Publications by authors named "Cezmi A Akdis"

346 Publications

IL-33 receptor expression on myeloid and plasmacytoid dendritic cells after allergen challenge in patients with allergic rhinitis.

Int Immunopharmacol 2021 Oct 12;101(Pt B):108233. Epub 2021 Oct 12.

Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address:

The diversity of immune responses in allergic diseases is critically mediated by dendritic cells (DCs), including myeloid and plasmacytoid DCs. Allergen inhalation increased the release of IL-33 from patients with allergic rhinitis (AR), which affecting the downstream cells by binding to its receptor (ST2). However, the effects of inhaled allergens on the expression of ST2 by DCs and IL-33 on the function of mDCs are unknown. The levels of ST2mDCs and ST2pDCs in the blood from patients with AR and healthy subjects were examined using flow cytometry. Moreover, the patients were challenged using the allergens and the levels of ST2mDCs and ST2pDCs were investigated at different time points. We found that there were higher levels of ST2 mDCs and ST2 pDCs in patients with AR, and these levels were further increased 0.5 h after allergen inhalation. Additionally, the type 2 immune response was upregulated after challenge. IL-33 treatment increased the expression of ST2 on mDCs. Our study demonstrated that ST2 was upregulated on DCs after allergen inhalation and that mDCs responded directly to IL-33 through ST2, suggesting that the IL-33/ST2 axis might play an important role in the pathogenesis of allergic rhinitis by DCs.
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http://dx.doi.org/10.1016/j.intimp.2021.108233DOI Listing
October 2021

Recent advances and developments in COVID-19 in the context of allergic diseases.

Clin Transl Allergy 2021 Sep;11(7):e12065

Department of Allergology, Zhongnan Hospital of Wuhan University, Wuhan, China.

Background: Since the first reports of coronavirus disease 2019 (COVID-19) in Wuhan, China, in December 2019, there have been 198 million confirmed cases worldwide as of August 2021. The scientific community has joined efforts to gain knowledge of the newly emerged virus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the immunopathological mechanisms leading to COVID-19, and its significance for patients with allergies and asthma.

Methods: Based on the current literature, recent advances and developments in COVID-19 in the context of allergic diseases were reviewed.

Results And Conclusions: In this review, we discuss the prevalence of COVID-19 in subjects with asthma, attacks of hereditary angioedema, and other allergic diseases during COVID-19. Underlying mechanisms suggest a protective role of allergy in COVID-19, involving eosinophilia, SARS-CoV-2 receptors expression, interferon responses, and other immunological events, but further studies are needed to fully understand those associations. There has been significant progress in disease evaluation and management of COVID-19, and allergy care should continue during the COVID-19 pandemic. The European Academy of Allergy & Clinical Immunology (EAACI) launched a series of statements and position papers providing recommendations on the organization of the allergy clinic, handling of allergen immunotherapy, asthma, drug hypersensitivity, allergic rhinitis, and other allergic diseases. Treatment of allergies using biologics during the COVID-19 pandemic has also been discussed. Allergic reactions to the COVID-19 vaccines, including severe anaphylaxis, have been reported. Vaccination is a prophylactic strategy that can lead to a significant reduction in the mortality and morbidity associated with SARS-CoV-2 infection, and in this review, we discuss the proposed culprit components causing rare adverse reactions and recommendations to mitigate the risk of anaphylactic events during the administration of the vaccines.
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http://dx.doi.org/10.1002/clt2.12065DOI Listing
September 2021

Physical activity in asthma control and its immune modulatory effect in asthmatic preschoolers.

Allergy 2021 Sep 21. Epub 2021 Sep 21.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.

Background: The impact of physical activity on immune response is a hot topic in exercise immunology, but studies involving asthmatic children are scarce. Our aims were to examine whether there were any differences in the level of physical activity and daily TV attendance, to assess its role on asthma control and immune responses to various immune stimulants.

Methods: Weekly physical activity and daily television attendance were obtained from questionnaires at inclusion of the PreDicta study. PBMC cultures were stimulated with phytohemagglutinin (PHA), R848, poly I:C, and zymosan. A panel of cytokines was measured and quantified in cell culture supernatants using luminometric multiplex immunofluorescence beads-based assay.

Results: Asthmatic preschoolers showed significantly more TV attendance than their healthy peers (58.6% vs. 41.5% 1-3 h daily and only 25.7% vs. 47.2% ≤1 h daily) and poor asthma control was associated with less frequent physical activity (PA) (75% no or occasional activity in uncontrolled vs. 20% in controlled asthma; 25% ≥3 times weekly vs. 62%). Asthmatics with increased PA exhibited elevated cytokine levels in response to polyclonal stimulants, suggesting a readiness of circulating immune cells for type 1, 2, and 17 cytokine release compared to subjects with low PA and high TV attendance. This may also represent a proinflammatory state in high PA asthmatic children. Low physical activity and high TV attendance were associated with a decrease in proinflammatory cytokines. Proinflammatory cytokines were correlating with each other in in vitro immune responses of asthmatic children, but not healthy controls, this correlation was more pronounced in children with sedentary behavior.

