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Division of Immunopathology
Department of Pathophysiology and Allergy Research
Center of Pathophysiology, Infectiology & Immunology

Medical University of Vienna

Vienna General Hospital, AKH, 3Q
Waehringer Guertel 18-20
A-1090 Vienna, Austria

Genetically targeted overexpression of defined IgE-receptor complexes in experimental animals-Tools for studying atopic diseases [Maurer]

Project summary 2005 - 2008

The interaction of high affinity IgE receptors (FcÎµRI) with allergen-specific IgE is of central importance for the occurrence of type 1 allergy. In the conventional pathophysiologic view, FcÎµRI on mast cells mediates the allergic symptoms following crosslinking by allergen ligation of cell-bound IgE. Previously, we and others have found that FcÎµRI is expressed not only on mast cells and basophils but is also present on professional antigen-presenting cells (APCs) such as dendritic cells (DCs) and monocytes. On human APCs, FcÎµRI functions as a receptor that allows IgE-dependent allergen binding and presentation to T lymphocytes. Thus, it is tempting to speculate that the pathophysiologic role of FcÎµRI in vivo extends beyond its role in mast cell activation and may be of importance for the activation of allergen-specific T cells with proallergic effector functions in vivo. To study this possibility in a comprehensive fashion, we have generated in this project transgenic mice that express human FcÎµRI (along with the green fluorescent marker protein EGFP) under control of a DC-specific (CD11c) promoter. These DC-FcÎµRI transgenic mice offer the unique possibility to study the in vivo role of FcÎµRI on DCs since wild type (wt) mice, in contrast to humans, fail to express this receptors on APCs. Initial investigations have revealed that the inserted transgene is expressed in a selective fashion in DCs residing in various organs that are targets of allergic inflammation (skin, lung, small intestine). We have now crossed DC-FcÎµRI mice on genetic backgrounds that allow the analysis of the functional impact of IgE-FcÎµRI interactions on DCs for the occurrence of antigen-specific T cell activation using the ovalbumin (OVA)-specific MHC class I-restricted (OT-1) and MHC class II-restricted TCR-transgenic T cells (DO11.10) as responders. Our results demonstrate that transgenic FcÎµRI, in an IgE-dependent fashion, augments MHC class II-dependent OVA presentation by DCs resulting in strongly augmented CD4+ T cell responses. In addition, we found that FcÎµRI on DCs may also serve as a allergen-uptake receptor of exogenous protein antigen for presentation in MHC class I. As the likely in vivo result of this IgE-enhanced allergen presentation by DCs observed that proallergic type 2 T cell responses are augmented in DC-FcÎµRI mice. Moreover, the severity of allergic tissue inflammation (i.e. allergic asthma) is increased in DC-FcÎµRI transgenic mice as compared to wt mice. We have now crossed our DC-FcÎµRI mice also onto an IgE-/- background to unequivocally demonstrate that importance of the IgE-FcÎµRI signaling axis on DCs for this proallergic phenotype of DC-FcÎµRI mice. If these experiments corroborate the assumption that FcÎµRI on DCs is a critical threshold regulator of the occurrence and magnitude of the type I allergic immune response it will be of interest to therapeutically target this pathway for interference with human type 1 allergy.