《免疫学》（英文版） Chapter 16 Hypersensitive Reactions

hypersensitive chapter 16 Reactions N IMMUNE RESPONSE MOBILIZES A BATTERY OF effector molecules that act to remove antigen by various mechanisms described in previous chap ters. Generally, these effector molecules induce a localized inflammatory response that eliminates antigen without extensively damaging the host's tissue. Under certain cir- cumstances, however, this inflammatory response can have deleterious effects, resulting in significant tissue damage or even death. This inappropriate immune response is termed hypersensitivity or allergy. Although the word hypersens A Second Exposure to Poison Oak May Result in Delayed-Type Hypersensitivity ivity implies an increased response, the response is not always heightened but may, instead, be an inappropriate im mune response to an antigen. Hypersensitive reactions may Gell and Coombs Classification develop in the course of either humoral or cell-mediated e IgE-Mediated (Type D) Hypersensitivity responses The ability of the immune system to respond inappro- a Antibody-Mediated Cytotoxic (Type Il) priately to antigenic challenge was recognized early in this Hypersensitivity century. Two French scientists, Paul Portier and Charles a Immune Complex-Mediated (Type lID Richet, investigated the problem of bathers in the Mediter- Hypersensitivity ranean reacting violently to the stings of Portuguese Man of Warjellyfish. Portier and Richet concluded that the localized Type IV or Delayed-Type Hypersensitivity(DTH) reaction of the bathers was the result of toxins To counteract this reaction, the scientists experimented with the use of isolated jellyfish toxins as vaccines. Their first attempts met with disastrous results. Portier and Richet injected dogs with the purified toxins, followed later by a booster of toxins Instead of reacting to the booster by producing antibodies against the toxins, the dogs immediately reacted with vomit- ing, diarrhea, asphyxia, and, in some instances, death. Clear- Gell and Coombs Classification the antigen Portier and Richet coined the term anaphylaxis, Several forms of hypersensitive reaction can be distin- loosely translated from Greek to mean the opposite of guished, reflecting differences in the effector molecules gen- prophylaxis, to describe this overreaction. Richet was subse- erated in the course of the reaction In immediate hypersen- quently awarded the Nobel Prize in Physiology or Medicine sitive reactions, different antibody isotypes induce different in 1913 for his work on anaphylaxis immune effector molecules. IgE antibodies, for example, bu We currently refer to anaphylactic reactions within the induce mast-cell degranulation with release of histamine Imoral branch initiated by antibody or antigen-antibody and other biologically active molecules. IgG and IgM anti- complexes as immediate hypersensitivity, because the symp- bodies, on the other hand, induce hypersensitive reactions toms are manifest within minutes or hours after a sensitized by activating complement. The effector molecules in the recipient encounters antigen. Delayed-type hypersensitiv- complement reactions are the membrane-attack complex ity (dTh) is so named in recognition of the delay of symp- and such complement split products as C3a, C4a, and C5a toms until days after exposure. This chapter examines t In delayed-type hypersensitivity reactions, the effector mechanisms and consequences of the four primary types of molecules are various cytokines secreted by activated TH hypersensitive reactions. Tc cells

■ Gell and Coombs Classification ■ IgE-Mediated (Type I) Hypersensitivity ■ Antibody-Mediated Cytotoxic (Type II) Hypersensitivity ■ Immune Complex–Mediated (Type III) Hypersensitivity ■ Type IV or Delayed-Type Hypersensitivity (DTH) A Second Exposure to Poison Oak May Result in Delayed-Type Hypersensitivity Hypersensitive Reactions A       effector molecules that act to remove antigen by various mechanisms described in previous chap￾ters. Generally, these effector molecules induce a localized inflammatory response that eliminates antigen without extensively damaging the host’s tissue. Under certain cir￾cumstances, however, this inflammatory response can have deleterious effects, resulting in significant tissue damage or even death. This inappropriate immune response is termed hypersensitivity or allergy. Although the word hypersensi￾tivity implies an increased response, the response is not always heightened but may, instead, be an inappropriate im￾mune response to an antigen. Hypersensitive reactions may develop in the course of either humoral or cell-mediated responses. The ability of the immune system to respond inappro￾priately to antigenic challenge was recognized early in this century. Two French scientists, Paul Portier and Charles