Publications by authors named "Carsten Schmidt-Weber"

121 Publications

An Exhausted Phenotype of T 2-Cells Is Primed by Allergen Exposure,But Not Reinforced by Allergen-specific Immunotherapy.

Allergy 2021 May 9. Epub 2021 May 9.

Center of Allergy & Environment (ZAUM), Technical University of Munichand Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Members of the German Center of Lung Research (DZL), CPC-M, Munich, Germany,and Member of the Helmholtz I&I Initiative, Germany.

Background: Studies show that proallergic T 2-cells decrease after successful allergen-specific immunotherapy (AIT). It is likely that iatrogenic administration of allergens drives these cells to exhaustion due to chronic T cell receptor stimulation. This study aimed to investigate the exhaustion of T cells in connection with allergenexposure during AIT in mice and two independent patient cohorts.

Methods: OVA-sensitized C57BL/6J mice were challenged and treated with OVA, and the development of exhaustion inlocal and systemic T 2-cells was analyzed.In patients, the expression of exhaustion-associated surface markers on T 2-cells was evaluated using flow cytometry in a cross-sectional grass pollen allergy cohort with and without AIT.The treatment effect was further studied in PBMC collected from a prospective long-termAIT cohort.

Results: The exhaustion-associated surface markers CTLA-4 and PD-1 were significantly upregulated on T 2-cells upon OVA aerosol exposure in OVA-allergic compared to non-allergic mice. CTLA-4 and PD-1decreased after AIT, in particular on the surface oflocal lung T 2-cells. Similarly, CTLA-4 and PD-1 expression were enhanced on T 2-cells from patients with allergic rhinitis with an even stronger effect in those with concomitant asthma. Using an unbiased Louvain clustering analysis, we discoveredalate-differentiated T 2 population expressing both markers that decreased during up-dosing but persisted long-term during the maintenance phase.

Conclusions: This study shows that allergen exposure promotes CTLA-4 and PD-1 expression onT 2-cells, andthat the dynamic change in frequencies of exhausted T 2-cells exhibits a differential pattern during the up-dosing versus the maintenance phases of AIT.
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http://dx.doi.org/10.1111/all.14896DOI Listing
May 2021

Constitutive immune activity promotes JNK- and FoxO-dependent remodeling of Drosophila airways.

Cell Rep 2021 Apr;35(1):108956

Zoology, Department of Molecular Physiology, Kiel University, 24118 Kiel, Germany; Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany. Electronic address:

Extensive remodeling of the airways is a major characteristic of chronic inflammatory lung diseases such as asthma or chronic obstructive pulmonary disease (COPD). To elucidate the importance of a deregulated immune response in the airways for remodeling processes, we established a matching Drosophila model. Here, triggering the Imd (immune deficiency) pathway in tracheal cells induced organ-wide remodeling. This structural remodeling comprises disorganization of epithelial structures and comprehensive epithelial thickening. We show that these structural changes do not depend on the Imd pathway's canonical branch terminating on nuclear factor κB (NF-κB) activation. Instead, activation of a different segment of the Imd pathway that branches off downstream of Tak1 and comprises activation of c-Jun N-terminal kinase (JNK) and forkhead transcription factor of the O subgroup (FoxO) signaling is necessary and sufficient to mediate the observed structural changes of the airways. Our findings imply that targeting JNK and FoxO signaling in the airways could be a promising strategy to interfere with disease-associated airway remodeling processes.
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http://dx.doi.org/10.1016/j.celrep.2021.108956DOI Listing
April 2021

Allergen-specific immunotherapy induces the suppressive secretoglobin 1A1 in cells of the lower airways.

Allergy 2021 Feb 2. Epub 2021 Feb 2.

Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Munich, Germany.

Background: While several systemic immunomodulatory effects of allergen-specific immunotherapy (AIT) have been discovered, local anti-inflammatory mechanisms in the respiratory tract are largely unknown. We sought to elucidate local and epithelial mechanisms underlying allergen-specific immunotherapy in a genome-wide approach.

Methods: We induced sputum in hay fever patients and healthy controls during the pollen peak season and stratified patients by effective allergen immunotherapy or as untreated. Sputum was directly processed after induction and subjected to whole transcriptome RNA microarray analysis. Nasal secretions were analyzed for Secretoglobin1A1 (SCGB1A1) and IL-24 protein levels in an additional validation cohort at three defined time points during the 3-year course of AIT. Subsequently, RNA was extracted and subjected to an array-based whole transcriptome analysis.

Results: Allergen-specific immunotherapy inhibited pro-inflammatory CXCL8, IL24, and CCL26mRNA expression, while SCGB1A1, IL7, CCL5, CCL23, and WNT5BmRNAs were induced independently of the asthma status and allergen season. In our validation cohort, local increase of SCGB1A1 occurred concomitantly with the reduction of local IL-24 in upper airways during the course of AIT. Additionally, SCGB1A1 was identified as a suppressor of epithelial gene expression.

Conclusions: Allergen-specific immunotherapy induces a yet unknown local gene expression footprint in the lower airways that on one hand appears to be a result of multiple regulatory pathways and on the other hand reveals SCGB1A1 as novel anti-inflammatory mediator of long-term allergen-specific therapeutic intervention in the local environment.
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http://dx.doi.org/10.1111/all.14756DOI Listing
February 2021

Noninvasive and minimally invasive techniques for the diagnosis and management of allergic diseases.

