Fcε receptors, 248, 249–250, Fig. 9.19 FcεRI, 407, Fig. 14.10 granules, 410–411, Fig. 14.15 intestinal helminth infections, 289, Fig. 10.27 mucosal, 411 Master regulators CD4 T-cell differentiation, 212, 213, 214 NKT-cell development, 356 MAVS (mitochondrial antiviral signaling) protein, 69, Fig. 3.32 MBL see Mannose-binding lectin M cells (microfold cells), 25, 277–278, Fig. 1.26 antigen uptake and transport, 277–278, Fig. 10.13 appearance, 277, Fig. 10.12 exploitation by pathogens, 279 MD2, TLR4 association, 51–52, Fig. 3.6, Fig. 3.7 MDA-5, 69 ME1, Fig. 17.10 Measles, 321–322 acquired immunity, 11 immunological memory, 299 incidence over time, 321, Fig. 11.24 vaccine, Fig. 11.25, Fig. 11.26 Measles, mumps and rubella (MMR) vaccine, 321, Fig. 11.15 Mediterranean fever, familial (FMF), 502, Fig. 16.41 Medullary sinus macrophages, 236 MEFV gene, 502 Megakaryocytes, 12, 14, Fig. 1.11 Melanoma monoclonal antibody therapy, 521–522, Fig. 17.19, Fig. 17.27 transplant-mediated transfer, 515 tumor antigens, 517, Fig. 17.10, Fig. 17.11 vaccination, 520–521, Fig. 17.18 Membrane-attack complex, 37–38, Fig. 2.11 inherited deficiency, 38, 381 membrane pore formation, 38, Fig. 2.13 regulation of formation, 38–39, Fig. 2.14 Membrane co-factor protein (MCP), 35–36, Fig. 2.9 Memory, immunological, 11–12, 295, 296–308 influenza virus escape, 306–307, Fig. 11.12 vaccination inducing, 299, Fig. 11.3 Memory B cells, 297–300 activation, 300–301, 302 antigen-independent survival, 299–300 differentiation, 169–170, 244, Fig. 9.15 duration of protection, 299, Fig. 11.3 production, 297–298, Fig. 11.2 vs naive and effector B cells, 300, 302 Memory cells, 11, 295 Memory T cells, 297–300, 302–305 activation, 301–302 antigen-independent survival, 299–300 antigen specificities, 304 cell-surface proteins, 302–304, Fig. 11.7 central (TCM), 304, Fig. 11.9 duration of protection, 299, Fig. 11.3 effector (TEM), 304, Fig. 11.9 γ:δ, 349, Fig. 12.21 generation in virus infections, 305, Fig. 11.10 production, 297–298, Fig. 11.2 Meningitis Neisseria meningitidis, 66, 315–316 vaccine, 315–316, Fig. 11.25 Meningococcus see Neisseria meningitidis Mepolizumab, 428 6-Mercaptopurine, 453, Fig. 15.25 Mesenteric lymph nodes, 272, Fig. 10.7 B- and T-cell activation, Fig. 10.15 transport of pathogens to, 279 Metastasis, 510 Methotrexate, 454, 461, Fig. 15.25, Fig. 15.30 MF59, 316, Fig. 11.21 MHC (major histocompatibility complex), 113–114, 135–144, 438 see also HLA alleles, 135–136 generation of new, 142–143, Fig. 5.38 allotypes, 136, Fig. 5.29 antigen presentation, 121–135, Fig. 5.27 class I molecules see MHC class I molecules class I region, 137, 138, Fig. 5.30 class II molecules see MHC class II molecules class II region, 137, 138, Fig. 5.30 class III region (central), 137, Fig. 5.30 diversity, 135–136 generation, 140–143, Fig. 5.35 importance for human survival, 142–143, Fig. 5.39 gene families, 135 gene organization, 137–138, Fig. 5.30 heterozygote advantage, 141, Fig. 5.36 heterozygotes, 136, 137 highly polymorphic genes, 136, Fig. 5.28, Fig. 5.29 homozygotes, 136, 137 isoforms, 136 autologous/allogeneic, 143 isotypes, 135, Fig. 5.28 monomorphic genes, 136, Fig. 5.28 oligomorphic genes, 136, Fig. 5.28 polymorphism, 113–114, 135–136, Fig. 5.28, Fig. 5.29 see also HLA, polymorphism antigen presentation effects, 138–140, Fig. 5.33 natural selection generating, 140–143, Fig. 5.37 transplant rejection, 143–144 restriction, 140, Fig. 5.35 self see Self-MHC molecules MHC class I-like molecules, non-polymorphic see also CD1; MR1 evolution, 359–360 restricting α:β T cells, 354–360 MHC class I molecules, 122, Fig. 5.11 see also HLA class I molecules anchor residues, 139, Fig. 5.34 antigen cross-presentation, 131–132, Fig. 5.24 antigen processing for, 126–127, Fig. 5.19 CD8 binding site, 124, Fig. 5.15 cells expressing, 132, Fig. 5.25 cytomegalovirus (CMV) and, 341–342 deficiency, 127, 385, Fig. 13.10, Fig. 13.16 genes, 135–136, Fig. 5.30 isotypes, 135–136, Fig. 5.28 KIR ligands or epitopes, 335–336, Fig. 12.8 NK-cell education detecting changes in, 336–339, Fig. 12.9 NK-cell receptors recognizing, 333–339, Fig. 12.2 killer-cell immunoglobulin-like receptors, 335–336, Fig. 12.7 NK-cell inhibition, 333–335, Fig. 12.6 peptide binding, 124–125, 127–128 allotype variability and, 139, Fig. 5.33 intracellular compartments, 126 peptide-loading complex, 127–128, Fig. 5.20 promiscuity, 124 T-cell receptor complex, 132–133, Fig. 5.26 peptide-binding groove, 124, Fig. 5.16 peptide-binding motifs, 139, Fig. 5.34 recycling to endoplasmic reticulum, 128 structure, 123, Fig. 5.14 trophoblast–uterine NK cell interactions, 343–344, Fig. 12.17 tumor cells, 515–516 virus interference mechanisms, 371–372, Fig. 13.7 I:17 I:18 Index MHC class II compartment (MIIC), 130–131 MHC class II molecules, 122, Fig. 5.11 see also HLA class II molecules allergic disease susceptibility and, 418, Fig. 14.25 anchor residues, 139, Fig. 5.34 antigen processing for, 126, 129–130, Fig. 5.22 CD4 binding site, 124, Fig. 5.15 cells expressing, 132, Fig. 5.25 deficiency, 192, 385, Fig. 13.16 effector T-cell activation, 219 genes, 135–136, Fig. 5.30, Fig. 5.32 invariant chain association, 130, Fig. 5.23 isotypes, 136, Fig. 5.28 naive B-cell activation, 237–238 peptide binding, 124–125, 126 allotype variability and, 139, Fig. 5.33 promiscuity, 124 regulation, 130–131, Fig. 5.23 self peptides, 126 T-cell receptor complex, 133, Fig. 5.26 vesicular system, 129–130, Fig. 5.22 peptide-binding groove, 124, Fig. 5.16 peptide-binding motifs, 139, Fig. 5.34 structure, 123–124, Fig. 5.14 superantigen interactions, 373, Fig. 13.8 MHC class II transactivator (CIITA), 138, 385 MIC glycoproteins (MIC-A and MIC-B) activation of NK cells, 334–335, Fig. 12.6 tumor cells, 518, Fig. 17.13 Microbiota, 3, 30 Microfold cells see M cells β2-Microglobulin, 123, Fig. 5.14 gene locus, 137 MR1, 358 peptide-loading complex, 127, 128, Fig. 5.20 Microorganisms causing human disease, Fig. 1.4 commensal see Commensal microorganisms pathogenic see Pathogens physical barriers against, 4–8, 29, Fig. 1.5 MIIC (MHC class II compartment), 130–131 Minor histocompatibility antigens, 464–465, Fig. 15.38 derivation from self proteins, 465, Fig. 15.40 HLA molecules presenting, 464, Fig. 15.39 Minor histocompatibility loci, 464 Mixed essential cryoglobulinemia, Fig. 16.1 Mixed lymphocyte reaction (MLR), 442–443, Fig. 15.10, Fig. 15.44 MLL5 (mixed-lineage leukemia protein 5), Fig. 12.2 Molecular mimicry, 493–494 Monkeypox, 310 Monoclonal antibodies, 88–91 allergic disease, 90, 409–410, 428, Fig. 14.14 cancer diagnosis, 526–528 cancer therapy see Cancer, monoclonal antibody therapy cell-surface markers, 88, Fig. 4.13 chimeric, 90, Fig. 4.14 conjugated, 528–529, Fig. 17.27 human, 90–91, Fig. 4.14 humanized, 90, Fig. 4.14 IgG4 subclass, 107 production, 