Mirela Curin

Medical University of Vienna

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Rudolf Valenta

Medical University of Vienna

АВ

А. В. Караулов

Sechenov University

Marianne van Hage

Karolinska Institutet

Margarete Focke‐Tejkl

Medical University of Vienna

Susanne Vrtala

Medical University of Vienna

Hans Grönlund

Karolinska Institutet

Musa Khaitov

Federal Medical-Biological Agency

Ines Swoboda

FH Campus Wien

Ksenja Riabova

Sechenov University

Raffaela Campana

Medical University of Vienna

Cooperative Institutions

Medical University of Vienna

Charité - Universitätsmedizin Berlin

Inserm

University of Vienna

Vienna General Hospital

ENT and Allergy

Karolinska Institutet

Instituto de Salud Carlos III

Karolinska University Hospital

Humboldt-Universität zu Berlin

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Mechanisms of the Development of Allergy (MeDALL): Introducing novel concepts in allergy phenotypes

Journal of Allergy and Clinical Immunology (2017)

Josep M. Antó Jean Bousquet Mübeccel Akdiş Charles Auffray Thomas Keil

10.1016/j.jaci.2016.12.940

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Citations (193)

Paving the way of systems biology and precision medicine in allergic diseases: the Me DALL success story

Allergy (2016)

Jean Bousquet Josep M. Antó Mübeccel Akdiş Charles Auffray Thomas Keil

MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010–2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.

Egg allergy

10.1111/all.12880

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Citations (82)

Molecular Aspects of Allergens and Allergy

Advances in immunology (2018)

Rudolf Valenta А. В. Караулов Verena Niederberger Pia Gattinger Marianne van Hage

10.1016/bs.ai.2018.03.002

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Citations (114)

Preventive Allergen-Specific Vaccination Against Allergy: Mission Possible?

Frontiers in Immunology (2020)

Inna Tulaeva Bernhard Kratzer Raffaela Campana Mirela Curin Marianne van Hage

Vaccines for infectious diseases have improved the life of the human species in a tremendous manner. The principle of vaccination is to establish de novo adaptive immune response consisting of antibody and T cell responses against pathogens which should defend the vaccinated person against future challenge with the culprit pathogen. The situation is completely different for immunoglobulin E (IgE)-associated allergy, an immunologically-mediated hypersensitivity which is already characterized by increased IgE antibody levels and T cell responses against per se innocuous antigens (i.e., allergens). Thus, allergic patients suffer from a deviated hyper-immunity against allergens leading to inflammation upon allergen contact. Paradoxically, vaccination with allergens, termed allergen-specific immunotherapy (AIT), induces a counter immune response based on the production of high levels of allergen-specific IgG antibodies and alterations of the adaptive cellular response, which reduce allergen-induced symptoms of allergic inflammation. AIT was even shown to prevent the progression of mild to severe forms of allergy. Consequently, AIT can be considered as a form of therapeutic vaccination. In this article we describe a strategy and possible road map for the use of an AIT approach for prophylactic vaccination against allergy which is based on new molecular allergy vaccines. This road map includes the use of AIT for secondary preventive vaccination to stop the progression of clinically silent allergic sensitization towards symptomatic allergy and ultimately the prevention of allergic sensitization by maternal vaccination and/or early primary preventive vaccination of children. Prophylactic allergy vaccination with molecular allergy vaccines may allow halting the allergy epidemics affecting almost 30% of the population as it has been achieved for vaccination against infectious diseases.

Allergic Inflammation

10.3389/fimmu.2020.01368

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Allergen Extracts for In Vivo Diagnosis and Treatment of Allergy: Is There a Future?

The Journal of Allergy and Clinical Immunology In Practice (2018)