Allergy 2021 04;76(4):1010-1023

Center of Allergy and Environment (ZAUM), Technical University and Helmholtz Zentrum München, München, Germany.

Allergic diseases of the (upper and lower) airways, the skin and the gastrointestinal tract, are on the rise, resulting in impaired quality of life, decreased productivity, and increased healthcare costs. As allergic diseases are mostly tissue-specific, local sampling methods for respective biomarkers offer the potential for increased sensitivity and specificity. Additionally, local sampling using noninvasive or minimally invasive methods can be cost-effective and well tolerated, which may even be suitable for primary or home care sampling. Non- or minimally invasive local sampling and diagnostics may enable a more thorough endotyping, may help to avoid under- or overdiagnosis, and may provide the possibility to approach precision prevention, due to early diagnosis of these local diseases even before they get systemically manifested and detectable. At the same time, dried blood samples may help to facilitate minimal-invasive primary or home care sampling for classical systemic diagnostic approaches. This EAACI position paper contains a thorough review of the various technologies in allergy diagnosis available on the market, which analytes or biomarkers are employed, and which samples or matrices can be used. Based on this assessment, EAACI position is to drive these developments to efficiently identify allergy and possibly later also viral epidemics and take advantage of comprehensive knowledge to initiate preventions and treatments.
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http://dx.doi.org/10.1111/all.14645DOI Listing
April 2021

Spotlight on microRNAs in allergy and asthma.

Allergy 2020 Oct 31. Epub 2020 Oct 31.

Department of Internal Medicine and Clinical Nutrition, Krefting Research Centre, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

In past 10 years, microRNAs (miRNAs) have gained scientific attention due to their importance in the pathophysiology of allergic diseases and their potential as biomarkers in liquid biopsies. They act as master post-transcriptional regulators that control most cellular processes. As one miRNA can target several mRNAs, often within the same pathway, dysregulated expression of miRNAs may alter particular cellular responses and contribute, or lead, to the development of various diseases. In this review, we give an overview of the current research on miRNAs in allergic diseases, including atopic dermatitis, allergic rhinitis, and asthma. Specifically, we discuss how individual miRNAs function in the regulation of immune responses in epithelial cells and specialized immune cells in response to different environmental factors and respiratory viruses. In addition, we review insights obtained from experiments with murine models of allergic airway and skin inflammation and offer an overview of studies focusing on miRNA discovery using profiling techniques and bioinformatic modeling of the network effect of multiple miRNAs. In conclusion, we highlight the importance of research into miRNA function in allergy and asthma to improve our knowledge of the molecular mechanisms involved in the pathogenesis of this heterogeneous group of diseases.
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http://dx.doi.org/10.1111/all.14646DOI Listing
October 2020

Increased estrogen to androgen ratio enhances immunoglobulin levels and impairs B cell function in male mice.

Sci Rep 2020 10 27;10(1):18334. Epub 2020 Oct 27.

Institute of Biomedicine, University of Turku, Turku, Finland.

Sex steroids, such as estrogens and androgens, are important regulators of the humoral immune response. Studies in female mice have demonstrated that alteration of circulating estrogen concentration regulates antibody-mediated immunity. As males have normally little endogenous estrogen, we hypothesized that in males high estrogens and low androgens affect the immune system and enhance the allergic inflammatory response. Here, we studied transgenic male mice expressing human aromatase (AROM+). These animals have a high circulating estrogen to androgen ratio (E/A), causing female traits such as gynecomastia. We found that AROM+ male mice had significantly higher plasma immunoglobulin levels, particularly IgE. Flow cytometry analyses of splenocytes revealed changes in mature/immature B cell ratio together with a transcriptional upregulation of the Igh locus. Furthermore, higher proliferation rate and increased IgE synthesis after IgE class-switching was found. Subsequently, we utilized an ovalbumin airway challenge model to test the allergic response in AROM+ male mice. In line with above observations, an increase in IgE levels was measured, albeit no impact on immune cell infiltration into the lungs was detected. Together, our findings suggest that high circulating E/A in males significantly alters B cell function without any significant enhancement in allergic inflammation.
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http://dx.doi.org/10.1038/s41598-020-75059-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591566PMC
October 2020

Ragweed plants grown under elevated CO levels produce pollen which elicit stronger allergic lung inflammation.

Allergy 2020 Oct 9. Epub 2020 Oct 9.

Center of Allergy & Environment (ZAUM), Technical University of Munich (TUM) and Helmholtz Zentrum München, Munich, Germany.

Background: Common ragweed has been spreading as a neophyte in Europe. Elevated CO levels, a hallmark of global climate change, have been shown to increase ragweed pollen production, but their effects on pollen allergenicity remain to be elucidated.

Methods: Ragweed was grown in climate-controlled chambers under normal (380 ppm, control) or elevated (700 ppm, based on RCP4.5 scenario) CO levels. Aqueous pollen extracts (RWE) from control- or CO -pollen were administered in vivo in a mouse model for allergic disease (daily for 3-11 days, n = 5) and employed in human in vitro systems of nasal epithelial cells (HNECs), monocyte-derived dendritic cells (DCs), and HNEC-DC co-cultures. Additionally, adjuvant factors and metabolites in control- and CO -RWE were investigated using ELISA and untargeted metabolomics.

