Cross-reactivity in plant food allergy

Clinical impact of Component Resolved Diagnostics (CRD)

Author: Jan Hed, MD, PhD Ass. Prof., Clinical Immunology Karolinska Institute, Stockholm, Sweden All rights reserved. No part of this publication may be reproduced in any form without the written consent of Phadia AB. Phadia AB, 2008 Design: RAK Design AB, 2008 Printed by: X-O Graf Tryckerier AB, Uppsala, Sweden

Contents
Glossary............................................................................................................4 I. Component Resolved Diagnostics (CRD) a new trend............................6 Panallergens important proteins in plant food allergy. .............................8 Relations between some common plants..................................................9 II. Factors important for the clinical expression of allergy. ........................10 Allergen concentration.............................................................................10 Allergen stability......................................................................................10 IgE antibody concentration and cross-linkage.........................................10 Polysensitization and multi-allergen exposure.........................................11 IgE antibody specicities.........................................................................11 III. Plant food allergy. .....................................................................................12 PR-10 related plant food allergy..............................................................13 Sensitizing plant allergen. ............................................................13 Clinical considerations..................................................................14 Diagnostic considerations. ...........................................................15 Summary PR-10 proteins (Bet v 1 homologues). .........................15 LTP-related plant food allergy .................................................................16 Sensitizing plant allergen. ............................................................16 Clinical considerations..................................................................17 Diagnostic considerations. ...........................................................17 Summary nsLTPs (PR-14 proteins)..............................................17 Prolin-related plant food allergy.............................................................18 Sensitizing plant allergen. ............................................................18 Clinical and diagnostic considerations..........................................19 Summary Prolins........................................................................19 Storage protein-related plant food allergy ...............................................20 Sensitizing plant allergen. ............................................................20 Clinical considerations..................................................................21 Diagnostic considerations. ...........................................................21 Summary Storage proteins. .........................................................21 CCD-related plant food allergy................................................................22 Sensitizing plant allergen. ............................................................22 Clinical considerations..................................................................23 Diagnostic considerations. ...........................................................23 Summary CCDs...........................................................................23 IV. Identied food components of important plant protein families...........24 References .....................................................................................................26 Recent reviews related to Plant Food Allergy..........................................26 References related to PR-10 proteins (Bet v 1 homologues)...................27 References related to nsLTPs (PR-14 proteins).......................................29 References related to Prolins.................................................................31 References related to Storage Proteins...................................................34 References related to CCDs....................................................................36 Allergen database references..................................................................36
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Glossary
Allergen vs. allergen components: allergen is here referring to an allergen source (e.g. birch pollen), while the allergen components are the single allergy provoking proteins. Apiaceae: the Apiaceae or Umbelliferae (both names are allowed by the International Code of Botanical Nomenclature, ICBN) is a family of usually aromatic plants with hollow stems. It includes cumin, parsley, carrot, dill, caraway, fennel, and other relatives. the major allergen component of birch pollen (Betula verrucosa). also called PR-10 proteins; Bet v 1 related proteins in other allergens (pollens and foods) with similar structure as Bet v 1 in birch pollen. Birch pollen prolin, regarded as a minor allergen. Cross-reacting Carbohydrate Determinant; allergens are often glycoproteins, i.e. proteins with attached carbohydrate chains (glycans). IgE antibodies to plant CCDs are prone to extensive cross-reactivity, regarded as minor allergens and to have low clinical relevance.

Bet v 1: Bet v 1 homologues: Bet v 2: CCD:

Component Resolved Diagnostics IgE antibodies to an allergen mixture of the source material are measured in (CRD) vs. traditional diagnostics: traditional testing, while in CRD IgE antibodies to the single allergen components can be detected. The allergen components have different features and thus may give rise to shifting symptoms and with varying severity. Cross-reaction: IgE antibodies to one allergen may cross-react to other allergens; the clinical relevance of these antibodies varies due to the individual reactivity of the patient and due to the structural similarity of the allergens in question with the original sensitizing allergen. the amino acid sequence of a protein corresponding to the allergen binding part of the IgE antibody (Fab), epitope is another name. see determinant. a mixture of all allergens available in the source material (e.g. peanut) is coupled to the solid phase of the test, and the test will detect all antibodies in a patient sample directed to this allergen. the Fabaceae (or Leguminosae) family is a large and nancially important family of owering plants, which is commonly known as the legume family, pea family, bean family or pulse family. refers here to the carbohydrate chains of glycoproteins (allergens). MUXF3 is a common plant glycan structure (ImmunoCAP Ro214). allergens are most often glycoproteins, i.e. proteins that contain oligosaccharide chains (glycans) covalently attached to their polypeptide. a vasoactive amine causing some of the symptoms of an allergic reaction. related protein with similar structure.

