Publications by authors named "Rudolf Valenta"

370 Publications

Identification of Epitopes on Rhinovirus 89 Capsid Proteins Capable of Inducing Neutralizing Antibodies.

Int J Mol Sci 2022 May 4;23(9). Epub 2022 May 4.

Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Patho-Physiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria.

Rhinoviruses (RVs) are major causes of the common cold, but they can also trigger exacerbations of asthma. More than 160 different RV strains exist and can be classified into three genetic species (RV-A, RV-B and RV-C) which bind to different receptors on human cells including intracellular adhesion molecule 1 (ICAM-1), the low-density lipoprotein receptor (LDLR) or the cadherin-related family member 3 (CDHR3). Epitopes located in the RV capsid have mainly been determined for RV2, a minor-group RV-A strain binding to LDLR, and for RV14, a major-group RV-B strain binding to ICAM-1. In order to study epitopes involved in the neutralization of RV89, an ICAM-1-binding RV-A strain which is highly different from RV2 and RV14 in terms of receptor specificity and sequence, respectively, we analyzed the specificity and epitopes of a highly neutralizing antiserum using recombinantly produced RV89 capsid proteins (VP1, VP2, VP3 and VP4), recombinant fragments and synthetic overlapping peptides thereof. We found that the antiserum which neutralized in vitro RV89 infection up to a dilution of 1:24,000 reacted with the capsid proteins VP1 and VP2 but not with VP3 and VP4. The neutralizing antibodies recognized recombinant fragments comprising approximately 100 amino acids of the N- and C-terminus of VP1 and the middle part of VP2, in particular, three peptides which, according to molecular modeling based on the three-dimensional structure of RV16, were surface-exposed on the viral capsid. Two recombinant fusion proteins containing the identified peptides fused to hepatitis B (HBV)-derived preS as a carrier protein induced upon immunization of rabbits antibodies capable of neutralizing in vitro RV89 infections. Interestingly, the virus-neutralizing epitopes determined for RV89 corresponded to those determined for minor-group RV2 binding to LDL and major-group RV14 belonging to the RV-B species, which are highly different from RV89. Our results indicate that highly different RV strains, even when reacting with different receptors, seem to engage similar parts of their capsid in the infection process. These results may be important for the design of active and passive immunization strategies for RV.
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http://dx.doi.org/10.3390/ijms23095113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9100655PMC
May 2022

Molecular reactivity profiling upon immunotherapy with a 300 IR sublingual house dust mite tablet reveals marked humoral changes towards major allergens.

Allergy 2022 Apr 26. Epub 2022 Apr 26.

Innovation & Science Department, Stallergenes SAS, Antony, France.

Background: Molecular antibody reactivity profiles have not yet been studied in depth in patients treated by sublingual house dust mite (HDM) tablet immunotherapy. Humoral immune responses to a large panel of HDM mite allergens were studied using allergen microarray technology in a subset of clinically defined high and low responder patients from a double-blind placebo-controlled allergen-specific immunotherapy (AIT) trial using sublingual 300 IR HDM tablets.

Methods: Serum levels of IgE, IgG and IgG to 13 Dermatophagoides pteronyssinus molecules were measured at baseline and after 1-year AIT, using allergen microarrays in 100 subjects exhibiting high or low clinical benefit.

Results: Der p 1, Der p 2 and Der p 23 were the most frequently recognized allergens in the study population. Patients with HDM-related asthma had significantly higher allergen-specific IgE levels to Der p 1 and Der p 23. No significant difference in the distribution of allergen sensitization pattern was observed between high and low responders. An increase in serum allergen-specific IgG and IgG occurred upon AIT, in particular to allergens Der p 1, Der p 2 and Der p 23 (p < 0.0001).

Conclusions: We confirm for our study population that Der p 1- and Der p 23-specific IgE levels are associated with asthma. IgE reactivity profiles were not predicitive of sublingual AIT outcomes, with 300 IR tablets as efficacious in pauci- and multi-sensitized subjects. Our study is the first to demonstrate the induction of IgG and IgG  specific for the HDM allergens Der p 1, Der p 2 and Der p 23 by sublingual AIT.
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http://dx.doi.org/10.1111/all.15327DOI Listing
April 2022

Review: The Nose as a Route for Therapy. Part 2 Immunotherapy.

Front Allergy 2021 1;2:668781. Epub 2021 Jul 1.

Royal National Ear Nose and Throat Hospital, University College London Hospitals NHS Foundation Trust, London, United Kingdom.

The nose provides a route of access to the body for inhalants and fluids. Unsurprisingly it has a strong immune defense system, with involvement of innate (e.g., epithelial barrier, muco- ciliary clearance, nasal secretions with interferons, lysozyme, nitric oxide) and acquired (e.g., secreted immunoglobulins, lymphocytes) arms. The lattice network of dendritic cells surrounding the nostrils allows rapid uptake and sampling of molecules able to negotiate the epithelial barrier. Despite this many respiratory infections, including SARS-CoV2, are initiated through nasal mucosal contact, and the nasal mucosa is a significant "reservoir" for microbes including . This review includes consideration of the augmentation of immune defense by the nasal application of interferons, then the reduction of unnecessary inflammation and infection by alteration of the nasal microbiome. The nasal mucosa and associated lymphoid tissue (nasopharynx-associated lymphoid tissue, NALT) provides an important site for vaccine delivery, with cold-adapted live influenza strains (LAIV), which replicate intranasally, resulting in an immune response without significant clinical symptoms, being the most successful thus far. Finally, the clever intranasal application of antibodies bispecific for allergens and Intercellular Adhesion Molecule 1 (ICAM-1) as a topical treatment for allergic and RV-induced rhinitis is explained.
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http://dx.doi.org/10.3389/falgy.2021.668781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8974912PMC
July 2021

Vaccine based on folded RBD-PreS fusion protein with potential to induce sterilizing immunity to SARS-CoV-2 variants.

