Michael B. Soyka

Defective epithelial barrier in chronic rhinosinusitis: The regulation of tight junctions by IFN-γ and IL-4

BACKGROUND Chronic rhinosinusitis (CRS) is a common disease with still unclear pathophysiologic mechanisms. Epithelial tight junctions (TJs) have been shown to be involved in different chronic disorders, including bronchial asthma, inflammatory bowel diseases, and skin disorders. The regulation of epithelial barrier function and TJ expression has not been extensively studied in patients with CRS and in the paranasal sinus epithelium thus far. OBJECTIVE We sought to elucidate the TJ expression pattern in the epithelium of the sinonasal mucosa and its regulation in patients with CRS. METHODS Trans-tissue resistance was measured in biopsy specimens from healthy control subjects and patients with CRS with and without nasal polyps. TJ protein expression was determined by using immunofluorescence, Western blotting, and real-time PCR. Primary epithelial cell cultures from patients with CRS and control subjects were used in air-liquid interface (ALI) cultures for the measurement of transepithelial resistance (TER) and TJ expression. The effect of IFN-γ, IL-4, and IL-17 on ALI cultures was assessed. RESULTS A decreased trans-tissue resistance was found in biopsy specimens from patients with CRS with nasal polyps along with an irregular, patchy, and decreased expression of the TJ molecules occludin and zonula occludens 1. TER was reduced in ALI cultures from patients with CRS with nasal polyps. The cytokines IFN-γ and IL-4 decreased TER, whereas IL-17 did not have any influence on epithelial integrity. CONCLUSION A defective epithelial barrier was found in patients with CRS with nasal polyps along with a decreased expression of TJ proteins. The disruption of epithelial integrity by IFN-γ and IL-4 in vitro indicates a possible role for these proinflammatory cytokines in the pathogenesis of patients with CRS.

Mechanisms of allergen-specific immunotherapy

Allergen-specific immunotherapy (allergen-SIT) is a potentially curative treatment approach in allergic diseases. It has been used for almost 100 years as a desensitizing therapy. The induction of peripheral T cell tolerance and promotion of the formation of regulatory T-cells are key mechanisms in allergen-SIT. Both FOXP3+CD4+CD25+ regulatory T (Treg) cells and inducible IL-10- and TGF-β-producing type 1 Treg (Tr1) cells may prevent the development of allergic diseases and play a role in successful allergen-SIT and healthy immune response via several mechanisms. The mechanisms of suppression of different pro-inflammatory cells, such as eosinophils, mast cells and basophils and the development of allergen tolerance also directly or indirectly involves Treg cells. Furthermore, the formation of non-inflammatory antibodies particularly IgG4 is induced by IL-10. Knowledge of these molecular basis is crucial in the understanding the regulation of immune responses and their possible therapeutic targets in allergic diseases.

On the effectiveness of treatment options in epistaxis: an analysis of 678 interventions.

BACKGROUND Epistaxis represents one of the most common emergencies in ENT clinics around the world. It creates great physical and emotional stress to the patient as well as a financial burden on health-care systems. A lot of research has been performed with regard to aetiology and possible treatment, however, not much effort has been put into analysing the effectiveness of common treatment forms. It is the objective of this study to clarify which of these treatment forms is reliable. STUDY DESIGN Retrospective cohort study. LEVEL OF EVIDENCE 2b. METHODS Between 03/2007 and 04/2008, all epistaxis therapies including relapses and treatment failures at the University Hospital of Zurich have been documented using a computerised questionnaire. Different treatments were compared to each other. RESULTS An analysis of 678 interventions in 537 patients was performed with emphasis on failure proportions and time to occurrence. The estimated failure proportions of coagulation in anterior epistaxis accounts for 14%. Successful treatment of epistaxis in posterior bleedings could be achieved in 62% by packing and in 97% by surgery with a statistically significant difference between the respective groups. CONCLUSION Using our treatment options, anterior epistaxis can be cured reliably by cauterisation. Surgical therapies in posterior bleedings are able to successfully salvage failed packing therapies.

Immune regulation by intralymphatic immunotherapy with modular allergen translocation MAT vaccine

Allergen‐specific immunotherapy (SIT) faces problems related to side effects and limited efficacy. Direct administration of allergen extracts into lymph nodes induces increased specific IgG production and T‐cell responses using significantly lower allergen doses.

