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Chapter: Medical Immunology: Hypersensitivity Reactions

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Type I Hypersensitivity Reactions (IGE-Mediated Hypersensitivity, Immediate Hypersensitivity)

A wide variety of hypersensitivity states can be classified as immediate hypersensitivity reactions.

TYPE I HYPERSENSITIVITY REACTIONS (IGE-MEDIATED HYPERSENSITIVITY, IMMEDIATE HYPERSENSITIVITY)

 

A. Historical Overview

Much of our early knowledge about immediate hypersensitivity reactions was derived from studies in guinea pigs. Guinea pigs immunized with egg albumin frequently suffer from an acute allergic reaction upon challenge with this same antigen. This reac-tion is very rapid (observed within a few minutes after the challenge) and is known as an anaphylactic reaction. It often results in the death of the animal in anaphylactic shock. If serum from a guinea pig sensitized 7–10 days earlier with a single injection of egg albumin and adjuvant is transferred to a nonimmunized animal that is challenged 48 hours later with egg albumin, this animal develops an anaphylactic reaction and may die in anaphylactic shock. Because hypersensitivity was transferred with serum, this |observation suggested that antibodies play a critical pathogenic role in this type of hypersensitivity.

The passive transfer of hypersensitivity can take less dramatic aspects if the reaction is limited to the skin. To study what is known as passive cutaneous anaphylaxis, nonsensi-tized animals are injected intradermally with the serum from a sensitized donor. The serum from the sensitized donor contains homocytotropic antibodies that become bound to the mast cells in and around the area where serum was injected. After 24–72 hours the antigen in question is injected intravenously, mixed with Evans blue dye. When the antigen reaches the area of the skin where antibodies were injected and became bound to mast cells, a lo-calized type I reaction takes place, characterized by a small area of vascular hyperperme-ability that results in edema and redness. When Evans blue is injected with the antigen, the area of vascular hyperpermeability will have a blue discoloration due to the transudation of the dye.

The Prausnitz-Küstner reaction, carried out in humans, contributed to our initial un-derstanding of the immediate hypersensitivity reaction. Serum from an allergic patient was injected intradermally into a nonallergic recipient. Twenty-four to 48 hours later the area of skin where the serum was injected was challenged with the antigen that was sus-pected to cause the symptoms in the patient. A positive reaction consisted of a wheal and flare appearing a few minutes after injection of the antigen. The reaction can also be per-formed in primates, which are injected intravenously with serum of an allergic individual and challenged later with intradermal injections of a battery of antigens that could be im-plicated as the cause of the allergic reaction. These reactions are no longer used for any clinical purpose.

B. Clinical Expression

A wide variety of hypersensitivity states can be classified as immediate hypersensitivity reactions. Some have a predominantly cutaneous expression (hives or urticaria), others affect the airways (hay fever, asthma), while still others are of a systemic nature. The latter are often designated as anaphylactic reactions, of which anaphylactic shock is the most severe form.

The expression of anaphylaxis is species specific. The guinea pig usually has bron-choconstriction and bronchial edema as its predominant expression, leading to death in acute asphyxiation. In the rabbit, on the contrary, the most affected organ is the heart, and the animals die of right heart failure. In humans, bronchial asthma in its most severe forms closely resembles the reaction in the guinea pig.

Most frequently, human type I hypersensitivity has a localized expression, such as the bronchoconstriction and bronchial edema that characterize bronchial asthma, the mu-cosal edema in hay fever, and the skin rash and subcutaneous edema that defines urticaria (hives). The factor(s) involved in determining the target organs that will be affected in dif-ferent types of immediate hypersensitivity reactions are not well defined, but the route of exposure to the challenging antigen seems an important factor. For example, allergic (ex-trinsic) asthma and hay fever are usually associated with inhaled antigens, while urticaria is seen as a frequent manifestation of food allergy.

Systemic anaphylaxis is usually associated with antigens that are directly introduced into the circulation, such as in the case of hypersensitivity to insect venom or to system-ically administered drugs. Systemic anaphylactic reactions in humans usually present with itching, erythema, vomiting, abdominal cramps, diarrhea, respiratory distress, and, in severe cases, laryngeal edema and vascular collapse leading to shock that may be irreversible.

Some individuals have an obvious tendency to develop hypersensitivity reactions. The term atopy is used to designate this tendency of some individuals to become sensitized to a variety of allergens (antigens involved in allergic reactions) including pollens, spores, animal danders, house dust, and foods. These individuals, when skin tested, are positive to several allergens, and successful therapy must take this multiple reactivity into account. A genetic background for atopy is suggested by the fact that this condition shows familial prevalence.

C. Pathogenesis

Immediate hypersensitivity reactions are a consequence of the predominant synthesis of specific IgE antibodies by the allergic individual; these IgE antibodies bind with high affinity to the membranes of basophils and mast cells. When exposed to the sensitizing antigen, the reaction with cell-bound IgE triggers the release of histamine through de-granulation, and the synthesis of leukotrienes C4, D4, and E4(this mixture constitutes what was formerly known as slow reacting substance of anaphylaxis or SRS-A). These substances are potent constrictors of smooth muscle and vasodilators and are responsible for the clinical symptoms associated with immediate hypersensitivity . Recent evidence, however, has shown that in animal models, IL-13, released by TH 2 cells, can induce clinical manifestations of asthma independently of IgE and eosinophils. Thus, the concept that immediate hypersensitivity is exclusively antibody-mediated may need to be revised.

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