Allergy 2022 Mar 31. Epub 2022 Mar 31.

Department of Pathophysiology and Allergy Research, Division of Immunopathology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global COVID-19 pandemic. One possibility to control the pandemic is to induce sterilizing immunity through the induction and maintenance of neutralizing antibodies preventing SARS-CoV-2 from entering human cells to replicate in.

Methods: We report the construction and in vitro and in vivo characterization of a SARS-CoV-2 subunit vaccine (PreS-RBD) based on a structurally folded recombinant fusion protein consisting of two SARS-CoV-2 Spike protein receptor-binding domains (RBD) fused to the N- and C-terminus of hepatitis B virus (HBV) surface antigen PreS to enable the two unrelated proteins serving as immunologic carriers for each other.

Results: PreS-RBD, but not RBD alone, induced a robust and uniform RBD-specific IgG response in rabbits. Currently available genetic SARS-CoV-2 vaccines induce mainly transient IgG responses in vaccinated subjects whereas the PreS-RBD vaccine induced RBD-specific IgG antibodies consisting of an early IgG and sustained IgG antibody response in a SARS-CoV-2 naive subject. PreS-RBD-specific IgG antibodies were detected in serum and mucosal secretions, reacted with SARS-CoV-2 variants, including the omicron variant of concern and the HBV receptor-binding sites on PreS of currently known HBV genotypes. PreS-RBD-specific antibodies of the immunized subject more potently inhibited the interaction of RBD with its human receptor ACE2 and their virus-neutralizing titers (VNTs) were higher than median VNTs in a random sample of healthy subjects fully immunized with registered SARS-CoV-2 vaccines or in COVID-19 convalescent subjects.

Conclusion: The PreS-RBD vaccine has the potential to serve as a combination vaccine for inducing sterilizing immunity against SARS-CoV-2 and HBV by stopping viral replication through the inhibition of cellular virus entry.
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http://dx.doi.org/10.1111/all.15305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9111473PMC
March 2022

Lack of Induction of RBD-Specific Neutralizing Antibodies despite Repeated Heterologous SARS-CoV-2 Vaccination Leading to Seroconversion and Establishment of T Cell-Specific Memory in a Patient in Remission of Multiple Myeloma.

Vaccines (Basel) 2022 Feb 27;10(3). Epub 2022 Feb 27.

Division of Cellular Immunology and Immunohematology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria.

Background: Prophylactic vaccination against infectious diseases may induce a state of long-term protection in the otherwise healthy host. However, the situation is less predictable in immunocompromised patients and may require adjustment of vaccination schedules and/or basic therapy.

Methods: A patient in full remission of multiple myeloma since the last three years and on long-term maintenance therapy with pomalidomide, a drug inhibiting angiogenesis and myeloma cell growth, was vaccinated twice with Comirnaty followed by two vaccinations with Vaxzevria. Seroconversion and SARS-CoV-2-specific cellular responses were monitored.

Results: No signs of seroconversion or T cellular memory were observed after the first "full immunization" with Comirnaty. Consequently, long-term-maintenance therapy with Pomalidomide was stopped and two additional shots of Vaxzevria were administered after which the patient seroconverted with Spike(S)-protein specific antibody levels reaching 49 BAU/mL, mild S-peptide pool-specific T cell proliferation, effector cytokine production (IL-2, IL-13), and T cellular activation with increased numbers of CD3CD4CD25 T cells as compared to vaccinated and non-vaccinated control subjects. However, despite suspension of immunosuppression and administration of in total four consecutive heterologous SARS-CoV-2 vaccine shots, the patient did not develop neutralizing RBD-specific antibodies.

Conclusions: Despite immunomonitoring-based adjustment of vaccination and/or therapy schedules vaccination success, with clear correlates of protection, the development of RBD-specific antibodies could not be achieved in the immunocompromised patient with current SARS-CoV-2 vaccines. Thus, our report emphasizes the need for improved active and passive immunization strategies for SARS-CoV-2 infections.
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http://dx.doi.org/10.3390/vaccines10030374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8949333PMC
February 2022

Changes in Non-Deamidated versus Deamidated Epitope Targeting and Disease Prediction during the Antibody Response to Gliadin and Transglutaminase of Infants at Risk for Celiac Disease.

Int J Mol Sci 2022 Feb 24;23(5). Epub 2022 Feb 24.

Department of Pediatrics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.