Richet, investigated the problem of bathers in the Mediter￾ranean reacting violently to the stings of Portuguese Man of War jellyfish. Portier and Richet concluded that the localized reaction of the bathers was the result of toxins. To counteract this reaction, the scientists experimented with the use of isolated jellyfish toxins as vaccines. Their first attempts met with disastrous results. Portier and Richet injected dogs with the purified toxins, followed later by a booster of toxins. Instead of reacting to the booster by producing antibodies against the toxins, the dogs immediately reacted with vomit￾ing, diarrhea, asphyxia, and, in some instances, death. Clear￾ly this was an instance where the animals “overreacted” to the antigen. Portier and Richet coined the term anaphylaxis, loosely translated from Greek to mean the opposite of prophylaxis, to describe this overreaction. Richet was subse￾quently awarded the Nobel Prize in Physiology or Medicine in 1913 for his work on anaphylaxis. We currently refer to anaphylactic reactions within the humoral branch initiated by antibody or antigen-antibody complexes as immediate hypersensitivity, because the symp￾toms are manifest within minutes or hours after a sensitized recipient encounters antigen. Delayed-type hypersensitiv￾ity (DTH) is so named in recognition of the delay of symp￾toms until days after exposure. This chapter examines the mechanisms and consequences of the four primary types of hypersensitive reactions. Gell and Coombs Classification Several forms of hypersensitive reaction can be distin￾guished, reflecting differences in the effector molecules gen￾erated in the course of the reaction. In immediate hypersen￾sitive reactions, different antibody isotypes induce different immune effector molecules. IgE antibodies, for example, induce mast-cell degranulation with release of histamine and other biologically active molecules. IgG and IgM anti￾bodies, on the other hand, induce hypersensitive reactions by activating complement. The effector molecules in the complement reactions are the membrane-attack complex and such complement split products as C3a, C4a, and C5a. In delayed-type hypersensitivity reactions, the effector molecules are various cytokines secreted by activated TH or TC cells. chapter 16

62 paRt III Immune Effector Mechanisms VISUALIZING CONCEPTS ADCC Immune Sensitized TpTH for Ige A Fc receptor activation activation b Neutrophil Immune pe Ty IgE-Mediated Hypersensitivity IgGI d Cytotoxic Immune Complex-Mediated Cell-Mediated Hypersensitivity Hypersensitivity Ag induces crosslinking of Ab directed against cell surface Ag-Ab complexes deposited Sensitized THl cells release antigens meditates cell various tissues induc cytokines that activat asophils with release of destruct ion via complement complement activation ar acrophages or Tc cells which ensuing inflammatory mediate direct cellular damage response mediated by massive Typical manifestations include Typical manifestations include Typical manifestations include manifestations include systemic anaphylaxis and blood transfusion reactions, localized Arthus reaction and yd2址计h=小间山油h =三 nd graft rejection allergies, and eczema vasculitis, glomeruLinephritis, heumatoid arthritis. and systemic lupus erythematosus FIGURE The four types of hypersensitive responses As it became clear that several different immune mecha- but it is important to point out that secondary effects blur the nisms give rise to hypersensitive reactions, P G. H. Gell and boundaries between the four categories. R.R. A Coombs proposed a classification scheme in which hypersensitive reactions are divided into four types. Three types of hypersensitivity ocur within the humoral branch IgE-Mediated (Type D) Hypersensitiv IgE-mediated(type D), antibody-mediated (type ID), and im- a type I hypersensitive reaction is induced by certain types of mune complex-mediated(type lID). A fourth type of hyper- antigens referred to as allergens, and has all the hallmarks of sensitivity depends on reactions within the cell-mediated a normal humoral response. That is, an allergen induces branch, and is termed delayed-type hypersensitivity, or DTH humoral antibody response by the same mechanisms type Iv). Each type involves distinct mechanisms, cells, and described in Chapter 11 for other soluble antigens, result mediator molecules( Figure 16-1). This classification scheme in the generation of antibody-secreting plasma cells has served an important function in identifying the mecha- memory cells. What distinguishes a type I hypersensitive stic differences among various hypersensitive reactions, response from a normal humoral response is that the plasma