Conclusion: Asthmatic children show more sedentary behavior than healthy subjects, while poor asthma control is associated with a substantial decrease in physical activity. Our results suggest that asthmatic children may profit from regular exercise, as elevated cytokine levels in stimulated conditions indicate an immune system prepared for responding strongly in case of different types of infections. However, it has to be considered that a hyperinflammatory state in high PA may not be beneficial in asthmatic children.
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http://dx.doi.org/10.1111/all.15105DOI Listing
September 2021

Advances and highlights in biomarkers of allergic diseases.

Allergy 2021 Sep 14. Epub 2021 Sep 14.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.

During the past years, there has been a global outbreak of allergic diseases, presenting a considerable medical and socioeconomical burden. A large fraction of allergic diseases is characterized by a type 2 immune response involving Th2 cells, type 2 innate lymphoid cells, eosinophils, mast cells, and M2 macrophages. Biomarkers are valuable parameters for precision medicine as they provide information on the disease endotypes, clusters, precision diagnoses, identification of therapeutic targets, and monitoring of treatment efficacies. The availability of powerful omics technologies, together with integrated data analysis and network-based approaches can help the identification of clinically useful biomarkers. These biomarkers need to be accurately quantified using robust and reproducible methods, such as reliable and point-of-care systems. Ideally, samples should be collected using quick, cost-efficient and noninvasive methods. In recent years, a plethora of research has been directed toward finding novel biomarkers of allergic diseases. Promising biomarkers of type 2 allergic diseases include sputum eosinophils, serum periostin and exhaled nitric oxide. Several other biomarkers, such as pro-inflammatory mediators, miRNAs, eicosanoid molecules, epithelial barrier integrity, and microbiota changes are useful for diagnosis and monitoring of allergic diseases and can be quantified in serum, body fluids and exhaled air. Herein, we review recent studies on biomarkers for the diagnosis and treatment of asthma, chronic urticaria, atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, food allergies, anaphylaxis, drug hypersensitivity and allergen immunotherapy. In addition, we discuss COVID-19 and allergic diseases within the perspective of biomarkers and recommendations on the management of allergic and asthmatic patients during the COVID-19 pandemic.
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http://dx.doi.org/10.1111/all.15089DOI Listing
September 2021

Climate change: A call to action for the united nations.

Allergy 2021 Sep 3. Epub 2021 Sep 3.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.

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http://dx.doi.org/10.1111/all.15079DOI Listing
September 2021

Persistent human bocavirus 1 infection and tonsillar immune responses.

Clin Transl Allergy 2021 Jul;11(6):e12030

Department of Pediatrics and Adolescent Medicine, Turku University Hospital and University of Turku, Turku, Finland.

Background: Persistent human bocavirus 1 (HBoV1) infection is a common finding in patients suffering from chronic tonsillar disease. However, the associations between HBoV1 infection and specific immune reactions are not completely known. We aimed to compare in vivo expression of T-cell cytokines, transcription factors, and type I/III interferons in human tonsils between HBoV1-positive and -negative tonsillectomy patients.

Methods: Tonsil tissue samples, nasopharyngeal aspirate (NPA), and serum samples were obtained from 143 immunocompetent adult and child tonsillectomy patients. HBoV1 and 14 other respiratory viruses were detected in NPAs and tonsil tissues by polymerase chain reaction (PCR). Serology and semi-quantitative PCR were used for diagnosing HBoV1 infections. Expression of 14 cytokines and transcription factors (IFN-α, IFN-β, IFN-γ, IL-10, IL-13, IL-17, IL-28, IL-29, IL-37, TGF-β, FOXP3, GATA3, RORC2, Tbet) was analyzed by quantitative reverse-transcription (RT)-PCR in tonsil tissues.

Results: HBoV1 was detected by PCR in NPA and tonsils from 25 (17%) study patients. Serology results indicated prior nonacute infections in 81% of cases. Tonsillar cytokine responses were affected by HBoV1 infection. The suppression of two transcription factors, RORC2 and FOXP3, was associated with HBoV1 infection (p < 0.05). Furthermore, intratonsillar HBoV1-DNA loads correlated negatively with IFN-λ family cytokines and IL-13.

Conclusions: Our study shows distinctively decreased T-helper and T-regulatory type immune responses in local lymphoid tissue in HBoV1-positive tonsillectomy patients. HBoV1 may act as a suppressive immune modulator.
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http://dx.doi.org/10.1002/clt2.12030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459348PMC
July 2021

Dysregulation of the epithelial barrier by environmental and other exogenous factors.

Contact Dermatitis 2021 Aug 21. Epub 2021 Aug 21.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos.