Results: In vivo, CO -RWE induced stronger allergic lung inflammation compared to control-RWE, as indicated by lung inflammatory cell infiltrate and mediators, mucus hypersecretion, and serum total IgE. In vitro, HNECs stimulated with RWE increased indistinctively the production of pro-inflammatory cytokines (IL-8, IL-1β, and IL-6). In contrast, supernatants from CO -RWE-stimulated HNECs, compared to control-RWE-stimulated HNECS, significantly increased TNF and decreased IL-10 production in DCs. Comparable results were obtained by stimulating DCs directly with RWEs. The metabolome analysis revealed differential expression of secondary plant metabolites in control- vs CO -RWE. Mixes of these metabolites elicited similar responses in DCs as compared to respective RWEs.

Conclusion: Our results indicate that elevated ambient CO levels elicit a stronger RWE-induced allergic response in vivo and in vitro and that RWE increased allergenicity depends on the interplay of multiple metabolites.
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http://dx.doi.org/10.1111/all.14618DOI Listing
October 2020

Predicting Success of Allergen-Specific Immunotherapy.

Front Immunol 2020 25;11:1826. Epub 2020 Aug 25.

Center of Allergy and Environment (ZAUM), Technical University and Helmholtz Center Munich, Member of the German Center of Lung Research (DZL), and Member of the Helmholtz I&I Initiative, Munich, Germany.

The immune response to antigens is a key aspect of immunology, as it provides opportunities for therapeutic intervention. However, the induction of immunological tolerance is an evolving area that is still not sufficiently understood. Allergen immunotherapy (AIT) is a disease-modulating therapy available for immunoglobulin E (IgE)-mediated airway diseases such as allergic rhinitis or allergic asthma. This disease-modifying effect is not only antigen driven but also antigen specific. The specificity and also the long-lasting, often life-long symptom reduction make the therapy attractive for patients. Additionally, the chance to prevent the onset of asthma by treating allergic rhinitis with AIT is important. The mechanism and, in consequence, therapy guiding biomarker are still in its infancy. Recent studies demonstrated that the interaction of T, B, dendritic, and epithelial cells and macrophages are individually contributing to clinical tolerance and therefore underline the need for a system to monitor the progress and success of AIT. As clinical improvement is often accompanied by decreases in numbers of effector cells in the tissue, analyses of cellular responses and cytokine pattern provide a good insight into the mechanisms of AIT. The suppression of type-2 immunity is accompanied by decreased levels of type-2 mediators such as epithelial CCL-26 and interleukin (IL)-4, IL-13 produced by T cells that are constituting the immune memory and are increasingly controlled by regulatory T and B cells following AIT. Immune tolerance is also associated with increased production of type-1 mediators like interferon-gamma, tissue-homeostating factors like indoleamine 2,3-dioxygenase (IDO) expressed by macrophages and dendritic cells. Although these individual genes were convincingly demonstrated to play a role immune tolerance, they do not predict therapy outcomes of AIT on an individual level. Therefore, combinations or ratios of gene expression levels are a promising way to achieve predictive value and definition of helpful biomarker.
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http://dx.doi.org/10.3389/fimmu.2020.01826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477353PMC
April 2021

An operational robotic pollen monitoring network based on automatic image recognition.

Environ Res 2020 12 16;191:110031. Epub 2020 Aug 16.

Center of Allergy & Environment (ZAUM), Member of the German Center for Lung Research (DZL), Technische Universität München/Helmholtz Center, Munich, Germany. Electronic address:

There is high demand for online, real-time and high-quality pollen data. To the moment pollen monitoring has been done manually by highly specialized experts. Here we evaluate the electronic Pollen Information Network (ePIN) comprising 8 automatic BAA500 pollen monitors in Bavaria, Germany. Automatic BAA500 and manual Hirst-type pollen traps were run simultaneously at the same locations for one pollen season. Classifications by BAA500 were checked by experts in pollen identification, which is traditionally considered to be the "gold standard" for pollen monitoring. BAA500 had a multiclass accuracy of over 90%. Correct identification of any individual pollen taxa was always >85%, except for Populus (73%) and Alnus (64%). The BAA500 was more precise than the manual method, with less discrepancies between determinations by pairs of automatic pollen monitors than between pairs of humans. The BAA500 was online for 97% of the time. There was a significant correlation of 0.84 between airborne pollen concentrations from the BAA500 and Hirst-type pollen traps. Due to the lack of calibration samples it is unknown which instrument gives the true concentration. The automatic BAA500 network delivered pollen data rapidly (3 h delay with real-time), reliably and online. We consider the ability to retrospectively check the accuracy of the reported classification essential for any automatic system.
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http://dx.doi.org/10.1016/j.envres.2020.110031DOI Listing
December 2020

Predicting persistence of atopic dermatitis in children using clinical attributes and serum proteins.

Allergy 2021 04 1;76(4):1158-1172. Epub 2020 Sep 1.

Department of Dermatology and Allergy, Technical University of Munich, Munich, Germany.

Background: Atopic dermatitis (AD) is the most common inflammatory skin disease in children, with 30% of all those diagnosed developing chronic or relapsing disease by adolescence. Such disease persistence cannot yet be predicted. The aim of the present study was to predict the natural course of AD using clinical parameters and serum proteins.

Methods: Sera of 144 children with AD (age 0-3 years) were analyzed for IgE and 33 cytokines, chemokines, and growth factors. Patient disease course until the age of 7 years was assessed retrospectively. Unsupervised k-means clustering was performed to define disease endotypes. Identified factors associated with AD persistence at the age of 7 years were validated in children with AD in an independent cohort (LISA Munich; n = 168). Logistic regression and XGBoosting methods followed by cross-validation were applied to predict individual disease outcomes.

