Allergic diseases such as asthma, atopic dermatitis and food allergies collectively affect 30-40% of adults and children in the U.S. and their prevalence is increasing. Current treatment strategies generally rely upon either neutralizing individual mediators and/or dampening the immune response. However, targeting single mediators in an inflammatory response only removes a fraction of the inflammatory ?pool? of mediators and effective novel therapeutics that directly and specifically target inflammatory mast cells is an unmet need. All allergic diseases share a common feature of altered mast cell phenotype resulting in chronic hypersecretion of proinflammatory mast cell mediators such as histamine, serotonin, leukotrienes, prostaglandins, proteases and cytokines. It is likely that inherited genetic characteristics and environmental/epigenetic alterations play important roles in development of this allergic mast cell phenotype. Interestingly, human linkage analysis has identified that the gene loci 11q12-q13 are strongly linked to allergy and asthma susceptibility. The Membrane Spanning (MS)4A gene cluster encodes a family of at least 16 genes in humans that are expressed in immune cells. Current evidence suggests a link between the MS4A family and diseases associated with inflammation. The entire MS4A gene cluster lies within 11q12-q13, suggesting a potential linkage to allergy. In this application, we propose that the MS4A gene cluster plays a critical role in the development of a hyper- responsive mast cell phenotype. Currently, only two of these genes have been studied in detail and both play important roles in immune cell signaling and function. In this study, we will establish the roles of the MS4A gene cluster in human mast cell function and identify MS4A proteins as novel regulators of Fc?RI trafficking and signaling that define human mast cell function and responsiveness to IgE signals in mast cells from non-diseased and asthmatic lung. In addition to novel mechanisms that regulate mast cell function, these proteins could represent new drug targets for asthma and other allergic diseases.
This project will study regulation of IgE receptor signaling in human mast cells by a family of proteins of unknown function. We will establish novel mechanisms that regulate mast cell responsiveness and IgE-mediated inflammation. By studying lung tissue from non-diseased and asthmatic subjects, we will determine potential roles for these genes in asthma and identify novel drug targets for the treatment of asthma and allergic diseases.