The "epithelial barrier hypothesis" proposes that the exposure to various epithelial barrier-damaging agents linked to industrialization and urbanization underlies the increase in allergic diseases. The epithelial barrier constitutes the first line of physical, chemical, and immunological defense against environmental factors. Recent reports have shown that industrial products disrupt the epithelial barriers. Innate and adaptive immune responses play an important role in epithelial barrier damage. In addition, recent studies suggest that epithelial barrier dysfunction plays an essential role in the pathogenesis of the atopic march by allergen sensitization through the transcutaneous route. It is evident that external factors interact with the immune system, triggering a cascade of complex reactions that damage the epithelial barrier. Epigenetic and microbiome changes modulate the integrity of the epithelial barrier. Robust and simple measurements of the skin barrier dysfunction at the point-of-care are of significant value as a biomarker, as recently reported using electrical impedance spectroscopy to directly measure barrier defects. Understanding epithelial barrier dysfunction and its mechanism is key to developing novel strategies for the prevention and treatment of allergic diseases. The aim of this review is to summarize recent studies on the pathophysiological mechanisms triggered by environmental factors that contribute to the dysregulation of epithelial barrier function.
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http://dx.doi.org/10.1111/cod.13959DOI Listing
August 2021

Direct platelet adhesion potentiates group 2 innate lymphoid cell functions.

Allergy 2021 Aug 17. Epub 2021 Aug 17.

Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.

Background: Platelets are thought to be involved in the pathophysiology of asthma, presumably through direct adhesion to inflammatory cells, including group 2 innate lymphoid cells (ILC2s). Here, we tried to elucidate the effects of platelet adhesion to ILC2s in vitro and in vivo, as well as the mechanisms involved.

Methods: Alternaria-induced ILC2-dependent airway inflammation models using wild-type and c-mpl mice were evaluated. Both purified CD41 and CD41 ILC2s were cultured with IL-2 and IL-33 to determine in vitro Type 2 (T2) cytokine production and cell proliferation. RNA-seq data of flow-cytometry-sorted CD41 and CD41 ILC2s were used to isolate ILC2-specific genes. Flow cytometry was performed to determine the expression of CD41 and adhesion-related molecules on ILC2s in both mouse and human tissues.

Results: T2 inflammation and T2 cytokine production from ILC2s were significantly reduced in the c-mpl mice compared to wild-type mice. Platelet-adherent ILC2s underwent significant proliferation and showed enhanced T2 cytokine production when exposed to IL-2 and IL-33. The functions of ILC2-specific genes were related to cell development and function. Upstream regulator analysis identified 15 molecules, that are thought to be involved in ILC2 activation. CD41 expression levels were higher in ILC2s from human PBMCs and mouse lung than in those from secondary lymphoid tissues, but they did not correlate with the P-selectin glycoprotein ligand-1 or CD24 expression level.

Conclusion: Platelets spontaneously adhere to ILC2s, probably in the peripheral blood and airways, thereby potentiating ILC2s to enhance their responses to IL-33.
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http://dx.doi.org/10.1111/all.15057DOI Listing
August 2021

Advances and highlights in asthma in 2021.

Allergy 2021 Aug 14. Epub 2021 Aug 14.

Department of Clinical Immunology, Wroclaw Medical University, Wroclaw, Poland.

Last year brought a significant advance in asthma management, unyielding to the pressure of the pandemics. Novel key findings in asthma pathogenesis focus on the resident cell compartment, epigenetics and the innate immune system. The precision immunology unbiased approach was supplemented with novel tools and greatly facilitated by the use of artificial intelligence. Several randomised clinical trials and good quality real-world evidence shed new light on asthma treatment and supported the revision of several asthma guidelines (GINA, Expert Panel Report 3, ERS/ATS guidelines on severe asthma) and the conception of new ones (EAACI Guidelines for the use of biologicals in severe asthma). Integrating asthma management within the broader context of Planetary Health has been put forward. In this review, recently published articles and clinical trials are summarised and discussed with the goal to provide clinicians and researchers with a concise update on asthma research from a translational perspective.
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http://dx.doi.org/10.1111/all.15054DOI Listing
August 2021

Inhaled Corticosteroids in early COVID-19-A tale of many facets.

Allergy 2021 Aug 9. Epub 2021 Aug 9.

Charité, Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

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http://dx.doi.org/10.1111/all.15041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441805PMC
August 2021

Cellular and molecular mechanisms of allergic asthma.

Mol Aspects Med 2021 Aug 4:100995. Epub 2021 Aug 4.

Swiss Institute of Allergy and Asthma Research (SIAF), Hermann-Burchard Strasse 9, CH7265, Davos Wolfgand, Switzerland; Christine Kühne - Center for Allergy Research and Education, Davos, Switzerland.

Asthma is a chronic disease of the airways, which affects more than 350 million people worldwide. It is the most common chronic disease in children, affecting at least 30 million children and young adults in Europe. Asthma is a complex, partially heritable disease with a marked heterogeneity. Its development is influenced both by genetic and environmental factors. The most common, as well as the most well characterized subtype of asthma is allergic eosinophilic asthma, which is characterized by a type 2 airway inflammation. The prevalence of asthma has substantially increased in industrialized countries during the last 60 years. The mechanisms underpinning this phenomenon are incompletely understood, however increased exposure to various environmental pollutants probably plays a role. Disease inception is thought to be enabled by a disadvantageous shift in the balance between protective and harmful lifestyle and environmental factors, including exposure to protective commensal microbes versus infection with pathogens, collectively leading to airway epithelial cell damage and disrupted barrier integrity. Epithelial cell-derived cytokines are one of the main drivers of the type 2 immune response against innocuous allergens, ultimately leading to infiltration of lung tissue with type 2 T helper (T2) cells, type 2 innate lymphoid cells (ILC2s), M2 macrophages and eosinophils. This review outlines the mechanisms responsible for the orchestration of type 2 inflammation and summarizes the novel findings, including but not limited to dysregulated epithelial barrier integrity, alarmin release and innate lymphoid cell stimulation.
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http://dx.doi.org/10.1016/j.mam.2021.100995DOI Listing
August 2021

Spermidine and spermine exert protective effects within the lung.

