Under some circumstances, immune responses produce damaging and sometimes fatal results. Such deleterious reactions are known collectively as hypersensitivity or allergic reactions; antigens that commonly cause hypersensitivity or allergic reactions are referred to as allergens. Mast cells, the main effector responsible for type I hypersensitivity responses, are a ubiquitous family of cells generally found around blood vessels in the connective tissue, in the lining of the gut, and in the lungs. One of the most important features of mast cells is the presence of high-affinity receptors for IgE (FceRI), on their cell membranes. When crosslinked by antigens, the IgE antibodies (bound to FceRs) trigger mast cells to release pharmacologically active agents that lead to clinical manifestations, including rhinitis, asthma, and, in severe cases, anaphylaxis. Aggregation of the high affinity receptor for IgE (FceRI) on Mast cells, trigger the Ca2+ dependent release of histamine containing granules, the synthesis of arachidonic acid-derived mediators and various cytokines, which together are responsible for the major symptoms of immediate hypersensitivity reactions. An understanding of mast cell activation, and Ca2+ signaling, therefore has obvious therapeutic implications. Current treatment for allergies is limited mainly to anti-histamines or treatment with steroids, both of which have very poor action and unwanted side effects.
Using a wide range of molecular, cellular and biochemical techniques, we are investigating the phospholipid signaling cascades triggered by FceRI in mast cells, with particular emphasis on the role of phospholipases A2, C, and D, and of lipid kinases, such as PI3-kinase, DAG kinase, and sphingosine kinase, in the triggering of Ca2+ fluxes, mast cell degranulation and cytokine release.
An understanding of the molecular mechanisms regulating the intracellular signaling pathways triggered by FceRI in mast cells has obvious therapeutic implications. This understanding has the potential to lead to the identification of novel and/or more selective and effective drugs for the treatment of allergies.