Abstract
Dendritic cells play a fundamental role in shaping the immune response to allergens. The events that lead to allergic sensitization or tolerance induction during the interaction of the major birch pollen allergen Bet v 1 and dendritic cells are not very well studied. Here, we analyzed the uptake of Bet v 1 and the cross-reactive celery allergen Api g 1 by immature monocyte-derived dendritic cells (iMoDCs) of allergic and normal donors. In addition, we characterized the allergen-triggered intracellular signaling and transcriptional events. Uptake kinetics, competitive binding, and internalization pathways of labeled allergens by iMoDCs were visualized by live-cell imaging. Surface-bound IgE was detected by immunofluorescence microscopy and flow cytometry. Allergen- and IgE-induced gene expression of early growth response genes and Th1 and Th2 related cytokines and chemokines were analyzed by real-time PCR. Phosporylation of signaling kinases was analyzed by Western blot. Internalization of Bet v 1 by iMoDCs of both donor groups, likely by receptor-mediated caveolar endocytosis, followed similar kinetics. Bet v 1 outcompeted Api g 1 in cell surface binding and uptake. MoDCs of allergic and healthy donors displayed surface-bound IgE and showed a pronounced upregulation of Th2 cytokine- and NFκB-dependent genes upon non-specific Fcε receptor cross-linking. In contrast to these IgE-mediated responses, Bet v 1-stimulation increased transcript levels of the Th2 cytokines IL-4 and IL-13 but not of NFκB-related genes in MoDCs of BP allergic donors. Cells of healthy donors were either unresponsive or showed elevated mRNA levels of Th1-promoting chemokines. Moreover, Bet v 1 was able to induce Erk1/2 and p38 MAPK activation in BP allergics but only a slight p38 activation in normal donors. In conclusion, our data indicate that Bet v 1 favors the activation of a Th2 program only in DCs of BP allergic individuals.
Highlights
Type 1 allergic diseases are mediated by antibodies of the IgE class that are induced by otherwise innocuous environmental substances in genetically predisposed individuals
In order to evaluate the impact of these bacterial contaminants, immature monocyte-derived dendritic cells (iMoDCs) were incubated with increasing concentrations of LPS and PGN and mRNA levels of the NFκB-responsive genes IL-1β, IL-6, and TNF-α were determined
We based this study on the comparative analysis of the interactions of iMoDCs from birch pollen (BP) allergic and normal donors with the major BP allergen Bet v 1 and the structurally homologous but weak allergen Api g 1 from celery
Summary
Type 1 allergic diseases are mediated by antibodies of the IgE class that are induced by otherwise innocuous environmental substances in genetically predisposed individuals. The interest in innate immune cells as important regulators of adaptive immune responses to allergens has increased considerably [2]. Pattern recognition receptors, which are expressed by all innate immune cells and detect conserved molecular patterns on invading pathogens, are able to recognize allergen-associated molecular signatures [3, 4]. Considerable effort has been made to identify distinct molecular features of allergens that trigger innate immune pathways. In addition to allergen-specific characteristics, external factors such as environmental pollutants [12, 13] and matrix components of the allergen source [4, 14, 15] can promote a Th2-favoring milieu via their immunomodulatory and adjuvant activities
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