Pharmacol Res Perspect 2021 08;9(4):e00837

Department of Medicine and School of Microbiology, APC Microbiome Ireland, University College Cork, Cork, Ireland.

Asthma is a heterologous disease that is influenced by complex interactions between multiple environmental exposures, metabolism, and host immunoregulatory processes. Specific metabolites are increasingly recognized to influence respiratory inflammation. However, the role of protein-derived metabolites in regulating inflammatory responses in the lung are poorly described. The aims of the present study were to quantify polyamine levels in bronchoalveolar lavages (BALs) from healthy volunteers and asthma patients, and to evaluate the impact of each polyamine on inflammatory responses using in vitro models and in a house dust mite (HDM)-induced respiratory allergy model. Spermidine levels were decreased, while cadaverine levels were increased in BALs from asthma patients compared to healthy controls, using Ultra Performance Liquid Chromatography (UPLC). Both spermine and spermidine inhibit lipopolysaccharide (LPS)-induced cytokine secretion from human peripheral blood mononuclear cells (PBMCs) and dendritic cells (DCs) in vitro. In addition, oral gavage with spermine or spermidine modulate HDM-induced cell infiltration, cytokine secretion, and epithelial cell tight junction expression in murine models. Spermidine also reduces airway hyper-responsiveness. These results suggest that modulation of polyamine metabolism, in particular spermidine, is associated with respiratory inflammation and these molecules and pathways should be further explored as biomarkers of disease and potential targets for novel therapies.
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http://dx.doi.org/10.1002/prp2.837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294051PMC
August 2021

COVID-19 vaccines - the way forward.

Allergy 2021 Jun 30. Epub 2021 Jun 30.

Department of Immunology and Pathology, Monash University, Melbourne, Vic., Australia; Department of Allergy, Immunology and Respiratory Medicine, Central Clinical School, Monash, Melbourne, Vic, Australia.

In a health crisis of the calibre of the COVID-19 pandemic, the development of effective and safe vaccines is considered the most powerful measure to save lives and minimise the tremendous negative impact on health, social systems and global economics. Vaccines must be evaluated and approved by the appropriate regulatory and/or health authorities. To date, the worldwide regulatory landscape for vaccines is very broad. Bringing COVID-19 vaccines to the market, the authorities followed at least 51 different pathways, offering various types of accelerated vaccine approval. China, Russia and the United Arab Emirates initiated the vaccine administration before the conclusion of clinical trials. This patchwork of approval processes has revived a long-standing question, how to better facilitate harmonization in vaccine regulation and whether a harmonized approval process would make the vaccine development procedures more effective, quicker, broadly accessible and administered by the whole world and even less expensive. In this issue, experts from the Paul-Ehrlich Institute, the regulatory institution for vaccine development in Germany, describe the regulatory procedures, concepts and requirements that are applied to guide and promote the accelerated development and licensure of safe and efficacious COVID-19 vaccines in Europe..
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http://dx.doi.org/10.1111/all.14995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441906PMC
June 2021

Experimental rhinovirus infection induces an antiviral response in circulating B cells which is dysregulated in patients with asthma.

Allergy 2021 Jun 25. Epub 2021 Jun 25.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.

Background: Rhinoviruses are the predominant cause of respiratory viral infections and are strongly associated with asthma exacerbations. While humoral immunity plays an important role during virus infections, cellular aspects of this response are less well understood. Here, we investigated the antiviral response of circulating B cells upon experimental rhinovirus infection in healthy individuals and asthma patients.

Methods: We purified B cells from experimentally infected healthy individuals and patients with asthma and subjected them to total RNA-sequencing. Rhinovirus-derived RNA was measured in isolated B cells using a highly sensitive PCR. B cells were stimulated with rhinovirus in vitro to further study gene expression, expression of antiviral proteins and B-cell differentiation in response rhinovirus stimulation. Protein expression of pro-inflammatory cytokines in response to rhinovirus was assessed using a proximity extension assay.

Results: B cells isolated from experimentally infected subjects exhibited an antiviral gene profile linked to IFN-alpha, carried viral RNA in vivo and were transiently infected by rhinovirus in vitro. B cells rapidly differentiated into plasmablasts upon rhinovirus stimulation. While B cells lacked expression of interferons in response to rhinovirus exposure, co-stimulation with rhinovirus and IFN-alpha upregulated pro-inflammatory cytokine expression suggesting a potential new function of B cells during virus infections. Asthma patients showed extensive upregulation and dysregulation of antiviral gene expression.