As it became clear that several different immune mecha￾nisms give rise to hypersensitive reactions, P. G. H. Gell and R. R. A. Coombs proposed a classification scheme in which hypersensitive reactions are divided into four types. Three types of hypersensitivity occur within the humoral branch and are mediated by antibody or antigen-antibody complexes: IgE-mediated (type I), antibody-mediated (type II), and im￾mune complex–mediated (type III). A fourth type of hyper￾sensitivity depends on reactions within the cell-mediated branch, and is termed delayed-type hypersensitivity, or DTH (type IV). Each type involves distinct mechanisms, cells, and mediator molecules (Figure 16-1). This classification scheme has served an important function in identifying the mecha￾nistic differences among various hypersensitive reactions, but it is important to point out that secondary effects blur the boundaries between the four categories. IgE-Mediated (Type I) Hypersensitivity A type I hypersensitive reaction is induced by certain types of antigens referred to as allergens, and has all the hallmarks of a normal humoral response. That is, an allergen induces a humoral antibody response by the same mechanisms as described in Chapter 11 for other soluble antigens, resulting in the generation of antibody-secreting plasma cells and memory cells. What distinguishes a type I hypersensitive response from a normal humoral response is that the plasma 362 PART III Immune Effector Mechanisms VISUALIZING CONCEPTS Type I IgE-Mediated Hypersensitivity Ag induces crosslinking of IgE bound to mast cells and basophils with release of vasoactive mediators Typical manifestations include systemic anaphylaxis and localized anaphylaxis such as hay fever, asthma, hives, food allergies, and eczema Typical manifestations include blood transfusion reactions, erythroblastosis fetalis, and autoimmune hemolytic anemia Typical manifestations include contact dermatitis, tubercular lesions and graft rejection Typical manifestations include localized Arthus reaction and generalized reactions such as serum sickness, necrotizing vasculitis, glomerulnephritis, rheumatoid arthritis, and systemic lupus erythematosus Ab directed against cell surface antigens meditates cell destruction via complement activation or ADCC Ag-Ab complexes deposited in various tissues induce complement activation and an ensuing inflammatory response mediated by massive infiltration of neutrophils Sensitized TH1 cells release cytokines that activate macrophages or TC cells which mediate direct cellular damage IgG-Mediated Cytotoxic Hypersensitivity Immune Complex-Mediated Hypersensitivity Cell-Mediated Hypersensitivity Type II Type III Type IV Allergen Allergen￾specific IgE Fc receptor for IgE Fc receptor Degranulation C3b C3b C3b Antigen Immune complex Complement activation Complement activation Immune complex C C Neutrophil Activated macrophage Cytokines Sensitized TDTH ADCC Cytotoxic cell Surface Target antigen cell FIGURE 16-1 The four types of hypersensitive responses

Hypersensitive Reactions CHAPTER 16 cells secrete IgE. This class of antibody binds with high affin- crease and remain high until the parasite is successfully ity to Fc receptors on the surface of tissue mast cells and cleared from the body. Some persons, however, may have an blood basophils. Mast cells and basophils coated by igE are abnormality called atopy, a hereditary predisposition to the said to be sensitized. A later exposure to the same allergen development of immediate hypersensitivity reactions against cross-links the membrane-bound IgE on sensitized mast cells common environmental antigens. The IgE regulatory defects and basophils, causing degranulation of these cells(figure suffered by atopic individuals allow nonparasitic antigens to 16-2). The pharmacologically active mediators released from stimulate inappropriate igE production, leading to tissue- the granules act on the surrounding tissues. The principal damaging type I hypersensitivity. The term allergen refers effects-vasodilation and smooth-muscle contraction-may specifically to nonparasitic antigens capable of stimulating be either systemic or localized, depending on the extent of type I hypersensitive responses in allergic individuals mediator release The abnormal IgE response of atopic individuals is at least partly genetic-it often runs in families. Atopic individuals have There Are Several components abnormally high levels of circulating IgE and also more tha of Type I Reactions normal numbers of circulating eosinophils. These individuals are more susceptible to allergies such as hay fever, eczema, and As depicted in Figure 16-2, several components are critical to asthma. The genetic propensity to atopic responses has been development of type I hypersensitive reactions. This section mapped to several candidate loci. One locus, on chromosome will consider these components first and then describe the 5q, is linked to a region that encodes a variety of cytokines, mechanism of degranulation including IL-3, IL-4, IL-5, IL-9, IL-13, and GM-CSE A second ALLERGENS locus, on chromosome 11q is linked to a region that encodes the chain of the high-affinity IgE receptor. It is known that inher- The majority of humans mount significant IgE responses ited atopy is multigenic and that other loci probably also are only as a defense against parasitic infections. After an indi- involved. Indeed, as information from the Human Genome vidual has been exposed to a parasite, serum igE levels in- Project is analyzed, other candidate genes may be revealed. B cel Tu cell Allergen Small blood vessel Fc receptor amines y。