88, 154–155, Fig. 4.12 rheumatoid arthritis, 490–491, Fig. 16.26 therapeutic uses, 90–91, Fig. 4.14 transplant recipients, 447, 450–451, 452– 453 Monocytes, 15, Fig. 1.11 development into intestinal macrophages, 276–277, Fig. 10.11 numbers in blood, Fig. 1.14 recruitment to infected tissue, 54 Monomorphic, 136 Montagu, Lady Mary Wortley, MR1, 354, 358–359, Fig. 12.35 mRNA splicing, alternative see Alternative RNA splicing μ heavy chains, immunoglobulin, 83, Fig. 4.5 allelic exclusion, 154–155, Fig. 6.8 alternative RNA splicing, 99–100, Fig. 4.24 B-cell precursor cells, 150–151 elimination of B cells unable to make, 153–154 synthesis, 96, 150–151, Fig. 4.22, Fig. 6.4 Mucins, 269, Fig. 10.2, Fig. 10.3 Mucopolysaccharidosis, Fig. 15.32 Mucosa-associated invariant T (MAIT) cells, 354, 357–359, Fig. 12.34 Mucosa-associated lymphoid tissue (MALT), 25 see also Gut-associated lymphoid tissues B- and T-cell commitment to, Fig. 10.15 dimeric IgA synthesis, 247 Mucosae, 267 Mucosal immunity, 267–307 vs systemic immunity, 273–275, Fig. 10.9 Mucosal mast cells, 411 Mucosal surfaces see also Epithelia; Gastrointestinal tract commensal microorganisms, 29–30 distinctive features of adaptive immunity, 290, Fig. 10.28 distribution in body, 267–268, Fig. 10.1 effector lymphocytes, 280–282, Fig. 10.17 lymphoid tissues, 25 mucins, 269, Fig. 10.3 neutralizing antibodies, 252–253, Fig. 9.24 physical barriers to infection, 6–8, 29, Fig. 1.5, Fig. 2.1 secretory immunoglobulins see IgA, dimeric; IgM, secreted vulnerability to infection, 267–268 Mucus, 6, 267 intestinal helminth infections, 289 mucins and viscoelastic properties, 269, Fig. 10.2 secretory immunoglobulins, 283–284, Fig. 10.19 Multiple sclerosis, 476–477, Fig. 16.1, Fig. 16.9 Mumps vaccine, Fig. 11.25 Muramyl dipeptide (MDP), NOD receptor, 55 Mutagens, 512 Mutations, 510 cancer causation, 510–513, Fig. 17.3 HIV, 393–394, Fig. 13.28 influenza virus genes, 366–368, Fig. 13.2 tumor-specific, 516–517, Fig. 17.10 Myasthenia gravis, 483, Fig. 16.1, Fig. 16.12, Fig. 16.14 HLA association, 483, Fig. 16.9 Mycobacteria evasion mechanisms, 130 lipid antigens presented by CD1, 354–356, Fig. 12.29 susceptibility to infection, 378, 385–386 Mycobacterium avium, 385, 396 Mycobacterium bovis, 386, 514 Mycobacterium leprae, 215, Fig. 8.16 Mycobacterium phlei, glucose monomycolate, Fig. 12.27 Mycobacterium tuberculosis, 322–323, 371, Fig. 1.3 see also Tuberculosis Mycolic acid, Fig. 12.29 Mycophenolate mofetil, 453, Fig. 15.30 Mycophenolic acid, 453, Fig. 15.25 MYC proto-oncogene, 161, Fig. 6.14 diagnostic monoclonal antibodies, 526, Fig. 17.24 MyD88 independent TLR signaling, 75, Fig. 3.39 NK cell activation, 74, Fig. 3.39 TLR4 signaling, 52, Fig. 3.6, Fig. 3.7 Myeloablative therapy, 460 Myeloid lineage cells, 14–15, Fig. 1.13 Myeloid progenitor cells, 14, Fig. 1.13 Myeloma, multiple, 170, Fig. 6.23 monoclonal antibody production, Fig. 4.12 treatment, 524–525 Myeloperoxidase deficiency, 383, Fig. 13.15 Myxoma virus, rabbit, Fig. 13.6 N NADPH oxidase inherited defects, 61–62, 383, Fig. 13.10, Fig. 13.15 microbial killing, 60–61, Fig. 3.16, Fig. 3.17 Naive B cells, 168 activation, 232–238 antigens captured by follicular dendritic cells, 235, Fig. 9.6 B-cell co-receptors, 232–234, Fig. 9.2, Fig. 9.3 cross-linking of surface immunoglobulin, 232, Fig. 9.1 in lymph nodes, 22 morphological effects, 239, Fig. 9.10 mucosal tissues, 280, Fig. 10.15 plasma cell differentiation, 168–169, Fig. 6.22 role of TFH cells, 225–226, Fig. 8.28 secondary response, 300–301, Fig. 11.5 T-cell-independent, 235, Fig. 9.4 commitment to mucosal tissues, 279–281, Fig. 10.15 encounter with antigen, 98, 168–169, Fig. 6.22 help from TFH cells, 225–226, Fig. 8.28 IgM and IgD production, 96, Fig. 4.22 suppression in secondary response, 300– 301, Fig. 11.5 vs memory B cells, 300, 302 vs plasma cells, 245, Fig. 9.16 Naive T cells, 203–210 activation, 193–194, 199–218 co-stimulatory signals, 206–207, Fig. 8.8 dendritic cell adhesion, 205–206, Fig. 8.7 inducing proliferation and differentiation, 209–210 inducing self tolerance, 211, Fig. 8.13 intracellular signaling pathways, 208– 209, Fig. 8.10, Fig. 8.11 mucosal tissues, 280, Fig. 10.15 adhesion to dendritic cells, 205–206, Fig. 8.7 Index commitment to mucosal tissues, 279–281, Fig. 10.15 differentiation of activated, 211–216 encounter with antigen, 203–204, Fig. 8.4 homing to secondary lymphoid tissues, 204–206, Fig. 8.6 induction of anergy, 210–211, Fig. 8.13 recirculation through lymph nodes, 203– 204, 206, Fig. 8.5 vs memory T cells, 302–303, Fig. 11.7 Narcolepsy, Fig. 16.9 Natural killer (NK)-cell receptors, 330–347, Fig. 12.2 diversity of expression, 332, Fig. 12.3 Fc receptors, 261, 332–333, Fig. 12.4 genomic complexes encoding, 339–340, Fig. 12.12 immunoglobulin-like, 335–336, 339–340, Fig. 12.2 lectin-like, 333, 339–340, Fig. 12.2 MHC class I and related molecules, 333–339 NKT cells, 356 summary of regulatory function, 345–347, Fig. 12.19 Natural killer (NK) cells, 16, 71–77, Fig. 1.11 activation by IL-12, 75–76, Fig. 3.40 inhibition by CD94:NKG2A, 334, Fig. 12.6 receptors of innate immunity, Fig. 12.4 by type I interferons, 71, 74, Fig. 3.34, Fig. 3.38 via Fc receptor, 332, Fig. 12.4 via NKG2D, 334, Fig. 12.6 via TLRs, 74, Fig. 3.39 antibody-dependent cytotoxicity, 261–262, Fig. 9.36 cancer immunotherapy targeting, 524–525, Fig. 17.22 CD56bright, 72 CD56dim, 72 cytomegalovirus infection, 341–342, Fig. 12.15 cytotoxicity, 72–74, Fig. 3.38 deficiency, 72, Fig. 13.10 dendritic cell interactions, 76–77, Fig. 3.41 differentiation from T cells, 72 education, 336–339, Fig. 12.9 evasion by tumor cells, 518–519, Fig. 17.13 evasion by viruses, 371–372 graft-versus-leukemia effect, 466, Fig. 15.42, Fig. 15.43 macrophage interactions, 75–76, Fig. 3.40 phenotypic diversity, 332, Fig. 12.3 recirculation, 71–72, Fig. 3.37 recruitment to infected tissue, 54 regulation of function, 330–347, Fig. 12.19 response to virus infections, 71–72, Fig. 3.36 similarity to γ:δ T cells, 348 subpopulations, 72–73 uterine (uNK), 71, 342–345 Natural killer (NK)-cell synapse, 74, Fig. 3.40 Natural killer complex (NKC), 339, 340, Fig. 12.12 Natural selection, MHC haplotypes, 140–143, Fig. 5.37 Negative selection B cells, 149–150, 164, Fig. 6.1 T cells, 192–193, Fig. 7.18 Neisseria complement activation, 256 increased susceptibility, 38, 381 Neisseria gonorrhoeae, antigenic variation, 369 Neisseria meningitidis (meningococcus), 315–316 factor H-binding protein (fHbp), 317, Fig. 11.22 IgA1 cleavage, 285 immunization schedule, Fig. 11.15 increased susceptibility, 66 protective role of IgG2, 261 vaccines, 315–316, 317, Fig. 11.25 NEMO deficiency, 53, Fig. 3.8, Fig. 13.10 Neoplasms, 510 Netosis, 61, Fig. 3.18 Neuraminidase, influenza, 318, 366–368 Neurotoxin, eosinophil-derived, Fig. 14.20 