IgE antibody produced in response to an allergen binds to high-affinity Fc receptors, specific for the ε heavy chain, that are expressed on mast cells (see Fig. 1). Thus, in an atopic individual, mast cells are coated with IgE antibody specific for the antigen(s) to which the individual is allergic. This process of coating mast cells with IgE is called sensitization, because it makes the mast cells sensitive to activation by subsequent encounter with that antigen. In normal individuals, by contrast, mast cells may carry IgE molecules of many different specificities because many antigens may elicit small IgE responses, and the amount of IgE specific for any one antigen is not enough to cause immediate hypersensitivity reactions upon exposure to that antigen.

Fig1. The sequence of events in immediate hypersensitivity. Immediate hypersensitivity reactions are initiated by the introduction of an allergen, which stimulates Th2 and IL-4/ IL-13–producing Tfh cells and immunoglobulin E (IgE) production. IgE binds to Fc receptors (FcεRI) on mast cells, and sub sequent exposure to the allergen activates the mast cells to secrete the mediators that are responsible for the pathologic reactions of immediate hypersensitivity.

Mast cells are present in all connective tissues, especially under epithelia, and they are usually located adjacent to blood vessels. Which of the body’s mast cells are activated by binding of an allergen often depends on the route of entry of the allergen. For example, inhaled allergens activate mast cells in the submucosal tissues of the bronchus, whereas ingested allergens activate mast cells in the wall of the intestine. Allergens that enter the blood via absorption from the intestine or by direct injection may be delivered to all tissues, resulting in systemic mast cell activation.

T he high-affinity receptor for IgE, called FcεRI, con sists of three polypeptide chains, one of which binds the Fc portion of the ε heavy chain very strongly, with a K_d of approximately 10⁻¹¹ M. (The concentration of IgE in the plasma is approximately 10⁻⁹ M, which explains why even in normal individuals, mast cells are always coated with IgE bound to FcεRI.) The other two chains of the receptor are signaling proteins. The same FcεRI is also present on basophils, which are circulating cells with many of the features of mast cells, but normally the number of basophils in the blood is very low and they are not present in tissues, so their role in immediate hypersensitivity is not as well established as the role of mast cells.

When mast cells sensitized by IgE are exposed to the allergen, they are activated to secrete inflammatory mediators (Fig. 2). Mast cell activation results from binding of the allergen to two or more IgE antibodies on the cell. When this happens, the FcεRI molecules that are carrying the IgE are cross-linked, triggering bio chemical signals from the signal-transducing chains of FcεRI. The signals lead to the release of inflammatory mediators.

Fig2. Production and actions of mast cell mediators. Cross-linking of IgE on a mast cell by an allergen stimulates phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the signaling chains of the IgE Fc receptor (FcεRI), which then initiates multiple signaling pathways. These signaling path ways stimulate the release of mast cell granule contents (amines, proteases), the synthesis of arachidonic acid metabolites (prostaglandins, leukotrienes), and the synthesis of various cytokines. TNF, Tumor necrosis factor.

The most important mediators produced by mast cells are vasoactive amines and proteases stored in and released from granules, newly generated and secreted products of arachidonic acid metabolism, and cytokines (see Fig. 2). These mediators have different actions. The major amine, histamine, causes increased vascular permeability and vasodilation, leading to the leak of fluid and plasma proteins into tissues, and stimulates the transient contraction of bronchial and intestinal smooth muscle. Proteases may cause damage to local tis sues. Arachidonic acid metabolites include prostaglandins, which cause vascular dilation, and leukotrienes, which stimulate prolonged bronchial smooth muscle contraction. Cytokines induce local inflammation (the late-phase reaction, described next). Thus, mast cell mediators are responsible for acute vascular and smooth muscle reactions and more prolonged inflammation, the hallmarks of immediate hypersensitivity.

Cytokines produced by mast cells stimulate the recruitment of leukocytes, which cause the late phase reaction. The principal leukocytes involved in this reaction are eosinophils, neutrophils, and Th2 cells. Mast cell–derived tumor necrosis factor (TNF) and IL-4 promote neutrophil- and eosinophil-rich inflammation. Chemokines produced by mast cells and by epithelial cells in the tissues also contribute to leukocyte recruitment. Eosinophils and neutrophils liberate proteases, which cause tissue damage, and Th2 cells may exacerbate the reaction by producing more cytokines. Eosinophils are prominent in many allergic reactions and are an important cause of tis sue injury in these reactions. These cells are activated by the cytokine IL-5, which is produced by Th2 cells and innate lymphoid cells. 

مواضيع ذات صلة

Hypersensitivity Disorders Caused by Immune Responses : Clinical Syndromes and Therapy

Activation of Th2 Cells and Production of IgE Antibody

Transplantation of Blood Cells and Hematopoietic Stem Cells

Prevention and Treatment of Graft Rejection

Monocytes–Macrophages: Host Defense Functions: Phagocytosis

Mononuclear Phagocyte System

Immune Mechanisms of Graft Rejection

Induction of Immune Responses Against Transplants

Transplantation Antigens

Glycans and Immunity

Immune Responses Against Transplants

Cancer Immunotherapy : Stimulation of Host Antitumor Immune Responses by Vaccination With Tumor Antigens