必 Mucous g 名 Blood platelets 9+Aller Plasma cell Sensitized mast cell Degranulation Allergen IGURE 16-2 General mechanism underlying a type I hypersens- tor ) Second exposure to the allergen leads to crosslinking of the ve reaction. Exposure to an allergen activates B cells to form IgE- bound ige, triggering the release of pharmacologically active media- secreting plasma cells. The secreted igE molecules bind to IgE- tors, vasoactive amines, from mast cells and basophils. The media specific Fc receptors on mast cells and blood basophils. ( Many mol- tors cause smooth-muscle contraction, increased vascular perme- cules of igE with various specificities can bind to the igE-Fc recep- ability, and vasodilation

cells secrete IgE. This class of antibody binds with high affin￾ity to Fc receptors on the surface of tissue mast cells and blood basophils. Mast cells and basophils coated by IgE are said to be sensitized. A later exposure to the same allergen cross-links the membrane-bound IgE on sensitized mast cells and basophils, causing degranulation of these cells (Figure 16-2). The pharmacologically active mediators released from the granules act on the surrounding tissues. The principal effects—vasodilation and smooth-muscle contraction—may be either systemic or localized, depending on the extent of mediator release. There Are Several Components of Type I Reactions As depicted in Figure 16-2, several components are critical to development of type I hypersensitive reactions. This section will consider these components first and then describe the mechanism of degranulation. ALLERGENS The majority of humans mount significant IgE responses only as a defense against parasitic infections. After an indi￾vidual has been exposed to a parasite, serum IgE levels in￾crease and remain high until the parasite is successfully cleared from the body. Some persons, however, may have an abnormality called atopy, a hereditary predisposition to the development of immediate hypersensitivity reactions against common environmental antigens. The IgE regulatory defects suffered by atopic individuals allow nonparasitic antigens to stimulate inappropriate IgE production, leading to tissue￾damaging type I hypersensitivity. The term allergen refers specifically to nonparasitic antigens capable of stimulating type I hypersensitive responses in allergic individuals. The abnormal IgE response of atopic individuals is at least partly genetic—it often runs in families.Atopic individuals have abnormally high levels of circulating IgE and also more than normal numbers of circulating eosinophils. These individuals are more susceptible to allergies such as hay fever, eczema, and asthma. The genetic propensity to atopic responses has been mapped to several candidate loci. One locus, on chromosome 5q, is linked to a region that encodes a variety of cytokines, including IL-3, IL-4, IL-5, IL-9, IL-13, and GM-CSF. A second locus,on chromosome 11q,is linked to a region that encodes the chain of the high-affinity IgE receptor. It is known that inher￾ited atopy is multigenic and that other loci probably also are involved. Indeed, as information from the Human Genome Project is analyzed, other candidate genes may be revealed. Hypersensitive Reactions CHAPTER 16 363 Memory cell Plasma cell Sensitized mast cell B cell TH cell Allergen CD4 IL-4 Allergen￾specific IgE Fc receptor for IgE + Allergen Allergen Eosinophil Sensory–nerve endings Blood platelets Mucous gland Vasoactive amines Small blood vessel Smooth muscle cell Degranulation FIGURE 16-2 General mechanism underlying a type I hypersensi￾tive reaction. Exposure to an allergen activates B cells to form IgE￾secreting plasma cells. The secreted IgE molecules bind to IgE￾specific Fc receptors on mast cells and blood basophils. (Many mol￾ecules of IgE with various specificities can bind to the IgE-Fc recep￾tor.) Second exposure to the allergen leads to crosslinking of the bound IgE, triggering the release of pharmacologically active media￾tors, vasoactive amines, from mast cells and basophils. The media￾tors cause smooth-muscle contraction, increased vascular perme￾ability, and vasodilation.

