Fc receptors, expressed on both professional antigen presenting cells (APCs) and myeloid effector cells, link the humoral and cellular arms at two key regulated steps in the host hypersensitive immune response to environmental antigens - the afferent limb or """"""""sensitization phase"""""""" and the efferent limb or """"""""challenge phase"""""""". Sensitization Phase: By directly influencing the initial steps of antigen delivery, processing and presentation, Fc receptors on APCs couple antigen uptake and resultant T cell activation thus shaping the proximal or afferent limb of the immune response. We have shown that loading of bone marrow-derived dendritic cells with OVA/anti-OVA immune complexes but not OVA alone results in efficient priming of both CD4 and CD8 anti-OVA responses. The greater efficiency of priming by immune complexes appears to depend on both facilitated antigen processing by FcR uptake and by the IC-triggered activation of dendritic cells, inducing the upregulation of costimulatory molecules (CD80, CD86), MHC antigens (class II) and adhesion proteins (ICAM-1). The upregulation of these molecules is consistent with an activating role of ICs for promoting cellular activation and maturation of DCs and parallels changes seen in vivo during maturation and migration of DCs from the tissue to the lymph node. The process of maturation induced by other maturation factors, including microbial products and T cell products, is accompanied by the production of cytokines and chemokines responsible for recruitment and activation of antigen-specific T cells, and for at least some of these maturation factors (e.g., LPS and CpG-rich sequences) T cell activation is induced in a polarized Th1-type fashion. Our preliminary data suggests that IC-activated dendritic cells preferentially prime Th1-type T cell responses suggesting possible approaches to immune deviation and a novel explanation of allergen immunotherapy. We will comprehensively determine the pattern of Th1- type and Th2-type cytokines and chemokines produced by dendritic cells after stimulation with IgG-containing immune complexes. The functional consequences of this expression of cytokines on T cell polarization will be determined in both in vitro and in vivo settings. Challenge Phase: The importance of IgE-mediated activation at a proximal step in the airway inflammatory response induced by recurrent antigenic exposure is demonstrated by the improved clinical outcomes of asthmatic patients treated with anti-IgE therapy. In this latter effector phase of the host immune response to antigen we have shown that the paired activating and inhibitory Fc receptors modulate the amplitude of antibody triggered inflammatory responses in models of cellular bound-IgG and immune complex (IC)-triggered hypersensitivity responses. However, the contributions of the specific Fc receptors in effector phases of murine models of asthma have not yet been determined. We will determine the role(s) of activating and inhibitory Fc receptors in modulating mucus production, inflammatory infiltration and bronchial smooth muscle reactivity in murine models of asthma.
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