The term atopic allergy implies a familial tendency to manifest such conditions as asthma, rhinitis, urticaria, and eczematous dermatitis (atopic dermatitis) alone or in combination, and in association with the presence of IgE. However, individuals without an atopic background may also develop hypersensitivity reactions, particularly urticaria and anaphylaxis, associated with the presence of IgE. Inasmuch as the mast cell is the key effector cell of the biologic response in allergic rhinitis, urticaria, anaphylaxis, and systemic mastocytosis, its developmental biology, activation pathway, product profile, and target tissues will be considered in the introduction to these clinical disorders.
The binding of IgE to human mast cells and basophils, a process termed sensitization, prepares these cells for subsequent antigen-specific activation. The sensitization of the high-affinity Fc receptor for IgE, designated FcϵRI, also stabilizes the cellular expression of the receptor. FcϵRI is composed of one α, one β, and two disulfide-linked γ chains, which together cross the plasma membrane seven times. The α chain is responsible for IgE binding, and the β and γ chains provide for signal transduction that follows the aggregation of the sensitized tetrameric receptors by polymeric antigen. Signal transduction is initiated through the action of an Src family–related tyrosine kinase, termed Lyn, that is constitutively associated with the β chain. Lyn transphosphorylates the canonical immunoreceptor tyrosine-based activation motifs (ITAMs) of the β and γ chains of the receptor, resulting in recruitment of more active Lyn to the β chain and of Syk tyrosine kinase. The phosphorylated tyrosines in the ITAMs function as binding sites for the tandem src homology two (SH2) domains within Syk. Syk activates not only phospholipase Cγ, which associates with the Linker of Activated T Cells at the plasma membrane, but also phosphatidylinositol 3-kinase to provide phosphatidylinositol-3,4,5-trisphosphate, which allows membrane targeting of the Tec family kinase Btk and its activation by Lyn. In addition, the Src family tyrosine kinase Fyn becomes activated after aggregation of IgE receptors and phosphorylates the adapter protein Gab2 that enhances activation of phosphatidylinositol 3-kinase. Indeed, this additional input is essential for mast cell activation, but it can be partially inhibited by Lyn, indicating that the extent of mast cell activation is in part regulated by the interplay between these Src family kinases. Activated phospholipase Cγ cleaves phospholipid membrane substrates to provide inositol-1,4,5-trisphosphate (IP3) and 1,2-diacylglycerols (1,2-DAGs) so as to mobilize intracellular calcium and activate protein kinase C, respectively. The subsequent opening of calcium-regulated activated channels provides the sustained elevations of intracellular calcium required to recruit the mitogen-activated protein kinases, ERK, JNK, and p38 (serine/threonine kinases), which provide cascades to augment arachidonic acid release and to mediate nuclear translocation of transcription factors for various cytokines. The calcium ion–dependent activation of phospholipases cleaves membrane phospholipids to generate lysophospholipids, which, like 1,2-DAG, may facilitate the fusion of the secretory granule perigranular membrane with the cell membrane, a step that releases the membrane-free granules containing the preformed mediators of mast cell effects.
The secretory granule of the human mast cell has a crystalline structure, unlike mast cells of lower species. IgE-dependent cell activation results in solubilization and swelling of the granule contents within the first minute of receptor perturbation; this reaction is followed by the ordering of intermediate filaments about the swollen granule, movement of the granule toward the cell surface, and fusion of the perigranular membrane with that of other granules and with the plasmalemma to form extracellular channels for mediator release while maintaining cell viability.
In addition to exocytosis, aggregation of FcϵRI initiates two other pathways for generation of bioactive products, namely, lipid mediators and cytokines. The biochemical steps involved in expression of such cytokines as tumor necrosis factor α (TNF-α), interleukin (IL) 1, IL-6, IL-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and others, including an array of chemokines, have not been specifically defined for mast cells. Inhibition studies of cytokine production (IL-1β, TNF-α, and IL-6) in mouse mast cells with cyclosporine or FK506 reveal binding to the ligand-specific immunophilin and attenuation of the calcium ion- and calmodulin-dependent serine/threonine phosphatase, calcineurin.
Lipid mediator generation (Fig. 317-1) involves translocation of calcium ion–dependent cytosolic phospholipase A2 to the outer nuclear membrane, with subsequent release of arachidonic acid for metabolic processing by the distinct prostanoid and leukotriene pathways. The constitutive prostaglandin endoperoxide synthase-1 (PGHS-1/cyclooxygenase-1) and the de novo inducible PGHS-2 (cyclooxygenase-2) convert released arachidonic acid to the sequential intermediates, prostaglandins G2 and H2. The glutathione-dependent hematopoietic prostaglandin D2 (PGD2) synthase then converts PGH2 to PGD2, the predominant mast cell prostanoid. The PGD2 receptors, DP1 and DP2, are distributed to smooth muscle as well as to TH2 lymphocytes, eosinophils, and basophils implicated in allergic inflammation.
Pathways for biosynthesis and release of membranederived lipid mediators from mast cells. In the 5-lipoxygenase pathway leukotriene A4 (LTA4) is the intermediate from which the terminal-pathway enzymes generate the distinct final products, leukotriene C4 (LTC4) and leukotriene B4 (LTB4), which leave the cell by separate saturable transport systems. Gamma glutamyl transpeptidase and a dipeptidase then cleave glutamic acid and glycine from LTC4 to form LTD4 and LTE4, respectively. The major mast cell product of the cyclooxygenase system is PGD2.
For the leukotriene biosynthetic pathway, the released arachidonic acid is metabolized by 5-lipoxygenase (5-LO) in the presence of an integral nuclear membrane protein, the 5-LO activating protein (FLAP). The calcium ion–dependent translocation of 5-LO to the nuclear membrane converts the arachidonic acid to the sequential intermediates, 5-hydroperoxyeicosatetraenoic acid (5-HPETE) and leukotriene (LT) A4. LTA4 is conjugated with reduced glutathione by LTC4 synthase, an integral nuclear membrane protein homologous to ...