Conclusion: These findings add to the understanding of systemic effects of rhinovirus infections on B-cell responses in the periphery, show potential dysregulation in patients with asthma and might also have implications during infection with other respiratory viruses.
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http://dx.doi.org/10.1111/all.14985DOI Listing
June 2021

Cutaneous and systemic hyperinflammation drives maculopapular drug exanthema in severely ill COVID-19 patients.

Allergy 2021 Jun 22. Epub 2021 Jun 22.

Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

Background: Coronavirus disease-2019 (COVID-19) has been associated with cutaneous findings, some being the result of drug hypersensitivity reactions such as maculopapular drug rashes (MDR). The aim of this study was to investigate whether COVID-19 may impact the development of the MDR.

Methods: Blood and skin samples from COVID-19 patients (based on a positive nasopharyngeal PCR) suffering from MDR (COVID-MDR), healthy controls, non-COVID-19-related patients with drug rash with eosinophilia and systemic symptoms (DRESS), and MDR were analyzed. We utilized imaging mass cytometry (IMC) to characterize the cellular infiltrate in skin biopsies. Furthermore, RNA sequencing transcriptome of skin biopsy samples and high-throughput multiplexed proteomic profiling of serum were performed.

Results: IMC revealed by clustering analyses a more prominent, phenotypically shifted cytotoxic CD8 T cell population and highly activated monocyte/macrophage (Mo/Mac) clusters in COVID-MDR. The RNA sequencing transcriptome demonstrated a more robust cytotoxic response in COVID-MDR skin. However, severe acute respiratory syndrome coronavirus 2 was not detected in skin biopsies at the time point of MDR diagnosis. Serum proteomic profiling of COVID-MDR patients revealed upregulation of various inflammatory mediators (IL-4, IL-5, IL-6, TNF, and IFN-γ), eosinophil and Mo/Mac -attracting chemokines (MCP-2, MCP-3, MCP-4 and CCL11). Proteomics analyses demonstrated a massive systemic cytokine storm in COVID-MDR compared with the relatively milder cytokine storm observed in DRESS, while MDR did not exhibit such features.

Conclusion: A systemic cytokine storm may promote activation of Mo/Mac and cytotoxic CD8 T cells in severe COVID-19 patients, which in turn may impact the development of MDR.
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http://dx.doi.org/10.1111/all.14983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441838PMC
June 2021

Loss of regulatory capacity in Treg cells following rhinovirus infection.

J Allergy Clin Immunol 2021 Oct 18;148(4):1016-1029.e16. Epub 2021 Jun 18.

Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos, Switzerland. Electronic address:

Background: Respiratory infections with rhinoviruses (RV) are strongly associated with development and exacerbations of asthma, and they pose an additional health risk for subjects with allergy.

Objective: How RV infections and chronic allergic diseases are linked and what role RV plays in the breaking of tolerance in regulatory T (Treg) cells is unknown. Therefore, this study aims to investigate the effects of RV on Treg cells.

Methods: Treg cells were isolated from subjects with asthma and controls after experimental infection with the RV-A16 (RV16) and analyzed with next-generation sequencing. Additionally, suppression assays, quantitative PCR assays, and protein quantifications were performed with Treg cells after in vitro RV16 infection.

Results: RV16 induced a strong antiviral response in Treg cells from subjects with asthma and controls, including the upregulation of IFI44L, MX1, ISG15, IRF7, and STAT1. In subjects with asthma, the inflammatory response was exaggerated and showed a dysregulated immune response compared with that in the controls. Furthermore, subjects with asthma failed to upregulate several immunosuppressive molecules such as CTLA4 and CD69, and they upregulated the inflammasome-related genes PYCARD and AIM2. Additionally, RV16 reduced the suppressive capacity of Treg cells from healthy subjects and subjects with asthma in vitro and increased T2 cell-type cytokine production.

Conclusions: Treg cells from healthy subjects and subjects with asthma displayed an antiviral response after RV infection and showed reduced suppressive capacity. These data suggest that Treg cell function might be altered or impaired during RV infections, which might play an important role in the association between RV and the development of asthma and asthma exacerbations.
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http://dx.doi.org/10.1016/j.jaci.2021.05.045DOI Listing
October 2021

Environment-dependent alterations of immune mediators in urban and rural south African children with atopic dermatitis.

Allergy 2021 Jun 4. Epub 2021 Jun 4.

Swiss Institute of Allergy and Asthma Research (SIAF, University of Zurich, Davos, Switzerland.

Background: In order to improve targeted therapeutic approaches for children with atopic dermatitis (AD), novel insights into the molecular mechanisms and environmental exposures that differentially contribute to disease phenotypes are required. We wished to identify AD immunological endotypes in South African children from rural and urban environments.

Methods: We measured immunological, socio-economic and environmental factors in healthy children (n = 74) and children with AD (n = 78), in rural and urban settings from the same ethno-linguistic AmaXhosa background in South Africa.