Celiac disease (CeD) is a conditional autoimmune disorder with T cell-mediated immune response to gluten coupled with antibody production to gliadin and the self-protein tissue transglutaminase (TG2). TG2 contributes to the CeD pathomechanism by deamidating gliadin, thereby generating more immunogenic peptides. Anti-gliadin antibodies may appear before the autoantibody production. The scope of this study was to dissect these early antibody responses by investigating serum samples collected during the PreventCD prospective double-blind study, where infants with high CeD risk were randomized to 200 mg daily gluten intake or placebo from 4 to 6 months of age, followed by frequent blood testing on regular gluten consumption in both groups. After primary gluten intake, children with or without later CeD produced IgA and IgG antibodies which preferentially recognized non-deamidated gliadin peptides. At CeD development with anti-TG2 seroconversion, there was a significant increase in the antibody reaction toward deamidated gliadin peptides (DGP), with maturation in the binding strength for the PEQPFP gamma-gliadin core peptide. The earliest produced autoantibodies targeted TG2's celiac epitope 2. Our results reveal a qualitative change in the gliadin-directed humoral immune response at the time when anti-TG2 antibodies appear, but anti-DGP antibodies in the absence of anti-TG2 antibodies are not disease-predictive.
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http://dx.doi.org/10.3390/ijms23052498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8909931PMC
February 2022

Characterization of the antibody response to SARS-CoV-2 in a mildly affected pediatric population.

Pediatr Allergy Immunol 2022 02;33(2):e13737

Division of Pediatric Pulmonology, Allergy and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Centre of Pediatrics, Medical University of Vienna, Vienna, Austria.

Background: While children usually experience a mild course of COVID-19, and a severe disease is more common in adults, the features, specificities, and functionality of the SARS-CoV-2-specific antibody response in the pediatric population are of interest.

Methods: We performed a detailed analysis of IgG antibodies specific for SARS-CoV-2-derived antigens S and RBD by ELISA in 26 SARS-CoV-2 seropositive schoolchildren with mild or asymptomatic disease course, and in an equally sized, age- and gender-matched control group. Furthermore, a detailed mapping of IgG reactivity to a panel of microarrayed SARS-CoV-2 proteins and S-derived peptides was performed by microarray technology. The capacity of the antibody response to block RBD-ACE2 binding and virus neutralization were assessed. Results were compared with those obtained in an adult COVID-19 convalescent population.

Results: After mild COVID-19, anti-S and RBD-specific IgG antibodies were developed by 100% and 84.6% of pediatric subjects, respectively. No difference was observed in regards to symptoms and gender. Mounted antibodies recognized conformational epitopes of the spike protein and were capable to neutralize the virus up to a titer of ≥80 and to inhibit the ACE2-RBD interaction by up to 65%. SARS-CoV-2-specific IgG responses in children were comparable to mildly affected adult patients.

Conclusion: SARS-CoV-2 asymptomatic and mildly affected pediatric patients develop a SARS-CoV-2-specific antibody response, which is comparable regarding antigen, epitope recognition, and the ability to inhibit the RBD-ACE2 interaction to that observed in adult patients after mild COVID-19.
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http://dx.doi.org/10.1111/pai.13737DOI Listing
February 2022

Omicron: A SARS-CoV-2 variant of real concern.

Allergy 2022 May 28;77(5):1616-1620. Epub 2022 Feb 28.

Department of Pathophysiology and Allergy Research, Division of Immunopathology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1111/all.15264DOI Listing
May 2022

Response to González-Pérez et al.

J Invest Dermatol 2022 03;142(3 Pt A):723-726

Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2021.09.006DOI Listing
March 2022

Tracing Human IgE B Cell Antigen Receptor-Bearing Cells With a Monoclonal Anti-Human IgE Antibody That Specifically Recognizes Non-Receptor-Bound IgE.

Front Immunol 2021 20;12:803236. Epub 2021 Dec 20.

National Research Centre (NRC) Institute of Immunology, Federal Medical-Biological Agency (FMBA) of Russia, Moscow, Russia.

Up to 30% of the population suffers from immunoglobulin E (IgE)-mediated allergies. Despite current stepwise gating approaches, the unambiguous identification of human IgE-producing cells by flow cytometry and immunohistology remains challenging. This is mainly due to the scarcity of these cells and the fact that IgE is not only expressed in a membrane-bound form on the surface of IgE-producing cells in form of the B cell antigen receptor (BCR), but is more frequently found on various cell types bound to the low and high affinity receptors, CD23 and FcϵRI, respectively. Here we sought to develop a sequential gating strategy for unambiguous detection of cells bearing the IgE BCR on their surface. To that aim we first tested the monoclonal anti-IgE antibody omalizumab for its ability to discriminate between IgE BCR and receptor-bound IgE using cells producing IgE or bearing IgE bound to CD23 as well as basophils exhibiting FcϵRI receptor-bound IgE. Using flow cytometry, we demonstrated that omalizumab recognized IgE producing cells with a high sensitivity of up to 1 IgE cell in 1000 human peripheral blood mononuclear cells (PBMCs). These results were confirmed by confocal microscopy both in cell suspensions as well as in nasal polyp tissue sections. Finally, we established a consecutive gating strategy allowing the clear identification of class-switched, allergen-specific IgE memory B cells and plasmablasts/plasma cells in human PBMCs. Birch pollen specific IgE memory B cells represented on average 0.734% of total CD19 B cells in allergic patients after allergen exposure. Thus, we developed a new protocol for exclusive staining of non-receptor bound allergen-specific IgE B cell subsets in human samples.
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http://dx.doi.org/10.3389/fimmu.2021.803236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721004PMC
February 2022

Preventive Administration of Non-Allergenic Bet v 1 Peptides Reduces Allergic Sensitization to Major Birch Pollen Allergen, Bet v 1.

Front Immunol 2021 26;12:744544. Epub 2021 Oct 26.

Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

IgE-mediated allergy to birch pollen affects more than 100 million patients world-wide. Bet v 1, a 17 kDa protein is the major allergen in birch pollen responsible for allergic rhinoconjunctivitis and asthma in birch pollen allergic patients. Allergen-specific immunotherapy (AIT) based on therapeutic administration of Bet v 1-containing vaccines is an effective treatment for birch pollen allergy but no allergen-specific forms of prevention are available. We developed a mouse model for IgE sensitization to Bet v 1 based on subcutaneous injection of aluminum-hydroxide adsorbed recombinant Bet v 1 and performed a detailed characterization of the specificities of the IgE, IgG and CD4 T cell responses in sensitized mice using seven synthetic peptides of 31-42 amino acids length which comprised the Bet v 1 sequence and the epitopes recognized by human CD4 T cells. We then demonstrate that preventive systemic administration of a mix of synthetic non-allergenic Bet v 1 peptides to 3-4 week old mice significantly reduced allergic immune responses, including IgE, IgG, IgE-mediated basophil activation, CD4 T cell and IL-4 responses to the complete Bet v 1 allergen but not to the unrelated major grass pollen allergen Phl p 5, without inducing Bet v 1-specific allergic sensitization or adaptive immunity. Our results thus demonstrate that early preventive administration of non-allergenic synthetic T cell epitope-containing allergen peptides could be a safe strategy for the prevention of allergen-specific IgE sensitization.
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http://dx.doi.org/10.3389/fimmu.2021.744544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594376PMC
December 2021

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

Allergy 2021 Oct 15. Epub 2021 Oct 15.

Laboratory of Transmission, Control and Immunobiology of Infections (LR11IPT02), Department of Immunology, Institut Pasteur de Tunis and University Tunis El Manar, Tunis, Tunisia.

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.
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http://dx.doi.org/10.1111/all.15143DOI Listing
October 2021

From Allergen Molecules to Molecular Immunotherapy of Nut Allergy: A Hard Nut to Crack.

Front Immunol 2021 23;12:742732. Epub 2021 Sep 23.

Division of Allergy and Asthma, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Peanuts and tree nuts are two of the most common elicitors of immunoglobulin E (IgE)-mediated food allergy. Nut allergy is frequently associated with systemic reactions and can lead to potentially life-threatening respiratory and circulatory symptoms. Furthermore, nut allergy usually persists throughout life. Whether sensitized patients exhibit severe and life-threatening reactions (e.g., anaphylaxis), mild and/or local reactions (e.g., pollen-food allergy syndrome) or no relevant symptoms depends much on IgE recognition of digestion-resistant class I food allergens, IgE cross-reactivity of class II food allergens with respiratory allergens and clinically not relevant plant-derived carbohydrate epitopes, respectively. Accordingly, molecular allergy diagnosis based on the measurement of allergen-specific IgE levels to allergen molecules provides important information in addition to provocation testing in the diagnosis of food allergy. Molecular allergy diagnosis helps identifying the genuinely sensitizing nuts, it determines IgE sensitization to class I and II food allergen molecules and hence provides a basis for personalized forms of treatment such as precise prescription of diet and allergen-specific immunotherapy (AIT). Currently available forms of nut-specific AIT are based only on allergen extracts, have been mainly developed for peanut but not for other nuts and, unlike AIT for respiratory allergies which utilize often subcutaneous administration, are given preferentially by the oral route. Here we review prevalence of allergy to peanut and tree nuts in different populations of the world, summarize knowledge regarding the involved nut allergen molecules and current AIT approaches for nut allergy. We argue that nut-specific AIT may benefit from molecular subcutaneous AIT (SCIT) approaches but identify also possible hurdles for such an approach and explain why molecular SCIT may be a hard nut to crack.
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http://dx.doi.org/10.3389/fimmu.2021.742732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496898PMC
December 2021

Specific T cells targeting Staphylococcus aureus fibronectin-binding protein 1 induce a type 2/type 1 inflammatory response in sensitized atopic dermatitis patients.

Allergy 2022 04 22;77(4):1245-1253. Epub 2021 Oct 22.

Division of Dermatology and Allergy, Department of Immunodermatology and Allergy Research, Hannover Medical School, Hannover, Germany.

Background: Atopic dermatitis (AD) is one of the most common inflammatory skin diseases worldwide and Staphylococcus aureus colonization and secondary infections occur in the majority of AD patients. Allergic sensitizations against microbial antigens have been discussed as possible trigger factors of AD. Recently, we reported IgE sensitization against fibronectin-binding protein 1 (FBP1), an essential virulence component in S. aureus, in a subgroup of patients suffering from AD. To expand these findings by investigating delayed-type immune reactions, the objective of this study was to detect and phenotypically characterize FBP1-specific T cells as possible trigger factors in AD.

Methods: Immunodominant T-cell epitopes were mapped by proliferation testing of patient-derived FBP1-specific T-cell lines after stimulation with single 15mer peptides, which were derived from different functional domains of the FBP1 sequence. Major histocompatibility complex class II tetramers carrying immunodominant epitopes successfully stained T helper cells in 8 out of 8 HLA-matched, IgE-sensitized AD patients.

Results: Cytokine profiling of multimer-sorted cells revealed that predominantly the type 2 cytokines IL-13 and IL-4 were secreted by these cells. In contrast, IL-17, the marker cytokine for response to extracellular pathogens, was scarcely detectable.

Conclusions: We demonstrate that FBP1 contains immunodominant peptides that induce a specific pro-inflammatory T helper cell response with increased Th2 levels that can drive an allergic inflammation in sensitized AD patients.
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http://dx.doi.org/10.1111/all.15120DOI Listing
April 2022

The Molecular Allergen Recognition Profile in China as Basis for Allergen-Specific Immunotherapy.

