Allergic diseases are characterized, in part, by the activities of mast cells and basophils. These cells bind circulating IgE and subsequently become responsive to allergen exposure. In addition to this IgE-dependent part of the reaction, the phenotype of the cell also determines the nature of its responses to both allergens and other biological molecules in the environment of the cell. A variety of studies have implicated the basophil in the immediate hypersensitivity reactions that are part of the allergic condition. In addition, studies during the last 3-4 decades have repeatedly made note of several basophil phenotypes that track with different allergic disease states. Despite the importance of the basophil in immediate hypersensitivity reactions, there have been only cursory efforts to understand the basis for the various basophil phenotypes. One reason for the lack of progress in understanding these phenotypes is that only recently are some of the molecular mechanisms that may modulate the basophil phenotype described well enough to develop hypotheses regarding the phenotypes'origins. Another reason is that the basophil is difficult to study and the tools to properly characterize its phenotype are not available. This application will provide a new set of analytical tools to explore basophil phenotypes with the intent of applying these tools to the question of basophil phenotypes. RNA signatures are a well- explored approach to characterizing complex phenotypes but they have not been applied to the question of basophil phenotypes due to the difficulties studying this cell. Two approaches are proposed, one based on developing well-defined signatures associated with specific modulators of basophil function and phenotype and the second based on the more general comparisons that can be made between natural phenotypes using a broad-based microarray profile. After developing the focused signatures that are associated with specific basophil modulators, the third specific aim of the proposal will examine three well described basophil phenotypes, the phenotype associated with omalizumab treatment and linked to marked increases in cellular sensitivity, the spontaneous release phenotype associated with food allergies and severe asthma and the suppressed phenotype associated with chronic idiopathic urticaria. It is expected that identification of the basis for the phenotypes will provide new insights into the underlying biolog that drives these allergic conditions.
One of the IgE-bearing cells important to the expression of allergic diseases, the basophil, shows a variety of characteristics (phenotypes) associated with specific allergic conditions. These phenotypes are not understood. Understanding these phenotypes molecularly will provide insight into allergic disease pathogenesis.