Results: Circulating eosinophils, monocytes, TARC, MCP-4, IL-16 and allergen-specific IgE levels were elevated, while IL-17A and IL-23 levels were reduced, in children with AD regardless of their location. Independent of AD, children living in a rural environment had the highest levels of TNFα, TNFβ, IL-1α, IL-6, IL-8, IL-21, MCP-1, MIP-1α, MIP-1β, MDC, sICAM1, sVCAM1, VEGFA, VEGFD and Tie2, suggesting a generalized microinflammation or a pattern of trained immunity without any specific T polarization. In contrast, IL-15, IL-22, Flt1, PIGF and βFGF were highest in urban children. Rural healthy children had the lowest levels of food allergen-specific IgG4. Early life nutritional factors, medications, animal exposures, indoor environment, sunlight exposure, household size, household income and parental education levels were associated with differences in circulating cytokine levels.

Conclusions: This study highlights the immunological impact of environmental exposures and socio-economic status in the manifestation of immune endotypes in children with AD living in urban and rural areas, which are important in selecting appropriately matched immunological therapies for treatment of AD.
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http://dx.doi.org/10.1111/all.14974DOI Listing
June 2021

Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions?

Authors:
Cezmi A Akdis

Nat Rev Immunol 2021 Apr 12. Epub 2021 Apr 12.

Swiss Institute of Allergy and Asthma Research (SIAF), University Zurich, Davos, Switzerland.

There has been a steep increase in allergic and autoimmune diseases, reaching epidemic proportions and now affecting more than one billion people worldwide. These diseases are more common in industrialized countries, and their prevalence continues to rise in developing countries in parallel to urbanization and industrialization. Intact skin and mucosal barriers are crucial for the maintenance of tissue homeostasis as they protect host tissues from infections, environmental toxins, pollutants and allergens. A defective epithelial barrier has been demonstrated in allergic and autoimmune conditions such as asthma, atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, coeliac disease and inflammatory bowel disease. In addition, leakiness of the gut epithelium is also implicated in systemic autoimmune and metabolic conditions such as diabetes, obesity, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis and autoimmune hepatitis. Finally, distant inflammatory responses due to a 'leaky gut' and microbiome changes are suspected in Alzheimer disease, Parkinson disease, chronic depression and autism spectrum disorders. This article introduces an extended 'epithelial barrier hypothesis', which proposes that the increase in epithelial barrier-damaging agents linked to industrialization, urbanization and modern life underlies the rise in allergic, autoimmune and other chronic conditions. Furthermore, it discusses how the immune responses to dysbiotic microbiota that cross the damaged barrier may be involved in the development of these diseases.
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http://dx.doi.org/10.1038/s41577-021-00538-7DOI Listing
April 2021

Electrical impedance spectroscopy for the characterization of skin barrier in atopic dermatitis.

Allergy 2021 10 15;76(10):3066-3079. Epub 2021 May 15.

Swiss Institute of Allergy and Asthma Research (SIAF, Davos, Switzerland.

Background: Allergic disorders such as atopic dermatitis (AD) are strongly associated with an impairment of the epithelial barrier, in which tight junctions and/or filaggrin expression can be defective. Skin barrier assessment shows potential to be clinically useful for prediction of disease development, improved and earlier diagnosis, lesion follow-up, and therapy evaluation. This study aimed to establish a method to directly assess the in vivo status of epithelial barrier using electrical impedance spectroscopy (EIS).

Methods: Thirty-six patients with AD were followed during their 3-week hospitalization and compared with 28 controls. EIS and transepidermal water loss (TEWL) were measured in lesional and non-lesional skin. Targeted proteomics by proximity extension assay in serum and whole-genome sequence were performed.

Results: Electrical impedance spectroscopy was able to assess epithelial barrier integrity, differentiate between patients and controls without AD, and characterize lesional and non-lesional skin of patients. It showed a significant negative correlation with TEWL, but a higher sensitivity to discriminate non-lesional atopic skin from controls. During hospitalization, lesions reported a significant increase in EIS that correlated with healing, decreased SCORAD and itch scores. Additionally, EIS showed a significant inverse correlation with serum biomarkers associated with inflammatory pathways that may affect the epithelial barrier, particularly chemokines such as CCL13, CCL3, CCL7, and CXCL8 and other cytokines, such as IRAK1, IRAK4, and FG2, which were significantly high at admission. Furthermore, filaggrin copy numbers significantly correlated with EIS on non-lesional skin of patients.

Conclusions: Electrical impedance spectroscopy can be a useful tool to detect skin barrier dysfunction in vivo, valuable for the assessment of AD severity, progression, and therapy efficacy.
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http://dx.doi.org/10.1111/all.14842DOI Listing
October 2021

Vaccines and allergic reactions: The past, the current COVID-19 pandemic, and future perspectives.

Allergy 2021 06 4;76(6):1640-1660. Epub 2021 Jun 4.

Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Vaccines are essential public health tools with a favorable safety profile and prophylactic effectiveness that have historically played significant roles in reducing infectious disease burden in populations, when the majority of individuals are vaccinated. The COVID-19 vaccines are expected to have similar positive impacts on health across the globe. While serious allergic reactions to vaccines are rare, their underlying mechanisms and implications for clinical management should be considered to provide individuals with the safest care possible. In this review, we provide an overview of different types of allergic adverse reactions that can potentially occur after vaccination and individual vaccine components capable of causing the allergic adverse reactions. We present the incidence of allergic adverse reactions during clinical studies and through post-authorization and post-marketing surveillance and provide plausible causes of these reactions based on potential allergenic components present in several common vaccines. Additionally, we review implications for individual diagnosis and management and vaccine manufacturing overall. Finally, we suggest areas for future research.
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http://dx.doi.org/10.1111/all.14840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251022PMC
June 2021

Management of anaphylaxis due to COVID-19 vaccines in the elderly.

