Critical signaling nodes regulating mast cell releasibility phenotypes

National Institute Of Allergy And Infectious Diseases

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Abstract

Mast cells play a pivotal role in the pathogenesis of asthma and other allergic diseases. These reactions are generally initiated by antigen-dependent aggregation of the high affinity IgE receptor (Fc-epsilon-RI) expressed on the cell surface and subsequent release of pro-inflammatory mediators (e.g. histamine, eicosanoids, proteases and cytokines). We wish to identify how the mast cell activation phenotype is regulated in health and disease, to identify disease states and clinical populations where hyper-responsive and hypo-responsive mast cell phenotypes exist and to identify specific signaling defects responsible for these phenotypes. In addition to the Fc-epsilon-RI, there is an increasing appreciation that other receptors (and other stimuli) may profoundly influence antigen-mediated degranulation. Activating polymorphisms/mutations in, and alternatively spliced forms of, receptors and/or signaling proteins may further modulate these responses. Such polymorphisms associated with disease states, like anaphylaxis, atopy, and mastocytosis may be manifested by exacerbated mast cell-dependent physiology. We wish therefore to also explore the role of other mast cell receptors in disease states and how polymorphisms or alternatively spliced variants of receptors or signaling proteins may produce a hyperactive phenotype. Finally, we wish to explore potential approaches for inhibiting these responses. The following observations were made since the last report: i. Stem cell factor and other critcal cytokines program the mast cell activation phenotype We identified a novel mechanism for the regulation of the extent of mast cell activation through SCF-dependent induction of a hypo-responsive phenotype with respect to both cytokine production and degranulation. This phenotype was not due to down-regulation of the expression of either Fc-epsilon-RI or KIT, but could be explained by an inability of the cells to undergo the cytoskeletal reorganization required for mediator release, potentially as a consequence of decreased expression of the Src kinase Hck. These findings revealed that the sensitivity of mast cells to IgE/antigen stimulation is highly regulated by SCF and, as recently discoverd, other cytokines in the surrounding tissue milieu and may thus have important implications for understanding how the activation capacity of tissue mast cells may be phenotypically modified in health and in disease. 2. Hyperactive/hyperproliferatve mast cell phenotype Mast cells are generated from peripheral blood progenitors from patients and a subset of these mast cells appear to have a hyper-proliferative, hyper-responsive phenotype. These features may be linked to exaggerated antigen-mediated signaling processes and the potential genes underlying these phenotypes are being investigated.