Front Immunol 2021 27;12:719573. Epub 2021 Aug 27.

Department of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Approximately 30% of the world population suffers from immunoglobulin-E (IgE)-mediated allergy. IgE-mediated allergy affects the respiratory tract, the skin and the gastrointestinal tract and may lead to life-threatening acute systemic manifestations such as anaphylactic shock. The symptoms of allergy are mediated by IgE-recognition of causative allergen molecules from different allergen sources. Today, molecular allergy diagnosis allows determining the disease-causing allergens to develop allergen-specific concepts for prevention and treatment of allergy. Allergen-specific preventive and therapeutic strategies include allergen avoidance, vaccination, and tolerance induction. The implementation of these preventive and therapeutic strategies requires a detailed knowledge of the relevant allergen molecules affecting a given population. China is the world´s most populous country with around 1.4 billion inhabitants and an estimated number of more than 400 million allergic patients. Research in allergy in China has dramatically increased in the last decade. We summarize in this review article what is known about the dominating allergen sources and allergen molecules in China and what further investigations could be performed to draw a molecular map of IgE sensitization for China as a basis for the implementation of systematic and rational allergen-specific preventive and therapeutic strategies to combat allergic diseases in this country.
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http://dx.doi.org/10.3389/fimmu.2021.719573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430339PMC
December 2021

Neutralization of SARS-CoV-2 requires antibodies against conformational receptor-binding domain epitopes.

Allergy 2022 01 22;77(1):230-242. Epub 2021 Sep 22.

Department of Pathophysiology and Allergy Research, Division of Immunopathology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

Background: The determinants of successful humoral immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of critical importance for the design of effective vaccines and the evaluation of the degree of protective immunity conferred by exposure to the virus. As novel variants emerge, understanding their likelihood of suppression by population antibody repertoires has become increasingly important.

Methods: In this study, we analyzed the SARS-CoV-2 polyclonal antibody response in a large population of clinically well-characterized patients after mild and severe COVID-19 using a panel of microarrayed structurally folded and unfolded SARS-CoV-2 proteins, as well as sequential peptides, spanning the surface spike protein (S) and the receptor-binding domain (RBD) of the virus.

Results: S- and RBD-specific antibody responses were dominated by immunoglobulin G (IgG), mainly IgG , and directed against structurally folded S and RBD and three distinct peptide epitopes in S2. The virus neutralization activity of patients´ sera was highly correlated with IgG antibodies specific for conformational but not sequential RBD epitopes and their ability to prevent RBD binding to its human receptor angiotensin-converting enzyme 2 (ACE2). Twenty percent of patients selectively lacked RBD-specific IgG. Only immunization with folded, but not with unfolded RBD, induced antibodies against conformational epitopes with high virus-neutralizing activity. Conformational RBD epitopes required for protection do not seem to be altered in the currently emerging virus variants.

Conclusion: These results are fundamental for estimating the protective activity of antibody responses after natural infection or vaccination and for the design of vaccines, which can induce high levels of SARS-CoV-2-neutralizing antibodies conferring sterilizing immunity.
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http://dx.doi.org/10.1111/all.15066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8653362PMC
January 2022

Multiprofessional perinatal care in a pregnant patient with acute respiratory distress syndrome due to COVID-19.

BMC Pregnancy Childbirth 2021 Aug 26;21(1):587. Epub 2021 Aug 26.

Department of Obstetrics and Gynecology, Division of Obstetrics and Feto-Maternal Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria.

Background: The coronavirus disease (COVID-19) pandemic has caused ongoing challenges in health services worldwide. Despite the growing body of literature on COVID-19, reports on perinatal care in COVID-19 cases are limited.

Case Presentation: We describe a case of severe acute respiratory distress syndrome (ARDS) in a 36-year-old G5/P2 pregnant woman with morbid obesity, confirmed severe acute respiratory syndrome coronavirus 2 infection, and fulminant respiratory failure. At 28 gestational weeks, the patient delivered an uninfected newborn. Using ImmunoCAP ISAC® technology, we found no immunoglobulin (Ig) M antibodies, suggesting that no mother-to-child viral transmission occurred during pregnancy or delivery. The maternal respiratory state improved rapidly after delivery; both maternal and neonatal outcomes were encouraging given the early gestational age and fulminant course of respiratory failure in our patient.

Conclusions: The management of ARDS in pregnant women with COVID-19 is complex and requires an individualized, multidisciplinary approach, while considering maternal and fetal outcomes.
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http://dx.doi.org/10.1186/s12884-021-04059-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390084PMC
August 2021

IgE recognition of the house dust mite allergen Der p 37 is associated with asthma.

J Allergy Clin Immunol 2022 03 20;149(3):1031-1043. Epub 2021 Aug 20.

Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria. Electronic address:

Background: House dust mite (HDM) allergens are major elicitors of allergic reactions worldwide.

Objective: Identification, characterization, and evaluation of diagnostic utility of a new important HDM allergen was performed.

Methods: A cDNA coding for a new Dermatophagoides pteronyssinus (Dp) allergen, Der p 37, was isolated from a Dp expression library with allergic patients' IgE antibodies. Recombinant Der p 37 (rDer p 37) expressed in Escherichia coli was purified, then characterized by mass spectrometry, circular dichroism, and IgE reactivity by ImmunoCAP ISAC technology with sera from 111 clinically defined HDM-allergic patients. The allergenic activity of rDer p 37 was studied by basophil activation and CD4 T-cell responses by carboxyfluorescein diacetate succinimidyl ester dilution assays. Specific antibodies raised against rDer p 37 were used for the ultrastructural localization of Der p 37 in mites by immunogold transmission electron microscopy.

