Can ACE2 expression explain SARS-CoV-2 infection of the respiratory epithelia in COVID-19?

Infection with severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) leads to coronavirus disease 2019 (COVID‐19), which poses an unprecedented worldwide health crisis, and has been declared a pandemic by the World Health Organization (WHO) on March 11, 2020. The angiotensin converting enzyme 2 (ACE2) has been suggested to be the key protein used by SARS‐CoV‐2 for host cell entry. In their recent work, Lindskog and colleagues (Hikmet et al, 2020) report that ACE2 is expressed at very low protein levels—if at all—in respiratory epithelial cells. Severe COVID‐19, however, is characterized by acute respiratory distress syndrome and extensive damage to the alveoli in the lung parenchyma. Then, what is the role of the airway epithelium in the early stages of COVID‐19, and which cells need to be studied to characterize the biological mechanisms responsible for the progression to severe disease after initial infection by the novel coronavirus

Allergen immunotherapy for allergic airway diseases:Use lessons from the past to design a brighter future

Allergic respiratory diseases, such as allergic dermatitis, food allergy, allergic rhino conjunctivitis and allergic asthma, are chronic inflammatory diseases with increasing prevalence. Symptoms include such as watery or itchy itching of the mouth, skin, or the eyes, swelling of the face or throat, sneezing, congestion or vomiting, wheezing, shortness of breath and coughing. For allergic asthma, additional symptoms include tightness of chest, cough, wheezing, and reversible airflow limitation. These symptoms can be triggered by inhalation of aller -gens such as food allergens or airborne allergens such as those from tree-or grass pollen and house dust mites. Pharmacological intervention in allergic disease includes the use of antihistamines, immune suppressive drugs and in case of asthma, the use of (long acting) beta-agonists for relaxation of the constricted airways. These treat-ment options merely suppress symptoms and do not cure the disease. Allergen immunotherapy (AIT), in con -trast, has the capacity of inducing long-term tolerance, with symptom relief persisting decennia after discontinuation of treatment, despite recurrent re-exposure to the allergen. However, AIT is not effective for all allergic disorders, and treatment for several years is required to obtain long-term protection. Moreover, some forms of AIT have safety concerns, with risk of mild to severe allergic reactions. To improve safety and efficacy of AIT, the underlying mechanisms have been studied extensively in the clinic as well as in experimental models of allergic airway inflammation.Despite more than a century of clinical experience and a vast body of experimental and translational studies into the immunological and cellular mechanisms underpinning its therapeutic potential, AIT is still not implemented in routine clinical care for allergic asthma. This review provides an overview of the substantial developments that contribute to our knowledge of the pathogenesis of allergic airway diseases, the mechanism of action of AIT, its treatment routes and schedules, the standardization of extracts and use of adjuvantia. Moreover, the main con-clusions from experimental models of AIT with regard to the safety and effectiveness of the treatment are summarized, and future directions for further improvements are outlined. AIT urgently requires further improvements in order to increase its efficiency and shorten the treatment duration while remaining safe and costeffective.(c) 2022 Published by Elsevier Inc

1,25(OH)2VitD3 supplementation enhances suppression of grass pollen-induced allergic asthma by subcutaneous and sublingual immunotherapy in a mouse model

Allergen specific immunotherapy (AIT) can provide long-term alleviation of symptoms for allergic disease but is hampered by suboptimal efficiency. We and others have previously shown that 1,25(OH)2-VitaminD3 (VitD3) can improve therapeutic efficacy of AIT. However, it is unknown whether VitD3 supplementation has similar effects in sublingual and subcutaneous immunotherapy. Therefore, we aimed to test VitD3 supplementation in both grass pollen (GP) subcutaneous-IT (SCIT) and sublingual-IT (SLIT) in a mouse model for allergic airway inflammation. To this end, GP-sensitized BALB/c mice received GP-SCIT or GP-SLIT with or without 10 ng VitD3, followed by intranasal GP challenges and measurement of airway hyperresponsiveness (AHR) and inflammation. VitD3 supplementation of GP-SCIT resulted in enhanced induction of GP-specific (sp)-IgG2a and suppression of spIgE after challenge. In addition, eosinophil numbers were reduced and levels of IL10 and Amphiregulin were increased in lung tissue. In GP-SLIT, VitD3 supplementation resulted in enhanced sp-IgG2a levels in serum, enhanced suppression of eosinophils and increased IL10 levels in lung tissue, as well as suppression of AHR to methacholine. These data show that VitD3 increases efficacy of both SCIT and SLIT, by enhancing induction of blocking antibodies and suppression of airway inflammation, underscoring the relevance of proficient VitD3 levels for successful AIT

