In humans, the IgE response, once initiated, can also be amplified by the capture of IgE by Fcε receptors on dendritic cells. Some populations of human immature dendritic cells—for example, the Langerhans cells of the skin— express surface FcεRI in an inflammatory setting, and once anti-allergen IgE antibodies have been produced, they can bind to these receptors. The bound IgE forms a highly effective trap for allergen, which is then efficiently processed by the dendritic cell for presentation to naive T cells, thus maintaining and reinforcing the TH2 response to the allergen. Eosinophils have also been reported to express IgE receptors, but this is still controversial. Eosinophils may act as antigen-presenting cells to T cells in a standard fashion after upregulation of eosinophil MHC class II and co-stimulatory molecules; however, this probably occurs in tissues where activated T cells have migrated rather than in lymph nodes where naive T cells are primed by dendritic cells.
14-2 Although many types of antigens can cause allergic sensitization, proteases are common sensitizing agents.
Most airborne allergens are relatively small, highly soluble proteins that are carried on dry particles such as pollen grains or mite feces (Fig. 14.4). On contact with the mucus-covered epithelia of the eyes, nose, or airways, the soluble allergen is eluted from the particle and diffuses into the mucosa, where it can be picked up by dendritic cells and provoke sensitization (see Fig. 14.2). At mucosal surfaces, allergens are typically presented to the immune system at low concentrations. It has been estimated that the maximum exposure of a person to the common pollen allergens in ragweed (Ambrosia species) does not exceed 1 μg per year. It is thought that low-dose sensitization favors formation of a strong TH2 response. Consequently, these minute doses of allergen can provoke irritating and even life-threatening TH2-driven IgE antibody responses in atopic individuals.
Antigen exposures that lead to allergic responses do not always involve such low doses of antigen, especially at other tissue sites. For example, bee venom is a frequent cause of allergic sensitization, and individual bee stings result in the injection into the skin of 20–75 μg of bee venom (1 to 2 orders of magnitude more than the total dose of ragweed antigen that is inhaled into the airways). In the case of food allergy, ingestion of many grams of an allergenic food into the gastrointestinal tract over prolonged periods of time can lead to sensitization. Sensitization can also occur in response to small or large doses of injected antigens. For example, before the introduction of recombinant
Top panel: IgE secreted by plasma cells binds to the high-affinity IgE receptor on basophils (illustrated here) and mast cells. Bottom panel: when the surface-bound IgE is cross-linked by antigen, these cells express CD40 ligand (CD40L) and secrete IL-4, which in turn binds to IL-4 receptors (IL-4R) on the activated B cell. Together with ligation of B-cell CD40 by basophil CD40L, this activates class switching by the B cell and the production of more IgE. These interactions can occur in vivo at the site of allergen-triggered inflammation, for example, in bronchus-associated lymphoid tissue.
human insulin, individuals with diabetes could develop allergy to porcine insulin, usually administered in doses of 1–2 milligrams per injection. In contrast, doses of penicillin-type drugs (including cephalosporins and other β-lactam-containing antibiotics) that can lead to sensitization when administered by intramuscular or intravenous injection are usually in the 1to 2-gram per injection range.