The late-phase reaction described above occurs under controlled experimental conditions to a single, relatively high dose of allergen and so does not reflect all the effects of long-term natural exposure. In IgE-mediated allergic diseases, a long-term consequence of allergen exposure can be chronic allergic inflammation, which consists of a persistent type 2 immune response with a dominant cellular quality that is driven by TH2 lymphocytes, basophils, eosinophils, and macrophages. These chronic reactions contribute importantly to serious long-term illnesses, such as chronic asthma. In long-standing asthma, for example, the cytokines released by TH2 cells and vasoactive mediators such as calcitonin gene-related peptide and vascular endothelial growth factor result in persistent edema, which results in persistent narrowing of the airways. They can also lead to airway tissue remodeling, which changes the bronchial tissue via smooth muscle hypertrophy (an increase in the size of the muscle cells) and hyperplasia (an increase in the number of cells), subepithelial deposition of collagen, and often goblet cell hyperplasia. Although TH2 cytokines appear to predominate in this chronic phase of asthma, TH1 cytokines (such as IFN-γ) and TH17 cytokines (IL-17, IL-21, and IL-22) can also participate.
In the natural situation, the clinical symptoms produced by an IgE-mediated allergic reaction depend critically on several variables: the amount of allergen-specific IgE present, the route by which the allergen is introduced, the dose of allergen, and most probably some underlying defect in barrier function in the particular tissue or organ affected. The outcomes produced by different combinations of allergen dose and route of entry are summarized in Fig. 14.12. When exposure to allergen in a sensitized individual triggers an allergic reaction, both the immediate and the chronic effects are focused on the site at which mast-cell degranulation occurs and they involve the recruitment of many soluble and cellular components of effector pathways.
14-10 Allergen introduced into the bloodstream can cause anaphylaxis.
If allergen is introduced directly into the bloodstream, for example, by a bee or wasp sting, or is rapidly absorbed into the bloodstream from the gut in a sensitized individual, connective-tissue mast cells associated with blood vessels throughout the body can become immediately activated, resulting in a widespread release of histamine and other mediators that causes the systemic reaction called anaphylaxis. The symptoms of anaphylaxis can range in severity from mild urticaria (hives) to fatal anaphylactic shock (see Fig. 14.12, first and last panels). Acute urticaria is a response to foreign allergens that are delivered to the skin via the systemic blood circulation. Activation of mast cells in the skin by allergen causes them to release histamine, which in turn causes itchy, red swellings all over the body—a disseminated version of the wheal-and-flare reaction. Although acute urticaria is commonly caused by an IgE-mediated reaction against an allergen, the causes of chronic urticaria, in which the urticarial rash persists or recurs over long periods, remain incompletely defined. Some cases of chronic urticaria are caused by autoantibodies
Connective tissue mast cells (MCCT) Mucosal mast cells (MCC) Route of allergen entry Intravenous Subcutaneous Inhalation Ingestion
Widespread release of histamine, Local release of histamine which acts on blood vessels to causes wheal-and-fare reaction.
increase permeability, leading to Airborne or topical allergens hives (low dose, ˜g or less) or penetrating skin can also be a anaphylactic shock (medium to high cause of atopic eczema dose, milligrams to grams)