Determinant: Epitope: Extract-based test:

Fabaceae:

Glycan: Glycoprotein: Histamine: Homologous protein:

Immediate vs. late phase reaction: an IgE-mediated reaction is typically developing within minutes (immediate) after exposure, while a late phase reaction may occur after hours when cells such as eosinophils have been recruited into the tissue. ImmunoCAP: In vitro test for measurement of IgE antibodies to allergens, from Phadia AB, Uppsala, Sweden. The most used test in this area and regarded as the gold standard. ImmunoCAP is also available for testing of other immunoglobulins (IgA/IgG) and other clinical areas (e.g. autoimmunity). also known as Protochordata, an animal lacking a vertebral column. Examples are insects, arachnids (e.g. mites) and crustaceans that consist of important allergy provoking glycoproteins with carbohydrate structures (glycans), which may cross-react with IgE antibodies to glycans on plant and food.

Invertebrate:

Linear peptide:

an epitope that is recognized by antibodies by its linear sequence of amino acids, or primary structure. In contrast, most antibodies recognize an epitope that has a specic three-dimensional shape as its protein structure (conformational epitope).

Major allergen vs. minor allergen: if the majority (> 50%) of the tested population reacts to an allergen or an allergen component it is described as a major allergen, while a minor allergen refers to less common reactions. Mast cell: Monovalent determinant: Multivalent determinant: Native allergen: nsLTP: a mast cell (or mastocyte) is a resident cell of several types of tissues and contains many granules rich in histamine and heparin, an effector cell in IgE mediated allergy. a single epitope. multiple epitopes. a native allergen is made from the original allergen source (e.g. peanut), i.e. extracted and/or puried (compare with recombinant allergen below). non-specic Lipid Transfer Protein; a protein family that plays a role in plant defense against fungi and bacteria, major allergen components of fruits from the Rosaceae family and clinically very important. Oral Allergy Syndrome; milder allergy reactions that most often only affect the mouth, the most well-known is the birch-fruit syndrome, caused by birch-related plant foods such as hazelnut, apple, peach and cherry, also called pollen-related food allergy. evolutionarily conserved and widely distributed allergen; ubiquitous component of several complex sources of allergens. IgE antibodies to a panallergen may cross-react with homologous allergens and thus also give rise to symptom in patients. is a short polymer formed from the linking, in a dened order, of a-amino acids. Proteins are polypeptide molecules (or consist of multiple polypeptide subunits). sensitization to several allergens; often related to more severe allergy. also called Bet v 1 homologue, belongs to the pathogenesis-related protein family PR-10, a subfamily of the Bet v 1-related superfamily, shows IgE antibody cross-reactivity between homologous allergens in pollens (Fagales) and various fruits and vegetables (Rosaceae). a protein family of actin-binding proteins involved in cytoskeleton dynamics found in most eukaryotic cells, regarded as a panallergen and showing great homology and cross-reactivity even between distantly related species, is described as a minor allergen with in general lower clinical relevance, but for some allergens (e.g. melon and tomato) prolins seem to be clinically important. enzymes present in the gastrointestinal tract that can destroy/denaturize proteins and thus the allergenicity in sensitive foods such as the Bet v 1-homologous proteins in the Rosaceae family. is a biotechnology produced allergen molecule originally identied from allergen extract. Often expressed in Escherichia coli (E. coli) and usually comparable with its natural templates in structural features and immunobiological properties, except for lacking carbohydrate chains (when produced in E. coli). the Rosaceae or rose family is a large family of plants including genera bearing fruits such as strawberry, raspberry, apple, pear, plum, almond and cherry. IgE antibody production as a result of allergen exposure in a sensitive individual. a heterogeneous group of proteins belonging to two superfamilies, Cupins (7/11 S globulins) and Prolamins (2S albumins), are dominating allergens in seeds, tree nuts and legumes, there seems to be limited cross-reactivity between storage proteins of different foods. a more general and severe allergy reaction that involves several organs and may in the worst scenario end up in an anaphylactic reaction.