Results: Three distinct endotypes were found in infancy, characterized by a unique inflammatory signature. Factors associated with disease persistence were disease score (SCORAD), involvement of the limbs, flexural lesion distribution at the age of 3 years, allergic comorbidities, and disease exacerbation by the trigger factors stress, pollen exposure, and change in weather. Persistence was predicted with a sensitivity of 81.8% and a specificity of 82.4%. Factors with a high impact on the prediction of persistence were SCORAD at the age of 3 years, trigger factors, and low VEGF serum levels.

Conclusion: Atopic dermatitis in infancy comprises three immunological endotypes. Disease persistence can be predicted using serum cytokines and clinical variables.
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http://dx.doi.org/10.1111/all.14557DOI Listing
April 2021

IgE autoantibodies and autoreactive T cells and their role in children and adults with atopic dermatitis.

Clin Transl Allergy 2020 3;10:34. Epub 2020 Aug 3.

Department of Dermatology, SKIN Research Group, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 103, Building D, Room D148, 1090 Brussels, Belgium.

The pathophysiology of atopic dermatitis (AD) is highly complex and understanding of disease endotypes may improve disease management. Immunoglobulins E (IgE) against human skin epitopes (IgE autoantibodies) are thought to play a role in disease progression and prolongation. These antibodies have been described in patients with severe and chronic AD, suggesting a progression from allergic inflammation to severe autoimmune processes against the skin. This review provides a summary of the current knowledge and gaps on IgE autoreactivity and self-reactive T cells in children and adults with AD based on a systematic search. Currently, the clinical relevance and the pathomechanism of IgE autoantibodies in AD needs to be further investigated. Additionally, it is unknown whether the presence of IgE autoantibodies in patients with AD is an epiphenomenon or a disease endotype. However, increased knowledge on the clinical relevance and the pathophysiologic role of IgE autoantibodies and self-reactive T cells in AD can have consequences for diagnosis and treatment. Responses to the current available treatments can be used for better understanding of the pathways and may shed new lights on the treatment options for patients with AD and autoreactivity against skin epitopes. To conclude, IgE autoantibodies and self-reactive T cells can contribute to the pathophysiology of AD based on the body of evidence in literature. However, many questions remain open. Future studies on autoreactivity in AD should especially focus on the clinical relevance, the contribution to the disease progression and chronicity on cellular level, the onset and therapeutic strategies.
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http://dx.doi.org/10.1186/s13601-020-00338-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398196PMC
August 2020

Antigen 5 Allergens of Hymenoptera Venoms and Their Role in Diagnosis and Therapy of Venom Allergy.

Curr Allergy Asthma Rep 2020 07 9;20(10):58. Epub 2020 Jul 9.

Experimental Dermatology and Allergy Research Group, Department of Dermatology and Allergology, Justus-Liebig-University Gießen, Giessen, Germany.

Purpose Of Review: Stings of Hymenoptera of the superfamily Vespoidea such as yellow jackets, paper wasps or stinging ants are common triggers for severe and even fatal allergic reactions. Antigen 5 allergens are potent allergens in the majority of these venoms with major importance for diagnosis and therapy. Reviewed here are the characteristics of antigen 5 allergens, their role in component-resolved diagnostics as well as current limitations of the available diagnostics for proper therapeutic decisions.

Recent Findings: Antigens 5 are proteins of unknown function in Hymenoptera venoms with high allergenic potency. They represent key elements in component-resolved diagnosis to discriminate between honeybee and vespid venom allergy. However, due to their pronounced cross-reactivity, there are remaining diagnostic and therapeutic challenges that have to be addressed. Antigens 5 are highly relevant venom allergens of the Vespoidea superfamily. Although their use in component-resolved diagnosis facilitates dissection of cross-reactivity and primary allergy in double sensitization to honeybee and vespid venom, new diagnostic concepts are needed to discriminate between allergies to different vespid species.
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http://dx.doi.org/10.1007/s11882-020-00954-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347709PMC
July 2020

Immunology of COVID-19: Mechanisms, clinical outcome, diagnostics, and perspectives-A report of the European Academy of Allergy and Clinical Immunology (EAACI).

Allergy 2020 10;75(10):2445-2476

Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Stanford University, Stanford, CA, USA.

With the worldwide spread of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulting in declaration of a pandemic by the World Health Organization (WHO) on March 11, 2020, the SARS-CoV-2-induced coronavirus disease-19 (COVID-19) has become one of the main challenges of our times. The high infection rate and the severe disease course led to major safety and social restriction measures worldwide. There is an urgent need of unbiased expert knowledge guiding the development of efficient treatment and prevention strategies. This report summarizes current immunological data on mechanisms associated with the SARS-CoV-2 infection and COVID-19 development and progression to the most severe forms. We characterize the differences between adequate innate and adaptive immune response in mild disease and the deep immune dysfunction in the severe multiorgan disease. The similarities of the human immune response to SARS-CoV-2 and the SARS-CoV and MERS-CoV are underlined. We also summarize known and potential SARS-CoV-2 receptors on epithelial barriers, immune cells, endothelium and clinically involved organs such as lung, gut, kidney, cardiovascular, and neuronal system. Finally, we discuss the known and potential mechanisms underlying the involvement of comorbidities, gender, and age in development of COVID-19. Consequently, we highlight the knowledge gaps and urgent research requirements to provide a quick roadmap for ongoing and needed COVID-19 studies.
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http://dx.doi.org/10.1111/all.14462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361752PMC
October 2020

Inflammatory macrophage memory in nonsteroidal anti-inflammatory drug-exacerbated respiratory disease.