Neutralization, antibody-mediated, 18, Fig. 1.18 Neutralizing antibodies, 103, 231 HIV, 396–397, Fig. 13.32 isotypes acting as, Fig. 4.30 microbial toxins and animal venoms, 253–255, Fig. 9.26 preventing pathogen entry to cells, 251– 253, Fig. 9.23, Fig. 9.24 Neutropenia, 381, 475 Neutrophil extracellular traps (NETs), 61, Fig. 3.18 Neutrophils, 14–15, 56–62 apoptosis and removal, 61, Fig. 3.16 azurophilic (primary) granules, 59, Fig. 3.16 defensins, 41–42, Fig. 2.19 extravasation, 58, Fig. 3.13 gelatinase (tertiary) granules, 59, 60 inherited defects, 382–383, Fig. 13.15 microbial killing, 59–61, Fig. 3.15, Fig. 3.16, Fig. 3.17 morphology, Fig. 1.11 netosis, 61, Fig. 3.18 numbers in blood, 57, Fig. 1.14 phagocytosis, 59, Fig. 3.15, Fig. 3.16 receptors for microbial products, 59, Fig. 3.15 recruitment to sites of infection, 53–54, 57–58, Fig. 3.13 specific (secondary) granules, 59, 60, Fig. 3.16 storage and mobilization, Fig. 1.15 Newborn babies see also Fetus; Infants colonization with commensals, 29–30 transient autoimmune disease, 483–484, Fig. 16.15 NFAT activation in T cells, 209, Fig. 8.11 induction of IL-2, 210 inhibition by cyclosporin/tacrolimus, 449, Fig. 15.19 NFκB activation of inflammation, 52–53, Fig. 3.7 corticosteroid actions, 448 defective, IKKγ deficiency, 53, Fig. 3.8 NOD receptor signaling, 55, Fig. 3.10 T-cell signaling, 209, Fig. 8.11 virus-infected cells, Fig. 3.32, Fig. 3.33 Nickel allergy, 402 Nitric oxide synthase, inducible (iNOS), 283 Nivolumab, 522 NK cells see Natural killer (NK) cells NKG2A see CD94:NKG2A NKG2D, 334–335, Fig. 12.2 evasion by tumor cells, 518, Fig. 17.13 NK-cell activation, 334, Fig. 12.4, Fig. 12.6 NKp30, Fig. 12.2 NKp44, Fig. 12.2 NKp46, Fig. 12.2 NKp80, Fig. 12.2 NKT cells, 354, 356–357 activation, 356–357, Fig. 12.32 effector functions, 357, Fig. 12.33 NLRP3, 55, 56, Fig. 3.11 NLRP3 gene mutations, 56 N nucleotides, 95–96, 115, Fig. 4.20, Fig. 5.9 NOD-like receptors (NLRs), 54–55, Fig. 3.10 NOD proteins (NOD1; NOD2), 54–55 intestinal epithelial cells, 276, Fig. 10.10 Non-Hodgkin’s lymphoma antibody-targeted radioisotope therapy, 529, Fig. 17.27, Fig. 17.29 monoclonal antibody therapy, 90, Fig. 17.27 Non-self, discrimination from self, 47–49, Fig. 3.2 Non-self peptides, 126 Non-self proteins, 126 Notch1, 180–181, Fig. 7.6, Fig. 7.14 NPM-ALK fusion protein, 527–528, Fig. 17.26 Nuclear factor κB see NFκB Nuclear factor of activated T cells see NFAT O Obstructed labor, 345, Fig. 12.18 Ofatumumab, Fig. 17.27 OKT3 monoclonal antibody, 450–451 Oligoadenylate synthetase, 70 Oligomorphic, 136 Omalizumab, 90, 409–410, Fig. 14.14 Omenn syndrome, 116, 385, Fig. 5.4, Fig. 13.10, Fig. 13.16 Oncogenes, 161, 511 Oncogenic viruses, 512–513, Fig. 17.4 Oncology, 510 Opportunistic infections, AIDS, 395–396, Fig. 13.31 Opportunistic pathogens, 3, 396 Opsonins acute-phase proteins, 63, 64, Fig. 3.24 antibodies, 103 Opsonization antibody-mediated, 19, 103, 259–260, Fig. 1.18, Fig. 4.30 complement-mediated, 36 Oral tolerance, 278 Organ donors cadaveric, 440–441, 455, Fig. 15.7, Fig. 15.27 living, 441, 455 shortages, 455–456, Fig. 15.26, Fig. 15.27 Organ transplantation, 440–458 baseline inflammatory state, 440–441, Fig. 15.7 global distribution, 455, Fig. 15.28 graft rejection see Transplant rejection HLA matching, 445, Fig. 15.14 immunosuppressive drugs, 445–454 induced tolerance for, 467, Fig. 15.44 mixed lymphocyte reaction, 442, Fig. 15.10 organ-specific differences, 456–457 I:19 I:20 Index previous, anti-HLA antibodies, 438 transfusion effect, 444 Original antigenic sin, 307, 367 Osteopetrosis, Fig. 15.32 P p53 gene mutations, 511, 512, Fig. 17.3 p53 protein, 511, 513, Fig. 17.10 Palindromic DNA sequences, 95, Fig. 4.20 Pancreas β-cell destruction, 496, Fig. 16.33 transplantation, Fig. 15.26 Pandemics, influenza, 367–368 Panel reactive antibody (PRA), 438 Paneth cells, 41, 277, Fig. 2.18 Panitumumab, Fig. 17.27 Papain, 417 Paracrine action, 209–210, 220 interferon-β, 69, Fig. 3.33 Parasites, 4, Fig. 1.4 see also Helminth parasites; Protozoan parasites adaptive immune response, 404, Fig. 14.3 antigens, similarity to allergens, 417–418, Fig. 14.24 conferring resistance to allergy, 428–429 global distribution, 404, Fig. 14.4 IgE-mediated responses, 248–250, 404, Fig. 9.20 TH2-mediated responses, 213, 288–290 Paratyphoid fever vaccine, Fig. 11.25 Paroxysmal nocturnal hemoglobinuria, 39, Fig. 13.10 Passive immunization, 255, 380 Passive transfer of immunity, 250 Pathogens, 3–4 antibody-mediated inactivation or destruction, 18–19 complement fixation, 31, 34, Fig. 2.8 complement-mediated lysis, 37–38 destruction mechanisms, 8, Fig. 1.6 diversity, 4, Fig. 1.3, Fig. 1.4 evasion of immune response, 365–375 genetic variation, 366–369 hidden (latent) infection, 369–371, Fig. 13.5 sabotage or subversion, 371–372, Fig. 13.6 evolutionary relationship with host, extracellular see Extracellular pathogens initiation of adaptive immunity, 20–23, Fig. 1.21 intracellular see Intracellular pathogens opportunistic, 3, 396 recognition mechanisms, 8, 10–11, Fig. 1.6, Fig. 1.9 routes of entry into host, selection of lymphocytes, 11, Fig. 1.9 Pax-5, 153 expression in Hodgkin’s disease, 527, Fig. 17.25 function, 159, Fig. 6.13 pattern of expression, 159, Fig. 6.12 PD-1 (programmed death 1), 522 PD-L1/PD-L2, 522 Pemphigus foliaceus, 485–486, Fig. 16.1, Fig. 16.18, Fig. 16.19 Pemphigus vulgaris, 485–486, Fig. 16.1 Penicillin allergy, 422, Fig. 14.32, Fig. 14.33 Pentraxins, 43, Fig. 2.20, Fig. 3.22 Peptide-binding motifs, 139–140, Fig. 5.34 Peptide editing, 128 Peptide-loading complex, 127–128, Fig. 5.20 Peptide:MHC complexes see also Self-peptide:self-MHC complexes naive CD8 T-cell activation, 215–216, Fig. 8.17 T-cell receptor binding, 132–133, Fig. 5.26 T-cell receptor signaling, 208–209, Fig. 8.10 transport to cell surface, 130, Fig. 5.27 Peptides (antigenic) binding by MHC molecules, 124–125, Fig. 5.16 presentation see Antigen presentation production see Antigen processing recognition by T cells, 113, 120–135, Fig. 5.10 self and non-self, 126 transport to endoplasmic reticulum, 127, Fig. 5.19 tumor-specific, 517, Fig. 17.10, Fig. 17.11 Peptide splicing, 517, Fig. 17.11 Peptidoglycan, 54–55, Fig. 3.3 Peptidyl arginine deiminases (PADs), 492, Fig. 16.28 Perforin, 220, 224 Periarteriolar lymphoid sheath (PALS), Fig. 1.24 Periodic fevers, 503 Peripheral blood mononuclear cells (PBMC), 442 Peripheral-supramolecular activation complex (p-SMAC), 208, Fig. 8.9 Peripheral tolerance, 166, 193 Peroxidase, eosinophil, Fig. 14.20 Persistent infections, 369–371, Fig. 13.5 Pertussis toxin, Fig. 9.25 Pertussis vaccine, 316, 319–321, Fig. 11.25 see also DTP vaccine Peyer’s patches, 25, 272, Fig. 1.26, Fig. 10.7 B- and T-cell activation, 280, Fig. 10.15 dendritic cells, 278 Phagocytes, 14, 56 see also Macrophages; Neutrophils