Primary (preformed) mediators produce relatively short-lived biological effects
Mast cells degranulation results in inflammatory reaction. Preformed mediators are mediators mast cells and basophils synthesize and store at all times. In other words, preformed mediators are always present in cytoplasmic granules of mast cells and basophils.
Upon allergen stimulation, the first set of chemical mediators mast cells and basophils release are the preformed mediators. Important preformed mediators released by mast cells are histamine, heparin, eosinophil chemotactic factor, and neutrophil chemotactic factor and proteases.
- Histamine: histamine is a principal component of mast cell granules. Histamine is a preformed mediator synthesized and stored by mast cells even in the absence of allergic stimuli. Preformed mediators instantly released by mast cells in response to an allergic stimulus, specifically cause immediate biological effects of type-1 hypersensitivity reactions. Histamine receptors: released histamine binds to receptors expressed on various tissue cells and exert its biological effects. More than three classes of receptors exist for histamine, but we shall restrict our discussion to the effects of histamine mediated by two histamine receptors (H1 and H2 receptors). Interestingly, each body tissue expresses one class of histamine receptor predominantly and histamine binding to different receptor subtype mediates different biological effects.Histamine binds to H1 receptors and cause contraction of bronchial and intestinal smooth muscles. In addition, histamine acting through H1 receptors cause increased secretion of mucus. In asthmatics, histamine causes the early phase contraction bronchial smooth muscles and increased mucus secretion. Histamine binds to H2 receptors and mediate increased vascular permeability and vasodilation. Perhaps the most clinically important biological effect mediated by H2 receptors is increased gastric acid secretion, which triggers peptic ulcer.
- Heparin, another preformed mediator released by mast cells upon allergen stimulation inhibits coagulation while increases vascular permeability and smooth muscle contraction.
- Proteases are a class of preformed mediators released by mast cells digests and degrade basement membranes of blood vessels. This damage on blood vessels contributes to the inflammatory process. Moreover, proteases catalyze complement cascade by cleaving complement proteins to generate smaller fragments consequently, promoting the generation of complement fragments. The complement fragments act as chemoattractant that attract other inflammatory cells to the site of reaction.
- Serotonin: serotonin is another mediator released by mast cells during type-1 hypersensitivity reactions. Serotonin promotes smooth muscle contraction and increased vascular permeability.
- Chemotactic factors: an eosinophil chemotactic factor and a neutrophil chemotactic factor induce the chemotaxis of eosinophils and neutrophils respectively to the site of allergic reaction.
Of all preformed mediators released by mast cells during allergic reactions, histamine plays the most significant role. Nevertheless, the biological effects mediated by primary mediators in allergic reactions are transient and short-lived.
Secondary mediators released by mast cells during type-1 hypersensitivity reactions mediate long-lasting effects
In addition to preformed mediators, mast cells synthesize and release a number of mediators called secondary mediators of allergic reactions.
Unlike histamine and other primary mediators of allergic reactions released by mast cells, secondary mediators are not preformed in mast cells but are generated from phospholipid precursors specifically on demand. In other words, mast cells generate secondary mediators in response to allergen stimulation.
Normally, they control many physiological processes. Moreover, they are among the most important mediators of the inflammation, which occurs during allergic reactions. In addition to mast cells, other cells of the body can produce secondary mediators when exposed to inflammatory stimuli.
The binding of allergens to mast cell fixed IgE molecules is the stimulus that triggers mast cells to synthesize and release the secondary mediators of allergy. Thus, unlike primary mediators of allergy, which are always present in mast cell granules, mast cells synthesize secondary mediators of allergy only after activation by allergen binding.
Secondary mediators are essentially eicosanoids
Secondary mediators of allergic reactions are lipid derivatives derived from the breakdown of membrane phospholipids. The binding of allergen to mast cell fixed IgE triggers signal transduction events that result in the activation of PLA2. In other words, allergen-antibody reaction on mast cells leads to the activation of PLA2. Activated phospholipase A2 liberates arachidonic acid from membrane phospholipid. Several intracellular pathways (within mast cells) metabolize liberated arachidonic acid into eicosanoids and other metabolites that play key role in allergic reactions.
These metabolites (secondary mediators) are among the most important mediators and modulators of allergic reaction. Prostaglandins, leukotrienes, thromboxanes, and lipoxins are all eicosanoids. However, principal eicosanoids released by mast cells during allergic reactions are prostaglandins and leukotrienes. Thromboxanes are the main secondary mediator released by platelets.
Prostaglandins and leukotrienes (LT) C4 and LTD4 cause bronchial smooth muscle contraction as part of the inflammatory process. They produce effects that last longer than the effects produced by histamine and other primary mediators of allergy.