OAS:

Panallergen:

Peptide: Polysensitization: PR-10 protein:

Prolin:

Protease:

Recombinant allergen:

Rosaceae: Sensitization: Storage protein:

Systemic reaction:

I. Component Resolved Diagnostics (CRD) a new trend

The result of an ImmunoCAP blood test to birch pollen is based on the detection of IgE antibodies to a number of different allergen components in the pollen extract (Figure 1a) coupled to the solid phase in the test. The serum prole of IgE antibodies to those allergen components (Figure 1b) differs, not only between patients but also geographically, due to local variation of allergen exposures. The inherent complexity of allergens and the variation between individual patient proles of induced IgE antibody specicities makes it difcult to relate extract-based test results to certain clinical phenomenon such as cross-reactivities. However, the use of molecular biology techniques has lately dramatically increased the knowledge and understanding of the clinical relevance of IgE antibody responses to the variety of components in complex allergen mixtures such as pollen and plant food allergen extracts. IgE antibodies to specic single allergen components of native allergen extracts can be used as clinical markers in estimating the clinical risk for specied food allergies. The introduction of ImmunoCAP tests based on single allergen components of native allergen extracts makes it possible to describe a unique component-specic IgE antibody prole of the patient (Figure 2). This increased knowledge will change the diagnostic routines in laboratory medicine and improve the usefulness of blood tests also in the clinical routine and thus the value for the patients. This new diagnostic routine has been described as Component Resolved Diagnostics (CRD).

a) Traditional diagnostics

b) Component Resolved Diagnostics CRD

Figure 1. Different allergen compositions in tests for traditional diagnostics (a) vs. tests for Component Resolved Diagnostics (b).

kUA /l
8.00 6.00

Patient 1

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25.00 15.00 5.00

Patient 2

0.00

Timothy rPhl p 1 rPhl p 2 nPhl p 4 rPhl p 5 rPhl p 6 rPhl p 7 rPhl p 11 rPhl p 12 (g6)

Timothy rPhl p 1 rPhl p 2 nPhl p 4 rPhl p 5 rPhl p 6 rPhl p 7 rPhl p 11 rPhl p 12 (g6)

kUA /l
1.40 1.20 1.00 0.80 0.60 0.40 0.20 0.00

Patient 3

kUA /l
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Patient 4

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10.00

Timothy rPhl p 1 rPhl p 2 nPhl p 4 rPhl p 5 rPhl p 6 rPhl p 7 rPhl p 11 rPhl p 12 (g6)

0.00

Timothy rPhl p 1 rPhl p 2 nPhl p 4 rPhl p 5 rPhl p 6 rPhl p 7 rPhl p 11 rPhl p 12 (g6)

15.00 10.00

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Patient 5

kUA /l
10.00 6.00

Patient 6

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Timothy rPhl p 1 rPhl p 2 nPhl p 4 rPhl p 5 rPhl p 6 rPhl p 7 rPhl p 11 rPhl p 12 (g6)

Timothy rPhl p 1 rPhl p 2 nPhl p 4 rPhl p 5 rPhl p 6 rPhl p 7 rPhl p 11 rPhl p 12 (g6)

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50.00 40.00 30.00 20.00 10.00 0.00

Patient 7

20.00 15.00 10.00

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Patient 8

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Timothy rPhl p 1 rPhl p 2 nPhl p 4 rPhl p 5 rPhl p 6 rPhl p 7 rPhl p 11 rPhl p 12 (g6)

0.00

Timothy rPhl p 1 rPhl p 2 nPhl p 4 rPhl p 5 rPhl p 6 rPhl p 7 rPhl p 11 rPhl p 12 (g6)

Figure 2. IgE antibody level to timothy pollen extract (Phleum pratense n) in 8 grass pollen allergic patients, compared with their IgE antibody prole to 8 different timothy components (Phl px n).