364 paRI I Immune Effector mechanisms TABLE 16-7 Common allergens associated bergens are small proteins or protein-bound substance with type I hypersensitivity aving a molecular weight between 15,000 and 40,000,at tempts to identify some common chemical property of these Proteins Foods antigens have failed. It a cons reIc Nuts quence of a complex series of interactions involving not only the allergen but also the dose the sens Plant pollens Peas, beans times an adjuvant, and-most important, as noted above- Rye grass the genetic constitution of the recipient. Insect products REAGINIC ANTIBODY(IGE) As described in Chapter 4, the existence of a human serum Drugs factor that reacts with allergens was first demonstrated by Penicillin Cockroach calyx K Prausnitz and h. Kustner in 1921. The local wheal and Sulfonamides Dust mites flare response that occurs when an allergen is injected into Local anesthetics sensitized individual is callled the p-k reaction because the Salicylates Mold spores serum components responsible for the P-K reaction dis Animal hair and dander played specificity for allergen, they were assumed to be anti bodies, but the nature of these p-K antibodies or reagins, was not demonstrated for many years Experiments conducted by K and T Ishizaka in the mid- 1960s showed that the biological activity of reaginic antibody Most allergic IgE responses occur on mucous membrane in a p-K test could be neutralized by rabbit antiserum against surfaces in response to allergens that enter the body by either whole atopic human sera but not by rabbit antiserum specific inhalation or ingestion. Of the common allergens listed in for the four human immunoglobulin classes known at that Table 16-1, few have been purified and characterized. Those time (IgA, IgG, IgM, and IgD)(Table 16-2). In addition, when that have include the allergens from rye grass pollen, ragweed rabbits were immunized with sera from ragweed-sensitive pollen, codfish, birch pollen, timothy grass pollen, and bee individuals, the rabbit antiserum could inhibit (neutralize)a venom. Each of these allergens has been shown to be a multi- positive ragweed P-K test even after precipitation of the rabbit antigenic system that contains a number of allergenic com- antibodies specific for the human IgG, IgA, IgM, and lgd iso- ponents. Ragweed pollen, a major allergen in the United types. The Ishizakas called this new isotype lgE in reference States, is a case in point. It has been reported that a square the E antigen of ragweed that they used to characterize it. mile of ragweed yields 16 tons of pollen in a single season Serum IgE levels in normal individuals fall within the Indeed, all regions of the United States are plagued by rag- range of 0. 1-0.4 ug/ml; even the most severely allergic indi- weed pollen as well as pollen from trees indigenous to the viduals rarely have lgE levels greater than 1 ug/ml. These low region. The pollen particles are inhaled, and their tough levels made physiochemical studies of Ige difficult; it was not outer wall is dissolved by enzymes in the mucous secretions, until the discovery of an IgE myeloma by S G O Johansson releasing the allergenic substances. Chemical fractionation of and H. Bennich in 1967 that extensive chemical analysis of ragweed has revealed a variety of substances, most of which IgE could be undertaken IgE was found to be composed of are not allergenic but are capable of eliciting an igM or igG two heavy e and two light chains with a combined molecular response Of the five fractions that are allergenic(i., able to weight of 190,000. The higher molecular weight as compared induce an IgE response), two evoke allergenic reactions in with IgG (150,000)is due to the presence of an additional about 95% of ragweed-sensitive individuals and are called constant-region domain(see Figure 4-13). This additional major allergens; these are designated the E and K fractions. domain( CH4)contributes to an altered conformation of the The other three, called Ra3, Ra4, and Ra5, are minor allergens Fc portion of the molecule that enables it to bind to glyco. that induce an allergic