Publications by authors named "Rob Aalberse"

92 Publications

Recombinant allergens need a reality check.

Authors:
Rob C Aalberse

J Allergy Clin Immunol 2021 Oct 12. Epub 2021 Oct 12.

Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands; Faculty of Science, University of Amsterdam, Amsterdam, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2021.09.033DOI Listing
October 2021

Do germinal centers protect most of us from becoming allergic?

Ann Allergy Asthma Immunol 2021 09 5;127(3):301-305. Epub 2021 Jun 5.

Division of Allergy and Immunology, Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, Ohio; Center for Clinical and Translational Research, the Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio.

Objective: To review the literature and discuss a hypothesis as to why most people do not have allergy. This hypothesis is dependent on the following 3 main components: (1) airborne allergens (eg, from pollen or mites) are weak antigens that induce a B-cell response only in immunologically most reactive subjects (ie, with atopy); (2) a roadblock to production of immunoglobulin E (IgE) is the T helper 2/interleukin 4 requirement for class switch to IgE; (3) activated germinal centers prevent the formation of mature IgE-switched B-cells, creating a second roadblock to IgE production.

Data Sources: Transgenic reporter mice and a cross-sectional human cohort.

Study Selections: From the mouse studies, we selected the data on histology and tissue-derived cell suspensions published by several groups in 2011 to 2014. From the human cohort, we selected our published microarray data on the levels of allergen-specific IgE and IgG in serum.

Results: The immune response to airborne atopic allergens entails both IgE and IgG antibodies rather than just an IgG or IgE response. However, as expected for an immune response without mature germinal centers, the specific IgG levels will be very low, typically in the ng/ml range.

Conclusion: Control of IgE production is not just through the T helper 2/interleukin 4-mediated class switch. Recent studies suggest that mature germinal centers are likely to provide protection against the development of allergy to airborne allergens, as well. This may explain why allergen exposure does not induce allergen-specific IgE in everyone.
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http://dx.doi.org/10.1016/j.anai.2021.06.002DOI Listing
September 2021

Carbohydrate epitopes currently recognized as targets for IgE antibodies.

Allergy 2021 08;76(8):2383-2394

WHO/IUIS Allergen Nomenclature Sub-Committee.

Until recently, glycan epitopes have not been documented by the WHO/IUIS Allergen Nomenclature Sub-Committee. This was in part due to scarce or incomplete information on these oligosaccharides, but also due to the widely held opinion that IgE to these epitopes had little or no relevance to allergic symptoms. Most IgE-binding glycans recognized up to 2008 were considered to be "classical" cross-reactive carbohydrate determinants (CCD) that occur in insects, some helminths and throughout the plant kingdom. Since 2008, the prevailing opinion on lack of clinical relevance of IgE-binding glycans has been subject to a reevaluation. This was because IgE specific for the mammalian disaccharide galactose-alpha-1,3-galactose (alpha-gal) was identified as a cause of delayed anaphylaxis to mammalian meat in the United States, an observation that has been confirmed by allergists in many parts of the world. Several experimental studies have shown that oligosaccharides with one or more terminal alpha-gal epitopes can be attached as a hapten to many different mammalian proteins or lipids. The classical CCDs also behave like haptens since they can be expressed on proteins from multiple species. This is the explanation for extensive in vitro cross-reactivity related to CCDs. Because of these developments, the Allergen Nomenclature Sub-Committee recently decided to include glycans as potentially allergenic epitopes in an adjunct section of its website (www.allergen.org). In this article, the features of the main glycan groups known to be involved in IgE recognition are revisited, and their characteristic structural, functional, and clinical features are discussed.
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http://dx.doi.org/10.1111/all.14802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489568PMC
August 2021

Sesame: An Increasingly Popular Word and Common Food Allergen.

J Allergy Clin Immunol Pract 2020 05;8(5):1689-1691

Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, The Netherlands.

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http://dx.doi.org/10.1016/j.jaip.2020.03.002DOI Listing
May 2020

Identification of the amino-terminal fragment of Ara h 1 as a major target of the IgE-binding activity in the basic peanut protein fraction.

Clin Exp Allergy 2020 03 7;50(3):401-405. Epub 2020 Feb 7.

Department of Biosciences, University of Salzburg, Salzburg, Austria.

