IgEbinding Fc Receptors

The reaginic activity of IgE depends on its ability to bind to a receptor specific for the Fc region of the € heavy chain. Two

membrane of a mast cell. (c) Granule releasing its contents (towards top left) during degranulation. [From S. Burwen and B. Satir, 1977, J. Cell Biol. 73:662.]

FIGURE 16-3

(a) Electron micrograph of a typical mast cell reveals numerous electron-dense membrane-bounded granules prior to degranulation. (b) Close-up of intact granule underlying the plasma membrane of a mast cell. (c) Granule releasing its contents (towards top left) during degranulation. [From S. Burwen and B. Satir, 1977, J. Cell Biol. 73:662.]

High-affinity IgE receptor

Low-affinity IgE receptor

High-affinity IgE receptor

Low-affinity IgE receptor

Fceri Fcerii

COOH COOH

CD3 complex of the T-cell receptor. (b) The low-affinity receptor is unusual because it is oriented in the membrane with its NH 2-terminus directed toward the cell interior and its COOH-terminus directed toward the extracellular space.

COOH COOH

FIGURE 16-4

Schematic diagrams of the high-affinity FceRI and low-affinity FceRII receptors that bind the Fc region of IgE. (a) Each 7 chain of the high-affinity receptor contains an ITAM, a motif also present in the Ig-a/Ig-p heterodimer of the B-cell receptor and in the

CD3 complex of the T-cell receptor. (b) The low-affinity receptor is unusual because it is oriented in the membrane with its NH 2-terminus directed toward the cell interior and its COOH-terminus directed toward the extracellular space.

classes of FceR been identified, designated FceRI and FceRII, which are expressed by different cell types and differ by 1000fold in their affinity for IgE.

HIGH-AFFINITY RECEPTOR (FCeRI) Mast cells and basophils express FceRI, which binds IgE with a high affinity (KD = 1-2 X 10-9 M). The high affinity of this receptor enables it to bind IgE despite the low serum concentration of IgE (1 X 10-7). Between 40,000 and 90,000 FceRI molecules have been shown to be present on a human basophil.

The FceRI receptor contains four polypeptide chains: an a and a p chain and two identical disulfide-linked 7 chains (Figure 16-4a). The external region of the a chain contains two domains of 90 amino acids that are homologous with the immunoglobulin-fold structure, placing the molecule in the immunoglobulin superfamily (see Figure 4-19). FceRI interacts with the Ch3/Ch3 and Ch4/Ch4 domains of the IgE molecule via the two Ig-like domains of the a chain. The p chain spans the plasma membrane four times and is thought to link the a chain to the 7 homodimer. The disulfide-linked 7 chains extend a considerable distance into the cytoplasm. Each 7 chain has a conserved sequence in its cytosolic domain known as an immunoreceptor tyrosine-based activation motif (ITAM). As described earlier, two other mem brane receptors that have this motif are CD3 and the associated £ chains of the T-cell receptor complex (see Figure 10-10) and the Ig-a/Ig-p chains associated with membrane immunoglobulin on B cells (see Figure 11-7). The ITAM motif on these three receptors interacts with protein tyrosine kinases to transduce an activating signal to the cell. Allergen-mediated crosslinkage of the bound IgE results in aggregation of the FceRI receptors and rapid tyrosine phosphoryla-tion, which initiates the process of mast-cell degranulation. The role of FceRI in anaphylaxis is confirmed by experiments conducted in mice that lack FceRI. These mice have normal levels of mast cells but are resistant to localized and systemic anaphylaxis.

LOW-AFFINITY RECEPTOR (FCeRII) The other IgE receptor, designated FceRII (or CD23), is specific for the CH3/ Ch3 domain of IgE and has a lower affinity for IgE (KD = 1 X 10-6M) than does FceRI (Figure 16-4b). The FceRII receptor appears to play a variety of roles in regulating the intensity of the IgE response. Allergen crosslinkage of IgE bound to FceRII has been shown to activate B cells, alveolar macrophages, and eosinophils. When this receptor is blocked with monoclonal antibodies, IgE secretion by B cells is diminished. A soluble form of FceRII (or sCD23), which is generated by autoproteolysis of the membrane receptor, has been shown to enhance IgE production by B cells. Interestingly, atopic individuals have higher levels of CD23 on their lymphocytes and macrophages and higher levels of sCD23 in their serum than do nonatopic individuals.

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