Regulation of mast-cell and basophil function and survival by IgE

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Abstract
Mast cells and basophils are important sources of effector function in IgE-associated immune responses and are also potential sources of immunoregulatory function. The best-understood mechanism for eliciting IgE-dependent effector function in mast cells and basophils is aggregation of FcɛRI, for example, by the crosslinking of FcɛRI-bound IgE with multivalent antigen. Protein-tyrosine kinase (PTK)-mediated activation mechanisms are triggered by FcɛRI aggregation. Several adaptor proteins and enzymes are involved in the activation of crucial signalling pathways, which lead to degranulation, lipid-mediator release, and cytokine and chemokine production and secretion. Inhibitory receptors, such as FcγRIIB, gp49B1, paired immunoglobulin-like receptor B (PIRB) and mast-cell function-associated antigen (MAFA) inhibit cell activation by using their immunoreceptor tyrosine-based inhibitory motifs (ITIMs) to recruit the SH2-domain-containing protein tyrosine phosphatases SHP1 and SHP2, or SH2-domain-containing inositol polyphosphate 5′ phosphatase 1 (SHIP1) and SHIP2. Binding of monomeric IgE to FcɛRI enhances the surface expression of FcɛRI, which is associated with increased sensitivity to antigen challenge and the increased production of mediators and cytokines after FcɛRI aggregation. Binding of monomeric IgE to FcɛRI can also enhance mast-cell survival, although the mechanism(s) that underlies this effect is not fully understood. Mast-cell development and growth are crucially regulated by the survival and developmental factor c-KIT ligand (stem-cell factor, SCF). However, many other cytokines can positively (for example, IL-3, IL-4 and IL-6) or negatively (for example, transforming growth factor-β) affect the survival and/or proliferation of various mast-cell populations. IL-3 is an important basophil survival and developmental factor, and it promotes basophilia in mice in vivo. However, IL-3 is not required for baseline levels of basophil production in mice. Depending on the circumstances, FcɛRI aggregation can enhance mast-cell survival and/or proliferation, promote apoptosis or have neutral effects on survival. Life-versus-death decisions in mast cells are influenced by many endogenous and exogenous factors. Endogenous factors include mast-cell-derived cytokines, cytokine receptors, adhesion molecules, death receptors, caspases, BCL-2-family proteins, intracellular signalling molecules (lipids and proteins) and transcription factors. The effects of IgE on FcɛRI surface expression and survival of mast cells and basophils are additional potential targets for anti-IgE therapy of allergic diseases.