Background: Small, basic peanut proteins are often poorly extracted in pH-neutral buffers that are optimal for the extraction of peanut storage proteins such as Ara h 1. As a result, such proteins are easily missed as potential allergens.

Objective: To analyse the allergenic composition of the basic peanut protein (BPP) fraction.

Methods: A peanut extract prepared at pH 4 was fractionated by physicochemical procedures. Chemical analysis was performed by SDS-PAGE and mass spectrometry. Because immunoblotting was found to be inefficient for most of these small basic proteins, IgE-binding activity was measured by coupling the fractions to CNBr-activated Sepharose, followed by incubation with sera from 55 Dutch peanut-allergic children and I-labelled anti-IgE.

Results: Most IgE reactivity of the BPP fraction was due to the 5-7 kDa amino-terminal fragment of Ara h 1. This finding was confirmed by the use of the fragment in recombinant form, to which 25/55 of the sera was IgE-positive.

Conclusion: The amino-terminal fragment of Ara h 1, a member of a family of small anti-microbial proteins, is an allergen independent of the carboxy-terminal fragment of Ara h 1.
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http://dx.doi.org/10.1111/cea.13554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047623PMC
March 2020

Does maternal IgG protect infants from allergen-specific IgE sensitization?

J Allergy Clin Immunol 2019 11 25;144(5):1454-1455. Epub 2019 Sep 25.

Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands; Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1016/j.jaci.2019.08.011DOI Listing
November 2019

Further investigations of the IgE response to tetanus and diphtheria following covaccination with acellular rather than cellular Bordetella pertussis.

Pediatr Allergy Immunol 2019 12;30(8):841-847

Department of Clinical and Experimental Medicine, Allergy Center, Linköping University, Linköping, Sweden.

Background: It has previously been shown in an uncontrolled study that the IgE response to vaccine antigens is downregulated by co-vaccination with cellular Bordetella pertussis vaccine.

Methods: In the present study, we compared in a controlled trial the humoral immune response to diphtheria toxoid (D) and tetanus toxoid (T) in relation to co-vaccinated cellular or acellular B pertussis vaccine. IgE, IgG4, and IgG to D and T were analyzed at 2, 7, and 12 months of age in sera of children vaccinated with D and T (DT, N = 68), cellular (DTPw, N = 68), 2- or 5-component acellular B pertussis vaccine (DTPa2, N = 64; DTPa5, N = 65).

Results: One month after vaccination, D-IgE was detected in 10% sera of DTPw-vaccinated children, whereas vaccination in the absence of whole-cell pertussis resulted in 50%-60% IgE positivity. Six months after vaccination, the IgE antibody levels were found to be more persistent than the IgG antibodies. These diphtheria findings were mirrored by those for tetanus. Only minor differences between vaccine groups were found with regard to D-IgG and T-IgG. No immediate-type allergic reactions were observed.

Conclusion: Cellular (but not acellular) B pertussis vaccine downregulates IgE to co-vaccinated antigens in infants. We assume that the absence of immediate-type allergic reactions is due to the high levels of IgG antibodies competing with IgE antibodies.
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http://dx.doi.org/10.1111/pai.13113DOI Listing
December 2019

Clinical Allergy at the Interface of Sticky Dust Particles and Crystal-Clear Proteins.

J Allergy Clin Immunol Pract 2018 Nov - Dec;6(6):1866-1868

Sanquin Research, Department of Immunopathology, Amsterdam, The Netherlands; Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1016/j.jaip.2018.09.013DOI Listing
November 2019

Unique patterns of glycosylation in immunoglobulin subclass G4-related disease and primary sclerosing cholangitis.

J Gastroenterol Hepatol 2019 Oct 22;34(10):1878-1886. Epub 2018 Nov 22.

Sanquin Research, Department of Immunopathology, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.

Background And Aim: Immunoglobulin subclass G4-related disease (IgG4-RD) is characterized by an abundance of IgG4 antibodies in the serum and tissue. Glycosylation status of antibodies can impact on immune effector functions and disease pathophysiology. We sought to establish glycosylation patterns in a prospective cohort of patients with IgG4-RD and the relationship with disease activity and response to treatment.