Results: Der p 37, a 26 kDa allergen with homology to chitin-binding proteins, is immunologically distinct from Der p 15, 18, and 23. It is located in the peritrophic membrane of fecal pellets. Der p 37 reacted with IgE antibodies from a third of HDM-allergic patients and induced specific basophil- and CD4 T-cell activation. Der p 37 IgE-positive patients had significantly higher IgE levels to major HDM allergens, reacted with more HDM allergens, and had a higher risk (odds ratio = 3.1) of asthma compared to Der p 37-negative patients.

Conclusions: Der p 37, a new Dp allergen recognized by a third of HDM-allergic patients, may serve as a surrogate marker for severe HDM sensitization and asthma.
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http://dx.doi.org/10.1016/j.jaci.2021.07.040DOI Listing
March 2022

IgE Epitopes of the House Dust Mite Allergen Der p 7 Are Mainly Discontinuous and Conformational.

Front Immunol 2021 15;12:687294. Epub 2021 Jun 15.

Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

Background: Several studies indicate that Der p 7 is an important and clinically relevant allergen of which should be included in vaccines for treatment of house dust mite (HDM) allergy. Aim of this study was to characterize the IgE epitopes of Der p 7.

Methods: Recombinant Der p 7 was expressed and purified, analyzed for fold by circular dichroism and tested for its allergenic activity by basophil activation. Seven overlapping, surface-exposed peptides (P1-P7) with a length of 27 to 37 amino acids, which spanned the Der p 7 sequence, were synthesized and tested for IgE reactivity and allergenic activity by basophil activation assay. Carrier-bound peptides were studied for their ability to induce allergen-specific IgG antibodies in rabbits. Peptide-specific antibodies were used to inhibit allergic patients` IgE binding to Der p 7 by ELISA for mapping of IgE epitopes.

Results: rDer p 7 showed high allergenic activity comparable with Der p 5, Der p 21, and Der p 23. None of the seven tested peptides showed any IgE reactivity or allergenic activity when tested with HDM- allergic patients indicating lack of sequential IgE epitopes on Der p 7. IgE inhibition experiments using anti-peptide specific IgGs and molecular modeling enabled us to identify discontinuous, conformational IgE epitopes of Der p 7.

Conclusion And Clinical Relevance: IgE epitopes of Der p 7 belong to the conformational and discontinuous type whereas sequential Der p 7 peptides lack IgE reactivity. It should thus be possible to construct hypoallergenic vaccines for Der p 7 based on carrier-bound allergen peptides.
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http://dx.doi.org/10.3389/fimmu.2021.687294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241568PMC
October 2021

Trajectories of IgE sensitization to allergen molecules from childhood to adulthood and respiratory health in the EGEA cohort.

Allergy 2022 02 8;77(2):609-618. Epub 2021 Jul 8.

Team of Environmental Epidemiology applied to the Development and Respiratory Health, IAB, Inserm, Univ. Grenoble Alpes, CNRS, Grenoble, France.

Background: Longitudinal studies assessing the association of profiles of allergen-specific IgE (sIgE) sensitization to a large range of allergen molecules and respiratory health are rare. We aimed to assess trajectories of molecular sIgE sensitization profiles from childhood to adulthood and their associations with respiratory health.

Methods: IgE reactivity to microarrayed allergen molecules were measured in childhood (EGEA1) and 12 years later in adult life (EGEA2) among 291 EGEA participants (152 with asthma). At each time point, sIgE sensitization profiles were identified by latent class analysis (LCA) by considering IgE-reactivity to the 38 most prevalent respiratory allergens. The LCA-defined profiles were then studied in association with respiratory health.

Results: At baseline, the mean (min-max) age of the population was 11 (4.5-16) years. The LCA identified four sIgE sensitization profiles which were very similar at both time points (% at EGEA1 and EGEA2); A: "no/few allergen(s)" (48%, 39%), B: "pollen/animal allergens" (18%, 21%), C: "most prevalent house dust mite allergens" (22%, 27%) and D: "many allergens" (12%, 13%). Overall, 73% of the participants remained in the same profile from childhood to adulthood. The profiles were associated with asthma and rhinitis phenotypes. Participants of profiles C and D had lower FEV % and FEF % as compared to profile A. Similar patterns of associations were observed for participants with asthma. There was no association with change in lung function.

Conclusion: Using high-resolution sIgE longitudinal data, the LCA identified four molecular sensitization profiles, mainly stable from childhood to adulthood, that were associated with respiratory health.
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http://dx.doi.org/10.1111/all.14987DOI Listing
February 2022

Microarray Technology May Reveal the Contribution of Allergen Exposure and Rhinovirus Infections as Possible Triggers for Acute Wheezing Attacks in Preschool Children.

Viruses 2021 05 15;13(5). Epub 2021 May 15.

Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria.

