Airways Eosinophils as Antigen-presenting Cells in Asthma

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DESCRIPTION (provided by applicant): Studies will investigate capabilities and mechanisms whereby eosinophils, including those recruited within airways in asthma, function as antigen-presenting cells that are of importance in propagating or modulating varied lymphocyte-dependent responses to respiratory tract encountered antigens. As antigen-presenting cells, eosinophils have distinct capabilities: First, airway eosinophils express requisite Class II MHC and lymphocyte costimulatory proteins. Second, eosinophils, like dendritic cells, function as "professional" antigen-presenting cells in expressing lymphocyte costimulatory proteins and activating unsensitized, naive T cells. Third, eosinophils, in contrast to other antigen-presenting cells, contain preformed stores of diverse cytokines that can be rapidly and selectively secreted to modulate varied lymphocyte responses. Fourth, eosinophils, like other antigen-presenting cells, utilize Fc receptor- mediated mechanisms to enhance antigen presentation by antigen-presenting cells. Eosinophil IgE, IgA and IgG receptors, together with airway allergen-specific IgE, IgA and IgG antibodies, can effectively present allergens. Fifth, airway eosinophils traffick into lymph nodes, spleen and even the thymus enabling airway antigens to be processed and transported into regional and systemic lymphoid tissues for presentation to varied lymphocytes. Sixth, eosinophils express ligands and receptors classically associated with dendritic cells, including DC-SIGN. Moreover, eosinophils can modulate B lymphocyte responses since eosinophils are critical participants in alum immunization-mediated B cell priming. Hypotheses to be tested are: that eosinophils trafficking from the airways are effective at presenting antigens to regulate, potentially differing, T lymphocyte responses in both regional and systemic lymphoid cells; that selective, restricted secretion of eosinophil cytokines mediates differential regulation of eosinophil antigen-presenting cell functions; and that eosinophils have roles in mediating the priming and responsiveness of B cells. Studies aim to investigate mechanisms by which eosinophils traffic and function as antigen-presenting cells to regulate regional and systemic T cell responses; eosinophil cytokines function in differential mediation of eosinophil antigen-presenting cell functions, and eosinophils function in B cell priming and activation. Roles for eosinophils as antigen-presenting cells in mediating allergic responses to airway antigens would provide novel insights into the characteristically chronic nature of asthma and other allergic airway diseases. PUBLIC HEALTH RELEVANCE. Asthma is an increasingly prevalent disease and a major public health problem. The research will help in understanding mechanisms that contribute to making asthma a chronic and persistent disease.