Regulation of ACE2 isoforms by type 2 inflammation and viral infection in human airway epithelium

SARS-CoV-2 enters human cells through its main receptor angiotensin-converting enzyme 2 (ACE2), which constitutes a limiting factor of an infection. Recent findings demonstrating novel ACE2 isoforms implicate that this receptor is regulated in a more complex way than previously anticipated. However, it remains unknown how various inflammatory conditions influence the abundance of these ACE2 variants. Hence, we studied expression of ACE2 mRNA and protein isoforms, together with its glycosylation and spatial localization in primary human airway epithelium upon allergic inflammation and viral infection. We found that interleukin-13, the main type 2 cytokine, decreased expression of long ACE2 mRNA and reduced glycosylation of full length ACE2 protein via alteration of N-linked glycosylation process, limiting its availability on the apical side of ciliated cells. House dust mite allergen did not affect the expression of ACE2. Rhinovirus infection increased short ACE2 mRNA, but it did not influence its protein expression. In addition, by screening other SARS-CoV-2 related host molecules, we found that IL-13 and RV significantly regulated mRNA, but not protein of TMPRSS2 and NRP1. Regulation of ACE2 and other host proteins was comparable in healthy and asthmatic epithelium, underlining lack of intrinsic differences but dependence on the inflammatory milieu in the airways

Distinct regulation of tonsillar immune response in virus infection

Cataloged from PDF version of article.Background: The relationships between tonsillar immune responses, and viral infection and allergy are incompletely known. Objective To study intratonsillar/nasopharyngeal virus detections and in vivo expressions of T-cell- and innate immune response-specific cytokines, transcription factors, and type I/II/III interferons in human tonsils. Methods: Palatine tonsil samples were obtained from 143 elective tonsillectomy patients. Adenovirus, bocavirus-1, coronavirus, enteroviruses, influenza virus, metapneumovirus, parainfluenza virus, rhinovirus, and respiratory syncytial virus were detected using PCR. The mRNA expression levels of IFN-α, IFN-β, IFN-γ, IL-10, IL-13, IL-17, IL-28, IL-29, IL-37, TGF-β, FOXP3, GATA3, RORC2, and Tbet were directly analyzed by quantitative RT-PCR. Results Fifty percentage of subjects reported allergy, 59% had ≥1 nasopharyngeal viruses, and 24% had ≥1 intratonsillar viruses. Tonsillar virus detection showed a strong negative association with age; especially rhinovirus or parainfluenza virus detection showed positive association with IFN-γ and Tbet expressions. IL-37 expression was positively associated with atopic dermatitis, whereas IFN-α, IL-13, IL-28, and Tbet expressions were negatively associated with allergic diseases. Network analyses demonstrated strongly polarized clusters of immune regulatory (IL-10, IL-17, TGF-β, FOXP3, GATA3, RORC2, Tbet) and antiviral (IFN-α, IFN-β, IL-28, IL-29) genes. These two clusters became more distinctive in the presence of viral infection or allergy. A negative correlation between antiviral cytokines and IL-10, IL-17, IL-37, FOXP3, and RORC2 was observed only in the presence of viruses, and interestingly, IL-13 strongly correlated with antiviral cytokines. Conclusions: Tonsillar cytokine expression is closely related to existing viral infections, age, and allergic illnesses and shows distinct clusters between antiviral and immune regulatory genes. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Environmental exposure and sensitization patterns in a Swiss alpine pediatric cohort

Background The level of environmental exposure throughout life may contribute to the prevalence of allergic sensitization and allergic disease. The alpine climate has been considered a healthy climate with little allergen exposure and pollution. We conducted a cross-sectional study to investigate local environmental exposure and concomitant prevalence of allergic sensitization among local school children born and raised in an alpine environment. Methods Clinical and demographic data were collected with a questionnaire. Allergen content was assessed in residential settled dust samples, lifetime exposure to pollen and air pollution was calculated using data from national pollen and air pollution monitoring stations, and the allergic sensitization profile was determined with component resolved diagnostics (ISAC®). Univariate and multivariate regression models were used to estimate the relation between exposure and sensitization. Results In a cohort of children born and raised in an alpine environment, sensitization to aeroallergens is quite common (38%), especially to grass (33%) and cat (16%). House dust mite allergen was detected in up to 38% of residential dust samples, but sensitization to HDM was low (2.5%). Pollutant levels were low, but an increasing trend was observed in the amount of ozone and PM10. Living close to a busy road was associated with increased odds OR (95% CI) for being sensitized to any allergen 2.7 (1.0–7.2), to outdoor allergens 2.8 (1.1–7.1) and being sensitized plus reporting symptoms of rhinoconjunctivitis 4.4 (1.3–14.8) and asthma 5.5 (1.4–21). Indoor living conditions, including the presence of visible mold, increased the odds of being sensitized to indoor allergens (1.9 (1.1–3.2) and being sensitized plus reporting symptoms of rhinoconjunctivitis 1.9 (1.0–3.6) and asthma 2.1 (1.0–4.1). Conclusion In a healthy alpine environment, pollution might still be an important factor contributing to allergic sensitization