antigen processing, 129–130 Fc receptors, 259–260, Fig. 9.34 inherited defects, 382–383, Fig. 13.15 innate immune response, Fig. 1.6 Phagocytic receptors macrophages, 49–50, Fig. 3.3 neutrophils, 59, Fig. 3.15 Phagocytosis macrophages see Macrophages, phagocytosis neutrophils, 59, Fig. 3.15, Fig. 3.16 opsonized pathogens, 19, Fig. 1.18 pathogenic proteins/particles, 129 Phagolysosomes antigen processing, 129–130 macrophages, 50, Fig. 1.16 neutrophils, 60–61, Fig. 3.16 Phagosomes, 129, Fig. 1.6 macrophages, 50, Fig. 1.16 neutrophils, 59, Fig. 3.16 Phosphatidylinositol mannoside, Fig. 12.29 Phosphoantigens, 350, Fig. 12.24 recognition by γ:δ T cells, 350–351, Fig. 12.25 Pigs, as organ donors, 455–456 Pilin, 369 Placenta evolution, 342–343 formation, 343–344, Fig. 12.16 IgG transfer, 250 Plague vaccine, Fig. 11.25 Plasma cells, 16, 81, Fig. 4.1 differentiation, 168–170, Fig. 6.22 from activated naive B cells, 238–239, Fig. 9.9 from centrocytes, 241, 244, Fig. 9.12, Fig. 9.15 initiating adaptive immunity, 22–23, Fig. 1.23 regulation by cytokines, 244, Fig. 9.15 secondary immune response, 302 synthesis of secreted antibodies, 99– 100, Fig. 4.24 long-lived population, 297 morphological features, 239, Fig. 1.11, Fig. 9.10 mucosal tissues, 281, 282–283 prospective, migration into lymphoid tissues, 170 vs memory B cells, 300 vs naive B cells, 245, Fig. 9.16 Plasmacytoid dendritic cells (PDCs), 71, Fig. 3.35 Plasma proteins acute-phase response, 62–63 innate immune response, 39–41 Platelets, 14 functions, 40 origins, 12, 14 Pluripotent hematopoietic stem cells, 12, 150, Fig. 1.13 Pneumococcus see Streptococcus pneumoniae Pneumocystis jirovecii (Pneumocystis carinii), 396, Fig. 1.3 Pneumonia vaccine, Fig. 11.25 P nucleotides, 95–96, 115, Fig. 4.20, Fig. 5.9 Poison ivy, 402 Poliomyelitis (polio), 311–313 progress towards elimination, 311–312, Fig. 11.17 vaccination-associated, 312–313 vaccines, 311–313, Fig. 11.7, Fig. 11.15 Poliovirus, 279 Pollen allergy, Fig. 14.23, Fig. 14.37 Polyadenylation, heavy chain, Fig. 4.22, Fig. 4.24 Poly-Ig receptor, 247, 283, Fig. 9.18 Polymorphism see Genetic polymorphism Polymorphonuclear leukocytes, 14, 56 see also Neutrophils Polyspecific antibodies, 161–162 Positive selection B cells, 150, Fig. 6.1 MAIT cells, 358–359, Fig. 12.35 NKT cells, 356 T cells, 189–192, Fig. 7.16 Pre-B-cell leukemia, Fig. 6.23 Pre-B-cell receptor, 153–154, Fig. 6.7 allelic exclusion due to, 154–155, Fig. 6.8 inherited deficiency, 154, Fig. 13.10 pro-B cell selection, 157, Fig. 6.11 regulation of expression, 159 Pre-B cells, 151, Fig. 6.16 bone marrow stromal cell interactions, Fig. 6.5 large, 151, 153, Fig. 6.4 Index clonal expansion, 155, 157 small, 151, Fig. 6.4 checkpoint, 157, Fig. 6.11 IgM expression, 156, Fig. 6.10 light chain gene rearrangements, 155– 157, Fig. 6.9 Prednisolone, 447, 448, Fig. 15.16 Prednisone, 447, Fig. 15.16 Pre-eclampsia, 344–345, Fig. 12.18 Pregnancy see also Fetus alloreactions, 144 anti-HLA antibodies, 437–438, Fig. 15.5 complications, 344–345, Fig. 12.18 hemolytic anemia of newborn, 305–306 HIV infection, 394 trophoblast–uterine NK cell interactions, 343–345 Pre-T-cell receptors expression in thymocytes, 183–184, Fig. 7.9 structure, 184, Fig. 7.10 Pre-T cells, 184 proliferation, 185 TCR α-chain gene rearrangements, 185–186, Fig. 7.12 Primary focus of clonal expansion, 238–239, Fig. 9.9 Primary follicles see Lymphoid follicles, primary Primary immune response, 11–12 antibody persistence after, 296–297, Fig. 11.1 B-cell activation, 169, 231–238 B-cell populations participating, 300–301, Fig. 11.4 common features with secondary response, 301–302 IgE production, 404–406, Fig. 14.5 memory T and B cell production, 297–298, Fig. 11.2 T-cell activation, 199–200, 203–204 vs secondary response, 307–308, Fig. 11.13 Priming, T cell, 199 Pro-B cells, 150–151, Fig. 6.3, Fig. 6.16 apoptosis, 153, 154 bone marrow stromal cell interactions, Fig. 6.5 early, 150, Fig. 6.4 heavy-chain gene rearrangements, 152– 153, Fig. 6.6 late, 150, Fig. 6.4 checkpoint, 157, Fig. 6.11 pre-B-cell receptor, 153–154, Fig. 6.7 program of protein expression, 158–159, Fig. 6.12 Procaspase 1, 55, Fig. 3.11 Pro-drugs, 447 Programmed cell death see Apoptosis Programmed death (PD-1) protein, 522 Prointerleukin-1β (proIL-1β), 55–56, Fig. 3.11 Proliferating cell nuclear antigen (PCNA), Fig. 12.2 Promyelocytic leukemia zinc finger protein (PLZF), 356 Properdin (factor P), 34, Fig. 2.9 inherited deficiency, 381, Fig. 13.13 Prostaglandins, 412, Fig. 14.18 Protease inhibitor drugs, HIV resistance, 394, Fig. 13.28 Protease inhibitors, 40–41, Fig. 2.16 serpin family, 382, Fig. 13.14 Proteases allergic reactions, 416–417 mast cell, 412 microbial, 40 Proteasome, 126–127, Fig. 5.18 constitutive, 127 genes, 138, Fig. 5.32 Protectin see CD59 Protective immunity, 11 long-term, 299, Fig. 11.3 primary immune response, 296–297, Fig. 11.1 Protein F, 252, Fig. 9.24 Protein kinase C-θ, 209, Fig. 8.11 Protein kinase R (PKR), 70 Protein tyrosine kinases B-cell activation, 232, Fig. 9.1 T-cell signaling, 208–209, Fig. 8.10 Proto-oncogenes, 161, 511 translocations involving, 161, Fig. 6.14 Protozoan parasites, Fig. 1.4 evasion/subversion of immune response, 368–369, 371 Provirus, 388 Pseudomembranous colitis, Psoriasis, Fig. 16.9 pTα, 184, Fig. 7.10 pattern of expression, 187, Fig. 7.14 Pterins, Fig. 12.34 PTX3, 43, Fig. 2.20 Purine nucleoside phosphorylase (PNP) deficiency, 383–384 Pus, 14–15, Fig. 1.16 Pyogenic infections, inherited susceptibility, 379–381 Pyridostigmine, 483 Pyrin, 502 Pyrogens, 62 R Rabbit antithymocyte globulin (rATG), 447, Fig. 15.30 Rabbit myxoma virus, Fig. 13.6 Rabies vaccine, Fig. 11.25 Radiation, carcinogenic effects, 513 Radioactive isotope–monoclonal antibody conjugates, 529, Fig. 17.29 RAG-1/RAG-2 see Recombination-activating genes Rapamycin (sirolimus), 210, 453, Fig. 15.30 Ras, T-cell signaling, 209, Fig. 8.11 Rb protein, 513, 520 Reactive arthritis, 494, Fig. 16.31 Receptor editing B cells, 165–166, Fig. 6.18 T cells, 191 Receptor-mediated endocytosis B cells, 129, 225–226 dendritic cells, 202, Fig. 8.3 macrophages, 50 Recessive diseases, 377 Recombination enzymes, 94–96, 115 influenza virus RNA, 367–368, Fig. 13.3 isotype switching, 101–102, Fig. 4.28 somatic see Somatic recombination V(D)J see V(D)J recombination Recombination-activating genes (RAG-1 and RAG-2), 94–95, 115 B-cell development pattern of expression, 158, Fig. 6.12 regulation of expression, 152, 154, 155 evolution, 117, Fig. 5.5 inherited defects, 115–116, 348, 385, Fig. 5.4, Fig. 13.10, Fig. 13.16 initiation of recombination, 94–95, Fig. 4.19 T-cell development, 185, 187, 190, Fig. 7.14 Recombination signal sequences (RSSs), 93, Fig. 4.18 evolution, 117, Fig. 5.5 initiation of recombination, 94–95, Fig. 4.19 T-cell receptor genes, 115 Red blood