Integrated signalling pathways for mast-cell activation

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Abstract
Mast cells have a central role in the initiation of allergic inflammatory reactions that are associated with disease states such as asthma. These reactions are generally a consequence of the aggregation of IgE-occupied high-affinity receptors for IgE (FcεRIs), which is induced by multivalent antigen. There is emerging evidence, however, that other receptors expressed by mast cells ? such as the receptors for stem-cell factor (that is, KIT), adenosine, complement component 3a, chemokines, sphingosine 1-phosphate and pathogen-associated molecular patterns ? might also markedly influence these responses either by potentiating FcεRI-dependent mediator release or by themselves inducing mast-cell activation. So, in vivo, these receptors might prime mast cells for subsequent activation by antigen, or ligands for these receptors might be co-activators for antigen-mediated mast-cell responses. Two main signalling pathways seem to regulate FcεRI-mediated mast-cell activation: first, the 'principle' pathway, which is regulated by the transmembrane adaptor molecule LAT (linker for activation of T cells) and is mediated by phospholipase Cγ; and second, the complementary pathway (also termed the amplification pathway), which is mediated by the SRC-family kinase FYN and phosphatidylinositol 3-kinase and might be regulated by the transmembrane adaptor molecule NTAL (non-T-cell activation linker). The existence of these interacting pathways might help to explain how the signals that are initiated by receptors such as KIT could be integrated with the signals that are mediated by FcεRI, leading to a synergistic increase in antigen-dependent release of mediators by mast cells. The ability of these receptors to modify FcεRI-mediated mast-cell signalling and activation might have important implications for the treatment of mast-cell-driven disorders.