Analysis of basophil function in secondary immune responses

University Of California, San Francisco, San Francisco CA

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Abstract

DESCRIPTION (provided by applicant): Allergic diseases are rapidly growing in prevalence in industrialized nations. One of the key factors promoting allergy is the generation of antibodies of the IgE isotype. In allergic disease, the IgE antibodies are directed toward harmless environmental substances, known as allergens, such as proteins in cat dander or pollen grains. These IgE antibodies are captured by specialized cells in tissues, known as mast cells, where they sensitize the mast cells to be able to rapidly release potent proinflammatory mediators upon exposure to the allergens. It is thought that this localized system evolved to provide tissue protection against parasite infection. However, another cell type captures high levels of IgE, known as basophils, yet these cells migrate throughout the body and their function is poorly understood. Specifically, little is known about how the basophils capture allergens, what occurs in vivo after they bind allergens, and whether or not the basophils interact with cells of the innae or adaptive immune system following IgE-mediated activation. We also do not fully understand the contribution of IgE-sensitized basophils to host immunity to parasite infection. We will use two-photon microscopy of the lymph nodes and lungs in order to directly visualize the behavior of basophils that have been coated with antigen-specific IgE and then exposed to antigen. We will consider the cellular interactions between basophils and other cell types of the innate or adaptive immune system. We will also visualize the process by which basophils encounter antigen and how this changes their behavior. We will follow up these studies with genetic manipulations to test the potential functions of basophils. Our direct visual observations in the physiological tissue setting will have the power to provide new paradigm-shifting insights into the function of these enigmatic cells. The specific aims of this study are to: 1) Characterize the IgE-mediated capture and transport of antigen by basophils in the lymph nodes and lungs, 2) Determine whether basophils that have captured antigen via IgE can enhance B or T cell responses, and 3) Test the function of IgE-activated basophils in macrophage polarization, lung pathology, and wound healing. The results from these studies will be helpful in understanding the role of these cells in allergic and parasite immunity as well as the underlying cross-talk and feedback between the innate and adaptive immune systems.