cells see Erythrocytes Reed–Sternberg cells, 170, 527, Fig. 17.25 Regulators of complement activation (RCA), 36 Regulatory T cells (Treg), 17, 193 development, 212, Fig. 8.14 effector functions, 214, 226–227 effector molecules, 226, Fig. 8.21 induced, 214 induction of tolerance, 193, Fig. 7.19 mucosal tissues, 275 natural, 214 oral tolerance, 278 prevention of autoimmunity, 478 recruitment by tumors, 519, Fig. 17.15 transfusion effect in transplant recipients, 444 Reiter’s syndrome, 494, Fig. 16.31 Respiratory burst, 61, Fig. 3.17 Respiratory tract IgE-mediated allergy, 421, 423–424, Fig. 14.29 inhaled allergens, 416–417, Fig. 14.23 lymphoid tissues, 25 physical barriers to infection, 6, Fig. 2.1 Retinoblastoma (Rb) protein, 513, 520 Retroviruses, 388 endogenous, 388 Reverse transcriptase inhibitors, HIV resistance, 394 Reverse vaccinology, 317 Rev protein, 389, Fig. 13.22, Fig. 13.23 RFX deficiency, 385 Rhesus (Rh) antigens hemolytic disease of newborn, 305–306, Fig. 11.11 incompatible blood transfusion, 434 matching, for blood transfusion, 435–436, Fig. 15.3 Rheumatic diseases, autoimmune nature, 490, Fig. 16.24 Rheumatic fever, 493–494, Fig. 16.1, Fig. 16.30, Fig. 16.31 Rheumatoid arthritis, 490–492, Fig. 16.1, Fig. 16.25 citrullinated protein antibodies, 492, Fig. 16.29 genetic and environmental factors, 491–492 HLA associations, 491–492, Fig. 16.9, Fig. 16.27 monoclonal antibody therapy, 91, 490–491, Fig. 16.26 thymic involution and, 502, Fig. 16.40 Rheumatoid factor, 490 Rhinitis, allergic, 423–424, Fig. 14.34 Riboflavin, 358, Fig. 12.34 Ricin, 50 RIG-I, 69 I:21 I:22 Index RIG-I-like receptors (RLRs), 69, Fig. 3.32 RIPK2, 55, Fig. 3.10 Rituximab antibody-dependent cell-mediated cytotoxicity, 261–262, Fig. 9.36 malignant disease, 90, Fig. 17.27 rheumatoid arthritis, 491 RNA alternative splicing see Alternative RNA splicing viral, recognition, 69, 74, Fig. 3.29, Fig. 3.32, Fig. 3.39 RORγT, 212, 214 Rotavirus, 271 celiac disease and, 501 childhood immunization, Fig. 11.15 childhood mortality, Fig. 11.18 vaccines, 313–314, 324, Fig. 11.19, Fig. 11.25 R-type lectin, 50 Rubella vaccine, Fig. 11.25 S Salmonella enteritidis, Fig. 1.3 Salmonella typhimurium, antigenic variation, 369 Salmonella typhi vaccine, 314, Fig. 11.25 Sarcomas, 510 Scarlet fever, Fig. 9.25 Scavenger receptors, 50, Fig. 3.3 Schistosoma mansoni cathepsin-β-like cysteine protease, 417, Fig. 14.24 IgE-mediated response, 250, Fig. 9.20 microscopic appearance, Fig. 1.3 Schistosomiasis, Fig. 11.26 SCID see Severe combined immunodeficiency syndrome Secondary follicles, 169, 239–240 Secondary immune response, 12, 295, 296– 308, Fig. 11.1 antibody response, 170, 298 B-cell populations participating, 300–301, Fig. 11.4 common features with primary response, 301–302 hemolytic anemia of newborn, 305, Fig. 11.11 memory T and B cells, 298 suppression of naive B cells, 300–301, Fig. 11.5 vs primary response, 307–308, Fig. 11.13 Secondary lymphoid tissues, 20–25, Fig. 1.19 see also Lymph nodes antigen encounter by naive T cells, 203–204, Fig. 8.4 B-cell activation, 168–169, Fig. 6.22, Fig. 9.7 B-cell development, 150, 164, 167–170, Fig. 6.2, Fig. 6.21 B-cell homing, 167–168, Fig. 6.21 gut, 25, 272–273, Fig. 10.7 HIV infection, 395 initiation of adaptive immunity, 20–23 mucosal surfaces, 25 naive T-cell activation, 200–201, Fig. 8.1 naive T-cell homing, 204–206, Fig. 8.6 T-cell differentiation, 193–194 Secretory component (secretory piece), 247, Fig. 9.18 Secretory IgA see IgA, dimeric Segmental exchange (interallelic conversion), 142, Fig. 5.38 Selectins, 57, Fig. 3.12, Fig. 3.13 Self, discrimination from non-self, 47–49, Fig. 3.2 Self antigens, 163 loss of T-cell tolerance, 480–481 monovalent, immature B cells specific for, 166 multivalent, immature B cells specific for, 164–166 Self-MHC molecules, 143 negative selection of T cells, 143, 192, Fig. 7.18 NK-cell education, 336–339, Fig. 12.9, Fig. 12.10, Fig. 12.11 positive selection of T cells, 189–190, Fig. 7.16 Self peptides, 126 Self-peptide:self-MHC complexes determination of CD4 vs CD8 T cells, 191–192, Fig. 7.17 positive selection of T cells, 189–190 Self proteins, 126 producing tumor-specific antigens from, 517, Fig. 17.11 Self-reactive B cells see B cell(s), autoreactive/ self-reactive Self-reactive cells/receptors, 163 Self-reactive T cells see T cell(s), autoreactive/ self-reactive Self renewal, 12 Self-tolerance see also Tolerance, immunological B-cell repertoire, 164, 166 failure of, 473, 477–478, 480–481 mechanisms, Fig. 16.5 Sensitization, to allergens, 416–417, Fig. 14.23 Septicemia, 246 Septic shock, 68 Serglycin, 220–221, 224 Serotypes, 366, Fig. 13.1 Serpins, 382, Fig. 13.14 Serum amyloid A protein, 63, Fig. 3.21 Serum amyloid P component (SAP), 43, Fig. 2.20 Serum sickness, 450–451, Fig. 15.22 Severe combined immunodeficiency syndrome (SCID), 383–385, Fig. 13.10, Fig. 13.16 RAG defects (radiation-sensitive), 115–116, Fig. 5.4, Fig. 13.16 X-linked forms, 384, Fig. 13.16 SH2D1A gene defects, 386 Sheddases, 409 Shigella, 279 Shingles, 370 SHP-1, 334, Fig. 12.6, Fig. 12.9 Sialic acid, 35–36, 269 Sialyl-Lewisx, 57, Fig. 3.13 Sickle-cell anemia, Fig. 15.32 Signal joint, 95, Fig. 4.19 Sipuleucel-T, 525, Fig. 17.23 Sirolimus, 210, 453, Fig. 15.30 Skin allergic reactions, 424–425, Fig. 14.37 blistering diseases, 484–485, Fig. 16.18, Fig. 16.19 cancer, 512 commensal microorganisms, 29–30 grafts, 439 infections, 200, Fig. 8.1 physical barrier to infection, 4–8, 29, Fig. 1.5, Fig. 2.1 Skin tests (intradermal), 419–420, Fig. 14.27, Fig. 14.37 SLE see Systemic lupus erythematosus Sleeping sickness, 369 Small intestine see also Gastrointestinal tract; Gutassociated lymphoid tissues B- and T-cell activation, 280–281, Fig. 10.15 defensins, 41, Fig. 2.18 effector lymphocytes, 281–282, Fig. 10.16, Fig. 10.17 epithelial cells see Intestinal epithelial cells follicle-associated epithelium, 277 secondary lymphoid tissues, 272, Fig. 10.7 Small lymphocytes, 16, 20, Fig. 1.11, Fig. 1.20 Smallpox, 299, 319 eradication, 309–310, Fig. 1.1 eyewitness account, 320 vaccination, 308–310, Fig. 11.14 changing demand for, 319 discovery, 1–2, 308–309 immunological memory, 299, Fig. 11.3 Smoking Goodpasture’s syndrome, 494–495 rheumatoid arthritis causation, 492, Fig. 16.29 Snake venom, 254–255 SOCS (suppressors of cytokine signaling) proteins, 221–222 Somatic hypermutation, 100–101, Fig. 4.25 B-cell zone of lymph node, 239–241 IgE vs IgG isotypes, 405, Fig. 14.6 secondary immune response, 298, 302 Somatic recombination immunoglobulin gene segments, 92–95, Fig. 4.16 T-cell receptor gene segments, 115 Sore throat, 252, Fig. 9.24 Specificity, antibody, 81, 96–97 Sphingosine 1-phosphate (S1P), 206, 237 Spleen, 20, 23–25, Fig. 1.24 Splenectomy, 25 S protein, 38 SR-A (scavenger receptor A), 50, Fig. 3.3 SR-B (scavenger