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BRIEF PROPOSAL MAST CELLS AND PRECURSOR PROTEIN MOLECULES THEOHARIS CONSTANTIN THEOHAR1DES* Mast cells were first identified as a distinct cell type by Paul Ehrlich who described them as "well-fed cells" (mastzellen in German) in 1877 [I]. Since then, at least five monographs and two symposia have been dedicated to mast cells. In addition, a great many reviews have also appeared on the morphology, biochemistry, and pharmacology of this so-called tissue basophil or wandering histiocyte, a connective tissue cell ubiquitous in all organs of the human body [2]. In spite of this intense interest in the mast cell and numerous more reviews on its involvement in allergic disease, in parasitic infections and possibly in cancer growth [3], its physiologic function in health still remains in the realm of speculation [4]. The lack of a definitive physiologic function for the mast cell was the topic of a recent editorial entitled, after Ehrlich first coined me expression, "The Mast Cell—a Fascinating Riddle" [5]. Mast cells participate in allergic reactions through an explosive release of mediators contained in their secretory granules. Because this release occurs by exocytosis (a general mechanism common to glandular and neural cells [6]) and mast cells, like most secretory cells, seemingly use calcium as a mediator in stimulus-secretion coupling [7], they have been increasingly used as a model system for the study of the cellular events involved in secretion [8]. In addition, from the clinical standpoint, mast cells have lent themselves to the study of the pharmacological properties both of those substances affecting mast cell secretion and integrity [2] as well as those secreted from them [9]. Heparin was the first molecule to be demonstrated in mast cell granules, followed by histamine and a variety of other powerful substances that include serotonin, chemotactic peptides, and enzymes [9]. Impressive as the variety and potential effects of these substances may be, their physiologic role has often been questioned, as in the case ofmastcell heparin, the anticoagulant function ofwhich has been recently cast in doubt [10]. One is then left wondering about the usefulness ofsuch a dramatic release mechanism, especially since the immunoglobulin E system, whereby IgE binds to mast cell surface receptors and can trigger mast cell secretion when it is bridged by specific antigen [8], certainly has not devel- *Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510. Permission to reprint this brief proposal may be obtained only from the author. Perspectives in Biology and Medicine ¦ Spring 1981 | 499 oped only for its participation in clinical allergy; or, to put it differently, "one does notdrop dead ofabee-stingeveryday" (Padawer, personalcommunication). It is therefore proposed that a functional, physiologic role for the mast cell could involve an ongoing, low-grade, possibly selective release of some of its mediators, especially those of enzymic nature. Furthermore, it is hypothesized that such enzymes could participate in the conversion of inactive "pro-forms" or "precursor forms" of protein molecules into their active shorter sequences. Recent evidence has shown that mast cells are capable of undergoing highly localized secretory responses involving exocytosis of individual granules [H]. Moreover, under certain conditions, mast cells have been shown to express selective release of some of their mediators without obvious release of all granule contents [12]. This finding may be related to the fact that in a healthy organism mast cells appear to have an extended life span without substantial release of their secretory granules [4]. Such findings support the premise that the mast cell is not limited to the explosive release of its secretory components, but that it is capable of supporting a graded and possibly selective release of some of its mediators. The list of mast cell mediators has steadily expanded over the past few years to include a variety of kinin-like molecules and enzymes, and it is quite fascinating that many of these molecules once released, have the capacity to act back on the mast cell and further stimulate their secretion. For instance, vasoactive intestinal peptide has been shown to be a potent inducer of mast cell secretion [2], and it was recently shown to be localized in and be released from mast cells [13]. Likewise...


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