There are two types of IgE-binding Fc receptors. The first, FcεRI, expressed on mast cells and basophils, is a high-affinity receptor of the immunoglobulin superfamily (see Section 10-24). When IgE bound to this receptor is cross-linked by specific antigen, it transduces an activating signal through the receptor-bound Lyn tyrosine kinase, which phosphorylates ITAMs on the intracellular domain of the receptor. This recruits and activates the amplifying tyrosine kinase Syk, which phosphorylates and activates a broad range of downstream effector pathways. High levels of IgE, such as those that exist in people with allergic diseases or parasite infections, can result in a marked increase in FcεRI on the surface of mast cells, an enhanced sensitivity of such cells to activation by low concentrations of specific antigen, and a markedly increased, IgE-dependent release of chemical mediators and cytokines.
The second IgE receptor, FcεRII, usually known as CD23, is a C-type lectin and is structurally unrelated to FcεRI; it binds IgE with low affinity. CD23 is present on many cell types, including B cells, activated T cells, monocytes, eosinophils, platelets, follicular dendritic cells, and some thymic epithelial cells. This receptor was thought to be crucial for the regulation of IgE levels, but mouse strains in which the gene for CD23 has been inactivated still develop relatively normal polyclonal IgE responses. Nevertheless, CD23 does seem to be involved in enhancing IgE antibody levels in some situations. Responses against a specific antigen are known to be increased in the presence of the antigen complexed with IgE, but such enhancement fails to occur in mice that lack the gene for CD23. This has been interpreted to indicate that CD23 on antigen-presenting cells has a role in the capture of antigen that is complexed with IgE.
14-7 Mast cells reside in tissues and orchestrate allergic reactions.
When Paul Ehrlich described mast cells found in the mesentery of rabbits, he called them Mastzellen (‘fattened cells’). Like basophils, mast cells contain granules rich in acidic proteoglycans that take up basic dyes. Mast cells are derived from hematopoietic stem cells but mature locally, often residing near surfaces exposed to pathogens and allergens, such as mucosal tissues and the connective tissues surrounding blood vessels. Mucosal mast cells differ in some of their properties from submucosal or connective tissue mast cells, but both can be involved in allergic reactions.
Fig. 14.9 Molecules released by activated mast cells. Mast cells release a wide variety of biologically active proteins and other chemical mediators. The enzymes and toxic mediators listed in the first two rows are released from the preformed granules. The cytokines, chemokines, and lipid mediators are mostly synthesized after activation.
The major factors for mast-cell growth and development include stem-cell factor (the ligand for the receptor tyrosine kinase Kit), IL-3, and TH2-associated cytokines such as IL-4 and IL-9. Mice with defective Kit lack differentiated mast cells, and although they produce IgE, they cannot make IgE-mediated inflammatory responses. This shows that such responses depend almost exclusively on mast cells. Mast-cell activation depends on the activation of phosphatidylinositol 3-kinase (PI 3-kinase) in mast cells by Kit, and pharmacological inactivation of the p110δ isoform of PI 3-kinase has been shown to protect mice against allergic responses. Inhibitors of the amplifying tyrosine kinase Syk are also showing promise as blockers of IgE-dependent mast-cell responses.