Immunologically mediated signaling in basophils and mast cells: finding therapeutic targets for allergic diseases in the human FcvarepsilonR1 signaling pathway.

The high affinity IgE receptor, FcvarepsilonRI, plays key roles in an array of acute and chronic human allergic reactions including asthma, allergic rhinitis, atopic dermatitis, urticaria and anaphylaxis. In humans and rodents, this receptor is found at high levels on basophils and mast cells where its activation by IgE and multivalent antigen produces mediators and cytokines responsible for FcvarepsilonRI-dependent acute inflammation. Mast cells can additionally contribute to sustained inflammatory responses by internalizing antigen bound to IgE-FcvarepsilonRI complexes for processing to peptides and presentation to T cells. In humans, the FcvarepsilonRI is also expressed, at lower density, on monocytes, macrophages and dendritic cells (DC) where its likely functions again include both signaling to mediator and cytokine production and antigen presentation. Our laboratories have focused on defining the earliest steps in the FcvarepsilonRI signaling cascade in basophils and mast cells and on developing new routes to control allergic inflammation based on inhibiting these events. Here, we describe novel strategies to limit antigen-stimulated FcvarepsilonRI signaling by: (1) sequestering the FcvarepsilonRI-associated protein-tyrosine kinase, Lyn, that initiates FcvarepsilonRI signaling; (2) eliminating; or (3) inactivating the protein-tyrosine kinase, Syk, that propagates FcvarepsilonRI signaling; and (4) establishing inhibitory crosstalk between FcvarepsilonRI and a co-expressed receptor, FcgammaRII, that again limits FcvarepsilonRI-mediated Syk activation. These strategies may form the basis for new therapies for allergic inflammation.