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 areMost 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