Variation in the IgE antibody proles inuences the clinical expression and reactivity of the patients.

Panallergens important proteins in plant food allergy

Proteins with similar functions in different plant species may have more or less similar molecular structures. Structural similarities between proteins decline with decreasing degree of biological relation between species. Some of the most well-studied allergen components in plants belong to protein families listed in the table below. They are widely distributed among plants and IgE antibodies to these proteins often show cross-reactivity, i.e. they may detect similarities between allergen molecules from several different sources. The term panallergens is often used for these widely distributed proteins.
Protein family Sensitivity to heat & proteases Examples of plant food allergen sources Clinical expression

PR-10 proteins Sensitive* (Bet v 1 homologues) nsLTPs (non-specic Stable Lipid Transfer Proteins) Prolins Sensitive (Bet v 2 homologues) Storage proteins Stable (2S albumins, 7S/11S globulins) CCDs (Cross-reactive Stable Carbohydrate Determinants)

Betulaceae: hazelnut* Mainly OAS* Rosaceae: e.g. apple, cherry, peach Apiaceae: e.g. carrot, celery*, fennel, parsley Fabaceae: e.g. peanut*, soybean*, mungbean Betulaceae: hazelnut Rosaceae: e.g. apple, cherry, peach Other: maize, peanut, barley, grape, cabbage Prolins are widely distributed in plants Typically: citrus fruits, melon, banana, tomato Systemic reactions common Mainly OAS**

Kernels/nuts/seeds: e.g. peanut/soybean, tree nuts, Systemic reactions seeds, cereals common CCDs are widely distributed in plant food CCD allergenicity has been proposed for celery, tomato and zucchini **

* Bet v 1 homologues in hazelnut, celery, peanut & soybean have been found to be partially heat stable and systemic reactions exist. ** IgE antibodies to prolins and CCDs are in general considered to have less clinical relevance than to other allergen components, but should not be neglected.

The probability of cross-reactivity between allergens is a function of both biology and chemistry. Peptide epitopes on native proteins can be very variable depending on the variation in amino acid sequences and complex conformations of the molecules. Therefore, it is unlikely to nd cross-reactivity between proteins that are not related to each other (non-homologous), or between similar (homologous) proteins from very distantly related species. This is in great contrast to carbohydrate epitopes on glycoproteins. The carbohydrate epitopes do not show the same variability as the peptide epitopes. Therefore they commonly show IgE antibody cross-reactivity between nonrelated allergens and even very distantly related species such as between plants and stinging insects. The amino acid sequence of prolin is a conserved structure and the epitopes are very similar in a wide range of distantly related plants. This is in contrast to the amino acid sequence of Bet v 1, which shows a high degree of identity in birch-related tree pollens and plant foods, but not to homologous proteins in more distantly related species. Therefore, IgE antibodies to prolin show a much more extended cross-reactivity to different plant food species than IgE antibodies to Bet v 1 homologues.
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Relations between some common plants

Sequence identity between some homologous proteins (%) in comparison to the reference protein for each group (100%)

Botanical relations

Division Class Family

0 50 100 0 50 100 0 50 100 0

Subclass Superorder Order

Genus

Common name

Bet v 1

Bet v 2

Pru p 3

Phl p 1
50

100

Platanaceae Fagaceae Betulaceae

Fagales

Juglandaceae Rosaceae

Platanus Castanea Quercus Fagus Alnus Betula Corylus Carpinus Carya Juglans Malus Pyrus Prunus

Fabaceae

Apiaceae Solanaceae Poaceae

Arachis Glycine Phaseolus Pisum Apium Daucus Lycopersicon Phleum Lolium Cynodon Triticum Zea

Plane Chestnut Oak Beech Alder Birch Hazel nut Hornbeam Pecan nut Walnut Apple Pear Peach Almond Cherry Peanut Soy bean Kidney bean Pea Celery Carrot Tomato Timothy grass English ryegrass Bermuda grass Wheat Corn

II. Factors important for the clinical expression of allergy

Allergen concentration
The allergen exposure is the obvious prerequisite for clinical allergic symptoms in a sensitized patient. However, the amount of inammation induced in the respiratory tract is dependent on the allergen concentration and the duration of exposure. A high concentration of an allergen might induce symptoms immediately, whereas a low concentration can induce a subclinical inammation without any obvious symptoms. This subclinical inammation, however, may amplify in the tissue over time and could later on result in clinical symptoms, even on exposure to a very low concentration of the allergen (the iceberg phenomenon).

