PhD ceremony Ms. S. Post: House dust mite and the integrity of the airway epithelium. Mechanisms involved in the development of the allergic asthma

PhD ceremony: Ms. S. Post, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: House dust mite and the integrity of the airway epithelium. Mechanisms involved in the development of the allergic asthma

Promotor(s): prof. A.J.M. van Oosterhout

Faculty: Medical Sciences

The airway epithelium forms the first barrier against aeroallergens, including house dust mite (HDM). It exerts pro-inflammatory activity when damaged, and is a key player in the initiation of allergic responses. Although it was initially thought that the serine proteolytic activity of HDM contributes to loss of the cell-cell contacts including E-cadherin, barrier dysfunction and pro-inflammatory reaction of the airway epithelium, we recently observed that the HDM-induced epithelial responses are independent on their serine protease activities. Additionally we investigated the role of protease-activated receptor-2 (PAR-2) in a HDM mouse model and found that HDM extracts that widely differed in protease activity evoked highly similar allergic reactions in Wt and PAR2 KO mice, with the exception of the IgE response. Instead, our experiments showed that HDM initiates the influx of calcium, which is responsible for both barrier dysfunction and secretion of the pro-inflammatory cytokine CCL20. Furthermore, we found that primary bronchial epithelial cells (PBECs) from asthmatics are more prone to develop barrier dysfunction and secretion of pro-inflammatory cytokines then healthy control PBECs in response to HDM. To test the role for loss of E-cadherin in allergic sensitization and airway remodelling, we generated a lung-specific E-cadherin deficient mouse where E-cadherin deficiency was induced in respiratory epithelial cells during development of the respiratory epithelium using doxycycline. These mice developed spontaneously goblet cell metaplasia, inflammation and bronchial epithelial aplasia when mice reached an adult age, and will be used in future experiments for additional investigations regarding the role of E-cadherin in the development of allergic asthma.