Generally, the effects of histamine and other primary mediators are brief whereas those of leukotrienes, prostaglandins and other secondary mediators are relatively long lasting. For instance, in asthmatics, histamine causes the initial bronchospasm whereas leukotrienes and prostaglandins cause the prolonged bronchospasm, which occurs in asthmatics.
A mix of cytokines produced by mast cells enhance the allergic reaction
In addition to preformed mediators and secondary mediators, mast cells also release a mix of cytokines during type-1 hypersensitivity reactions. The cytokines contribute strongly to allergic symptoms. IL-5 (eotaxin) and eosinophil chemotactic factor released by mast cells attract eosinophils to the site of reaction. Moreover, IL-5 promotes the activation and proliferation of eosinophils.
Type-1 reactions typically comprise early phase and late phase reactions
A typical type-1 hypersensitivity reaction has two phases, an early, and short-lived phase that culminates into a late long-lasting phase. The demarcation between the two phases is somehow blurry and not particularly distinct.
The symptoms of both phases are similar, the difference being that each phase has a different time of onset. Moreover, the mediators responsible for the events of the early phase are different from those responsible for the events of the late phase.
- The early phase occurs within 15 to 20 minutes after contact with allergen. Primary/preformed mediators are responsible for the allergic symptoms that occur during the early phase of type-1 reactions. Among the preformed mediators, histamine plays the most significant role.
Histamine particularly causes bronchial smooth muscle contraction and bronchospasm, vasodilation, and increased mucus secretion by mucus membranes.
- The late phase response occurs 5 to 8 hours after the individual contacts the allergen. Secondary mediators of allergy are responsible for the allergic symptoms that occur during the late phase of allergy. Besides, it takes some hours for mast cells to synthesize the secondary mediators of allergy (arachidonic acid-derived mediators). The principal secondary mediators released by mast cells, during allergy, are prostaglandins and leukotrienes. Leukotrienes and prostaglandins are the principal mediators that cause symptoms that occur during late phase of allergic reactions.
The symptoms of both the early and late phase of allergy are the same, the difference being that the symptoms of the late phase sustain and persist for longer duration.
Histamine and other preformed mediators are responsible for the symptoms of the early phase whereas leukotrienes and prostaglandins (secondary mediators) prolong and sustain the reaction and consequently are responsible for the symptoms of the late phase.
Anaphylaxis, a severe but rare form of type-1 reaction
Anaphylaxis is an extreme, severe, but rare form of allergic reaction. Unlike other type-1 reactions, anaphylaxis is a systemic, severe, life-threatening allergic reaction triggered by allergens present in:
There is that tendency for an individual to develop anaphylaxis when the individual encounters an antigen, which he/she is allergic. Among the commonest causes of anaphylaxis are:
- Drug allergies (e.g. penicillin),
- Food allergies (e.g. fish, eggs, milk, cashews, peanuts)
- Venom in insect bites and sting ( e.g. bee, wasps, ants)
Inhaled allergens such as pollen, house dust, molds, etc rarely, if they ever, cause anaphylaxis.
In contrast to most allergic reactions, which are mainly local tissue responses, anaphylaxis is a systemic (whole-body) reaction that has fatal effects on virtually all body organ systems.
Anaphylaxis occurs immediately (often within seconds or minutes) after exposure to the inducing allergen. During anaphylaxis, tissue mast cells, all over the body, release histamine and other pro-inflammatory mediators into blood (i.e. a systemic release of histamine occurs). These mediators cause:
- Bronchial smooth muscle contraction and resultant narrowing/tightening of airways (bronchoconstriction)
- Generalized arteriolar dilation which, can result in extensive peripheral pooling of blood, and loss of vasomotor tone (circulatory shock)
Generally, anaphylaxis has fatal effects on the cardiovascular, respiratory, central nervous systems, GIT, and skin.
Anaphylactoid reactions (also called anaphylactic-like reactions) are mast cells degranulation triggered by non-immunological mechanisms. Anaphylactoid reactions occur, following mast cells degranulation in the absence of IgE antibodies. Few drugs such as aspirin and morphine can induce anaphylactoid reactions in sensitive individuals upon first encounter. Unlike typical type-1 reactions, in anaphylactoid reactions, prior exposure and sensitization does not occur and IgE antibodies are not required. Thus, in anaphylactoid reactions, histamine release by mast cells is independent of prior exposure to allergen, sensitization, and IgE antibodies.
However, mast cells release histamine during both reactions, and the signs and symptoms of both reactions are similar since histamine is the principal mediator responsible for both reactions.