response in only 20% to 30% of sensi- protein receptors on the surface of basophils and mast cells. tive subjects. lthough the half-life of igE in the serum is only 2-3 days b Why are some pollens(e.g, ragweed) highly allergenic, once IgE has been bound to its receptor on mast cells and hereas other equally abundant pollens (e.g, nettle)are basophils, it is stable in that state for a number of weeks rarely allergenic? No single physicochemical property seem to distinguish the highly allergenic e and K fractions of rag- MAST CELLS AND BASOPHILS weed from the less allergenic Ra3, Ra4, and Ra5 fractions and The cells that bind lgE were identified by incubating human from the nonallergenic fractions. Rather, allergens as a group leukocytes and tissue cells with either I-labeled IgE mye appear to possess diverse properties. Some allergens, includ- loma protein or I-labeled anti-IgE. In both cases, autoradi- ing foreign serum and egg albumin, are potent antigens; oth- ography revealed that the labeled probe bound with high ers, such as plant pollens, are weak antigens. Although most affinity to blood basophils and tissue mast cells. Basophils are

Most allergic IgE responses occur on mucous membrane surfaces in response to allergens that enter the body by either inhalation or ingestion. Of the common allergens listed in Table 16-1, few have been purified and characterized. Those that have include the allergens from rye grass pollen, ragweed pollen, codfish, birch pollen, timothy grass pollen, and bee venom. Each of these allergens has been shown to be a multi￾antigenic system that contains a number of allergenic com￾ponents. Ragweed pollen, a major allergen in the United States, is a case in point. It has been reported that a square mile of ragweed yields 16 tons of pollen in a single season. Indeed, all regions of the United States are plagued by rag￾weed pollen as well as pollen from trees indigenous to the region. The pollen particles are inhaled, and their tough outer wall is dissolved by enzymes in the mucous secretions, releasing the allergenic substances. Chemical fractionation of ragweed has revealed a variety of substances, most of which are not allergenic but are capable of eliciting an IgM or IgG response. Of the five fractions that are allergenic (i.e., able to induce an IgE response), two evoke allergenic reactions in about 95% of ragweed-sensitive individuals and are called major allergens; these are designated the E and K fractions. The other three, called Ra3, Ra4, and Ra5, are minor allergens that induce an allergic response in only 20% to 30% of sensi￾tive subjects. Why are some pollens (e.g., ragweed) highly allergenic, whereas other equally abundant pollens (e.g., nettle) are rarely allergenic? No single physicochemical property seems to distinguish the highly allergenic E and K fractions of rag￾weed from the less allergenic Ra3, Ra4, and Ra5 fractions and from the nonallergenic fractions. Rather, allergens as a group appear to possess diverse properties. Some allergens, includ￾ing foreign serum and egg albumin, are potent antigens; oth￾ers, such as plant pollens, are weak antigens. Although most allergens are small proteins or protein-bound substances having a molecular weight between 15,000 and 40,000, at￾tempts to identify some common chemical property of these antigens have failed. It appears that allergenicity is a conse￾quence of a complex series of interactions involving not only the allergen but also the dose, the sensitizing route, some￾times an adjuvant, and—most important, as noted above— the genetic constitution of the recipient. REAGINIC ANTIBODY (IGE) As described in Chapter 4, the existence of a human serum factor that reacts with allergens was first demonstrated by K. Prausnitz and H. Kustner in 1921. The local wheal and flare response that occurs when an allergen is injected into a sensitized individual is called the P-K reaction. Because the serum components responsible for the P-K reaction dis￾played specificity for allergen, they were assumed to be anti￾bodies, but the nature of these P-K antibodies, or reagins, was not demonstrated