Allergen stability
The stability of the allergen molecules in the gastrointestinal tract is important for the clinical expression in plant food allergy. There is a great variability between allergen components with respect to stability to heat and protease digestion mimicking the gastric environment (see page 8). Stable allergens such as nsLTPs and storage proteins are still functional in the gastrointestinal tract and may result in systemic reactions (urticaria, dyspnea and anaphylaxis) in contrast to Bet v 1 homologues and prolins, which are easily destroyed and mainly give rise to the oral allergy syndrome (OAS).

IgE antibody concentration and cross-linkage

The concentration of IgE antibodies to an allergen is crucial for triggering clinical symptoms. Most of the IgE antibodies are, however, not circulating in the blood stream, but bound to the effector cells (mast cells) in the tissue. Equilibrium exists between free and cell bound IgE. Therefore, the concentration of IgE antibodies in patient sera reects the amount of allergen-specic IgE antibodies bound to the cell surface of effector cells. Cross-linkage of cell surface IgE antibodies by allergens is a prerequisite to induce cell activation. The probability of cell activation increases with the number of cross-linked IgE molecules on the cell surface. This indicates that there must be at least two epitopes on the allergen component, which can bind to two different IgE molecules on the cell surface to achieve the activation. It could be two identical (A and C) or two different epitopes (B) on the allergen. In case B, IgE antibodies with different specicities (polysensitization) are needed to result in cross-linking and cell activation. If the patient only has IgE antibodies to one of the epitopes there will not be any cross-linking unless the epitopes are not repetitive.
A B C

Epitope 1 Epitope 2
Figure 3. Cross-linking of surface IgE antibodies on a mast cell by different types of allergens (A-C).

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This complexity in cross-linking of cell bound IgE antibodies might explain some of the controversy over the clinical relevance of IgE antibodies to some allergens as described below (see page 22 about CCD-related plant food allergy).

Polysensitization and multi-allergen exposure

As described earlier, cell activation and inammation are related to the amount of crosslinking of surface bound IgE. It is also known that the risk to develop asthma symptoms is related to the number of IgE antibody specicities in the sensitization prole of the allergic patient. Furthermore, a polysensitized patient has an increased risk for triggering effector cell activation when exposed to several allergens due to an increase in the total amount of cross-linking of IgE on the cell-surfaces. This stresses the importance of describing the sensitizing prole (different IgE antibody specicities) in a patient related to actual allergen exposure since each IgE specicity adds to the cell activation process if the allergen is present. Each IgE antibody specicity adds to the cell activation process if the allergen is present.

IgE antibody specificities

It is important to be aware of the fact that the concentration of allergen-specic IgE measured by extract-based tests is the sum of IgE-antibodies to different allergen components in the extracts and thus consists of different specicities. This difference in specicity prole is dependent on the individual sensitivity, but also the type of allergen that initially sensitized the patient. To gain more information, especially in food allergy, it is of great value to analyze the separate allergen specicities of the different IgE-antibodies since some components: u are widely distributed and may be involved in IgE antibody cross-reactivity and thus important to be aware of u have a high molecular stability to heat and proteases and will thus immunologically functional in the gastrointestinal tract, giving rise to anaphylaxis (e.g. nsLTPs and storage proteins) u will easily be destroyed by proteases in the gastric environment (Bet v 1 homologues and prolins) and thus immunologically functional only in the mouth, giving rise to the oral allergy syndrome (OAS) u will easily be destroyed by heat and thus not immunologically functional as cooked (e.g. Bet v 1 homologues and prolins) u are univalent (only one binding site for IgE) with respect to the IgE response of the patient and are thus inefcient to activate effector cells by cross-linking IgE-receptors (some CCD-containing allergens)