receptor B), 50, Fig. 3.3 SSLP7, 374–375, Fig. 13.9 Staphylococcus aureus, 379 complement evasion strategy, 36 enterotoxin B (SEB), 373, Fig. 13.8 exotoxins, Fig. 9.25 increased susceptibility to, 160 morphology, Fig. 1.3 superantigen-like proteins (SSLPs), 374–375, Fig. 13.9 superantigens, 373 STATs, 221, Fig. 8.22 Stem-cell factor (SCF), 152, Fig. 6.5 Stem cells cancer, 515 hematopoietic see Hematopoietic stem cells Streptococcus pneumoniae (pneumococcus), 23–24, 379 C-reactive protein and, 63, 263 genetic variation/serotypes, 366, Fig. 13.1 IgA1 cleavage, 285 increased susceptibility to, 160 Index morphology, Fig. 1.3 vaccine, 314–315, 316, Fig. 11.15, Fig. 11.25 Streptococcus pyogenes, 379 complement evasion strategy, 36 exotoxins, Fig. 9.25 increased susceptibility to, 160 neutralizing antibodies, 252–253, Fig. 9.24 protease, 40 rheumatic fever, 493–494, Fig. 16.30 superantigens, 373 Stress proteins, 334 Subcapsular sinus macrophages, 236 Subtilisin, 417 Sulfatide, 352–353, Fig. 12.28 Superantigens, bacterial, 373–374, Fig. 13.8 Superoxide dismutase, 60, Fig. 3.17 Superoxide radicals, 60 Suppressors of cytokine signaling (SOCS) proteins, 221–222 Supramolecular activation complex central (c-SMAC), 208, Fig. 8.9 peripheral (SMAC), 208, Fig. 8.9 Surfactant proteins A and D (SP-A and SP-D), 64 Surrogate α chain, pre-T-cell receptor, 184, Fig. 7.10 Surrogate light chain, 153, Fig. 6.7 Survival signals, 153 Switch sequences (regions), 101, 243, Fig. 4.28 “Swollen glands,” 22, 240 Syk, B-cell receptor signaling, 232, Fig. 9.1 Symbiotic relationships, gut bacteria, 30 Sympathetic ophthalmia, 495, Fig. 16.32 Synapse natural killer (NK) cell, 74, Fig. 3.40 T cell see T-cell synapse Syngeneic transplant, 439 Syphilis, 371 Systemic lupus erythematosus (SLE), 476, Fig. 16.1 anti-DNA antibodies, 166 complement component deficiency, 257 facial rash, 476, Fig. 16.4 immune complex deposition, 258, 476, 487, Fig. 16.20 intermolecular epitope spreading, 487–488, Fig. 16.21 joint involvement, 490 T Tacrolimus, 210, 450, 455 immunological effects, 450, Fig. 15.20 mechanism of action, Fig. 15.19, Fig. 15.30 TAK1, 55, Fig. 3.10 Talin, 208, Fig. 8.9, Fig. 9.8 TAP see Transporter associated with antigen processing Tapasin, 127, Fig. 5.20 gene, 138, Fig. 5.32 Target cells, 211 cytotoxic CD8 T-cell killing, 222–224, Fig. 8.23, Fig. 8.24 effector T cells, 219, 220 Tasmanian devil, facial tumors, 515–516, Fig. 17.8 Tat protein, 389, Fig. 13.22, Fig. 13.23 T-bet, TH1 development, 213, Fig. 8.14 T cell(s), 16–17 activation effector T cells, 219, Fig. 8.20 immunosuppressive drugs targeting, 448–453 induced cell death, 193 naive T cells see Naive T cells, activation adoptive transfer, 523, Fig. 17.21 alloreactive see Alloreactive T cells α:β see α:β T cells anergy, 193, 210–211, Fig. 8.13 antigen receptors see T-cell receptor(s) antigen recognition, 113–145 autoimmune diseases mediated by, 476, Fig. 16.1 autoreactive/self-reactive, 193, 481, Fig. 7.19 cryptic epitopes, 486 induction of anergy, 210–211, Fig. 8.13 systemic lupus erythematosus, 487–488, Fig. 16.21 CD4 see CD4 T cells CD8 see CD8 T cells classes, 118, Fig. 5.7 development, 177–196 see also Thymocytes checkpoints, 184, 186, Fig. 7.15 early phase, 177–188, Fig. 7.1, Fig. 7.15 patterns of gene expression, 186–188, Fig. 7.14 selection of T-cell repertoire, 188–193 sites, 20, Fig. 1.19 stages, 194–195, Fig. 7.21 differentiation after encounter with antigen, 17, 193–194 effector see Effector T cells γ:δ see γ:δ T cells help for B cells, 122, 225–226, Fig. 5.13, Fig. 8.28 IL-2-induced differentiation and proliferation, 209–210, Fig. 8.12 immunosuppressive drugs targeting, 448– 454 inherited defects, 178–179, 380–381, 383– 385, Fig. 13.16 lineages, 118, 177–178 memory see Memory T cells MHC restriction, 140, Fig. 5.35 naive see Naive T cells negative selection, 192–193, Fig. 7.18 positive selection, 189–192, Fig. 7.16 precursors, 178, Fig. 7.1 priming, 199 regulatory see Regulatory T cells senescence, autoimmunity and, 501–502, Fig. 16.40 splenic white pulp, Fig. 1.24 tolerance, 193, 211, Fig. 8.13 failure, autoimmune disease, 480–481 T-cell area see under Lymph nodes T-cell co-receptors, 122 see also CD4; CD8 binding to MHC molecules, 124, Fig. 5.15 clustering, T-cell activation, 208 γ:δ T cells, 348 T-cell receptor(s) (TCR), 16–17, 113, 114–120 α:β, 118, Fig. 5.7 expression on cell surface, 117–118, Fig. 5.6 MAIT cells, 357–358 synthesis, 116–117 antigen-binding site, 114–115, 132, Fig. 5.2 antigen recognition, 121–135, Fig. 5.10 MHC polymorphism effects, 139, Fig. 5.33 peptide:MHC complexes, 132–133, Fig. 5.26 chimeric, cancer immunotherapy, 522–523, Fig. 17.21 clustering on T-cell activation, 208, Fig. 8.10 complex, 118, Fig. 5.6 dendritic cell adhesion and, 205–206, Fig. 8.7 diversity, 114–120 mechanisms of generation, 115–117 vs immunoglobulins, 120, Fig. 5.9 editing, 191 expression on cell surface, 117–118, Fig. 5.6 γ:δ, 118–119, Fig. 5.7 antigens recognized, 350–353 expression in thymocytes, 183–184, Fig. 7.9 γ:δ T-cell subpopulations, 349–350, Fig. 12.22 lack of diversity, 347, 348 gene organization, 115, 118–119, Fig. 5.3, Fig. 5.8 gene rearrangements, 115, 119, Fig. 5.3 initiation, 180–181, Fig. 7.5 lineage commitment and, 181–184, Fig. 7.7, Fig. 7.9 productive and nonproductive, 183 regulation, 186, Fig. 7.14 thymocytes, 183–186 NKT cells, 356 signaling pathways, 208–209, Fig. 8.11 structure, 114–115, Fig. 5.1 vs antibodies and B-cell receptors, 16–17, 120, Fig. 1.17 T-cell receptor α chain (TCRα), 114, Fig. 5.1 gene polymorphism, allergic disease, 418, Fig. 14.25 gene rearrangements, 115, 185–186, Fig. 5.3 δ-chain gene deletion, 186, Fig. 7.13 during positive selection, 190–191 role in lineage commitment, 183–184, Fig. 7.9 successive, 185–186, Fig. 7.12 genes, 115, Fig. 5.3, Fig. 5.8 surrogate, 184, Fig. 7.10 synthesis, 116–117, 186 TCR assembly, 116–117, 186 T-cell receptor β chain (TCRβ), 114, Fig. 5.1 gene rearrangements, 115, Fig. 5.3 rescue of nonproductive, 184–185, Fig. 7.11 role in lineage commitment, 183–184, Fig. 7.9 genes, 115, Fig. 5.3 pre-T-cell receptor, 184, Fig. 7.10 synthesis, 116–117 TCR assembly, 116–117, 186 T-cell receptor δ chain (TCRδ), 118–119 gene deletion, 186, Fig. 7.13 gene loci, 118–119, Fig. 5.8 gene rearrangements, 119, 183–184, Fig. 7.9 T-cell receptor γ chain (TCRγ), 118 gene loci, 119, Fig. 5.8 gene rearrangements, 119, 183–184, Fig. 7.9 T-cell synapse see also Cognate pairs B cell–effector TFH cell, 238, Fig. 9.8 I:23 I:24 Index cytotoxic CD8 T cells, 222–223, Fig. 8.23 effector T cells, 218, 220, 221 naive T-cell activation, 207–208, Fig. 8.9 T-cell zone see under Lymph nodes TCR see T-cell receptor(s) TdT see Terminal deoxynucleotidyl transferase Teichoic acids, 50 Terminal deoxynucleotidyl transferase (TdT), 95, Fig. 4.20 B-cell