Is severe epistaxis associated with acetylsalicylic acid intake

Epistaxis represents a very common emergency in any ear, nose, and throat (ENT) department around the world. Despite other risk factors, acetylsalicylic acid (ASA) contributes to nosebleeds by its intrinsic ability to impair thrombocyte aggregation. The aim of this study was to investigate the influence of ASA on the severity of epistaxis and to compare it with other potential risk factors.

Regulation and expression of IL-32 in chronic rhinosinusitis

Activated T lymphocytes and their interaction with resident tissue cells, particularly epithelium, play important roles in inflammatory processes in chronic rhinosinusitis (CRS). IL‐32 is a recently described cytokine, which is expressed in a variety of tissue cells and involved in the pathogenesis of several chronic inflammatory diseases.

Scientific foundations of allergen-specific immunotherapy for allergic disease.

Allergen-specific immunotherapy (AIT) was described as a therapeutic option for the treatment of allergies > 100 years ago. It is based on administration of allergen extracts and leads to the development of clinical allergen tolerance in selected patients. According to current knowledge, AIT results in the restoration of immune tolerance toward the allergen of interest. It is mainly accompanied by the induction of regulatory and suppressive subsets of T and B cells, the production of IgG4 isotype allergen-specific blocking antibodies, and decreased inflammatory responses to allergens by effector cells in inflamed tissues. Currently, AIT is mainly applied subcutaneously or sublingually and is suitable for both children and adults for pollen, pet dander, house dust mite, and venom allergies. It not only affects rhinoconjunctival symptoms but also has documented short- and long-term benefits in asthma treatment. Clinically, a fast onset of tolerance is achieved during desensitization, with a tolerable amount of side effects. The disease modification effect leads to decreased disease severity, less drug usage, prevention of future allergen sensitizations, and a long-term curative effect. Increasing safety while maintaining or even augmenting efficiency is the main goal of research for novel vaccine development and improvement of treatment schemes in AIT. This article reviews the principles of allergen-specific immune tolerance development and the effects of AIT in the clinical context.

Discomfort and costs in epistaxis treatment

Epistaxis is a very common ENT event. Apart from the effectiveness of the different treatment options, the discomfort and the financial burden are of great importance. It has been the aim of this study to obtain data regarding the discomfort/pain of the epistaxis treatments and to calculate the financial burden. During the period between April 2010 and July 2011 epistaxis patients at our hospital had the opportunity to rate the discomfort/pain they experienced during their treatment on a 0–10 VAS scale. The costs of epistaxis treatments were calculated in an extended cohort. 84 VAS scores in 61 patients were acquired and the costs of treatment were calculated in 96 patients. The lowest VAS scores were found in chemical and electric coagulation with 1.5 and 2.0, respectively, followed by surgery (3.0), Rapid Rhino® packing (6.0) and balloon pack (7.5). The costs of treatments depended on whether the treatment was in an out- or inpatient setting. Surgery was not significantly more expensive than packing methods in the inpatient setting. Anterior epistaxis could be managed by local coagulation with an acceptable impact/cost ratio. At our institution, surgery was the most cost effective and the least troublesome procedure in posterior bleedings, preceded by Rapid Rhino® packing if required.

The broad spectrum of interepithelial junctions in skin and lung

and serum 25(OH)D concentration correlates positively with Foxp3 Treg cells in the peripheral blood. A, Representative dot plots demonstrating the gating strategy to define Treg cells. Values represent % of gated live CD4CD3 lymphocyte population. B, Frequency of Foxp3 Treg cells in SS and SR asthmatic patients. Data shown asmean, 5%-95% CI, assessed by t test. C, Correlation of Foxp3 Treg cells with serum 25(OH)D in all the patients with moderate to severe asthma. Assessed by Pearson correlation test. J ALLERGY CLIN IMMUNOL AUGUST 2012 544 LETTERS TO THE EDITOR

Regulatory cells in allergen-specific immunotherapy.

Allergen-specific immunotherapy (SIT) is currently the best available curative treatment in allergies and has been used for the treatment of patients for the past 100 years. The formation of a Th2 cell predominant inflammation in addition to production of allergen-specific IgE, the attraction of proinflammatory cells and the degranulation of effector cells, such as mast cells, are essential mechanisms in allergy development. Tregs aim to diminish these effects by IL-10- and TGF-β-mediated anti-inflammatory reactions and therefore are one of the main targets in SIT. The induction of allergen tolerance is the key to successful SIT. With a special focus on Tregs, this review aims to clarify what is currently known about allergy development and the mode of action in allergen-SIT, which helps to develop further therapeutic strategies in the fight against allergic diseases.