Immunologically mediated signaling in basophils and mast cells: finding therapeutic targets for allergic diseases in the human Fc epsilon R1 signaling pathway

The high affinity IgE receptor, Fc epsilon RI, plays key roles in an array of acute and chronic human allergic reactions including asthma, allergic rh initis, atopic dermatitis, urticaria and anaphylaxis. In humans and rodents , this receptor is found at high levels on basophils and mast cells where i ts activation by IgE and multivalent antigen produces mediators and cytokin es responsible for Fc epsilon RI-dependent acute inflammation. Mast cells c an additionally contribute to sustained inflammatory responses by internali zing antigen bound to IgE-Fc epsilon RI complexes for processing to peptide s and presentation to T cells. In humans, the Fc epsilon RI is also express ed, at lower density, on monocytes, macrophages and dendritic cells (DC) wh ere its likely functions again include both signaling to mediator and cytok ine production and antigen presentation. Our laboratories have focused on d efining the earliest steps in the Fc epsilon RI signaling cascade in basoph ils and mast cells and on developing new routes to control allergic inflamm ation based on inhibiting these events. Here, we describe novel strategies to limit antigen-stimulated Fc epsilon RI signaling by: (1) sequestering th e Fc epsilon R1-associated protein-tyrosine kinase, Lyn, that initiates Fc epsilon RI signaling; (2) eliminating; or (3) inactivating the protein-tyro sine kinase, Syk, that propagates Fc epsilon RI signaling; and (4) establis hing inhibitory crosstall between Fc epsilon RI and a co-expressed receptor , Fc gamma RZI, that again limits Fc epsilon RI-mediated Syk activation. Th ese strategies may form the basis for new therapies for allergic inflammati on. (C) 2000 Elsevier Science B.V. All rights reserved.