development, 158, Fig. 6.12 T-cell development, 187, Fig. 7.14 Tertiary immune response, 298 Tetanus toxin, 253, 314, Fig. 9.25 vaccine, 253, 314, Fig. 11.25 TFH cells (T follicular helper cells), 232 cytokines regulating isotype switching, 243–244, Fig. 9.13 development, 212, 214, Fig. 8.14 effector functions, 218, 225–226, Fig. 8.28 effector molecules, Fig. 8.21 naive B-cell activation, 234, 236–238, Fig. 9.7, Fig. 9.8 rescue of centrocytes from apoptosis, 241, Fig. 9.12 secondary immune response, 302 TGF-β see Transforming growth factor-β TH1 cells development, 212, 213, Fig. 8.14 effector functions, 213, 218–219, 224–225 effector molecules, 224–225, Fig. 8.21 helminth infections, 289, Fig. 10.27 macrophage activation, 224–225, Fig. 8.27 multiple sclerosis, 476 polarized response, 214–215, Fig. 8.15, Fig. 8.16 type IV hypersensitivity reactions, 402 TH2 cells allergic asthma, 424, Fig. 14.35 basophil-mediated induction, 213, 415 development, 212, 213, Fig. 8.14 effector functions, 213, 218–219 effector molecules, Fig. 8.21 eosinophil recruitment, 414, 415 IgE-mediated allergic disease, 416, Fig. 14.22, Fig. 14.23 inhibition of macrophage activation, 225 intestinal helminth infections, 288–290, Fig. 10.26, Fig. 10.27 parasitic infections, 404, Fig. 14.3 penicillin allergy, 422, Fig. 14.33 polarized response, 214–215, Fig. 8.15 TH17 cells development, 212, 213–214, Fig. 8.14 effector functions, 218–219 effector molecules, Fig. 8.21 Thalassemia major, Fig. 15.32 6-Thioinosinic acid, 453, Fig. 15.25 Thoracic duct, 20 Th-POK, 188, 192, Fig. 7.14 Thrombocytopenia, immune, 489 Thrombocytopenic purpura, autoimmune, Fig. 16.1 Thymectomy, 180 Thymic anlage, 178 Thymic epithelial cells, 178, Fig. 7.2 antigen processing and presentation, 192–193 positive selection of T cells, 189–190, Fig. 7.16 Thymic stroma, 178 Thymic stromal lymphopoietin (TSLP), 289 Thymocytes, 178, Fig. 7.2 apoptosis, 182–183, 190, Fig. 7.8 cell-surface markers, 180, Fig. 7.5 commitment to T-cell lineage, 180–181, Fig. 7.5 double-negative see Double-negative (DN) thymocytes double-positive see Double-positive (DP) thymocytes locations, 178, Fig. 7.3 negative selection, 192–193, Fig. 7.18 patterns of gene expression, 186–188, Fig. 7.14 positive selection, 189–192, Fig. 7.16 single-positive, 191–192 Thymus, 20, 178–180 absent, 178–179 cellular organization, 178, Fig. 7.3 early T-cell development, 177–188, Fig. 7.1, Fig. 7.15 expression of tissue-specific genes, 192–193 involution, 179–180, Fig. 7.4 autoimmune disease and, 501–502, Fig. 16.40 MAIT cell development, 358–359, Fig. 12.35 NKT cell development, 356 selection of T-cell repertoire, 188–193 Thymus-dependent lymphocytes, 177 Thymus-independent (TI) antigens, 235, Fig. 9.4 Thyroglobulin, Fig. 16.13 Thyroid gland autoimmune diseases, 482, 484, Fig. 16.17 ectopic lymphoid tissue, 484, Fig. 16.16 Thyroiditis chronic (Hashimoto’s), 484, Fig. 16.16 subacute, Fig. 16.9 Thyroid-stimulating hormone (TSH), 482, Fig. 16.13 Thyroid-stimulating hormone (TSH) receptor autoantibodies, 482, Fig. 16.13 Thyroxine (T4), 482, Fig. 16.13 TIM proteins, 418, Fig. 14.25 Tingible body macrophages, 241 TIR domain IL-1 receptor, 55 Toll-like receptors, 51–52, Fig. 3.5 Tissue transglutaminase, 500–501, Fig. 16.39 TLR1:TLR2 heterodimer, Fig. 3.29, Fig. 3.30 TLR2:TLR6 heterodimer, Fig. 3.29 TLR3, 67, 74, Fig. 3.29 cellular location, Fig. 3.30 signaling pathway, 75, Fig. 3.39 TLR4, 51–53, Fig. 3.29 allotypes, septic shock risk, 68 cellular location, 66, Fig. 3.30 recognition of lipopolysaccharide, 51–52, Fig. 3.6 signaling pathways, 52–53, Fig. 3.7 structure, 51, Fig. 3.5 TLR5, Fig. 3.29 TLR7, 71, 74, Fig. 3.29, Fig. 3.39 TLR8, 74, Fig. 3.29 TLR9, 67, 71, Fig. 3.29 TLR10, Fig. 3.29 TLRs see Toll-like receptors T lymphocytes see T cell(s) TNF-α see Tumor necrosis factor-α Tolerance, immunological see also Self-tolerance to allografts, induced, 467, Fig. 15.44 B cell, 164, 166 central, 166, 193 failure, autoimmune disease, 480–481 oral, 278 peripheral, 166, 193 T cell, 193, 211, Fig. 8.13 Toll-like receptors (TLRs), 66–68 see also specific receptors (TLR1–TLR10) cellular locations, 66–67, Fig. 3.30 dendritic cells, 203 genetic variation, 67–68, Fig. 3.31 intestinal epithelial cells, 275–276, Fig. 10.10 macrophages, 51–52, Fig. 3.3 NK cells, 74 recognition of microbial products, 66–67, Fig. 3.29 structure, 51, Fig. 3.5 Toll receptor-associated activator of interferon (TRIF), 75, Fig. 3.39 Tonsillitis, 242 Tonsils, 25, 272, Fig. 10.6 Toxic-shock syndrome, Fig. 9.25 Toxic-shock syndrome toxin-1 (TSST-1), 373 Toxin–monoclonal antibody conjugates (immunotoxins), 529, Fig. 17.28 Toxins, microbial as cause of disease, 253, Fig. 9.25 neutralization by antibodies, 253–254, Fig. 9.26 superantigens, 373–374, Fig. 13.8 vaccines against, 314 Toxoids, 253, 314 Toxoplasma gondii, 371 TRADD, Fig. 3.32 TRAF6, 52, Fig. 3.7, Fig. 3.32 Transcytosis, 278 dimeric IgA, 247, Fig. 9.18 exploitation by pathogens, 279 secretory IgM, 283 Transforming growth factor-β (TGF-β) anterior chamber of eye, 457 control of isotype switching, 283, Fig. 9.13 inhibition of macrophage activation, 225 regulatory T cells, 226 TH17-cell development, 214 tumors secreting, 519, Fig. 17.15 Transfusion see Blood transfusion Transfusion effect, organ transplant recipients, 444 Transglutaminase, 500–501, Fig. 16.39 Translocations see Chromosomal translocations Transpeptidase, penicillin binding, Fig. 14.32 Transplantation, 433–468 alloreactions, 438–439, Fig. 15.6 antigens, 438 cancer risk after, 446, 513–514 hypersensitivity reactions to allogeneic, 433–440 solid organ see Organ transplantation tumors, 515, Fig. 17.7 Transplant rejection, 438, Fig. 15.6 acute, 441, Fig. 15.8, Fig. 15.9 monoclonal antibody therapy, 450–451, Fig. 15.21 chronic, 443–444, Fig. 15.11 Index direct and indirect allorecognition, 443– 444, Fig. 15.12 hyperacute, 436–437, Fig. 15.4 MHC polymorphism and, 143–144 monoclonal antibodies for, 90 vs allergy and autoimmunity, 503–504, Fig. 16.42 Transplant tourism, 455 Transporter associated with antigen processing (TAP), 127, Fig. 5.19 genes, 138, Fig. 5.32 inherited defects, 127, 385, Fig. 13.10, Fig. 13.16 peptide-loading complex, 127–128, Fig. 5.20 Transposase, 117, Fig. 5.5 Transposon, 117, Fig. 5.5 Trastuzumab, Fig. 17.27 Trauma, initiating autoimmunity, 495, Fig. 16.32 Treg see Regulatory T cells Treponema pallidum, 371 TRIF, 75, Fig. 3.39 Tri-iodothyronine (T3), 482, Fig. 16.13 Trophoblast cells HLA expression, 344 inadequate invasion, 344–345, Fig. 12.18 uterine NK-cell interactions, 343–344, Fig. 12.16, Fig. 12.17 Trypanosoma brucei, Fig. 1.3 Trypanosomes, antigenic variation, 368–369, Fig. 13.4 Tryptase, mast cell, 411, 412 TSH see Thyroid-stimulating hormone Tuberculosis, Fig. 11.26 see also Mycobacterium tuberculosis AIDS patients, 396 