Regulation of mast cell function and food allergic responses by aryl hydrocarbonreceptor activation

Klaver, E. (Esther) (2015) Regulation of mast cell function and food allergic responses by aryl hydrocarbonreceptor activation. thesis, Medicine.

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Abstract

Background and aim: Food allergies are a growing health problem in the westernized world. Because of the impact and possible deadly outcome it is important to identify the immune effectors and regulators. One of the possible regulators is the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, whose activation influences multiple pathways, including inflammatory responses. Mast cells express AhR and play a central role in allergic responses through food-antigen induced cross linking of immunoglobulin E (IgE) bound to FcεRI, the high affinity IgE receptor, resulting in release of pro-inflammatory mediators and cytokines. Mice express FcεRI on mast cells but not on dendritic cells, in contrast to humans. The aim of this study was to look at the influence of AhR activation on mast cell functions in vitro and food allergic responses in mice and simultaneously look at the influence of FcεRI expression on dendritic cells. Materials & Methods: Different concentrations of the AhR ligand 6-formylindolo[3,2- b]carbazole (FICZ) were added to bone marrow derived mast cells and differences in FcεRI expression, IgE binding, degranulation and cytokine production were measured by immunofluorescence staining, degranulation assays with detection of lysosome-associated membrane protein 1(Lamp-1) on the surface of activated cells and cytokine measurement in supernatants. Transgenic mice that express FcεRI on dendritic cells and wild type (WT) mice were sensitized to OVA by intra-peritoneal injection before OVA in the presence or absence of FICZ was administered by gavage. Serum levels of OVA-specific IgE, IgG1, MCPT1 and mRNA expression of jejunum tissue were measured to determine food allergic responses. Results: A FICZ concentration of 100nM caused a significant decrease in FceRI expression, while no significant differences in IgE-binding was seen. Concentrations of 0.1 and 1nM of FICZ caused an enhancement in degranulation. No significant differences in cytokine production were detected. In the in vivo experiment OVA-specific IgG1 and OVA-specific IgE serum levels were decreased in the FICZ-positive group of the WT mice compared to the FICZ-negative group. Mice were non-equally sensitized and the repeat experiment showed inconsistent results. Conclusions: AhR activation by a high FICZ concentration leads to reduced FcεRI expression in mast cells and degranulation is enhanced by low concentrations of FICZ. In vivo results suggest that AhR activation by FICZ has an inhibiting effect on the allergic response in wild type mice. No conclusions can be drawn yet about the influence of AhR activation and FcεrI expression on dendritic cells on food allergic responses in mice, because of non-equally sensitized mice and inconsistent results. Our results suggest that the AhR pathway is a potential therapeutic target in research about food allergy treatment and more research is necessary for better understanding of the involved mechanisms.

Item Type:	Thesis (Thesis)
Supervisor name:	Faculty supervisor : and Dullemen, Dr. H.M. van
Supervisor name:	Local Supervisor : and Fiebiger, Edda and Edda Fiebiger Lab and GI/Nutrition department and Boston Children’s Hospital, Boston
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 11:02
Last Modified:	25 Jun 2020 11:02
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/2245

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