Vasoactive amines released from granule stores. The granules of mast cells contain histamine, which is released within seconds or minutes of activation. Histamine causes vasodilation, increased vascular permeability, smooth muscle contraction, and increased secretion of mucus. Other rapidly released mediators include chemotactic factors for neutrophils and eosinophils as well as neutral proteases (e.g., tryptase), which may damage tissues and also generate kinins and cleave complement components to produce additional chemotactic and inflammatory factors (e.g., C5a) (Chapter 3). The granules also contain acidic proteoglycans (heparin, chondroitin sulfate), the main function of which seems to be as a storage matrix for the amines.
Newly synthesized lipid mediators. Mast cells synthesize and secrete prostaglandins and leukotrienes by the same pathways as do other leukocytes (Chapter 3). These lipid mediators have several actions that are important in immediate hypersensitivity reactions. Prostaglandin D2 (PGD2) is the most abundant mediator generated by the cyclooxygenase pathway in mast cells. It causes intense bronchospasm as well as increased mucus secretion. The leukotrienes LTC4 and LTD4 are the most potent vasoactive and spasmogenic agents known; on a molar basis, they are several thousand times more active than histamine in increasing vascular permeability and in causing bronchial smooth muscle contraction. LTB4 is highly chemotactic for neutrophils, eosinophils, and monocytes.
• Cytokines. Activation of mast cells results in the synthesis and secretion of several cytokines that are important for the late-phase reaction. These include TNF and chemokines, which recruit and activate leukocytes (Chapter 3), and IL-4 and IL-5, which amplify the TH2-initiated immune reaction.
The reactions of immediate hypersensitivity clearly did not evolve to cause human discomfort and disease. The TH2 response plays an important protective role in combating parasitic infections. IgE antibodies target helminths for destruction by eosinophils and mast cells. Mast cells also are involved in defense against bacterial infections. And snake aficionados will be relieved to hear that their mast cells may protect them from some snake venoms by releasing granule proteases that degrade the toxins. Why these beneficial responses are inappropriately activated by harmless environmental antigens, giving rise to allergies, remains a puzzle.
Development of Allergies
Susceptibility to immediate hypersensitivity reactions is genetically determined. An increased propensity to develop immediate hypersensitivity reactions is called atopy. Atopic individuals tend to have higher serum IgE levels and more IL-4–producing TH2 cells than does the general population. A positive family history of allergy is found in 50% of atopic individuals. The basis of familial predisposition is not clear, but genes that are implicated in susceptibility to asthma and other atopic disorders include those encoding HLA molecules (which may confer immune responsiveness to particular allergens), cytokines (which may control TH2 responses), a component of the FcεRI, and ADAM33, a metalloproteinase that may be involved in tissue remodeling in the airways.
Environmental factors are also important in the development of allergic diseases. Exposure to environmental pollutants, all too common in industrialized societies, is an important predisposing factor for allergy. It is notable that dogs and cats living in the same environment as humans develop allergies, whereas chimps living in the wild do not despite their much closer genetic similarity to humans. This simple observation suggests that environmental factors may be more important in the development of allergic disease than genetics. Viral infections of the airways are important triggers for bronchial asthma, an allergic disease affecting the lungs (Chapter 13). Bacterial skin infections are strongly associated with atopic dermatitis.