Methods: We assessed IgG Fc-tail and Fab-arm glycosylation status in patients with IgG4-RD (n = 22), disease controls with primary sclerosing cholangitis (PSC) (n = 22), and healthy controls (n = 22). Serum IgG and subclasses were quantified using ELISA. Fc and Fab glycosylation were analyzed by mass spectrometry and lectin affinity chromatography, respectively. Disease activity, organ damage, and response to treatment were assessed using the IgG4 Responder Index.

Results: Immunoglobulin G Fab sialylation was increased in IgG4-RD compared with PSC and healthy control (P = 0.01), with a preferential increase in IgG4-specific Fab sialylation, which was independent of IgG4 Fab-arm exchange. There was a reduction in IgG1-specific Fc bisection and hybrid structures in IgG4-RD (P < 0.01), which recovered upon steroid treatment and correlated with disease activity. Overall, IgG Fc galactosylation was reduced in both IgG4-RD and PSC (P < 0.01), with a preferential reduction in IgG1-specific sialylation and enhancement of IgG4-specific bisection in PSC. IgG4 fucosylation and IgG1/2/3 hybrid structures negatively correlated with complement C3 and C4 levels in IgG4-RD (P < 0.01), but not PSC.

Conclusion: We report the first study showing unique antibody glycosylation status in a prospective cohort of IgG4-RD and PSC patients, which may determine modulation of the immune system and contribute to disease pathophysiology.
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http://dx.doi.org/10.1111/jgh.14512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899843PMC
October 2019

sIgE and sIgG to airborne atopic allergens: Coupled rather than inversely related responses.

Allergy 2018 11 31;73(11):2239-2242. Epub 2018 Jul 31.

Asthma and Allergic Diseases Center, University of Virginia Health System, Charlottesville, Virginia.

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http://dx.doi.org/10.1111/all.13548DOI Listing
November 2018

Increases in IgE, Eosinophils, and Mast Cells Can be Used in Diagnosis and to Predict Relapse of IgG4-Related Disease.

Clin Gastroenterol Hepatol 2017 Sep 20;15(9):1444-1452.e6. Epub 2017 Feb 20.

Immunopathology Department, Sanquin, Amsterdam, The Netherlands. Electronic address:

Background & Aims: IgG subclass 4-related disease (IgG4-RD) is characterized by increased serum levels of IgG4 and infiltration of biliary, pancreatic, and other tissues by IgG4-positive plasma cells. We assessed the prevalence of allergy and/or atopy, serum, and tissue IgE antibodies, and blood and tissue eosinophils in patients with IgG4-RD. We investigated the association between serum IgE and diagnosis and relapse of this disease.

Methods: We performed a prospective study of 48 patients with IgG4-RD, 42 patients with an increased serum level of IgG4 with other inflammatory and autoimmune conditions (disease control subjects), and 51 healthy individuals (healthy control subjects) recruited from Oxford, United Kingdom from March 2010 through March 2014, and followed for a median of 41 months (range, 3-73 months). Serum levels of immunoglobulin were measured at diagnosis, during steroid treatment, and at disease relapse for patients with IgG4-RD; levels at diagnosis were compared with baseline levels of control subjects. Allergen-specific IgEs were measured using the IgE ImmunoCAP. Levels and distribution of IgG4 and IgE antibodies in lymphoid, biliary, and pancreatic tissues from patients with IgG4-RD and disease control subjects were measured by immunohistochemistry. We analyzed data using the Spearman rank correlation and receiver operating characteristic curves.

Results: Serum levels of IgG4 increased to 1.4 g/L or more, and IgE increased to 125 kIU/L or more, in 81% and 54% of patients with IgG4-RD, respectively, compared with 6% and 16% of healthy control subjects (P < .0001). Peripheral blood eosinophilia was detected in 38% of patients with IgG4-RD versus 9% of healthy control subjects (P = .004). Of patients with IgG4-RD, 63% had a history of allergy and 40% had a history of atopy with an IgE-specific response; these values were 60% and 53% in patients with increased serum levels of IgE (P < .05). Level of IgE at diagnosis >480 kIU/L distinguished patients with IgG4-RD from disease control subjects with 86% specificity, 36% sensitivity, and a likelihood ratio of 3.2. Level of IgE at diagnosis >380 kIU/L identified patients with disease relapse with 88% specificity, 64% sensitivity, and a likelihood ratio of 5.4. IgE-positive mast cells and eosinophilia were observed in lymphoid, biliary, and pancreatic tissue samples from 50% and 86% of patients with IgG4-RD, respectively.