J Allergy Clin Immunol 2021 Feb 12;147(2):587-599. Epub 2020 Jun 12.

Center of Allergy and Environment, Technical University of Munich and Helmholtz Zentrum München, Munich, Germany. Electronic address:

Background: Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is a chronic inflammatory condition, which is driven by an aberrant arachidonic acid metabolism. Macrophages are major producers of arachidonic acid metabolites and subject to metabolic reprogramming, but they have been neglected in N-ERD.

Objective: This study sought to elucidate a potential metabolic and epigenetic macrophage reprogramming in N-ERD.

Methods: Transcriptional, metabolic, and lipid mediator profiles in macrophages from patients with N-ERD and healthy controls were assessed by RNA sequencing, Seahorse assays, and LC-MS/MS. Metabolites in nasal lining fluid, sputum, and plasma from patients with N-ERD (n = 15) and healthy individuals (n = 10) were quantified by targeted metabolomics analyses. Genome-wide methylomics were deployed to define epigenetic mechanisms of macrophage reprogramming in N-ERD.

Results: This study shows that N-ERD monocytes/macrophages exhibit an overall reduction in DNA methylation, aberrant metabolic profiles, and an increased expression of chemokines, indicative of a persistent proinflammatory activation. Differentially methylated regions in N-ERD macrophages included genes involved in chemokine signaling and acylcarnitine metabolism. Acylcarnitines were increased in macrophages, sputum, nasal lining fluid, and plasma of patients with N-ERD. On inflammatory challenge, N-ERD macrophages produced increased levels of acylcarnitines, proinflammatory arachidonic acid metabolites, cytokines, and chemokines as compared to healthy macrophages.

Conclusions: Together, these findings decipher a proinflammatory metabolic and epigenetic reprogramming of macrophages in N-ERD.
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http://dx.doi.org/10.1016/j.jaci.2020.04.064DOI Listing
February 2021

Shedding Light on the Venom Proteomes of the Allergy-Relevant Hymenoptera (European Paper Wasp) and spp. (Yellow Jacket).

Toxins (Basel) 2020 05 14;12(5). Epub 2020 May 14.

Center of Allergy and Environment (ZAUM), Technical University of Munich, School of Medicine and Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Munich, Germany.

Allergic reactions to stings of Hymenoptera species can have serious or even fatal consequences. If the identification of the culprit insect is possible, venom-specific immunotherapy effectively cures Hymenoptera venom allergies. Although component-resolved diagnostics has strongly evolved in recent years, the differentiation between allergies to closely related species such as and spp. is still challenging. In order to generate the basis for new diagnostic and therapeutic strategies, this study aims at resolving the venom proteomes (venomes) of these species. The venoms of and spp. (, ) were analyzed by liquid chromatography-mass spectrometry. Resulting proteins were characterized regarding their function, localization and biochemical properties. The analyses yielded 157 proteins in spp. and 100 in venom; 48 proteins, including annotated allergens, were found in both samples. In addition to a variety of venom trace molecules, new allergen candidates such as icarapin-like protein and phospholipase A2 were identified. This study elucidates the venomes of closely related allergy-eliciting Hymenoptera species. The data indicates that relying on marker allergens to differentiate between and spp. venom allergy is probably insufficient and that strategies using cross-reactive major allergens could be more promising.
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http://dx.doi.org/10.3390/toxins12050323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291082PMC
May 2020

An anti-inflammatory eicosanoid switch mediates the suppression of type-2 inflammation by helminth larval products.

Sci Transl Med 2020 04;12(540)

Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, 80802 Munich, Germany.

Eicosanoids are key mediators of type-2 inflammation, e.g., in allergy and asthma. Helminth products have been suggested as remedies against inflammatory diseases, but their effects on eicosanoids are unknown. Here, we show that larval products of the helminth (), known to modulate type-2 responses, trigger a broad anti-inflammatory eicosanoid shift by suppressing the 5-lipoxygenase pathway, but inducing the cyclooxygenase (COX) pathway. In human macrophages and granulocytes, the -driven induction of the COX pathway resulted in the production of anti-inflammatory mediators [e.g., prostaglandin E (PGE) and IL-10] and suppressed chemotaxis. also abrogated the chemotaxis of granulocytes from patients suffering from aspirin-exacerbated respiratory disease (AERD), a severe type-2 inflammatory condition. Intranasal treatment with extract attenuated allergic airway inflammation in mice, and intranasal transfer of -conditioned macrophages led to reduced airway eosinophilia in a COX/PGE-dependent fashion. The induction of regulatory mediators in macrophages depended on p38 mitogen-activated protein kinase (MAPK), hypoxia-inducible factor-1α (HIF-1α), and glutamate dehydrogenase (GDH), which we identify as a major immunoregulatory protein in GDH activity was required for anti-inflammatory effects of in macrophages, and local administration of recombinant GDH to the airways abrogated allergic airway inflammation in mice. Thus, a metabolic enzyme present in helminth larvae can suppress type-2 inflammation by inducing an anti-inflammatory eicosanoid switch, which has important implications for the therapy of allergy and asthma.
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http://dx.doi.org/10.1126/scitranslmed.aay0605DOI Listing
April 2020

In-vivo diagnostic test allergens in Europe: A call to action and proposal for recovery plan-An EAACI position paper.

