In vivo role of high-affinity immunoglobulin E receptors on dendritic cells

Eva Mitterhumer
2009 unpublished
Type 1 allergy, in particular allergic asthma, is a severe inflammatory disease of high socioeconomic importance. Pathophysiologically, type 1 allergic responses consist of an early (EAR) and a late-phase allergic reaction (LAR). The short-lived EAR is initiated by allergen-dependent crosslinking of mast cell-expressed high-affinity IgE receptors (FcεRI). The LAR, in contrast, persists for hours to days and is independent of mast cell activation but depends on tissue infiltration with
more » ... pecific Th2 lymphocytes, dendritic cells (DCs), and eosinophils. Eosinophils release soluble mediators of tissue damage and, thus, are the main effector cells of LARs. In human allergic asthma, LAR-associated inflammation is the main cause for ventilatory insufficiency. Frequent occurrence of severe LARs can promote chronic asthma and irreversible fibrotic lung remodelling. As the consequence, the LAR, even more the EAR, is the main reason of morbidity and mortality in human type 1 allergy. Besides its presence on mast cells, FcεRI is also expressed on human antigen-presenting cells such as DCs in various tissues like the lung. In vitro studies demonstrated that IgE bound to FcεRI on DCs increases antigen uptake, processing and peptide presentation to CD4+ T helper (Th) lymphocytes. Accordingly, it can be speculated that DC-expressed FcεRI contributes to the induction and the severity of LARs in vivo. However, the in vivo relevance of FcεRI on DCs remained enigmatic due to the lack of suitable animal models. Mice, for instance, express FcεRI on mast cells and basophils but, unlike humans, lack FcεRI expression on any type of their antigen-presenting cells. In order to study the in vivo role of DC-expressed FcεRI for T cell activation and its contribution to allergic inflammation, we generated transgenic mice which display a "human-like" expression pattern of FcεRI. These α-DC TG mice express the IgE binding α-chain of human FcεRI and green fluorescent protein under the control of the murine DC-specific CD11c promoter. α-DC [...]
doi:10.25365/thesis.6633 fatcat:npqu46vpnrfkbbj57t7fzciv7e