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Hypersensitivity Reactions: Mechanisms of Immune-Mediated Injury 113

Table 4–2  Summary of the Action of Mast Cell Mediators in                    exposure. Systemic exposure to protein antigens (e.g., in
Immediate (Type I) Hypersensitivity                                           bee venom) or drugs (e.g., penicillin) may result in sys-
                                                                              temic anaphylaxis. Within minutes of the exposure in a
Action                                Mediators                               sensitized host, itching, urticaria (hives), and skin ery-
                                                                              thema appear, followed in short order by profound respira-
Vasodilation, increased               Histamine                               tory difficulty caused by pulmonary bronchoconstriction
   vascular permeability              PAF                                     and accentuated by hypersecretion of mucus. Laryngeal
                                      Leukotrienes C4, D4, E4                 edema may exacerbate matters by causing upper airway
Smooth muscle spasm                   Neutral proteases that activate         obstruction. In addition, the musculature of the entire gas-
                                                                              trointestinal tract may be affected, with resultant vomiting,
                                         complement and kinins                abdominal cramps, and diarrhea. Without immediate
                                      Prostaglandin D2                        intervention, there may be systemic vasodilation with a fall
                                      Leukotrienes C4, D4, E4                 in blood pressure (anaphylactic shock), and the patient
                                      Histamine                               may progress to circulatory collapse and death within
                                      Prostaglandins                          minutes.
                                      PAF
                                                                                 Local reactions generally occur when the antigen is con-
Cellular infiltration                 Cytokines (e.g., chemokines, TNF)       fined to a particular site, such as skin (contact, causing
                                      Leukotriene B4                          urticaria), gastrointestinal tract (ingestion, causing diar-
                                      Eosinophil and neutrophil chemotactic   rhea), or lung (inhalation, causing bronchoconstriction).
                                                                              The common forms of skin and food allergies, hay fever,
                                         factors (not defined biochemically)  and certain forms of asthma are examples of localized aller-
                                                                              gic reactions. However, ingestion or inhalation of allergens
PAF, platelet-activating factor; TNF, tumor necrosis factor.                  also can trigger systemic reactions.

and other chemokines released from TNF-activated epithe-                         Susceptibility to localized type I reactions has a strong
lium and are important effectors of tissue injury in the                      genetic component, and the term atopy is used to imply
late-phase response. Eosinophils produce major basic                          familial predisposition to such localized reactions. Patients
protein and eosinophil cationic protein, which are toxic to                   who suffer from nasobronchial allergy (including hay fever
epithelial cells, and LTC4 and platelet-activating factor,                    and some forms of asthma) often have a family history of
which promote inflammation. TH2 cells produce cytokines                       similar conditions. Genes that are implicated in susceptibil-
that have multiple actions, as described earlier. These                       ity to asthma and other atopic disorders include those
recruited leukocytes can amplify and sustain the inflamma-                    encoding HLA molecules (which may confer immune
tory response even in the absence of continuous allergen                      responsiveness to particular allergens), cytokines (which
exposure. In addition, inflammatory leukocytes are respon-                    may control TH2 responses), a component of the FcεRI, and
sible for much of the epithelial cell injury in immediate                     ADAM33, a metalloproteinase that may be involved in
hypersensitivity. Because inflammation is a major compo-                      tissue remodeling in the airways.
nent of many allergic diseases, notably asthma and atopic
dermatitis, therapy usually includes anti-inflammatory                           The reactions of immediate hypersensitivity clearly did
drugs such as corticosteroids.                                                not evolve solely to cause human discomfort and disease.
                                                                              The immune response dependent on TH2 cells and IgE—in
Clinical and Pathologic Manifestations                                        particular, the late-phase inflammatory reaction—plays an
                                                                              important protective role in combating parasitic infections.
An immediate hypersensitivity reaction may occur as a
systemic disorder or as a local reaction. The nature of the
reaction is often determined by the route of antigen

                           Immediate        Late-
                         Allergen     phase reaction
                         exposure
                                                                       Mast cells

Clinical manifestations                                                Edema       Vascular    Eosinophils
                                                                                   congestion

                                                            B                                  C

     0 1 4 8 12 16 20

A Hours after allergen exposure

Figure 4–9  Immediate 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 person), 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.

(B and C, Courtesy of Dr. Daniel Friend, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts.)
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