Allergy 2020 09;75(9):2161-2169

Allergy Section, Department of Internal Medicine, Hospital Valld'Hebron, Barcelona, Spain.

Diagnostic allergens are defined as medicinal products in the EU. Marketing authorization by national authorities is necessary; however, diagnostic allergens are not homogeneously regulated in different EU member states. Allergen manufacturers argue with increasing costs forcing them to continuously reduce the diagnostic allergen portfolios offered to allergists. In contrast, EAACI and national European Allergy Societies see the need for the availability of a wide range of high-quality diagnostic allergens for in vivo diagnosis of IgE-mediated allergies not only covering predominant but also less frequent allergen sources. In a recent EAACI task force survey, the current practice of allergy diagnosis was shown to rely on skin tests as first option in almost 2/3 of all types of allergic diseases and in 90% regarding respiratory allergies. With the need to ensure the availability of high-quality diagnostic allergens in the EU, an action plan has been set up by EAACI to analyse the current regulatory demands in EU member states and to define possible solutions stated in this document: (a) simplification of authorization for diagnostic allergens; (b) specific regulation of special types of diagnostic allergens; (c) new models beyond the current model of homologous groups; (d) simplification of pharmacovigilance reporting; (e) reduction of regulation fees for diagnostic allergens; (f) reimbursement for diagnostic allergens. Joining forces of allergists, manufacturers and authorities are of high importance to ensure remaining relevant allergens in the EU markets to facilitate a sustainable and comprehensive service for the diagnosis and treatment of allergic diseases.
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http://dx.doi.org/10.1111/all.14329DOI Listing
September 2020

ARIA guideline 2019: treatment of allergic rhinitis in the German health system.

Allergol Select 2019 30;3(1):22-50. Epub 2019 Dec 30.

Department of Dermatology, University Medical Center Mainz,Mainz, Germany.

Background: The number of patients affected by allergies is increasing worldwide. The resulting allergic diseases are leading to significant costs for health care and social systems. Integrated care pathways are needed to enable comprehensive care within the national health systems. The ARIA (Allergic Rhinitis and its Impact on Asthma) initiative develops internationally applicable guidelines for allergic respiratory diseases.

Methods: ARIA serves to improve the care of patients with allergies and chronic respiratory diseases. In collaboration with other international initiatives, national associations and patient organizations in the field of allergies and respiratory diseases, real-life integrated care pathways have been developed for a digitally assisted, integrative, individualized treatment of allergic rhinitis (AR) with comorbid asthma. In the present work, these integrated care pathways have been adapted to the German situation and health system.

Results: The present ICP (integrated care pathway) guideline covers key areas of the care of AR patients with and without asthma. It includes the views of patients and other healthcare providers.

Discussion: A comprehensive ICP guideline can reflect real-life care better than traditional guideline models.
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http://dx.doi.org/10.5414/ALX02120EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066682PMC
December 2019

Perspectives in allergen immunotherapy: 2019 and beyond.

Allergy 2019 12;74 Suppl 108:3-25

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

The seventh "Future of the Allergists and Specific Immunotherapy (FASIT)" workshop held in 2019 provided a platform for global experts from academia, allergy clinics, regulatory authorities and industry to review current developments in the field of allergen immunotherapy (AIT). Key domains of the meeting included the following: (a) Biomarkers for AIT and allergic asthma; (b) visions for the future of AIT; (c) progress and data for AIT in asthma and the updates of GINA and EAACI Asthma Guidelines (separated for house dust mite SCIT, SLIT tablets and SLIT drops; patient populations) including a review of clinically relevant endpoints in AIT studies in asthma; (d) regulatory prerequisites such as the "Therapy Allergen Ordinance" in Germany; (e) optimization of trial design in AIT clinical research; (f) challenges planning and conducting phase III (field) studies and the future role of Allergen Exposure Chambers (AEC) in AIT product development from the regulatory point of view. We report a summary of panel discussions of all six domains and highlight unmet needs and possible solutions for the future.
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http://dx.doi.org/10.1111/all.14077DOI Listing
December 2019

State-of-the-art in marketed adjuvants and formulations in Allergen Immunotherapy: A position paper of the European Academy of Allergy and Clinical Immunology (EAACI).

Allergy 2020 04;75(4):746-760

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

Since the introduction of allergen immunotherapy (AIT) over 100 years ago, focus has been on standardization of allergen extracts, with reliable molecular composition of allergens receiving the highest attention. While adjuvants play a major role in European AIT, they have been less well studied. In this Position Paper, we summarize current unmet needs of adjuvants in AIT citing current evidence. Four adjuvants are used in products marketed in Europe: aluminium hydroxide (Al(OH) ) is the most frequently used adjuvant, with microcrystalline tyrosine (MCT), monophosphoryl lipid A (MPLA) and calcium phosphate (CaP) used less frequently. Recent studies on humans, and using mouse models, have characterized in part the mechanisms of action of adjuvants on pre-existing immune responses. AIT differs from prophylactic vaccines that provoke immunity to infectious agents, as in allergy the patient is presensitized to the antigen. The intended mode of action of adjuvants is to simultaneously enhance the immunogenicity of the allergen, while precipitating the allergen at the injection site to reduce the risk of anaphylaxis. Contrasting immune effects are seen with different adjuvants. Aluminium hydroxide initially boosts Th2 responses, while the other adjuvants utilized in AIT redirect the Th2 immune response towards Th1 immunity. After varying lengths of time, each of the adjuvants supports tolerance. Further studies of the mechanisms of action of adjuvants may advise shorter treatment periods than the current three-to-five-year regimens, enhancing patient adherence. Improved lead compounds from the adjuvant pipeline are under development and are explored for their capacity to fill this unmet need.
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http://dx.doi.org/10.1111/all.14134DOI Listing
April 2020

In-depth phenotyping reveals common and novel disease symptoms in a hemizygous knock-in mouse model (Mut-ko/ki) of mut-type methylmalonic aciduria.