Rudolf Valenta А. В. Караулов Verena Niederberger Yury V. Zhernov O G Elisyutina

Today, in vivo allergy diagnosis and allergen-specific immunotherapy (AIT) are still based on allergen extracts obtained from natural allergen sources. Several studies analyzing the composition of natural allergen extracts have shown severe problems regarding their quality such as the presence of undefined nonallergenic materials, contaminants as well as high variabilities regarding contents and biological activity of individual allergens. Despite the increasing availability of sophisticated analytical technologies, these problems cannot be overcome because they are inherent to allergen sources and methods of extract production. For in vitro allergy diagnosis problems related to natural allergen extracts have been largely overcome by the implementation of recombinant allergen molecules that are defined regarding purity and biological activity. However, no such advances have been made for allergen preparations to be used in vivo for diagnosis and therapy. No clinical studies have been performed for allergen extracts available for in vivo allergy diagnosis that document safety, sensitivity, and specificity of the products. Only for very few therapeutic allergen extracts state-of-the-art clinical studies have been performed that provide evidence for safety and efficacy. In this article, we discuss problems related to the inconsistent quality of products based on natural allergen extracts and share our observations that most of the products available for in vivo diagnosis and AIT do not meet the international standards for medicinal products. We argue that a replacement of natural allergen extracts by defined recombinantly produced allergen molecules and/or mixtures thereof may be the only way to guarantee the supply of clinicians with state-of-the-art medicinal products for in vivo diagnosis and treatment of allergic patients in the future.

Allergen Immunotherapy

10.1016/j.jaip.2018.08.032

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Citations (104)

Allergy (2018)

Mirela Curin Tetiana Garmatiuk Yvonne Resch Kuan‐Wei Chen Gerhard Höfer

Due to high IgE recognition frequency and high allergenic activity, Der p 5 and Der p 21 are clinically important house dust mite (HDM) allergens. The objective of this study was to characterize the immunodominant IgE epitopes of Der p 5 and Der p 21 responsible for their high allergenic activity.A panel of 12 overlapping peptides spanning the Der p 5 and Der p 21 sequence were synthesized to search for sequential IgE epitopes by direct testing for allergic patients' IgE reactivity. Peptide-specific antibodies raised in rabbits were used in inhibition studies for localizing conformational IgE epitopes which were visualized on the surfaces of the allergen structures by molecular modelling. IgE cross-reactivity between the allergens was investigated by IgE inhibition studies.Immunodominant IgE epitopes defined by allergic patients' IgE on Der p 5 and Der p 21 were primarily of the conformational, discontinuous type including N- and C-terminal portions of the protein. They could be located on each allergen on one area with similar localization, but despite similar structure of the allergens, no relevant IgE cross-reactivity could be detected.Our study shows that Der p 5 and Der p 21 contain a major conformational IgE epitope-containing area located on similar portions of their structure, but they lack relevant IgE cross-reactivity. These data are important for the development of modern allergy vaccines based on defined molecules for allergen-specific immunotherapy of HDM allergy.

Cross-reactivity

Pyroglyphidae

10.1111/all.13398

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Citations (28)

Clustering of conformational IgE epitopes on the major dog allergen Can f 1

Scientific Reports (2017)

Mirela Curin Milena Weber Gerhard Höfer Danijela Apostolović Walter Keller

Immunoglobulin E (IgE)-associated allergy affects more than 25% of the population. Can f 1 is the major dog allergen associated with respiratory symptoms but the epitopes recognized by allergic patients IgE on Can f 1 are unknown. To characterize IgE epitopes of Can f 1 recognized by dog allergic patients, six overlapping peptides spanning the Can f 1 sequence were synthesized. In direct IgE epitope mapping experiments peptides were analyzed for IgE reactivity by dot blot and Enzyme-linked immunosorbent assay (ELISA) with sera from dog allergic patients. For indirect epitope-mapping, rabbits were immunized with the peptides to generate specific IgG antibodies which were used to inhibit allergic patients' IgE binding to Can f 1. IgE binding sites were visualized on a model of the Can f 1 three-dimensional structure. We found that Can f 1 does not contain any relevant sequential IgE epitopes. However, IgE inhibition experiments with anti-peptide specific IgGs showed that Can f 1 N- and C-terminal portion assembled a major conformational binding site. In conclusion, our study is the first to identify the major IgE epitope-containing area of the dog allergen Can f 1. This finding is important for the development of allergen-specific treatment strategies.

Epitope mapping

10.1038/s41598-017-11672-5

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Citations (14)

Hypoallergenic derivatives of Fel d 1 obtained by rational reassembly for allergy vaccination and tolerance induction

Clinical & Experimental Allergy (2014)