Allergy 2021 10;76(10):2952-2964

Regional Ministry of Health of Andalusia, Seville, Spain.

Older adults, especially men and/or those with diabetes, hypertension, and/or obesity, are prone to severe COVID-19. In some countries, older adults, particularly those residing in nursing homes, have been prioritized to receive COVID-19 vaccines due to high risk of death. In very rare instances, the COVID-19 vaccines can induce anaphylaxis, and the management of anaphylaxis in older people should be considered carefully. An ARIA-EAACI-EuGMS (Allergic Rhinitis and its Impact on Asthma, European Academy of Allergy and Clinical Immunology, and European Geriatric Medicine Society) Working Group has proposed some recommendations for older adults receiving the COVID-19 vaccines. Anaphylaxis to COVID-19 vaccines is extremely rare (from 1 per 100,000 to 5 per million injections). Symptoms are similar in younger and older adults but they tend to be more severe in the older patients. Adrenaline is the mainstay treatment and should be readily available. A flowchart is proposed to manage anaphylaxis in the older patients.
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http://dx.doi.org/10.1111/all.14838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251336PMC
October 2021

Differentiation of COVID-19 signs and symptoms from allergic rhinitis and common cold: An ARIA-EAACI-GA LEN consensus.

Allergy 2021 08 14;76(8):2354-2366. Epub 2021 May 14.

Division of Allergy, Department of Pediatric Medicine, The Bambino Gesù Children's Research Hospital Holy see, IRCCS, Rome, Italy.

Background: Although there are many asymptomatic patients, one of the problems of COVID-19 is early recognition of the disease. COVID-19 symptoms are polymorphic and may include upper respiratory symptoms. However, COVID-19 symptoms may be mistaken with the common cold or allergic rhinitis. An ARIA-EAACI study group attempted to differentiate upper respiratory symptoms between the three diseases.

Methods: A modified Delphi process was used. The ARIA members who were seeing COVID-19 patients were asked to fill in a questionnaire on the upper airway symptoms of COVID-19, common cold and allergic rhinitis.

Results: Among the 192 ARIA members who were invited to respond to the questionnaire, 89 responded and 87 questionnaires were analysed. The consensus was then reported. A two-way ANOVA revealed significant differences in the symptom intensity between the three diseases (p < .001).

Conclusions: This modified Delphi approach enabled the differentiation of upper respiratory symptoms between COVID-19, the common cold and allergic rhinitis. An electronic algorithm will be devised using the questionnaire.
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http://dx.doi.org/10.1111/all.14815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250633PMC
August 2021

Efficacy and safety of treatment with biologicals for severe chronic rhinosinusitis with nasal polyps: A systematic review for the EAACI guidelines.

Allergy 2021 08 24;76(8):2337-2353. Epub 2021 Mar 24.

Department of Clinical Immunology, University of Wroclaw, Wroclaw, Poland.

This systematic review evaluates the efficacy and safety of biologicals for chronic rhinosinusitis with nasal polyps (CRSwNP) compared with the standard of care. PubMed, Embase, and Cochrane Library were searched for RCTs. Critical and important CRSwNP-related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. RCTs evaluated (dupilumab-2, omalizumab-4, mepolizumab-2, and reslizumab-1) included 1236 adults, with follow-up of 20-64 weeks. Dupilumab reduces the need for surgery (NFS) or oral corticosteroid (OCS) use (RR 0.28; 95% CI 0.20-0.39, moderate certainty) and improves with high certainty smell evaluated with UPSIT score (mean difference (MD) +10.54; 95% CI +9.24 to +11.84) and quality of life (QoL) evaluated with SNOT-22 (MD -19.14; 95% CI -22.80 to -15.47), with fewer treatment-related adverse events (TAEs) (RR 0.95; 95% CI 0.89-1.02, moderate certainty). Omalizumab reduces NFS (RR 0.85; 95% CI 0.78-0.92, high certainty), decreases OCS use (RR 0.38; 95% CI 0.10-1.38, moderate certainty), and improves high certainty smell (MD +3.84; 95% CI +3.64 to +4.04) and QoL (MD -15.65; 95% CI -16.16 to -15.13), with increased TAE (RR 1.73; 95% CI 0.60-5.03, moderate certainty). There is low certainty for mepolizumab reducing NFS (RR 0.78; 95% CI 0.64-0.94) and improving QoL (MD -13.3; 95% CI -23.93 to -2.67) and smell (MD +0.7; 95% CI -0.48 to +1.88), with increased TAEs (RR 1.64; 95% CI 0.41-6.50). The evidence for reslizumab is very uncertain.
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http://dx.doi.org/10.1111/all.14809DOI Listing
August 2021

Mesenchymal stem cells regulate type 2 innate lymphoid cells via regulatory T cells through ICOS-ICOSL interaction.