Allergen exposure and rhinovirus (RV) infections are common triggers of acute wheezing exacerbations in early childhood. The identification of such trigger factors is difficult but may have therapeutic implications. Increases of IgE and IgG in sera, were shown against allergens and the N-terminal portion of the VP1 proteins of RV species, respectively, several weeks after allergen exposure or RV infection. Hence, increases in VP1-specific IgG and in allergen-specific IgE may serve as biomarkers for RV infections or allergen exposure. The MeDALL-allergen chip containing comprehensive panels of allergens and the PreDicta RV chip equipped with VP1-derived peptides, representative of three genetic RV species, were used to measure allergen-specific IgE levels and RV-species-specific IgG levels in sera obtained from 120 preschool children at the time of an acute wheezing attack and convalescence. Nearly 20% of the children (22/120) showed specific IgE sensitizations to at least one of the allergen molecules on the MeDALL chip. For 87% of the children, increases in RV-specific IgG could be detected in the follow-up sera. This percentage of RV-specific IgG increases was equal in IgE-positive and -negative children. In 10% of the children, increases or appearances of IgE sensitizations indicative of allergen exposure could be detected. Our results suggest that, in the majority of preschool children, RV infections trigger wheezing attacks, but, in addition, allergen exposure seems to play a role as a trigger factor. RV-induced wheezing attacks occur in IgE-sensitized and non-IgE-sensitized children, indicating that allergic sensitization is not a prerequisite for RV-induced wheeze.
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http://dx.doi.org/10.3390/v13050915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155838PMC
May 2021

The role of allergen-specific IgE, IgG and IgA in allergic disease.

Allergy 2021 12 8;76(12):3627-3641. Epub 2021 Jun 8.

Wageningen University & Research, Wageningen, The Netherlands.

Immunoglobulin E (IgE)-mediated allergy is the most common hypersensitivity disease affecting more than 30% of the population. Exposure to even minute quantities of allergens can lead to the production of IgE antibodies in atopic individuals. This is termed allergic sensitization, which occurs mainly in early childhood. Allergen-specific IgE then binds to the high (FcεRI) and low-affinity receptors (FcεRII, also called CD23) for IgE on effector cells and antigen-presenting cells. Subsequent and repeated allergen exposure increases allergen-specific IgE levels and, by receptor cross-linking, triggers immediate release of inflammatory mediators from mast cells and basophils whereas IgE-facilitated allergen presentation perpetuates T cell-mediated allergic inflammation. Due to engagement of receptors which are highly selective for IgE, even tiny amounts of allergens can induce massive inflammation. Naturally occurring allergen-specific IgG and IgA antibodies usually recognize different epitopes on allergens compared with IgE and do not efficiently interfere with allergen-induced inflammation. However, IgG and IgA antibodies to these important IgE epitopes can be induced by allergen-specific immunotherapy or by passive immunization. These will lead to competition with IgE for binding with the allergen and prevent allergic responses. Similarly, anti-IgE treatment does the same by preventing IgE from binding to its receptor on mast cells and basophils. Here, we review the complex interplay of allergen-specific IgE, IgG and IgA and the corresponding cell receptors in allergic diseases and its relevance for diagnosis, treatment and prevention of allergy.
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http://dx.doi.org/10.1111/all.14908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601105PMC
December 2021

Natural History of IgE-Mediated Fish Allergy in Children.

J Allergy Clin Immunol Pract 2021 08 15;9(8):3147-3156.e5. Epub 2021 Apr 15.

Allergy Department, 2nd Pediatric Clinic, National and Kapodistrian University of Athens, Athens, Greece; Division of Infection, Immunity, and Respiratory Medicine, The University of Manchester, Manchester, United Kingdom. Electronic address:

Background: Fish allergy is not uncommon, especially in countries with high fish consumption, it can frequently be severe and may affect dietetic and lifestyle choices. Nevertheless, data on its clinical course and natural history are scarce.

Objective: To describe the natural history of immunoglobulin E-mediated fish allergy and the potential differential reactivity to various fish species and identify prognostic markers in children with confirmed disease.

Methods: Clinical history, specific immunoglobulin E, and skin prick tests to various fish were recorded in 126 children with confirmed immunoglobulin E-mediated fish allergy. Immunoglobulin E reactivity was also evaluated by immunoblotting. Eligible participants proceeded to a series of food challenges to tuna, swordfish, and codfish. In total, 234 challenges were performed.

Results: Fifty-eight children (9.7 ± 3.9 years) were included in the analysis. Age at first reaction was 0.5 to 5 years (median, 1.3 years). Thirteen children (22%) tolerated all fish tested, including cod, 1 to 14 years (mean, 8.2 ± 4.2 years) following their first reported reaction. Complete fish tolerance increased with age, ranging from 3.4% in preschool children to over 45% in adolescents (95% confidence interval, 26.3%-79.7%). Most children were able to tolerate swordfish (94%) and tuna (95%). Prechallenge specific immunoglobulin E to cod greater than 4.87 kUA/L was the best positive predictive marker for fish allergy persistence (94%), followed by skin prick tests to sardine greater than 6.5 mm (92%).

Conclusions: A considerable proportion of fish-allergic children develop tolerance around adolescence. Most fish-allergic children can consume tuna and swordfish, which, thus, provide safe alternatives for a balanced diet.
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http://dx.doi.org/10.1016/j.jaip.2021.04.007DOI Listing
August 2021

Silencing of SARS-CoV-2 with modified siRNA-peptide dendrimer formulation.

Allergy 2021 09 10;76(9):2840-2854. Epub 2021 May 10.

NRC Institute of Immunology FMBA, Moscow, Russia.

Background: First vaccines for prevention of Coronavirus disease 2019 (COVID-19) are becoming available but there is a huge and unmet need for specific forms of treatment. In this study we aimed to evaluate the anti-SARS-CoV-2 effect of siRNA both in vitro and in vivo.