Conclusions: In a prospective study, we associated IgG4-RD with allergy, atopy, eosinophilia, increased serum levels of IgE, and IgE-positive mast cells in lymphoid, biliary, and pancreatic tissue. An IgE-mediated allergic response therefore seems to develop in most patients with IgG4-RD; levels of IgE might be used in diagnosis and predicting relapse.
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http://dx.doi.org/10.1016/j.cgh.2017.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592233PMC
September 2017

Room temperature structure of human IgG4-Fc from crystals analysed in situ.

Mol Immunol 2017 01 1;81:85-91. Epub 2016 Dec 1.

King's College London, Randall Division of Cell and Molecular Biophysics, New Hunt's House, London SE1 1UL, United Kingdom; Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom. Electronic address:

The Fc region of IgG antibodies (Cγ2 and Cγ3 domains) is responsible for effector functions such as antibody-dependent cell-mediated cytotoxicity and phagocytosis, through engagement with Fcγ receptors, although the ability to elicit these functions differs between the four human IgG subclasses. A key determinant of Fcγ receptor interactions is the FG loop in the Cγ2 domain. High resolution cryogenic IgG4-Fc crystal structures have revealed a unique conformation for this loop, which could contribute to the particular biological properties of this subclass. To further explore the conformation of the IgG4 Cγ2 FG loop at near-physiological temperature, we solved a 2.7Å resolution room temperature structure of recombinant human IgG4-Fc from crystals analysed in situ. The Cγ2 FG loop in one chain differs from the cryogenic structure, and adopts the conserved conformation found in IgG1-Fc; however, this conformation participates in extensive crystal packing interactions. On the other hand, at room temperature, and free from any crystal packing interactions, the Cγ2 FG loop in the other chain adopts the conformation previously observed in the cryogenic IgG4-Fc structures, despite both conformations being accessible. The room temperature human IgG4-Fc structure thus provides a more complete and physiologically relevant description of the conformation of this functionally critical Cγ2 FG loop.
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http://dx.doi.org/10.1016/j.molimm.2016.11.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226057PMC
January 2017

The Developmental History of IgE and IgG4 Antibodies in Relation to Atopy, Eosinophilic Esophagitis, and the Modified TH2 Response.

Curr Allergy Asthma Rep 2016 06;16(6):45

Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, P.O. Box 9190, 1006 AD, Amsterdam, The Netherlands.

A common reaction from anyone confronted with allergy is the question: what prevents universal allergy? We will discuss recent findings in the mouse system that have provided us with clues on why allergy is not more common. We will also address one crucial aspect of atopic allergy in humans, which is absent in most mouse model systems, an IgG/IgE ratio <10. We consider the typical mouse IgE response to be more closely related to the "modified TH2" response in humans. We will discuss the similarities and differences between the IgE and IgG4 response to allergens and an update on the IgG4 B cell, partly derived from studies on eosinophilic esophagitis and IgG4-related diseases.
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http://dx.doi.org/10.1007/s11882-016-0621-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026408PMC
June 2016

A Tale of 2 Tails: The Interpretation of Changes in Allergen-Specific IgE Following Incidental Allergen Exposure.

J Allergy Clin Immunol Pract 2016 Mar-Apr;4(2):246-7

Division of Research, Department of Immunopathology, Sanquin Blood Supply, Amsterdam, The Netherlands; Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1016/j.jaip.2016.01.001DOI Listing
August 2016

Molecular Allergen-Specific IgE Assays as a Complement to Allergen Extract-Based Sensitization Assessment.

J Allergy Clin Immunol Pract 2015 Nov-Dec;3(6):863-9; quiz 870

Laboratory for Translational Immunology, Department of Pediatric Immunology, University Medical Center, Utrecht, The Netherlands.

