Roles of Mast Cells in Immediate Type Hypersensitivity

Although allergies can cause extreme discomfort and alter quality of life, they also have the potential to be life threatening. Allergic responses generally are classified as immediate, occurring within minutes of allergen exposure; late phase, occurring within hours; or chronic, during which symptoms can relapse and remit over time, as is the case with asthma (1). These responses generally occur locally at mucosal surfaces, such as the airway passages and the gut, as well as in the skin, where mast cells are prevalent. Although there are differences in the particular manifestations of immediate-type allergic reactions at various sites, all pathology is the direct result of inflammation that gives rise to itch, redness, edema, and cellular influx. When allergen is encountered systemically, anaphylaxis occurs, resulting in rapid onset of these symptoms at several sites simultaneously (31). The precipitous drop in blood pressure can be deadly in this circumstance.

Mast cells are the central effector cells in the early events associated with allergic inflammatory responses. Poised at the interface of the external environment in the skin and at mucosal surfaces, mast cells are situated to be among the first cells to encounter antigens that elicit allergic reactions (32). The high-affinity IgE receptor that associates with IgE through its Fc region forms a stable antigen receptor that shares a remarkably similar downstream signaling pathway with the transmembrane T-cell receptor complex. Interaction of multivalent allergen with cell-bound IgE results in: (1) the immediate release of contents of mast cell secretory granules, which includes preformed mediators such as histamine, neutral proteases, some cytokines, and proteoglycans; and (2) newly synthesized mediators include the products of endogenous arachi-donic acid metabolism, such as prostaglandin D and leukotrienes (e.g., LTB4 and LTC4). The inducible expression of a large array of cytokines and chemokines also occurs. Collectively, these mediators initiate rapid vascular permeability, leading to plasma extravasation and tissue edema, bronchoconstriction, mucous overproduction, and leukocyte recruitment. Mast cells also are implicated in the late-phase responses. A prolonged secretion of chemoattractive and immunomodulatory molecules contributes to the continuing tissue edema, cellular influx, and inflammation observed hours after initial mast cell activation. Using the mast cell-deficient mouse model, it has been shown that all of the tissue swelling, increased vascular permeability, intersitial clotting, and neutrophil recruitment in both immediate and late phases of an IgE-mediated cutaneous inflammatory response are dependent on mast cells (13).

Although mast cells have an established role in these processes, what is not known is where mast cells first exert their influence. The classic model pur ports that mast cells are players in immediate-type hypersensitive responses only after the adaptive immune response is established (33). In many respects, an allergic response is very similar to responses to conventional antigens. T cells must be primed (sensitized) via antigen presentation by dendritic cells in the lymph nodes. In allergic responses, this process is thought to be dominated by the generation of Th2 cells, which express IL-4, IL-5, and IL-10 among other cytokines. This Th2 "milieu" has effects on developing B cells, inducing class switching to IgE production, primarily by IL-4 and IL-13. Allergen-specific IgE binds to mast cells and only upon secondary exposure to allergen are the mast cells triggered. However, new findings suggest that mast cells can have a more direct influence on very early events and thus contribute to shaping the character of the adaptive immune response. Evidence to support this comes from studies showing that B cells can undergo isotype switching, leading to the production of IgE in the absence of T cells (34). This switching is dependent on the expression of CD40L (CD154) and IL-4 by mast cells. T-cell responses, as assessed by interferon-y production and activation markers such as CD44 and CD11a, also are attenuated in mast cell-deficient mice after immunization with peptide and adjuvant (Robbie-Ryan and Brown, unpublished results). Finally, mast cells express IL-4 and IL-12, as well as histamine, molecules that regulate T-helper cell fate decisions. Histamine may exert its effects on T cells, either directly during initial antigen encounter in the lymph node or indirectly through effects on dendritic cells at sites of antigen entry (Fig. 1. [35-38]).

How mast cells are activated through Ig-independent modes in initial phases of an allergic response is still a matter of speculation. Evidence exists that allergens, many of which are serine proteases, can directly activate mast cells, as has been demonstrated for eosinophils (39,40). As discussed previously in this chapter, a multitude of nonmicrobial agonists of mast cells exist, including neuropeptides, cytokines, and stress hormones, that could also have an influence on mast cell activation in this setting.

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