Preformed Enzymes in Mast Cell Granules and Their Potential Role in Allergic Rhinitis Smruti A. Parikh, MD, Seong H. Cho, MD, and Chad K. Oh, MD Address UCLA School of Medicine, Harbor-UCLA Medical Center, Bldg. N-25, 1000 W. Carson Street, Torrance, CA 90509, USA. E-mail: coh@rei.edu Current Allergy and Asthma Reports 2003, 3:266–272 Current Science Inc. ISSN 1529-7322 Copyright © 2003 by Current Science Inc. Introduction Mast cells (MCs) produce and secrete a vast array of media- tors that play a key role in producing the clinical symptoms of allergic rhinitis (AR). The allergic response in sensitized nasal mucosa following exposure to an allergen is commonly divided into the early-phase response (EPR), the late-phase response (LPR), and the chronic inflammatory response. It is well established that MC mediators are essen- tial in producing the EPR. There is growing evidence that these mediators also propagate the LPR and contribute to the development of chronic inflammation associated with AR. Increasing knowledge concerning the role of MCs in the various aspects of AR might lead to the development of novel approaches to the prevention and treatment of this common disorder. In this review, we focus on the major mediators produced by MCs and their effects on AR. Sensitization/T-helper Cell Differentiation The condition of AR is induced by sensitization of an indi- vidual to inhaled allergens such as pollen grain, animal dander, or dust mite particles. Once these allergen parti- cles are inhaled and deposited on the mucosa, they are taken up by antigen presenting cells (APCs) and cleaved into short peptide units for presentation by major histo- compatibility complex (MHC) class II molecules. The rec- ognition of these antigenic peptides by naïve T-helper cells (Th0) leads to the differentiation of these lymphocytes into Th2 cells, thus beginning the cascade that results in the development of AR. When an antigen is recognized by a Th0 cell, it can dif- ferentiate into either a Th1 or Th2 cell depending on the type of antigen, APC, and cytokine milieu present. Th1 cells are characterized by the secretion of interferon (IFN)-γ, and are known to activate cell-mediated immunity. Th2 lympho- cytes, however, promote a pro-atopic environment by secret- ing a variety of cytokines including: interleukin (IL)-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, and granulocyte macrophage- colony stimulating factor (GM-CSF). These cytokines (espe- cially IL-4) maintain the pro-Th2 environment, induce IgE production by plasma cells, and suppress the Th1 response. Through adhesion molecule-dependent interactions, acti- vated T cells might directly affect MC degranulation and cytokine synthesis [1•]. Plasma cells begin production and release of antigen- specific IgE antibodies. These IgE antibodies then bind FcεRI (high affinity IgE receptors) on MCs and other inflammatory cells. Re-exposure to the same allergen causes cross-linking of Fc εRI, leading to MC activation and degranulation. Early-phase Response The symptom complex associated with the release of MC mediators immediately following antigen exposure is known as the EPR of AR. The preformed mediators released during EPR include histamine, kinins, and neutral proteases, as well as cytokines such as tumor necrosis factor (TNF)-α and a vari- ety of ILs. In addition, MCs release kininogenase that can con- vert plasma kininogens into bradykinin (BK). Activation of MCs also leads to the production of leukotrienes (LTs) and prostaglandins (PGs) from arachidonic acid. Together these Mast cells not only function as effector cells but also influence nearly every other cell involved in causing allergic rhinitis. Mast cell-derived mediators such as histamine, bradykinin, tryptase, and the arachidonic acid derivatives produce the symptoms of the early-phase reaction of allergic rhinitis and also attract and activate other leukocytes involved in the late- phase reaction. In addition, activated mast cells are known to secrete a number of cytokines, both preformed and newly synthesized, that can modulate T- and B-cell function, propa- gate the early- and late-phase reactions, and contribute to tis- sue remodeling. Most currently available therapies work by antagonizing the mediators secreted by mast cells and other leukocytes. With the possible exception of immunotherapy, these therapies do not provide long-term protection against allergic disorders. Exciting new developments in gene-based therapies seem promising in both reducing and reversing the development of allergic rhinitis.