for many years. Experiments conducted by K. and T. Ishizaka in the mid- 1960s showed that the biological activity of reaginic antibody in a P-K test could be neutralized by rabbit antiserum against whole atopic human sera but not by rabbit antiserum specific for the four human immunoglobulin classes known at that time (IgA, IgG, IgM, and IgD) (Table 16-2). In addition, when rabbits were immunized with sera from ragweed-sensitive individuals, the rabbit antiserum could inhibit (neutralize) a positive ragweed P-K test even after precipitation of the rabbit antibodies specific for the human IgG, IgA, IgM, and IgD iso￾types. The Ishizakas called this new isotype IgE in reference to the E antigen of ragweed that they used to characterize it. Serum IgE levels in normal individuals fall within the range of 0.1–0.4 g/ml; even the most severely allergic indi￾viduals rarely have IgE levels greater than 1 g/ml. These low levels made physiochemical studies of IgE difficult; it was not until the discovery of an IgE myeloma by S. G. O. Johansson and H. Bennich in 1967 that extensive chemical analysis of IgE could be undertaken. IgE was found to be composed of two heavy  and two light chains with a combined molecular weight of 190,000. The higher molecular weight as compared with IgG (150,000) is due to the presence of an additional constant-region domain (see Figure 4-13). This additional domain (CH4) contributes to an altered conformation of the Fc portion of the molecule that enables it to bind to glyco￾protein receptors on the surface of basophils and mast cells. Although the half-life of IgE in the serum is only 2–3 days, once IgE has been bound to its receptor on mast cells and basophils, it is stable in that state for a number of weeks. MAST CELLS AND BASOPHILS The cells that bind IgE were identified by incubating human leukocytes and tissue cells with either 125I-labeled IgE mye￾loma protein or 125I-labeled anti-IgE. In both cases, autoradi￾ography revealed that the labeled probe bound with high affinity to blood basophils and tissue mast cells. Basophils are 364 PART III Immune Effector Mechanisms TABLE 16-1 Common allergens associated with type I hypersensitivity Proteins Foods Foreign serum Nuts Vaccines Seafood Eggs Plant pollens Peas, beans Rye grass Milk Ragweed Timothy grass Insect products Birch trees Bee venom Wasp venom Drugs Ant venom Penicillin Cockroach calyx Sulfonamides Dust mites Local anesthetics Salicylates Mold spores Animal hair and dander

Hypersensitive Reactions CHAPTER 16 365 TABLE 16-2 Identification of IgE based on reactivity of atopic serum in P-K test Treatment Allergen added P-K reaction at skin site A None antiserum to human atopic serum Rabbit antiserum to human igM, igG, IgA, and IgD Serum from an atopic individual was injected into rabbits to produce antiserum against human atopic serum. When this antiserum was reacted with human atopic serum, it neutralized the p-k reaction. SOURCE: Based on K Ishizaka and T Ishizaka, 1967, J Immunol. 99: 1187. granulocytes that circulate in the blood of most vertebrates; mm. Electron micrographs of mast cells reveal numerous in humans, they account for 0.5%-1.0% of the circulating membrane-bounded granules distributed throughout the white blood cells. Their granulated cytoplasm stains with cytoplasm, which, like those in basophils, contain pharmaco- basic dyes, hence the name basophil. Electron microscopy re- logically active mediators(Figure 16-3). After activation, these veals a multilobed nucleus, few mitochondria, numerous mediators are released from the granules, resulting in the clin- glycogen granules, and electron-dense membrane-bound ical manifestations of the type I hypersensitive reaction. granules scattered throughout the cytoplasm that contain Mast cell populations in different anatomic sites differ sig pharmacologically active mediators(see Figure 2-10c) nificantly in the types and amounts of allergic mediators they Mast-cell precursors are formed in the bone marrow dur- contain and in their sensitivity to activating sti ing hematopoiesis and are carried to virtually all vascularized