Molecular allergen-based component-resolved diagnostic IgE antibody tests have emerged in the form of singleplex assays and multiplex arrays. They use both native and recombinant allergen molecules, sometimes in combination with each other, to supplement allergen extract-based IgE antibody analyses. The total number of available allergenic molecules has reached a diagnostically useful level; however, more molecules are needed to cover all the clinically important allergen specificities. Thus, for the foreseeable future, molecular allergen-specific IgE analyses will remain a supplement for initial allergen extract-based IgE antibody analyses in the diagnostic workup of the allergic patient. As a spin-off, it will enable manufacturers to improve the quality of extracts for in vitro testing. The 2 most exciting diagnostic developments linked to component-resolved diagnostic tests are the possibility to increase diagnostic sensitivity by the inclusion of allergens that are underrepresented in the current extracts and in vitro assays and to increase the diagnostic specificity by taking the information on allergen cross-reactivity into account. Particularly the latter application is still under development. This requires additional studies on the clinical relevance of serological cross-reactivity.
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http://dx.doi.org/10.1016/j.jaip.2015.09.013DOI Listing
August 2016

Shrimp Serology: We Need Tests with More and Less Cross-reactivity.

Authors:
Rob C Aalberse

J Allergy Clin Immunol Pract 2015 Jul-Aug;3(4):530-1

Department of Immunopathology, Sanquin Research, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2015.03.004DOI Listing
April 2016

Increased IgG4 responses to multiple food and animal antigens indicate a polyclonal expansion and differentiation of pre-existing B cells in IgG4-related disease.

Ann Rheum Dis 2015 May 2;74(5):944-7. Epub 2015 Feb 2.

Sanquin Blood Supply, Division Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Background: IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition, characterised by an elevated serum IgG4 concentration and abundant IgG4-positive plasma cells in the involved organs. An important question is whether the elevated IgG4 response is causal or a reflection of immune-regulatory mechanisms of the disease.

Objectives: To investigate if the IgG4 response in IgG4-RD represents a generalised polyclonal amplification by examining the response to common environmental antigens.

Methods: Serum from 24 patients with IgG4-RD (14 treatment-naive, 10 treatment-experienced), 9 patients with primary sclerosing cholangitis and an elevated serum IgG4 (PSC-high IgG4), and 18 healthy controls were tested against egg white and yolk, milk, banana, cat, peanut, rice and wheat antigens by radioimmunoassay.

Results: We demonstrated an elevated polyclonal IgG4 response to multiple antigens in patients with IgG4-RD and in PSC-high IgG4, compared with healthy controls. There was a strong correlation between serum IgG4 and antigen-specific responses. Responses to antigens were higher in treatment-naive compared with treatment-experienced patients with IgG4-RD. Serum electrophoresis and immunofixation demonstrated polyclonality.

Conclusions: This is the first study to show enhanced levels of polyclonal IgG4 to multiple antigens in IgG4-RD. This supports that elevated IgG4 levels reflect an aberrant immunological regulation of the overall IgG4 response, but does not exclude that causality of disease could be antigen-driven.
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http://dx.doi.org/10.1136/annrheumdis-2014-206405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392210PMC
May 2015

Historic overview of allergy research in the Netherlands.

Immunol Lett 2014 Dec 18;162(2 Pt B):163-72. Epub 2014 Oct 18.

Department of Immunology, University Medical Center Utrecht, The Netherlands; Department of Dermatology and Allergology, University Medical Center Utrecht, The Netherlands. Electronic address:

Research in allergy has a long history in the Netherlands, although the relation with immunology has not always been appreciated. In many aspects Dutch researchers have made major contribution in allergy research. This ranges from the first characterization of house dust mite as an important allergen, the first characterization of human Th2 and Th1 T cell clones, to the development of diagnostic test systems. In this overview Aalberse and Knol have made an overview of the major contributions of Dutch immunologists in allergy.
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http://dx.doi.org/10.1016/j.imlet.2014.10.015DOI Listing
December 2014

A lesson from component-resolved testing: we need better extracts.

J Allergy Clin Immunol Pract 2014 Sep-Oct;2(5):635-6

Sanquin Research, Department Immunopathology, Amsterdam, The Netherlands; Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2014.07.006DOI Listing
May 2015

Mammalian airborne allergens.

Authors:
Rob C Aalberse

Chem Immunol Allergy 2014 22;100:243-7. Epub 2014 May 22.

Sanquin Blood Supply Foundation and Academic Medical Centre, Amsterdam, The Netherlands.