Detection of clonal mast cell disease in wasp venom allergic patients with normal tryptase

Background: Clonal mast cell disease (CMD) is an underlying aggravating condition in wasp venom allergy (WVA) which requires a different treatment strategy. CMD is increasingly recognized in patients with normal basal serum tryptase (bsT). However, methods to identify at risk patients have not yet been assessed in large cohorts of WVA patients with normal bsT. Methods: This retrospective study evaluated the reliability of the REMA score in detecting CMD in a cohort of grade IV WVA patients with normal bsT and assessed the added value of other clinical parameters, KIT D816V mutation analysis in peripheral blood (PB) and the diagnosis of hereditary alpha tryptasemia (HAT). All patients had a conclusive bone marrow evaluation that demonstrated or excluded underlying CMD. Results: In total 35 CMD and 96 non-CMD patients were included. REMA score had a sensitivity of 72% (95% CI 56%-88%) and specificity of 79% (95% CI 70%-87%) in this cohort. Loss of consciousness during systemic reaction and bsT between 6.3 and 11.4 ng/ml were additional parameters independently associated with CMD. Sensitivity of KIT in PB was relatively low, 56% (95% CI 36%-75%), but had added value as screening method in patients with a low REMA score due to 100% specificity. Conclusion: The REMA score is a relatively reliable method to detect patients at risk of CMD among WVA patients with normal bsT. KIT mutation analysis in PB could serve as additional screening method in patients with low REMA scores

Epithelial cell dysfunction, a major driver of asthma development

Airway epithelial barrier dysfunction is frequently observed in asthma and may have important implications. The physical barrier function of the airway epithelium is tightly interwoven with its immunomodulatory actions, while abnormal epithelial repair responses may contribute to remodelling of the airway wall. We propose that abnormalities in the airway epithelial barrier play a crucial role in the sensitization to allergens and pathogenesis of asthma. Many of the identified susceptibility genes for asthma are expressed in the airway epithelium, supporting the notion that events at the airway epithelial surface are critical for the development of the disease. However, the exact mechanisms by which the expression of epithelial susceptibility genes translates into a functionally altered response to environmental risk factors of asthma are still unknown. Interactions between genetic factors and epigenetic regulatory mechanisms may be crucial for asthma susceptibility. Understanding these mechanisms may lead to identification of novel targets for asthma intervention by targeting the airway epithelium. Moreover, exciting new insights have come from recent studies using single-cell RNA sequencing (scRNA-Seq) to study the airway epithelium in asthma. This review focuses on the role of airway epithelial barrier function in the susceptibility to develop asthma and novel insights in the modulation of epithelial cell dysfunction in asthma

The air–liquid interface model

The airway epithelium lining the airways is in first contact with the inhaled environment, which contains allergens, gaseous pollutants, particulates, and pathogenic microorganisms. It forms an ion- and size-selective barrier between the inhaled environment and the underlying tissue by the formation of intercellular tight junctions and adhesion junctions. Additionally, the airway epithelium plays an important role in innate immune defense, expressing receptors that recognize molecular patterns from pathogenic microbes, parasites, fungi, and allergens and danger signals from damaged cells, directing proinflammatory processes. Chronic lung diseases, such as asthma and chronic obstructive pulmonary disease, involve changes in airway epithelial function. For valuable insights into these changes, in vitro models should closely recapitulate human airway epithelial composition, three-dimensional structure, and function as an immunological barrier. The goal of this chapter is to review the literature on the use of air–liquid interface cultures to model the lung epithelium in health and disease.</p