No abstract

Our data demonstrate that barrier leakiness in asthmatic patients is induced by T2 cells, IL-4, and IL-13 and HDAC activity. The inhibition of endogenous HDAC activity reconstitutes defective barrier by increasing TJ expression.

Background: Allergen-specific immunotherapy (AIT) is the only available treatment for allergic diseases that can induce specific immune tolerance to allergens. The key mechanisms involved in this process include changes in allergen-specific regulatory T (Treg) cells. Methods:We studied 25 allergic rhinitis patients undergoing subcutaneous house dust mite-specific immunotherapy. Peripheral blood mononuclear cells were studied before and after 10, 30 weeks, and 3 years of AIT. Der p 1-specific T regulatory cell responses were investigated by characterization of Der p 1-MHC class II tetramerpositive cells and correlated with nasal symptom score. Results: Twelve of 25 AIT patients matched with their MHC class II expression to the Der p 1 peptide-MHC class II tetramers. A significant increase in the numbers of Der p 1-specific FOXP3 + Helios + CD25 + CD127 − Treg cells after 30 weeks was observed, which slightly decreased after 3 years of AIT. In contrast, Der p 1-specific immunoglobulin-like transcript 3 (ILT3) + CD25 + Treg cells decreased substantially from baseline after 3 years of AIT. ILT3 + Treg cells displayed compromised suppressive function and low FOXP3 expression. In addition, Der p 1-specific IL-10 and IL-22 responses have increased after 30 weeks, but only IL-10 + Der p 1-specific Treg cells remained present at high frequency after 3 years of AIT. Increased number of FOXP3 + Helios + and IL-10 + and decreased ILT3 + Treg cell responses correlated with improved allergic symptoms. Conclusion: The results indicate that AIT involves upregulation of the activated allergen-specific Treg cells and downregulation of dysfunctional allergen-specific Treg cell subset. Correction of dysregulated Treg cells responses during AIT is associated with improved clinical response. K E Y W O R D Sallergen-specific T cells, antigen-specific immunotherapy, house dust mite allergy, Treg Abbreviations: AIT, antigen-specific immunotherapy; AR, allergic rhinitis; HDM, house dust mite; ILT3, immunoglobulin-like transcript 3; Treg, T regulatory.

Respiratory syncytial virus (RSV) is an important risk factor of asthma development and is responsible for severe respiratory tract infections. However, the influence of RSV infection on barrier function of bronchial epithelial cells in vitro and in vivo is still unclear. The aim of this study was to analyse the role of RSV in tight junction (TJ) regulation and to compare epithelial integrity between asthmatic and healthy individuals upon RSV infection. Healthy and asthmatic human bronchial epithelial cells (HBECs) were differentiated at air-liquid interface (ALI) and infected with RSV and ultraviolet (UV)-irradiated RSV. TJ expression and their integrity were analysed by quantitative polymerase chain reaction (qPCR), transepithelial resistance (TER) and paracellular flux. To determine the effect in vivo, BALB/c mice were infected intranasally with RSV or UV-irradiated RSV A2. Bronchoalveolar lavage and TJ integrity were analysed on days 1, 2, 4 and 6 post-infection by qPCR, bioplex and confocal microscopy. RSV increased barrier integrity in ALI cultures of HBEC from healthy subjects, but no effect was found in HBECs from asthmatics. This was not associated with an increase in TJ mRNA expression. In vivo, RSV induced lung inflammation in mice and down-regulated claudin-1 and occludin mRNA expression in whole lungs. Surprisingly, RSV infection was not observed in bronchial epithelial cells, but was found in the lung parenchyma. Decreased expression of occludin upon RSV infection was visible in mouse bronchial epithelial cells in confocal microscopy. However, there was no regulation of claudin-1 and claudin-7 at protein level.