Historically, horse dandruff was a favorite allergen source material. Today, however, allergic symptoms due to airborne mammalian allergens are mostly a result of indoor exposure, be it at home, at work or even at school. The relevance of mammalian allergens in relation to the allergenic activity of house dust extract is briefly discussed in the historical context of two other proposed sources of house dust allergenic activity: mites and Maillard-type lysine-sugar conjugates. Mammalian proteins involved in allergic reactions to airborne dust are largely found in only 2 protein families: lipocalins and secretoglobins (Fel d 1-like proteins), with a relatively minor contribution of serum albumins, cystatins and latherins. Both the lipocalin and the secretoglobin family are very complex. In some instances this results in a blurred separation between important and less important allergenic family members. The past 50 years have provided us with much detailed information on the genomic organization and protein structure of many of these allergens. However, the complex family relations, combined with the wide range of post-translational enzymatic and non-enzymatic modifications, make a proper qualitative and quantitative description of the important mammalian indoor airborne allergens still a significant proteomic challenge.
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http://dx.doi.org/10.1159/000358862DOI Listing
April 2015

Food-derived peptides in a diagnostic context: the fewer the better?

Authors:
Rob C Aalberse

Pediatr Allergy Immunol 2014 May;25(3):206-7

Department of Immunopathology, Sanquin Blood Supply Foundation and Academic Medical Centre, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1111/pai.12226DOI Listing
May 2014

Dynamics of inter-heavy chain interactions in human immunoglobulin G (IgG) subclasses studied by kinetic Fab arm exchange.

J Biol Chem 2014 Feb 14;289(9):6098-109. Epub 2014 Jan 14.

From Sanquin Research, 1066 CX Amsterdam, The Netherlands, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, 1105 AZ, The Netherlands.

Interdomain interactions between the CH3 domains of antibody heavy chains are the first step in antibody assembly and are of prime importance for maintaining the native structure of IgG. For human IgG4 it was shown that CH3-CH3 interactions are weak, resulting in the potential for half-molecule exchange ("Fab arm exchange"). Here we systematically investigated non-covalent interchain interactions for CH3 domains in the other human subclasses, including polymorphisms (allotypes), using real-time monitoring of Fab arm exchange with a FRET-based kinetic assay. We identified structural variation between human IgG subclasses and allotypes at three amino acid positions (Lys/Asn-392, Val/Met-397, Lys/Arg-409) to alter the strength of inter-domain interactions by >6 orders of magnitude. Each substitution affected the interactions independent from the other substitutions in terms of affinity, but the enthalpic and entropic contributions were non-additive, suggesting a complex interplay. Allotypic variation in IgG3 resulted in widely different CH3 interaction strengths that were even weaker for IgG3 than for IgG4 in the case of allotype G3m(c3c5*/6,24*), whereas G3m(s*/15*) was equally stable to IgG1. These interactions are sufficiently strong to maintain the structural integrity of IgG1 during its normal life span; for IgG2 and IgG3 the inter-heavy chain disulfide bonds are essential to prevent half-molecule dissociation, whereas the labile hinge disulfide bonds favor half-molecule exchange in vivo for IgG4.
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http://dx.doi.org/10.1074/jbc.M113.541813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937676PMC
February 2014

Structural determinants of unique properties of human IgG4-Fc.

J Mol Biol 2014 Feb 6;426(3):630-44. Epub 2013 Nov 6.

Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, United Kingdom; Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, London SE1 9RT, United Kingdom. Electronic address:

Human IgG4, normally the least abundant of the four subclasses of IgG in serum, displays a number of unique biological properties. It can undergo heavy-chain exchange, also known as Fab-arm exchange, leading to the formation of monovalent but bispecific antibodies, and it interacts poorly with FcγRII and FcγRIII, and complement. These properties render IgG4 relatively "non-inflammatory" and have made it a suitable format for therapeutic monoclonal antibody production. However, IgG4 is also known to undergo Fc-mediated aggregation and has been implicated in auto-immune disease pathology. We report here the high-resolution crystal structures, at 1.9 and 2.35 Å, respectively, of human recombinant and serum-derived IgG4-Fc. These structures reveal conformational variability at the CH3-CH3 interface that may promote Fab-arm exchange, and a unique conformation for the FG loop in the CH2 domain that would explain the poor FcγRII, FcγRIII and C1q binding properties of IgG4 compared with IgG1 and -3. In contrast to other IgG subclasses, this unique conformation folds the FG loop away from the CH2 domain, precluding any interaction with the lower hinge region, which may further facilitate Fab-arm exchange by destabilisation of the hinge. The crystals of IgG4-Fc also display Fc-Fc packing contacts with very extensive interaction surfaces, involving both a consensus binding site in IgG-Fc at the CH2-CH3 interface and known hydrophobic aggregation motifs. These Fc-Fc interactions are compatible with intact IgG4 molecules and may provide a model for the formation of aggregates of IgG4 that can cause disease pathology in the absence of antigen.
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http://dx.doi.org/10.1016/j.jmb.2013.10.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905167PMC
February 2014

Hen's egg, not cow's milk, sensitization in infancy is associated with asthma: 10-year follow-up of the PIAMA birth cohort.

J Allergy Clin Immunol 2013 Dec 13;132(6):1427-8. Epub 2013 Oct 13.

Centre for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2013.07.053DOI Listing
December 2013

Meta-analysis of air pollution exposure association with allergic sensitization in European birth cohorts.

J Allergy Clin Immunol 2014 Mar 4;133(3):767-76.e7. Epub 2013 Oct 4.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.

Background: Evidence on the long-term effects of air pollution exposure on childhood allergy is limited.

Objective: We investigated the association between air pollution exposure and allergic sensitization to common allergens in children followed prospectively during the first 10 years of life.

Methods: Five European birth cohorts participating in the European Study of Cohorts for Air Pollution Effects project were included: BAMSE (Sweden), LISAplus and GINIplus (Germany), MAAS (Great Britain), and PIAMA (The Netherlands). Land-use regression models were applied to assess the individual residential outdoor levels of particulate matter with an aerodynamic diameter of less than 2.5 μm (PM2.5), the mass concentration of particles between 2.5 and 10 μm in size, and levels of particulate matter with an aerodynamic diameter of less than 10 μm (PM10), as well as measurement of the blackness of PM2.5 filters and nitrogen dioxide and nitrogen oxide levels. Blood samples drawn at 4 to 6 years of age, 8 to 10 years of age, or both from more than 6500 children were analyzed for allergen-specific serum IgE against common allergens. Associations were assessed by using multiple logistic regression and subsequent meta-analysis.

Results: The prevalence of sensitization to any common allergen within the 5 cohorts ranged between 24.1% and 40.4% at the age of 4 to 6 years and between 34.8% and 47.9% at the age of 8 to 10 years. Overall, air pollution exposure was not associated with sensitization to any common allergen, with odds ratios ranging from 0.94 (95% CI, 0.63-1.40) for a 1 × 10(-5) ∙ m(-1) increase in measurement of the blackness of PM2.5 filters to 1.26 (95% CI, 0.90-1.77) for a 5 μg/m(3) increase in PM2.5 exposure at birth address. Further analyses did not provide consistent evidence for a modification of the air pollution effects by sex, family history of atopy, or moving status.

Conclusion: No clear associations between air pollution exposure and development of allergic sensitization in children up to 10 years of age were revealed.
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http://dx.doi.org/10.1016/j.jaci.2013.07.048DOI Listing
March 2014

Phenotypic differences between IgG4+ and IgG1+ B cells point to distinct regulation of the IgG4 response.

J Allergy Clin Immunol 2014 Jan 26;133(1):267-70.e1-6. Epub 2013 Sep 26.

Sanquin Blood Supply, Division of Research, Amsterdam, The Netherlands; Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2013.07.044DOI Listing
January 2014

Nanomolar to sub-picomolar affinity measurements of antibody-antigen interactions and protein multimerizations: fluorescence-assisted high-performance liquid chromatography.

Anal Biochem 2013 Jun 13;437(2):118-22. Epub 2013 Mar 13.

Sanquin Research, 1066 CX Amsterdam, The Netherlands.