T-cell responses to lipid antigens, 354–356 vaccine see Bacille Calmette–Guérin vaccine Tumor antigens, 516–518, Fig. 17.9, Fig. 17.10 γ:δ T-cell response, 351–352 primed dendritic cells, cancer therapy, 525, Fig. 17.23 vaccination, cancer therapy, 520–521, Fig. 17.18 Tumor-associated antigens, 516, 517–518, Fig. 17.9, Fig. 17.12 Tumor necrosis factor-α (TNF-α), 53–54 monoclonal antibodies, 91, 490–491, Fig. 16.26 neutrophil recruitment, 57 release by mast cells, 412, Fig. 14.16 role in inflammation, 53–54, Fig. 3.9 secretion by macrophages, 53 systemic effects, 62–63, 68, Fig. 3.20 Tumor necrosis factor (TNF) receptorassociated periodic syndrome, Fig. 16.41 Tumors, 510 see also Cancer benign, 510, Fig. 17.1 contagious, 515–516, Fig. 17.8 evasion of immune response, 518–519, Fig. 17.13, Fig. 17.14 growth, 514, Fig. 17.6 malignant, 510, Fig. 17.1 manipulation of immune response, 519, Fig. 17.15 transplantation studies, 515, Fig. 17.7 Tumor-specific antigens, 516–517, Fig. 17.9, Fig. 17.10, Fig. 17.11 Tumor suppressor genes, 511 Twins dizygotic, tolerance between, 467, Fig. 15.44 identical, transplants between, 439, 445 Tyk2, 70 Typhoid vaccine, 314, Fig. 11.25 Typhus fever vaccine, Fig. 11.25 U UL-binding proteins (ULBPs), 372, Fig. 12.2 Ultraviolet radiation, overexposure to, 512 Umbilical cord blood, hematopoietic stem cells, 463–464 Uracil-DNA-glycosylase (UNG), 101 Urogenital tract, physical barriers to infection, Urticaria, 424, 427, Fig. 14.38 Uterine natural killer cells (uNK), 71, 342–345 cooperation with trophoblast cells, 343, Fig. 12.16 fetal MHC class I interactions, 343–344, Fig. 12.17 pregnancy complications and, 344–345, Fig. 12.18 V Vaccination, 1–2, 295, 308–325 asplenia/post-splenectomy, 24 cancer prevention, 519–520 cancer therapy, 520–521, Fig. 17.18 changing demands, 319–322 childhood schedule, Fig. 11.15 disease inadvertently caused by, 312–313 immunological memory, 12, 299, Fig. 11.3 Vaccines, 308 adjuvants, 211, 316, Fig. 11.21 bacterial, 314–316 cancer, 525 combination, 316 conjugate, 315–316, Fig. 11.20 currently available, 322, Fig. 11.25 development, 2, 316–317, 323–324 diseases needing better, 322–323, Fig. 11.26 killed/inactivated virus, 310 live-attenuated bacterial, 314 live-attenuated virus, 310–311, Fig. 11.16 neutralizing antibodies, 231 public acceptance, 319–322, 324 side-effects, 324 subunit, 313, 316 toxoid, 253, 314 viral, 310–314 Vaccinia virus (cowpox virus), 2, 308–309, Fig. 11.14 immunological memory, 299, Fig. 11.3 subversion of immune response, Fig. 13.6 Variable (V) domains antibodies, 84, Fig. 4.6, Fig. 4.7 framework regions, 85–86 hypervariable regions (HV), 85–86, Fig. 4.8 T-cell receptors, 114–115, Fig. 5.1 engineered, 523, Fig. 17.20 Variable (V) gene segments immunoglobulins, 92, Fig. 4.15, Fig. 4.17 recombination signal sequences (RSSs), 93, Fig. 4.18 somatic recombination, 92–95, Fig. 4.16 T-cell receptors, 115, Fig. 5.3, Fig. 5.8 T-cell vs B-cell receptors, Fig. 5.9 Variable (V) regions antibodies, 83, Fig. 4.2 construction from gene segments, 92, Fig. 4.16 genes, 91–92, Fig. 4.15 recombination of gene segments, 92–95, Fig. 4.16 somatic hypermutation see Somatic hypermutation T-cell receptors, 114, Fig. 5.1 Variable surface glycoproteins (VSGs), trypanosome, 368–369, Fig. 13.4 Varicella vaccine, Fig. 11.15, Fig. 11.25 Varicella-zoster virus, 370 Variola, 309 Variolation, 309 Vascular addressins, Fig. 3.12 mucosal (MAdCAM-1), Fig. 10.16 naive T cell homing, 205 Vasodilation, in inflammation, Vav1 protein, 334, Fig. 12.6, Fig. 12.9 VCAM-1, 219, Fig. 6.5, Fig. 8.19 V(D)J recombinase, 94–95 V(D)J recombination immunoglobulins, 94–96, Fig. 4.19, Fig. 4.20 T-cell receptors, 115, 117, Fig. 5.3 Vemurafenib, 522 Venomous animals/insects, 254–255, 422 Vesicular system, intracellular, 125, Fig. 5.17 antigen processing, 126, 129–130, Fig. 5.22 CD1 protein recycling, 352, 355, Fig. 12.28 pathogens exploiting, 130 peptide:MHC class I complex transport, 128 Vibrio cholerae, 284–285 Villi, small intestinal, 272, 277, Fig. 10.7 Viruses, 4, Fig. 1.4 antigen cross-presentation, 131–132, Fig. 5.24 antigen processing, 126, 202–203, Fig. 8.3 cytotoxic T cell responses, 222, 223, 224 evasion of immune response, 366–369, 369–371, Fig. 13.2 γ:δ T-cell response, 351–352 innate immune response, 68–77 interferon response, 70–71, Fig. 3.33, Fig. 3.34 memory CD8 T-cell response, 305, Fig. 11.10 naive CD8 T-cell activation, 215–216, Fig. 8.17 neutralizing antibodies, 251–253, Fig. 9.23 NK-cell activation, 71–72, Fig. 3.36 NK cell cytotoxicity, 72–74, Fig. 3.38 NK cell–dendritic cell interactions, 77, Fig. 3.41 NK cell–macrophage interactions, 75–76, Fig. 3.40 oncogenic, 512–513, Fig. 17.4 plasmacytoid dendritic cell responses, 71 RIG-1-like receptors recognizing, 69, Fig. 3.32 subversion of immune response, 371–372, Fig. 13.6 TLRs recognizing, 66–67, Fig. 3.29 vaccines against, 310–314 Vitamin K, 271, Fig. 10.5 I:25 I:26 Index VLA-4 developing B cells, Fig. 6.5 effector T cells, 219, Fig. 8.18, Fig. 8.19 Vomiting, food allergies, 426, Fig. 14.38 VpreB pre-B-cell receptor, 153–154, Fig. 6.7 regulation of expression, 158, Fig. 6.12 W Waldenström’s macroglobulinemia, Fig. 6.23 Waldeyer’s ring, 272, Fig. 10.6 Warfare, Wasp stings, 421 Wheal and flare, 420, Fig. 14.27 White blood cells see Leukocytes Whooping cough, 316, 319–321, Fig. 9.25 vaccine see Pertussis vaccine Wiskott–Aldrich syndrome, 384, Fig. 13.16, Fig. 15.32 Wiskott–Aldrich syndrome protein (WASP), 384 Worms see Helminth parasites X Xenoantibodies, 456 Xenoantigens, 456 Xenograft, 455 Xenotransplantation, 455–456 X-linked agammaglobulinemia (XLA), 160, 379–380, Fig. 13.10 passive immunization, 380 typing of carriers, 379, Fig. 13.12 X-linked diseases, 377 X-linked hypohydrotic ectodermal dysplasia and immunodeficiency, 53, Fig. 3.8, Fig. 13.10 X-linked lymphoproliferative syndrome, 386 Y Yellow fever vaccine, Fig. 11.25 Z ZAP-70, 188, Fig. 7.14 deficiency, 208, Fig. 13.10 initiation of TCR signaling, 208–209, Fig. 8.10, Fig. 8.11 ζ chain, 118, Fig. 5.6 ITAMs, 208, Fig. 8.10 pre-T-cell receptors, 184 ζ chain-associated protein of 70 kDa see ZAP-70 Zidovudine (AZT), 394 Zoledronate, 350, Fig. 12.24 Zymogens, 31, 64 Zymosan, Fig. 3.29 ... tissues of both the systemic and the mucosal compartments of the immune system Like the spleen and other lymph nodes, the Peyer’s patches and mesenteric lymph nodes release chemokines CCL21 and CCL19,... cells make APRIL, which drives the switch to the IgA2 isotype in the resident B cells In general, the synthesis of IgA2 is higher in toxin IS4 i10. 12/ 10 .20 28 5 28 6 Chapter 10: Preventing Infection... 10.9 The systemic and mucosal immune systems use different strategies for coping with infections Compared here are the immune responses made to infecting bacteria by the systemic immune system