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III. Plant food allergy

A number of different plant food allergy syndromes have been described based on the plant related foods that trigger the symptoms. Examples of such syndromes are ragweedbanana-melon, birch-fruit-vegetable, birch-mugwort-hazelnut, latex-banana, mugwortcelery-spice syndrome, and so on. New knowledge about diverse sensitization proles in different geographic areas and cross-reacting allergen components (panallergens) in pollens and plant foods indicates that the syndromes vary a lot and are overlapping. The appearance of polysensitization, when testing for IgE antibodies to different plant foods or pollen allergens, is often due to quite a few dened cross-reacting allergenic components (panallergens) rather than to many different pollen species and plant foods. In this presentation, we prefer to group different plant food allergies according to the allergen component triggering the symptoms: u PR-10 proteins (Bet v 1 homologues) u non-specic Lipid Transfer Proteins (nsLTPs) u Prolins u Storage proteins u Cross-reacting carbohydrate determinants (CCDs) The list is certainly not complete, but represents the most established and studied allergy triggering plant protein families of today. The number of clinically relevant panallergens will increase with increased knowledge of this complexity. The suggested type of classication used in this presentation also seems to be the current opinion in recent publications. Moreover, it is most likely a good and pedagogical starting point for evaluation and understanding in the clinical practice to predict plant food cross-reactivity and possible related clinical expressions.

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PR-10 related plant food allergy

Sensitizing plant allergen
The major allergen component Bet v 1 from birch pollen (Betula verrucosa) belongs to a group of plant proteins termed pathogenesis-related protein family number 10 (PR-10). Homologous proteins to Bet v 1 are widely distributed in the plant kingdom. These types of far and wide distributed allergens are described as panallergens. The food reactions seen in birch pollen allergic patients are primarily explained by IgE antibodies to Bet v 1, induced by birch pollen, which cross-react with Bet v 1 homologous proteins in different plant foods. Bet v 1 homologues are primarily localized to the pulp of the fruit, in contrast to nsLTPs which are localized to the peel, and storage proteins which are localized to the fruit stone (seed/nut/kernel). In the birch-rich areas of northern and central Europe almost all birch pollen allergic patients are sensitized to Bet v 1 and most of them have Bet v 1-IgE antibodies as the only specicity. In southern Europe, where birch trees are uncommon or absent, a positive test to birch pollen often reects sensitization to Bet v 1 homologues in other trees closely related to birch (e.g. alder, hazel, hornbeam, beech and chestnut) or sensitization to other pollen allergens such as prolins (Bet v 2 homologues) in grass and weed (e.g. mugwort and Parietaria).
Table 1. Some identied PR-10 related plant food components (see extended list on page 24-25). [Family] Food allergen [Betulaceae] Hazelnut [Rosaceae] Apple Apricot Cherry Peach Pear Raspberry Strawberry [Apiaceae] Carrot Celery Parsley PR-10 protein (Bet v 1 superfamily) Cor a 1 Mal d 1 Pru ar 1 Pru av 1;Pru c 1 Pru p 1 Pyr c 1 Rub i 1 Fra a 1 Dau c 1 Api g 1 Pet c 1 [Family] Food allergen [Fabaceae] Mung bean Peanut Soybean [Asparagaceae] Asparagus [Solanaceae] Bell pepper Bonnet pepper Potato [Anacardiaceae] Mango [Cucurbitaceae] Melon PR-10 protein (Bet v 1 superfamily) Vig r 1 Ara h 8 Gly m 4 Aspa o PR-protein Cap a 17 kDa Cap ch 17 kDa STH-2/STH-21 Man i 14 kDa Cuc m 3

