Allergens

The majority of humans mount significant IgE responses only as a defense against parasitic infections. After an individual 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 p chain of the high-affinity IgE receptor. It is known that inherited 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.

Allergen

Allergen

Allergen

Allergen

Type Hypersensitivity Cells Ige

Memory cell

FIGURE 16-2

General mechanism underlying a type I hypersensitive 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 molecules of IgE with various specificities can bind to the IgE-Fc recep-

Vasoactive amines *

Memory cell

Smooth muscle cell

Small blood vessel

Mucous gland

Blood platelets

'.Sensory nerve endings

'.Sensory nerve endings

Eosinophil

FIGURE 16-2

General mechanism underlying a type I hypersensitive 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 molecules of IgE with various specificities can bind to the IgE-Fc recep-

Eosinophil tor.) Second exposure to the allergen leads to crossl inking of the bound IgE, triggering the release of pharmacologically active mediators, vasoactive amines, from mast cells and basophils. The mediators cause smooth-muscle contraction, increased vascular permeability, and vasodilation.

TABLE 16-1

Common allergens associated with type I hypersensitivity

TABLE 16-1

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

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 components. 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 ragweed 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 sensitive 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 ragweed 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, including foreign serum and egg albumin, are potent antigens; others, 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, attempts to identify some common chemical property of these antigens have failed. It appears that allergenicity is a consequence of a complex series of interactions involving not only the allergen but also the dose, the sensitizing route, sometimes an adjuvant, and—most important, as noted above— the genetic constitution of the recipient.

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