Biochim Biophys Acta Mol Basis Dis 2020 03 23;1866(3):165622. Epub 2019 Nov 23.

Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland; radiz - Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. Electronic address:

Isolated methylmalonic aciduria (MMAuria) is primarily caused by deficiency of methylmalonyl-CoA mutase (MMUT or MUT). Biochemically, MUT deficiency results in the accumulation of methylmalonic acid (MMA), propionyl-carnitine (C3) and other metabolites. Patients often exhibit lethargy, failure to thrive and metabolic decompensation leading to coma or even death, with kidney and neurological impairment frequently identified in the long-term. Here, we report a hemizygous mouse model which combines a knock-in (ki) missense allele of Mut with a knock-out (ko) allele (Mut-ko/ki mice) that was fed a 51%-protein diet from day 12 of life, constituting a bespoke model of MMAuria. Under this diet, mutant mice developed a pronounced metabolic phenotype characterized by drastically increased blood levels of MMA and C3 compared to their littermate controls (Mut-ki/wt). With this bespoke mouse model, we performed a standardized phenotypic screen to assess the whole-body impairments associated with this strong metabolic condition. We found that Mut-ko/ki mice show common clinical manifestations of MMAuria, including pronounced failure to thrive, indications of mild neurological and kidney dysfunction, and degenerative morphological changes in the liver, along with less well described symptoms such as cardiovascular and hematological abnormalities. The analyses also reveal so far unknown disease characteristics, including low bone mineral density, anxiety-related behaviour and ovarian atrophy. This first phenotypic screening of a MMAuria mouse model confirms its relevance to human disease, reveals new alterations associated with MUT deficiency, and suggests a series of quantifiable readouts that can be used to evaluate potential treatment strategies.
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http://dx.doi.org/10.1016/j.bbadis.2019.165622DOI Listing
March 2020

Building an automatic pollen monitoring network (ePIN): Selection of optimal sites by clustering pollen stations.

Sci Total Environ 2019 Oct 11;688:1263-1274. Epub 2019 Jun 11.

Center of Allergy & Environment (ZAUM), Member of the German Center for Lung Research (DZL), Technische Universität München/Helmholtz Center, Munich, Germany. Electronic address:

Airborne pollen is a recognized biological indicator and its monitoring has multiple uses such as providing a tool for allergy diagnosis and prevention. There is a knowledge gap related to the distribution of pollen traps needed to achieve representative biomonitoring in a region. The aim of this manuscript is to suggest a method for setting up a pollen network (monitoring method, monitoring conditions, number and location of samplers etc.). As a case study, we describe the distribution of pollen across Bavaria and the design of the Bavarian pollen monitoring network (ePIN), the first operational automatic pollen network worldwide. We established and ran a dense pollen monitoring network of 27 manual Hirst-type pollen traps across Bavaria, Germany, during 2015. Hierarchical cluster analysis of the data was then performed to select the locations for the sites of the final pollen monitoring network. According to our method, Bavaria can be clustered into three large pollen regions with eight zones. Within each zone, pollen diversity and distribution among different locations does not vary significantly. Based on the pollen zones, we opted to place one automatic monitoring station per zone resulting in the ePIN network, serving 13 million inhabitants. The described method defines stations representative for a homogeneous aeropalynologically region, which reduces redundancy within the network and subsequent costs (in the study case from 27 to 8 locations). Following this method, resources in pollen monitoring networks can be optimized and allergic citizens can then be informed in a timely and effective way, even in larger geographical areas.
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http://dx.doi.org/10.1016/j.scitotenv.2019.06.131DOI Listing
October 2019

RelB Deficiency in Dendritic Cells Protects from Autoimmune Inflammation Due to Spontaneous Accumulation of Tissue T Regulatory Cells.

J Immunol 2019 11 2;203(10):2602-2613. Epub 2019 Oct 2.

Zentrum Allergie und Umwelt, Technische Universität und Helmholtz Zentrum München, 85764 Neuherberg, Germany;

Foxp3 regulatory T cells are well-known immune suppressor cells in various settings. In this study, we provide evidence that knockout of the gene in dendritic cells (DCs) of C57BL/6 mice results in a spontaneous and systemic accumulation of Foxp3 T regulatory T cells (Tregs) partially at the expense of microbiota-reactive Tregs. Deletion of does not fully recapitulate this phenotype, indicating that alternative NF-κB activation via the RelB/p52 complex is not solely responsible for Treg accumulation. Deletion of RelB in DCs further results in an impaired oral tolerance induction and a marked type 2 immune bias among accumulated Foxp3 Tregs reminiscent of a tissue Treg signature. Tissue Tregs were fully functional, expanded independently of IL-33, and led to an almost complete Treg-dependent protection from experimental autoimmune encephalomyelitis. Thus, we provide clear evidence that RelB-dependent pathways regulate the capacity of DCs to quantitatively and qualitatively impact on Treg biology and constitute an attractive target for treatment of autoimmune diseases but may come at risk for reduced immune tolerance in the intestinal tract.
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http://dx.doi.org/10.4049/jimmunol.1801530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826119PMC
November 2019

Near-ground effect of height on pollen exposure.

