Mast cells express FcεRI constitutively on their surface and are activated when antigens cross-link IgE bound to these receptors (see Fig. 10.43). A relatively low level of allergen is sufficient to trigger degranulation. There are many mast-cell precursors in tissues, and they can rapidly differentiate into mature mast cells in conditions of allergic inflammation, thus aiding the continuation of the allergic response. Mast-cell degranulation begins within seconds of antigen binding, releasing an array of preformed and newly generated inflammatory mediators (Fig. 14.9). Granule contents include the short-lived vasoactive amine histamine, serine esterases, and proteases such as chymase and tryptase.
Histamine has four known receptors through which it acts—H1 through H4, each a G-protein-coupled receptor. Histamine acts via the H1 receptor on local blood vessels to cause an immediate increase in local blood flow and vessel permeability. This leads to edema and local inflammation. Histamine is also a major stimulus for itching and sneezing, by virtue of its activation of neural receptors. Acting through the H1 receptor on dendritic cells, histamine can increase antigen-presenting capacity and TH1 cell priming; acting through the H1 receptor on T cells, it can enhance TH1 cell proliferation and IFN-γproduction. By acting through H2, H3, and H4 receptors on a variety of leukocytes and tissue cells, histamine participates in atopic dermatitis, chronic urticaria, and several autoimmune disorders.
Human mast cells are classified into subtypes on the basis of their protease content and tissue location. Mast cells in mucosal epithelia express tryptase as their primary serine protease. These cells are designated MCT. Mast cells in the submucosa and other connective tissues predominantly express chymase, tryptase, carboxypeptidase A, and cathepsin G and are designated MCCT. The proteases released by the mast cells activate matrix metalloproteinases, which break down extracellular matrix proteins, causing tissue disintegration and damage. These proteases can exert beneficial effects such as degrading snake and bee venoms, thus helping to suppress allergic responses to these agents.
Following activation through FcεRI, in addition to releasing preformed mediators such as histamine and serine proteases that are stored in their intracellular granules, mast cells also synthesize de novo and release chemokines, cytokines, and lipid mediators—prostaglandins, leukotrienes, thromboxanes (collectively called eicosanoids), and platelet-activating factor. MCT and MCCT mast cells, for example, produce the cytokine IL-4, which helps perpetuate type 2 immune responses. These secreted products contribute to both acute and chronic inflammation. The lipid mediators, in particular, can act both rapidly and persistently to cause smooth muscle contraction, increased vascular permeability, and the secretion of mucus, as well as induce the influx and activation of leukocytes, which contribute to allergic inflammation.