Considerations on biologicals for patients with allergic disease in times of the COVID-19 pandemic: An EAACI statement

The outbreak of the SARS-CoV-2-induced coronavirus disease 2019 (COVID-19) pandemic re-shaped doctor-patient interaction and challenged capacities of healthcare systems. It created many issues around the optimal and safest way to treat complex patients with severe allergic disease. A significant number of the patients are on treatment with biologicals, and clinicians face the challenge to provide optimal care during the pandemic. Uncertainty of the potential risks for these patients is related to the fact that the exact sequence of immunological events during SARS-CoV-2 is not known. Severe COVID-19 patients may experience a “cytokine storm” and associated organ damage characterized by an exaggerated release of pro-inflammatory type 1 and type 3 cytokines. These inflammatory responses are potentially counteracted by anti-inflammatory cytokines and type 2 responses. This expert-based EAACI statement aims to provide guidance on the application of biologicals targeting type 2 inflammation in patients with allergic disease. Currently, there is very little evidence for an enhanced risk of patients with allergic diseases to develop severe COVID-19. Studies focusing on severe allergic phenotypes are lacking. At present, noninfected patients on biologicals for the treatment of asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, or chronic spontaneous urticaria should continue their biologicals targeting type 2 inflammation via self-application. In case of an active SARS-CoV-2 infection, biological treatment needs to be stopped until clinical recovery and SARS-CoV-2 negativity is established and treatment with biologicals should be re-initiated. Maintenance of add-on therapy and a constant assessment of disease control, apart from acute management, are demanded

Changes in Exercise Capacity and Ventricular Function in Arrhythmogenic Right Ventricular Cardiomyopathy: The Impact of Sports Restriction during Follow-Up

(1) Background: Physical exercise has been suggested to promote disease progression in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). We aimed to investigate the exercise performance and ventricular function of ARVC patients during follow-up, while taking into account their adherence to exercise restriction recommendations. (2) Methods: This retrospective study included 49 patients (33 male, 67%) who had an exercise test at baseline and after 4.2 ± 1.6 years. Of the 49 ARVC patients, 27 (55%) were athletes, while 22 (45%) were non-athletes. Of the athletes, 12 (44%) continued intensive sports activity (non-adherent), while 15 (56%) stopped intensive physical activity upon recommendation (adherent). The maximum workload in Watts (W), percentage of the target workload (W%), and double product (DP) factor were measured for all patients. (3) Results: The non-adherent cohort had a significant decrease in physical performance (W at baseline vs. follow-up, p = 0.012; W% at baseline vs. follow-up, p = 0.025; DP-factor at baseline vs. follow-up, p = 0.012) over time. Left ventricular (LV) function (LV ejection fraction at baseline vs. follow-up, p = 0.082) showed a decreasing trend in the non-adherent cohort, while the performance of the adherent cohort remained at a similar level. (4) Conclusions: If intensive sports activities are not discontinued, exercise capacity and left ventricular function of athletes with ARVC deteriorates during follow-up. All patients with ARVC need to strictly adhere to the recommendation to cease intense sports activity in order to halt disease progression

Efficacy and safety of treatment with omalizumab for chronic spontaneous urticaria: A systematic review for the EAACI Biologicals Guidelines

This systematic review evaluates the efficacy and safety of omalizumab for chronic spontaneous urticaria (CSU). PubMed, Embase, and Cochrane Library were searched for RCTs. Critical and important CSU-related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. Ten RCTs including 1620 subjects aged 12 to 75 years old treated with omalizumab for 16 to 40 weeks were evaluated. Omalizumab 150 mg does not result in clinically meaningful improvement (high certainty) of the urticaria activity score (UAS)7 (mean difference (MD) −5; 95%CI −7.75 to −2.25), and the itch severity score (ISS)7 (MD −2.15; 95% CI −3.2 to −1.1) does not increase (moderate certainty) quality of life (QoL) (Dermatology Life Quality Index (DLQI); MD −2.01; 95%CI −3.22 to −0.81) and decreases (moderate certainty) rescue medication use (MD −1.68; 95%CI −2.95 to −0.4). Omalizumab 300 mg results in clinically meaningful improvements (moderate certainty) of the UAS7 (MD −11.05; 95%CI −12.87 to −9.24), the ISS7 (MD −4.45; 95%CI −5.39 to −3.51), and QoL (high certainty) (DLQI; MD −4.03; 95% CI −5.56 to −2.5) and decreases (moderate certainty) rescue medication use (MD −2.04; 95%CI −3.19 to −0.88) and drug-related serious AEs (RR 0.77; 95%CI 0.20 to 2.91)