Environ Res 2019 07 29;174:160-169. Epub 2019 Apr 29.

Chair and Institute of Environmental Medicine, UNIKA-T, Technical University of Munich and Helmholtz Zentrum München, Research Center for Environmental Health, Augsburg, Germany; CK CARE Crhistine Kühne Center for Allergy Research and Education, Switzerland.

The effect of height on pollen concentration is not well documented and little is known about the near-ground vertical profile of airborne pollen. This is important as most measuring stations are on roofs, but patient exposure is at ground level. Our study used a big data approach to estimate the near-ground vertical profile of pollen concentrations based on a global study of paired stations located at different heights. We analyzed paired sampling stations located at different heights between 1.5 and 50 m above ground level (AGL). This provided pollen data from 59 Hirst-type volumetric traps from 25 different areas, mainly in Europe, but also covering North America and Australia, resulting in about 2,000,000 daily pollen concentrations analyzed. The daily ratio of the amounts of pollen from different heights per location was used, and the values of the lower station were divided by the higher station. The lower station of paired traps recorded more pollen than the higher trap. However, while the effect of height on pollen concentration was clear, it was also limited (average ratio 1.3, range 0.7-2.2). The standard deviation of the pollen ratio was highly variable when the lower station was located close to the ground level (below 10 m AGL). We show that pollen concentrations measured at >10 m are representative for background near-ground levels.
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http://dx.doi.org/10.1016/j.envres.2019.04.027DOI Listing
July 2019

Prioritizing research challenges and funding for allergy and asthma and the need for translational research-The European Strategic Forum on Allergic Diseases.

Allergy 2019 11 2;74(11):2064-2076. Epub 2019 Jun 2.

Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University of Madrid, Madrid, Spain.

The European Academy of Allergy and Clinical Immunology (EAACI) organized the first European Strategic Forum on Allergic Diseases and Asthma. The main aim was to bring together all relevant stakeholders and decision-makers in the field of allergy, asthma and clinical Immunology around an open debate on contemporary challenges and potential solutions for the next decade. The Strategic Forum was an upscaling of the EAACI White Paper aiming to integrate the Academy's output with the perspective offered by EAACI's partners. This collaboration is fundamental for adapting and integrating allergy and asthma care into the context of real-world problems. The Strategic Forum on Allergic Diseases brought together all partners who have the drive and the influence to make positive change: national and international societies, patients' organizations, regulatory bodies and industry representatives. An open debate with a special focus on drug development and biomedical engineering, big data and information technology and allergic diseases and asthma in the context of environmental health concluded that connecting science with the transformation of care and a joint agreement between all partners on priorities and needs are essential to ensure a better management of allergic diseases and asthma in the advent of precision medicine together with global access to innovative and affordable diagnostics and therapeutics.
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http://dx.doi.org/10.1111/all.13856DOI Listing
November 2019

Supporting allergen-specific immunotherapy by inhibition of Janus kinases.

Allergy 2019 09 20;74(9):1814-1816. Epub 2019 May 20.

Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, Member of the German Center of Lung Research (DZL), Munich, Germany.

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http://dx.doi.org/10.1111/all.13808DOI Listing
September 2019

House dust mite drives proinflammatory eicosanoid reprogramming and macrophage effector functions.

Allergy 2019 06 8;74(6):1090-1101. Epub 2019 Jan 8.

Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, Munich, Germany.

Background: Eicosanoid lipid mediators play key roles in type 2 immune responses, for example in allergy and asthma. Macrophages represent major producers of eicosanoids and they are key effector cells of type 2 immunity. We aimed to comprehensively track eicosanoid profiles during type 2 immune responses to house dust mite (HDM) or helminth infection and to identify mechanisms and functions of eicosanoid reprogramming in human macrophages.

Methods: We established an LC-MS/MS workflow for the quantification of 52 oxylipins to analyze mediator profiles in human monocyte-derived macrophages (MDM) stimulated with HDM and during allergic airway inflammation (AAI) or nematode infection in mice. Expression of eicosanoid enzymes was studied by qPCR and western blot and cytokine production was assessed by multiplex assays.

Results: Short (24 h) exposure of alveolar-like MDM (aMDM) to HDM suppressed 5-LOX expression and product formation, while triggering prostanoid (thromboxane and prostaglandin D and E ) production. This eicosanoid reprogramming was p38-dependent, but dectin-2-independent. HDM also induced proinflammatory cytokine production, but reduced granulocyte recruitment by aMDM. In contrast, high levels of cysteinyl leukotrienes (cysLTs) and 12-/15-LOX metabolites were produced in the airways during AAI or nematode infection in mice.

Conclusion: Our findings show that a short exposure to allergens as well as ongoing type 2 immune responses are characterized by a fundamental reprogramming of the lipid mediator metabolism with macrophages representing particularly plastic responder cells. Targeting mediator reprogramming in airway macrophages may represent a viable approach to prevent pathogenic lipid mediator profiles in allergy or asthma.
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http://dx.doi.org/10.1111/all.13700DOI Listing
June 2019