Preformed Mast Cell Mediators

Tiwari N. Wang CC. Brochetta C, Ke G. Vita F. Qi Z. Rivera J. Soranzo MR, Zabucchi G, Hong W, Blank U VAMP-8 segregates mast cell-preformed mediator exocytosis from cytokine trafficking pathways. Blood 2008 11 3665-3674. 

Marshall JS. Leal-Berumen I. Nielsen L. Glibetic M. Jordana M Interleukin (IL)-IO inhibits long-term IL-6 production but not preformed mediator release from rat peritoneal mast cells. J Clin Invest 1996 97 1122-1128. 

Type I reactions occur when the drug or its bound hapten incites an IgE antibody response. IgE binds to high-affinity receptors on mast cells and basophils. When the original antigen cross-links the cell-bound IgE, the effector cell releases enormous amounts of preformed mediators, producing the... 

In sensitized asthmatic individuals, antigen challenge generally causes a Type I (IgE-mediated) immediate hypersensitivity response by release of preformed mediators, including histamine, and prostaglandins, which are responsible for bronchoconstric-tion and increased vascular permeability. Between 2 and 8 hours after the immediate response, asthmatics experience a more severe and prolonged (late phase) reaction that is characterized by mucus hyper-secretion, bronchoconstriction, airway hyperresponsiveness to a variety of nonspecific stimuli (e.g., histamine, methacholine), and airway inflammation characterized by eosinophils. This later response is driven by leukotrienes, chemokines and cytokines synthesized by activated mast cells and Th2 cells. Both proteins and haptens have been associated with these types of reactions. 

Adenosine facilitates preformed mediator and possibly cytokine release from mast cells by activating A3 receptors. 

Histamine A mediator of inflammatory reactions in the body, which may be part of an allergic reaction. Present in preformed granules in mast cells and basophils. 

Mast cell A granulated cell containing numerous preformed and formed mediators of inflammation. Distributed within the body but particularly concentrated in the lungs. 

Figure 32.9. Schematic representation of Type I hypersensitivity. Induction Resident respiratory tract dendritic cells (DC) take and process antigen, mature, migrate to the draining lymph nodes, and present antigen to T lymphocytes. Activated T-lymphocytes, in turn, activate B-cell differentiation into antibody-producing plasma cells. IL-4 promotes Ig isotype class switching from IgM to IgE and promotes mast cell development. IgE is associated with mast cells. Elicitation Allergen crosslinks the mast-cell-bound IgE, thereby causing the release of preformed mediators and cytokines. (See Table 32.7.) Inflammation and bronchoconstriction occur.

Once sensitivity has been established, that is, once hapten-specific IgE-producing B cells have been formed, exposure to even small amounts of hapten can induce a cascade of events that lead to immediate reactions, such as anaphylaxis (210). Briefly, preformed IgE antibodies to drug determinants recognize the hapten-carrier complex and fix to the surface of mast cells or basophils, triggering the release of a series of mediators, such as histamine, neutral proteases, biologically active arachidonic acid products, and cytokines. This ultimately leads to a clinical spectrum that ranges from a mUd local reaction to anaphylactic shock. 

Figure 4.4 The releaee of preformed mast cell mediators by compound exocytosis. Note the progressive way In which successive granules merge with each other and with the cell membrane.

Figure 3 Mast cell activation and mediators. A variety of provocative stimuli act on mast cells to cause degranulation and consequent release of stored or preformed substances or mediators and the synthesis of newly formed substances or mediators.

Both immediate and late-phase reactions are observed after allergen exposure. The immediate reaction occurs within minutes, resulting in the rapid release of preformed mediators and newly generated mediators from the arachidonic acid cascade as the mast cell membrane is disturbed (Table 93-1). These mediators of immediate hypersensitivity include histamine, leukotrienes (LTs) C4, LTD4, LTE4, prostaglandin D2, tryptase, and kinins. In addition, the mast... 

L stimulates in vitro the release of preformed and de novo synthesized vasoactive and proinflammatory mediators (histamine, tryptase and cysteinyl leukotriene) by human mast cells isolated from heart tissue [45], As shown in figure 1, protein L binds ex vivo to B cells expressing human k L-chain-positive Igs. 

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