Immediate (Type I) Hypersensitivity

Immediate, or type I, hypersensitivity is a rapidly developing immunologic reaction occurring within minutes after the combination of an antigen with antibody bound to mast cells in

individuals previously sensitized to the antigen.[20] [21] These reactions are often called allergy, and the antigens that elicit them are allergens. Immediate hypersensitivity may occur as a

systemic disorder or as a local reaction. The systemic reaction usually follows injection of an antigen to which the host has become sensitized. Often within minutes, a state of shock is

produced, which is sometimes fatal. The nature of local reactions varies depending on the portal of entry of the allergen and may take the form of localized cutaneous swellings (skin

allergy, hives), nasal and conjunctival discharge (allergic rhinitis and conjunctivitis), hay fever, bronchial asthma, or allergic gastroenteritis (food allergy). Many local type I

hypersensitivity reactions have two well-defined phases ( Fig. 6-11 ). The immediate, or initial, response is characterized by vasodilation, vascular leakage, and depending on the location,

smooth muscle spasm or glandular secretions. These changes usually become evident within 5 to 30 minutes after exposure to an allergen and tend to subside in 60 minutes. In many

instances (e.g., allergic rhinitis and bronchial asthma), a second, late-phase reaction sets in 2 to 24 hours later without additional exposure to antigen and may last for several days. This latephase

reaction is characterized by infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells as well as tissue destruction, typically in the form of mucosal

epithelial cell damage.

Because mast cells are central to the development of immediate hypersensitivity, we first review some of their salient characteristics and then discuss the immune mechanisms that underlie

this form of hypersensitivity.[22] Mast cells are bone

Figure 6-11Immediate hypersensitivity. A, Kinetics of the immediate and late-phase reactions. The immediate vascular and smooth muscle reaction to allergen develops within minutes

after challenge (allergen exposure in a previously sensitized individual), and the late-phase reaction develops 2 to 24 hours later. B, C, Morphology: The immediate reaction (B) is

characterized by vasodilation, congestion, and edema, and the late phase reaction (C) is characterized by an inflammatory infiltrate rich in eosinophils, neutrophils, and T cells. (Courtesy of

Dr. Daniel Friend, Department of Pathology, Brigham and Women's Hospital, Boston, MA.)

Figure 6-12Pathogenesis of immediate (type I) hypersensitivity reaction. The late-phase reaction is dominated by leukocyte infiltration and tissue injury. TH 2, T-helper type 2 CD4 cells.

Figure 6-13Activation of mast cells in immediate hypersensitivity and release of their mediators. ECF, eosinophil chemotactic factor; NCF, neutrophil chemotactic factor; PAF, plateletactivating

factor.

TABLE 6-3-- Summary of the Action of Mast Cell Mediators in Immediate (Type I) Hypersensitivity

Action Mediator

Vasodilation, increased vascular permeability Histamine

PAF

Leukotrienes C4 , D4 , E4

Neutral proteases that activate complement and kinins

Prostaglandin D2

Smooth muscle spasm Leukotrienes C4 , D4 , E4

Histamine

Prostaglandins

PAF

Cellular infiltration Cytokines, e.g., TNF

Leukotriene B4

Eosinophil and neutrophil chemotactic factors (not defined biochemically)

PAF

PAF, platelet-activating factor; TNF, tumor necrosis factor.

produce leukotriene C4 and PAF and directly activate mast cells to release mediators. Thus, the recruited cells amplify and sustain the inflammatory response without additional exposure

to the triggering antigen. It is now believed that this late-phase inflammatory response is a major cause of symptoms in some type I hypersensitivity disorders, such as allergic asthma.

Therefore, treatment of these diseases requires the use of broad-spectrum anti-inflammatory drugs, such as steroids.

A final point that should be mentioned in this general discussion of immediate hypersensitivity is that susceptibility to these reactions is genetically determined. The term atopy refers to a

predisposition to develop localized immediate hypersensitivity reactions to a variety of inhaled and ingested allergens. Atopic individuals tend to have higher serum IgE levels, and more

IL-4-producing TH 2 cells, compared with the general population. A positive family history of allergy is found in 50% of atopic individuals. The basis of familial predisposition is not clear,

but studies in patients with asthma reveal linkage to several gene loci.[27] Candidate genes have been mapped to 5q31, where genes for the cytokines IL-3, IL-4, IL-5, IL-9, IL-13, and GMCSF

are located, consistent with the idea that these cytokines are involved in the reactions. Linkage has also been noted to 6p, close to the HLA complex, suggesting that the inheritance of

certain HLA alleles permits reactivity to certain allergens. Another asthma-associated locus is on chromosome 11q13, the location of the gene encoding the b chain of the high-affinity IgE

receptor, but many studies have failed to establish a linkage of atopy with the FcepsilonRI b chain chain or even this chromosomal region.

To summarize, immediate (type I) hypersensitivity is a complex disorder resulting from an IgE-mediated triggering of mast cells and subsequent accumulation of inflammatory cells at sites

of antigen deposition. These events are regulated in large part by the induction of TH 2-type helper T cells that promote synthesis of IgE and accumulation of inflammatory cells,

particularly eosinophils. The clinical features result from release of mast-cell mediators as well as the accumulation of an eosinophilrich inflammatory exudate. With this consideration of

the basic mechanisms of type I hypersensitivity, we turn to some conditions that are important examples of IgE-mediated disease.

Date: 2016-04-22; view: 740