T-cell Subset Regulation in Atopy

Presentation of processed allergen by antigen-presenting cells to T-helper (Th) lymphocytes, which is influenced costimulatory signals, cytokines, chemokines, and regulatory T cells (Tregs), determines the development of different types of T-cell immunity. The discovery of Tregs revolutionized the primary concepts of immune regulation interpreted within the framework of a binary Th1/Th2 paradigm. Tregs play a central role in the maintenance of peripheral homeostasis, the establishment of controlled immune responses, and the inhibition of allergen-specific effector cells. Recently, some other T-cell subsets appeared, including Th17 and Th9 cells, which control local tissue inflammation through upregulation of proinflammatory cytokines and chemokines. This review aims to discuss our understanding of the T-cell subset reciprocal interaction in atopy

Tracking Antigen-Specific T-Cells during Clinical Tolerance Induction in Humans

Allergen immunotherapy presents an opportunity to define mechanisms of induction of clinical tolerance in humans. Significant progress has been made in our understanding of changes in T cell responses during immunotherapy, but existing work has largely been based on functional T cell assays. HLA-peptide-tetrameric complexes allow the tracking of antigen-specific T-cell populations based on the presence of specific T-cell receptors and when combined with functional assays allow a closer assessment of the potential roles of T-cell anergy and clonotype evolution. We sought to develop tools to facilitate tracking of antigen-specific T-cell populations during wasp-venom immunotherapy in people with wasp-venom allergy. We first defined dominant immunogenic regions within Ves v 5, a constituent of wasp venom that is known to represent a target antigen for T-cells. We next identified HLA-DRB1*1501 restricted epitopes and used HLA class II tetrameric complexes alongside cytokine responses to Ves v 5 to track T-cell responses during immunotherapy. In contrast to previous reports, we show that there was a significant initial induction of IL-4 producing antigen-specific T-cells within the first 3–5 weeks of immunotherapy which was followed by reduction of circulating effector antigen-specific T-cells despite escalation of wasp-venom dosage. However, there was sustained induction of IL-10-producing and FOXP3 positive antigen-specific T cells. We observed that these IL-10 producing cells could share a common precursor with IL-4-producing T cells specific for the same epitope. Clinical tolerance induction in humans is associated with dynamic changes in frequencies of antigen-specific T-cells, with a marked loss of IL-4-producing T-cells and the acquisition of IL-10-producing and FOXP3-positive antigen-specific CD4+ T-cells that can derive from a common shared precursor to pre-treatment effector T-cells. The development of new approaches to track antigen specific T-cell responses during immunotherapy can provide novel insights into mechanisms of tolerance induction in humans and identify new potential treatment targets

International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis

Background: Critical examination of the quality and validity of available allergic rhinitis (AR) literature is necessary to improve understanding and to appropriately translate this knowledge to clinical care of the AR patient. To evaluate the existing AR literature, international multidisciplinary experts with an interest in AR have produced the International Consensus statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR). Methods: Using previously described methodology, specific topics were developed relating to AR. Each topic was assigned a literature review, evidence-based review (EBR), or evidence-based review with recommendations (EBRR) format as dictated by available evidence and purpose within the ICAR:AR document. Following iterative reviews of each topic, the ICAR:AR document was synthesized and reviewed by all authors for consensus. Results: The ICAR:AR document addresses over 100 individual topics related to AR, including diagnosis, pathophysiology, epidemiology, disease burden, risk factors for the development of AR, allergy testing modalities, treatment, and other conditions/comorbidities associated with AR. Conclusion: This critical review of the AR literature has identified several strengths; providers can be confident that treatment decisions are supported by rigorous studies. However, there are also substantial gaps in the AR literature. These knowledge gaps should be viewed as opportunities for improvement, as often the things that we teach and the medicine that we practice are not based on the best quality evidence. This document aims to highlight the strengths and weaknesses of the AR literature to identify areas for future AR research and improved understanding