Stem Cells 2021 Jul 19;39(7):975-987. Epub 2021 Mar 19.

Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.

Group 2 innate lymphoid cells (ILC2s) are recognized as key controllers and effectors of type 2 inflammation. Mesenchymal stem cells (MSCs) have been shown to alleviate type 2 inflammation by modulating T lymphocyte subsets and decreasing T 2 cytokine levels. However, the effects of MSCs on ILC2s have not been investigated. In this study, we investigated the potential immunomodulatory effects of MSCs on ILC2s in peripheral blood mononuclear cells (PBMCs) from allergic rhinitis patients and healthy subjects. We further investigated the mechanisms involved in the MSC modulation using isolated lineage negative (Lin ) cells. PBMCs and Lin cells were cocultured with induced pluripotent stem cell-derived MSCs (iPSC-MSCs) under the stimulation of epithelial cytokines IL-25 and IL-33. And the ILC2 levels and functions were examined and the possible mechanisms were investigated based on regulatory T (Treg) cells and ICOS-ICOSL pathway. iPSC-MSCs successfully decreased the high levels of IL-13, IL-9, and IL-5 in PBMCs in response to IL-25, IL-33, and the high percentages of IL-13 ILC2s and IL-9 ILC2s in response to epithelial cytokines were significantly reversed after the treatment of iPSC-MSCs. However, iPSC-MSCs were found directly to enhance ILC2 levels and functions via ICOS-ICOSL interaction in Lin cells and pure ILC2s. iPSC-MSCs exerted their inhibitory effects on ILC2s via activating Treg cells through ICOS-ICOSL interaction. The MSC-induced Treg cells then suppressed ILC2s by secreting IL-10 in the coculture system. This study revealed that human MSCs suppressed ILC2s via Treg cells through ICOS-ICOSL interaction, which provides further insight to regulate ILC2s in inflammatory disorders.
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http://dx.doi.org/10.1002/stem.3369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360040PMC
July 2021

Allergenic components of the mRNA-1273 vaccine for COVID-19: Possible involvement of polyethylene glycol and IgG-mediated complement activation.

Allergy 2021 Mar 3. Epub 2021 Mar 3.

Swiss Institute of Allergy and Asthma Research (SIAF, University of Zurich, Davos, Switzerland.

Following the emergency use authorization of the mRNA-1273 vaccine on the 18 of December 2020, two mRNA vaccines are in current use for the prevention of coronavirus disease 2019 (COVID-19). For both mRNA vaccines, the phase III pivotal trials excluded individuals with a history of allergy to vaccine components. Immediately after the initiation of vaccination in the United Kingdom, Canada, and the United States, anaphylactic reactions were reported. While the culprit trigger requires investigation, initial reports suggested the excipient polyethylene glycol 2000 (PEG-2000)-contained in both vaccines as the PEG-micellar carrier system-as the potential culprit. Surface PEG chains form a hydrate shell to increase stability and prevent opsonization. Allergic reactions to such PEGylated lipids can be IgE-mediated, but may also result from complement activation-related pseudoallergy (CARPA) that has been described in similar liposomes. In addition, mRNA-1273 also contains tromethamine (trometamol), which has been reported to cause anaphylaxis to substances such as gadolinium-based contrast media. Skin prick, intradermal and epicutaneous tests, in vitro sIgE assessment, evaluation of sIgG/IgM, and basophil activation tests are being used to demonstrate allergic reactions to various components of the vaccines.
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http://dx.doi.org/10.1111/all.14794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013891PMC
March 2021

Potential Interplay between Nrf2, TRPA1, and TRPV1 in Nutrients for the Control of COVID-19.

Int Arch Allergy Immunol 2021 10;182(4):324-338. Epub 2021 Feb 10.

Division of Infection, Immunity & Respiratory Medicine, Royal Manchester Children's Hospital, University of Manchester, Manchester, United Kingdom.

In this article, we propose that differences in COVID-19 morbidity may be associated with transient receptor potential ankyrin 1 (TRPA1) and/or transient receptor potential vanilloid 1 (TRPV1) activation as well as desensitization. TRPA1 and TRPV1 induce inflammation and play a key role in the physiology of almost all organs. They may augment sensory or vagal nerve discharges to evoke pain and several symptoms of COVID-19, including cough, nasal obstruction, vomiting, diarrhea, and, at least partly, sudden and severe loss of smell and taste. TRPA1 can be activated by reactive oxygen species and may therefore be up-regulated in COVID-19. TRPA1 and TRPV1 channels can be activated by pungent compounds including many nuclear factor (erythroid-derived 2) (Nrf2)-interacting foods leading to channel desensitization. Interactions between Nrf2-associated nutrients and TRPA1/TRPV1 may be partly responsible for the severity of some of the COVID-19 symptoms. The regulation by Nrf2 of TRPA1/TRPV1 is still unclear, but suggested from very limited clinical evidence. In COVID-19, it is proposed that rapid desensitization of TRAP1/TRPV1 by some ingredients in foods could reduce symptom severity and provide new therapeutic strategies.
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http://dx.doi.org/10.1159/000514204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018185PMC
April 2021
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