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Clinical considerations
Oral Allergy Syndrome (OAS)
50 to 90% of birch pollen allergic patients have been reported to have some pollen related food allergy. Bet v 1-related food allergy is closely associated with OAS to hazelnut and different plant foods of the Rosaceae family such as apple, peach and cherry. The clinical sensitivity can be expanded to other plant foods, but not without having clinical reactions to hazelnut and Rosaceae fruits as well. Other clinically important food allergies commonly associated with Bet v 1 are reactions to foods from the Apiaceae family (e.g. celery and carrot) and/or to the Fabaceae family (e.g. peanut and soybean). The risk to develop clinical symptom such as OAS is related to the concentration of IgE antibodies to Bet v 1. Birch pollen sensitized patients who remain OAS-free often have low concentrations of IgE antibodies to birch. The Bet v 1 homologous proteins in the Rosaceae family are very sensitive to heat and proteases. Therefore, allergic reactions to Rosaceae fruits in Bet v 1 homologous food allergy are mainly triggered by fresh fruits and primarily restricted to the mouth (OAS) since Bet v 1 will be destroyed in the stomach. This is in great contrast to Rosaceae fruit reactions provoked by IgE antibodies to nsLTPs, which often give more serious and sometimes life threatening reactions. However, OAS may also occur due to nsLTP and allergic reactions from Bet v 1 homologous foods may occasionally be more severe. Patients with Bet v 1 homologous food allergy will neither get symptoms when drinking processed fruit juice or eating heated fruits, also in contrast to the serious Rosacea fruit reactions based on nsLTP food allergy. Furthermore, since the nsLTPs, but not Bet v 1 homologues, are primarily concentrated to the peel of the apple or the fuzz and peel of the peach, peeling will not decrease the symptoms of OAS in Bet v 1-related food allergy.

Systemic reactions
The Bet v 1 homologous proteins in hazelnut, celery and peanut/soybean have been shown in some studies to be more heat stable than fruits from the Rosaceae family. This may explain why those plant foods sometimes trigger more serious systemic reactions in Bet v 1-related food allergy. During recent years this has been clearly shown with some products based on soybean. Allergic reactions to celery/carrot (Apiaceae) and soybean/peanut (Fabaceae) are also associated with higher concentrations of IgE antibodies to Bet v 1.

Difference in triggering immediate and late phase allergic reaction

Most of the plant-related allergen determinants described in IgE-mediated food allergy are exposed on the native allergen molecule. Recently it has been shown that birch pollen-related foods may induce worsening of atopic dermatitis two days after food exposure to fresh food. Furthermore, heat treatment of Bet v 1-related food allergens destroys the ability to trigger an immediate symptom such as OAS, whereas the denatured allergen still can trigger the lymphocytes relevant for late clinical reactions. This has been shown to be the case in some patients with atopic dermatitis and might be relevant for other clinical conditions as well.

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The mechanistic background is that heat treatment destroys the native three-dimensional molecular structure, which is important for binding to the IgE molecule and the immediate reaction, but does not affect the linear peptides important for the late phase cellular reaction. This phenomenon has also been proposed as a possible mechanism to explain why serum IgE antibody levels to pollen allergens remain high outside the pollen season. Heat treatment destroys the native three-dimensional molecular structure of PR-10 proteins, which is important for binding to the IgE molecule and the immediate reaction, but does not affect linear peptides important for the late phase cellular reaction.

Diagnostic considerations
The most important clinical question in food allergy is to identify those patients with a high risk for systemic reactions. As described above, apple allergy (Rosaceae allergy) in northern Europe is in most cases a rather mild food allergic reaction in Bet v 1 sensitized patients and most often restricted to the mouth (OAS). This is in great contrast to apple allergy in southern Europe where it more often triggers a severe systemic reaction based on IgE antibodies to nsLTP. This serious form of apple allergy is often seen without any sensitization to common pollen allergens and without clinical symptom of pollen allergy. Such cases of IgE sensitization to nsLTP do also exist in the birch-rich areas of northern Europe, but might be disguised by a concomitant positive test to birch pollen and the presence of IgE antibodies to Bet v 1. In birch pollen sensitized patients, with low sensitization to Bet v 1 and high sensitization to species of the Rosaceae family and/or hazelnut, the possibility of sensitization to nsLTP (and/or storage proteins) should be suspected with an obvious risk for more severe clinical reactions. Furthermore only about 50% of hazelnut sensitized children in birch-rich areas have a clinical sensitivity to hazelnut and those with systemic reactions often have lower concentration of antibodies to Bet v 1 and are often sensitized to other nuts/peas (tree nuts and peanuts) as well. u It is important to investigate the presence of IgE antibodies to Bet v 1 and nsLTP in patients sensitized to Rosaceae food allergens or having clinical symptoms to Rosaceae foods to evaluate the risk for serious systemic reactions u Sensitization or clinical symptoms to Rosaceae plant foods and hazelnut, without broad sensitization to other fruits and vegetables, are typical markers of Bet v 1(or nsLTP) but not prolin sensitization u High concentration of IgE antibodies to Bet v 1 might be a risk factor for serious reactions to hazelnut, celery, soybean and peanut, even if these food products are processed to a certain degree