cytokines. Mast cells also secrete a large variety of cytokine peripheral tissues, where they differentiate into mature cells. that affect a broad spectrum of physiologic, immunologic, Mast cells are found throughout connective tissue, particu- and pathologic processes(see Table 12-1) larly near blood and lymphatic vessels. Some tissues, includ- ing the skin and mucous membrane surfaces of the respira- IgE-BINDING FC RECEPTORS tory and gastrointestinal tracts, contain high concentrations The reaginic activity of igE depends on its ability to bind to a of mast cells; skin, for example, contains 10,000 mast cells receptor specific for the Fc region of the e heavy chain. Two FIGURE 16-3(a)Electron micrograph of a typical mast cell reveals membrane of a mast cell. (c)Granule releasing its contents(towards numerous electron-dense membrane- bounded granules prior to top left) during degranulation. / From S. Burwen and B. Satir, 1977, degranulation. (b) Close-up of intact granule underlying the plasma J Cell Biol. 73: 662. 1

granulocytes that circulate in the blood of most vertebrates; in humans, they account for 0.5%–1.0% of the circulating white blood cells. Their granulated cytoplasm stains with basic dyes, hence the name basophil. Electron microscopy re￾veals a multilobed nucleus, few mitochondria, numerous glycogen granules, and electron-dense membrane-bound granules scattered throughout the cytoplasm that contain pharmacologically active mediators (see Figure 2-10c). Mast-cell precursors are formed in the bone marrow dur￾ing hematopoiesis and are carried to virtually all vascularized peripheral tissues, where they differentiate into mature cells. Mast cells are found throughout connective tissue, particu￾larly near blood and lymphatic vessels. Some tissues, includ￾ing the skin and mucous membrane surfaces of the respira￾tory and gastrointestinal tracts, contain high concentrations of mast cells; skin, for example, contains 10,000 mast cells per mm3 . Electron micrographs of mast cells reveal numerous membrane-bounded granules distributed throughout the cytoplasm, which, like those in basophils, contain pharmaco￾logically active mediators (Figure 16-3). After activation, these mediators are released from the granules, resulting in the clin￾ical manifestations of the type I hypersensitive reaction. Mast cell populations in different anatomic sites differ sig￾nificantly in the types and amounts of allergic mediators they contain and in their sensitivity to activating stimuli and cytokines. Mast cells also secrete a large variety of cytokines that affect a broad spectrum of physiologic, immunologic, and pathologic processes (see Table 12-1). IgE-BINDING Fc RECEPTORS The reaginic activity of IgE depends on its ability to bind to a receptor specific for the Fc region of the  heavy chain. Two Hypersensitive Reactions CHAPTER 16 365 TABLE 16-2 Identification of IgE based on reactivity of atopic serum in P-K test Serum Treatment Allergen added P-K reaction at skin site Atopic None – – Atopic None + + Nonatopic None + – Atopic Rabbit antiserum to human atopic serum* + – Atopic Rabbit antiserum to human IgM, IgG, IgA, and IgD† + + *Serum from an atopic individual was injected into rabbits to produce antiserum against human atopic serum. When this antiserum was reacted with human atopic serum, it neutralized the P-K reaction. † Serum from an atopic individual was reacted with rabbit antiserum to the known classes of human antibody (IgM, IgA, IgG, and IgD) to remove these isotypes from the atopic serum. The treated atopic serum continued to give a positive P-K reaction, indicating that a new immunoglobulin isotype was responsible for this reactivity. SOURCE: Based on K. Ishizaka and T. Ishizaka, 1967, J. Immunol. 99:1187. (a) (b) (c) FIGURE 16-3 (a) Electron micrograph of a typical mast cell reveals numerous electron-dense membrane-bounded granules prior to degranulation. (b) Close-up of intact granule underlying the plasma membrane of a mast cell. (c) Granule releasing its contents (towards top left) during degranulation. [From S. Burwen and B. Satir, 1977, J. Cell Biol. 73:662.]