Several Pharmacologic Agents Mediate Type I Reactions

The clinical manifestations of type I hypersensitive reactions are related to the biological effects of the mediators released during mast-cell or basophil degranulation. These mediators are pharmacologically active agents that act on local tissues as well as on populations of secondary effector cells, including eosinophils, neutrophils, T lymphocytes, monocytes, and platelets. The mediators thus serve as an amplifying terminal effector mechanism, much as the complement system serves

Methylation cAMP

Methylation cAMP

Effector Kinetics

Time, min

Time, min

FIGURE 16-7

Kinetics of major biochemical events that follow crosslinkage of bound IgE on cultured human basophils with F(ab')2 fragments of anti-IgE. Curves are shown for phospholipid methylation (solid blue), cAMP production (solid black), Ca2+ infl ux (dashed blue), and histamine release (dashed black). In control experiments with anti-IgE Fab fragments, no significant changes were observed. [Adapted from T. Ishizaka et al., 1985, Int. Arch. Allergy Appl. Immunol. 77:137.]

as an amplifier and effector of an antigen-antibody interaction. When generated in response to parasitic infection, these mediators initiate beneficial defense processes, including vasodilation and increased vascular permeability, which brings an influx of plasma and inflammatory cells to attack the pathogen. On the other hand, mediator release induced by inappropriate antigens, such as allergens, results in unnecessary increases in vascular permeability and inflammation whose detrimental effects far outweigh any beneficial effect.

The mediators can be classified as either primary or secondary (Table 16-3). The primary mediators are produced before degranulation and are stored in the granules. The most significant primary mediators are histamine, proteases, eosinophil chemotactic factor, neutrophil chemotactic factor, and heparin. The secondary mediators either are synthesized after target-cell activation or are released by the breakdown of membrane phospholipids during the degranulation process. The secondary mediators include platelet-activating factor, leukotrienes, prostaglandins, bradykinins, and various cytokines. The differing manifestations of type I hypersensi-tivity in different species or different tissues partly reflect variations in the primary and secondary mediators present. The main biological effects of several of these mediators are described briefly in the next sections.

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