Methods: To identify the most effective molecule out of a panel of 15 in silico designed siRNAs, an in vitro screening system based on vectors expressing SARS-CoV-2 genes fused with the firefly luciferase reporter gene and SARS-CoV-2-infected cells was used. The most potent siRNA, siR-7, was modified by Locked nucleic acids (LNAs) to obtain siR-7-EM with increased stability and was formulated with the peptide dendrimer KK-46 for enhancing cellular uptake to allow topical application by inhalation of the final formulation - siR-7-EM/KK-46. Using the Syrian Hamster model for SARS-CoV-2 infection the antiviral capacity of siR-7-EM/KK-46 complex was evaluated.

Results: We identified the siRNA, siR-7, targeting SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) as the most efficient siRNA inhibiting viral replication in vitro. Moreover, we showed that LNA-modification and complexation with the designed peptide dendrimer enhanced the antiviral capacity of siR-7 in vitro. We demonstrated significant reduction of virus titer and lung inflammation in animals exposed to inhalation of siR-7-EM/KK-46 in vivo.

Conclusions: Thus, we developed a therapeutic strategy for COVID-19 based on inhalation of a modified siRNA-peptide dendrimer formulation. The developed medication is intended for inhalation treatment of COVID-19 patients.
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http://dx.doi.org/10.1111/all.14850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251148PMC
September 2021

Are the Terms Major and Minor Allergens Useful for Precision Allergology?

Front Immunol 2021 8;12:651500. Epub 2021 Mar 8.

Institute for Immunological Research, University of Cartagena, Cartagena, Colombia.

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http://dx.doi.org/10.3389/fimmu.2021.651500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982392PMC
September 2021

Associations between specific IgE sensitization to 26 respiratory allergen molecules and HLA class II alleles in the EGEA cohort.

Allergy 2021 08 7;76(8):2575-2586. Epub 2021 Apr 7.

Inserm, CNRS, IAB, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, University Grenoble Alpes, Grenoble, France.

Background: Allergy, the most frequent immune disorder affecting 30% of the world's population, is the consequence of immunoglobin E (IgE) sensitization to allergens. Among the genetic factors suspected to be involved in allergy, the HLA class-II genomic region is a strong candidate.

Objective: To assess the association between HLA class-II alleles and specific IgE (sIgE) sensitization to a large number of respiratory allergen molecules.

Methods: The analysis relied on 927 participants of the EGEA cohort, including 497 asthmatics. The study focuses on 26 aeroallergens recognized by sIgE in at least 5% of the study population (determined with the MEDALL chip with sIgE ≥ 0.3 ISU) and 23 imputed HLA class-II alleles. For each sIgE sensitization and HLA class-II allele, we fitted a logistic regression model accounting for familial dependence and adjusted for gender, age, and genetic principal components. p-values were corrected for multiple comparisons (False Discovery Rate).

Results: Most of the 19 statistically significant associations observed regard pollen allergens (mugwort Art v 1, olive tree Ole e 1, timothy grass Phl p 2, Phl p 5 and plantain Pla l 1), three were mold allergen (Alternaria Alt a 1), and a single one regards house dust mite allergen (Der p 7). No association was observed with pet allergens. The strongest associations were found with mugwort Art v 1 (OR = 5.42 (95%CI, 3.30; 8.88), 4.14 (2.65; 6.47), 3.16 (1.88; 5.31) with DQB1*05:01, DQA1*01:01 and DRB1*01:01, respectively).

Conclusion: Our results support the important role of HLA class-II alleles as immune response genes predisposing their carriers for sensitization to various major pollen allergens.
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http://dx.doi.org/10.1111/all.14820DOI Listing
August 2021

Microarray-Based Allergy Diagnosis: Quo Vadis?

Front Immunol 2020 12;11:594978. Epub 2021 Feb 12.

Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

More than 30% of the world population suffers from allergy. Allergic individuals are characterized by the production of immunoglobulin E (IgE) antibodies against innocuous environmental allergens. Upon allergen recognition IgE mediates allergen-specific immediate and late-phase allergic inflammation in different organs. The identification of the disease-causing allergens by demonstrating the presence of allergen-specific IgE is the key to precision medicine in allergy because it allows tailoring different forms of prevention and treatment according to the sensitization profiles of individual allergic patients. More than 30 years ago molecular cloning started to accelerate the identification of the disease-causing allergen molecules and enabled their production as recombinant molecules. Based on recombinant allergen molecules, molecular allergy diagnosis was introduced into clinical practice and allowed dissecting the molecular sensitization profiles of allergic patients. In 2002 it was demonstrated that microarray technology allows assembling large numbers of allergen molecules on chips for the rapid serological testing of IgE sensitizations with small volumes of serum. Since then microarrayed allergens have revolutionized research and diagnosis in allergy, but several unmet needs remain. Here we show that detection of IgE- and IgG-reactivity to a panel of respiratory allergens microarrayed onto silicon elements is more sensitive than glass-based chips. We discuss the advantages of silicon-based allergen microarrays and how this technology will allow addressing hitherto unmet needs in microarray-based allergy diagnosis. Importantly, it described how the assembly of silicon microarray elements may create different microarray formats for suiting different diagnostic applications such as quick testing of single patients, medium scale testing and fully automated large scale testing.
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http://dx.doi.org/10.3389/fimmu.2020.594978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928321PMC
June 2021
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