Although several techniques exist for the measurement of high-affinity interactions, it is still challenging to determine dissociation constants around or even below 1pM. During the analysis of several human-derived monoclonal antibodies to adalimumab, we found a clone with a very high affinity that could not be measured using conventional surface plasmon resonance assays. We developed a straightforward and robust method to measure affinities in the nanomolar to sub-picomolar range. The assay is based on separation of bound and free fluorescently labeled antigen using size exclusion chromatography and quantification by in-line fluorescence detection. We describe optimal conditions and procedures that result in a very sensitive assay that can be used to reliably determine ultra-high affinities. Using the method described in this article, a dissociation constant of 0.78pM could be determined for the anti-adalimumab antibody.
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http://dx.doi.org/10.1016/j.ab.2013.02.027DOI Listing
June 2013

The enigma of IgE+ B-cell memory in human subjects.

J Allergy Clin Immunol 2013 Apr 8;131(4):972-6. Epub 2013 Feb 8.

Lung and Allergy Research Centre, School of Medicine, University of Queensland, and the Translational Research Institute, Woolloongabba, Australia.

Our understanding of the origin and fate of the IgE-switched B cell has been markedly improved by studies in mouse models. The immediate precursor of the IgE-switched B cell is either a relatively naive nonswitched B cell or a mature IgG-switched B cell. These 2 routes are referred to as the direct and indirect pathways, respectively. IgE responses derived from each pathway differ significantly, largely reflecting the difference in time spent in a germinal center and thus time for clonal expansion, somatic hypermutation, affinity maturation, and acquisition of a memory phenotype. The clinical and therapeutic implications for IgE responses in human subjects are still a matter of debate, largely because the immunization procedures used in the animal models are significantly different from classical atopic sensitization to allergens from pollen and mites. On the basis of the limited information available, it seems likely that these atopic IgE responses are characterized by a relatively low IgG/IgE ratio, low B-cell memory, and modest affinity maturation, which fits well with the direct switching pathway. It is still unresolved how the IgE response evolves to cover a wide epitope repertoire involving many epitopes per allergen, as well as many different allergens from a single allergen source.
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http://dx.doi.org/10.1016/j.jaci.2012.12.1569DOI Listing
April 2013

IgE production to α-gal is accompanied by elevated levels of specific IgG1 antibodies and low amounts of IgE to blood group B.

PLoS One 2013 4;8(2):e55566. Epub 2013 Feb 4.

Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, The Netherlands.

IgE antibodies to gal-α-1,3-gal-β-1,4-GlcNAc (α-gal) can mediate a novel form of delayed anaphylaxis to red meat. Although IgG antibodies to α-gal (anti-α-gal or anti-Gal) are widely expressed in humans, IgE anti-α-gal is not. We explored the relationship between the IgG and IgE responses to both α-gal and the related blood group B antigen. Contradicting previous reports, antibodies to α-gal were found to be significantly less abundant in individuals with blood group B or AB. Importantly, we established a connection between IgE and IgG responses to α-gal: elevated titers of IgG anti-α-gal were found in IgE-positive subjects. In particular, proportionally more IgG1 anti-α-gal was found in IgE-positive subjects against a background of IgG2 production specific for α-gal. Thus, two types of immune response to α-gal epitopes can be distinguished: a 'typical' IgG2 response, presumably in response to gut bacteria, and an 'atypical', Th2-like response leading to IgG1 and IgE in addition to IgG2. These results suggest that IgE to a carbohydrate antigen can be formed (probably as part of a glycoprotein or glycolipid) even against a background of bacterial immune stimulation with essentially the same antigen.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0055566PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563531PMC
July 2013

Cohort profile: the prevention and incidence of asthma and mite allergy (PIAMA) birth cohort.

Int J Epidemiol 2014 Apr 11;43(2):527-35. Epub 2013 Jan 11.

Centre for Prevention and Health Services Research, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands, Department of Epidemiology, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands, Institute for Risk Assessment Sciences (IRAS), Division of Environmental Epidemiology, Utrecht University, Utrecht, The Netherlands, Department of Pediatrics, Division of Respiratory Medicine, Erasmus University Medical Center/Sophia Children's Hospital, Rotterdam, The Netherlands, Department of Pulmonology, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands, Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands, Department of Pediatric Pulmonology and Pediatric Allergology, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands and Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands.

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http://dx.doi.org/10.1093/ije/dys231DOI Listing
April 2014
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