Mirela Curin Milena Weber Theresa Thalhamer Ines Swoboda Margarete Focke‐Tejkl

The major cat allergen Fel d 1 represents one of the most important respiratory allergens. Aim of this study was to engineer recombinant Fel d 1 derivatives with reduced IgE reactivity and preserved T cell epitopes for vaccination and tolerance induction.Seven recombinant mosaic proteins were generated by reassembly of non-IgE-reactive peptides of Fel d 1 which contained the sequence elements for induction of allergen-specific blocking IgG antibodies and T cell epitopes. Mosaic proteins were expressed in Escherichia coli using codon-optimized synthetic genes and compared with Fel d 1 regarding structural fold by circular dichroism, IgE-binding capacity, activation of allergic patients' basophils and ability to induce allergen-specific blocking IgG antibodies upon immunization.Although each of the mosaic proteins had lost the alpha-helical fold typical for Fel d 1, a strong reduction in IgE reactivity as well as allergenic activity in basophil activation assays was only obtained for three constructs, two reassembled fragments (Fel d 1 MB, Fel d 1 MC) and a fusion of the latter two (Fel d 1 MF) in which the cysteines of Fel d 1 MC were replaced by serines. Immunization of rabbits with Fel d 1 MB, MC and MF induced high levels of IgG antibodies that inhibited IgE reactivity of cat-allergic patients to Fel d 1 in a comparable manner as IgG induced with the wild-type allergen.We report the development of hypoallergenic reassembled Fel d 1 proteins suitable for vaccination and tolerance induction in cat-allergic patients.

Hypoallergenic

10.1111/cea.12294

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Citations (35)

Profound differences in IgE and IgG recognition of micro‐arrayed allergens in hyper‐IgE syndromes

Allergy (2021)

Victoria Garib Meriem Ben‐Ali Michael Kundi Mirela Curin Roukaya Yaakoubi

Abstract Background The specificities of IgE and IgG for allergen molecules in patients with inborn errors of immunity (IEI) have not been investigated in detail. Objective To study IgE and IgG antibody specificities in patients with defined hyper‐IgE syndromes (HIES) using a comprehensive panel of allergen molecules. Methods We used chips containing micro‐arrayed allergen molecules to analyze allergen‐specific IgE and IgG levels in sera from two groups of HIES patients: Autosomal recessive mutations in phosphoglucomutase‐3 (PGM3); Autosomal dominant negative mutations of STAT3 (STAT3); and age‐matched subjects with allergic sensitizations. Assays with rat basophil leukemia cells transfected with human FcεRI were performed to study the biological relevance of IgE sensitizations. Results Median total IgE levels were significantly lower in the sensitized control group (212.9 kU/L) as compared to PGM3 (5042 kU/L) and STAT3 patients (2561 kU/L). However, PGM3 patients had significantly higher allergen‐specific IgE levels and were sensitized to a larger number of allergen molecules as compared to STAT3 patients. Biological relevance of IgE sensitization was confirmed for PGM3 patients by basophil activation testing. PGM3 patients showed significantly lower cumulative allergen‐specific IgG responses in particular to milk and egg allergens as compared to STAT3 patients and sensitized controls whereas total IgG levels were comparable to STAT3 patients and significantly higher than in controls. Conclusion The analysis with multiple micro‐arrayed allergen molecules reveals profound differences of allergen‐specific IgE and IgG recognition in PGM3 and STAT3 patients which may be useful for classification of IEI and clinical characterization of patients.

10.1111/all.15143

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Citations (6)

Skin Prick Test Extracts for Dog Allergy Diagnosis Show Considerable Variations Regarding the Content of Major and Minor Dog Allergens

International Archives of Allergy and Immunology (2010)

Mirela Curin Renate Reininger Ines Swoboda M. Focke Rudolf Valenta

Background: Commercial skin prick test (SPT) extracts used for the diagnosis of dog allergy are prepared by extracting allergens from natural sources, e.g. dog hair and dander. Due to different starting material and extraction methods used, it is likely that extracts differ regarding their allergen contents. Methods: The total protein content and composition of dog SPT extracts from 5 European manufacturers were compared by silver-stained SDS-PAGE. Specific antibody probes were generated to detect major and minor allergens in each extract by immunoblotting. Additionally, sera of patients suffering from dog allergy were used to detect dog allergens in SPT extracts. Results: SPT extracts showed a 20-fold variation regarding the total protein content. The contents of the major dog allergen Can f 1 and of Can f 2 varied considerably between the extracts. In one of the extracts, neither Can f 1 nor Can f 2 could be detected by immunoblotting. The contents of the minor dog allergen Can f 3, albumin, also showed great variability. In one of the dog SPT extracts, the presence of human serum albumin (HSA) was detected with HSA-specific antibodies. Conclusion: The observed variability of commercial dog SPT extracts regarding their allergen contents likely has a negative influence on the accuracy of diagnosis of dog allergy.

Dander

Radioallergosorbent test

10.1159/000321113

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Citations (102)