Summary PR-10 proteins (Bet v 1 homologues)

l Heat labile proteins, primarily localized to the pulp of l Cooked and processed foods are often tolerated l Often associated with local symptoms such as oral allergy syndrome (OAS) l Commonly related to allergic reactions to fruit and vegetables in northern Europe 15

the fruit

LTP-related plant food allergy

Sensitizing plant allergen
Non-specic lipid transfer proteins (nsLTP) are very stable small molecules widespread in plants. IgE sensitization to nsLTP has primarily been described from southern Europe in patients with severe reactions to peach and other fruits belonging to the Rosaceae family and not associated with pollen allergy. The sensitization pathway is not yet completely understood, but an association with mugwort and plane tree has been described. Since nsLTP is very concentrated in the fuzz of peach this has also been proposed. The presence of nsLTP sensitization in food allergic patients in central and northern Europe and the US is not well investigated but has been described.

Table 2. Some identied LTP-related plant food components (see extended list on page 24-25). [Family] Food allergen [Betulaceae] Hazelnut [Rosaceae] Almond Apple Apricot Cherry Peach Pear Plum Raspberry Strawberry [Asparagaceae] Asparagus [Brassicaceae] Cabbage Turnip [Apiaceae] Carrot Parsley [Euphorbiaceae] Castor bean nsLTP [Family] Food allergen [Lamiaceae] Rape seed [Vitaceae] Grape [Asteraceae (Compositae)] Lettuce Sunower [Poaceae (Gramineae)] Barley Maize Rice Spelt Wheat [Rutaceae] Citrus fruits [Fabaceae] Peanut [Solanaceae] Tomato [Juglandaceae] Walnut nsLTP

Cor a 8 Pru du LTP Mal d 3 Pru ar 3 Pru av 3 Pru p 3 Pyr c 3 Pru d 3 Rub i 3 Fra a 3 Aspa o 1 Bra o 3 Bra r LTP Dau c LTP Pet c LTP Ric c LTP

Bra n LTP Vit v 1 Lac s 1 Hel a 3 Hor v LTP Zea m 14 Ory s LTP Tri s LTP Tri a 14 Cit s 3;Cit l 3;Cit r 3 Ara h 9 Lyc e 3 Jug r 3

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Clinical considerations
LTP-related plant food allergy has primarily been described to peach, cherry and apple, plants belonging to the Rosaceae family, but also to hazelnut (Betulaceae). Severe clinical symptoms based on IgE antibodies to nsLTP have furthermore been shown for less related food allergens such as maize, peanut, barley, grape, cabbage and more (see page 24-25). In Rosacea allergy, based on nsLTP, it is therefore important to be aware of the possibility of severe reactions also to unrelated vegetables and fruits. However, it has recently been shown that nsLTP-allergic patients seem to tolerate typical Bet v 1-related plant foods such as potato, and carrot but also banana and melon (prolin-related). The important characteristic of nsLTP, which explains its clinical relevance, is the high resistance to heat and proteases. The molecule will not be destroyed by the gastric uid and will thus be immunologically functional in the gastrointestinal tract with the possibility to trigger systemic reactions such as anaphylaxis, urticaria/angioedema and asthma. The chemical stability of nsLTP, in contrast to Bet v1 and prolin, is the explanation why these patients will get symptoms after drinking processed juice or heated food. Since the allergen component is primarily localized to the peel of the fruit patients get less symptoms after eating peeled fruit than patients with allergy based on Bet v 1 homologues or prolins. The prevalence of systemic reactions in apple allergic patient in northern Italy has been described to be 35% compared to less than 10% in apple allergic patients in the birch-rich areas of Europe. However, how common nsLTP-sensitization is in northern Europe and the US has not been thoroughly investigated. In two very recent studies from birch endemic areas, IgE-antibodies to nsLTP were common in children with provocation veried apple allergy, and in children with objective symptoms to hazelnut challenge. The risk of clinical symptoms is related to the concentration of IgE antibodies to nsLTP.

Diagnostic considerations
The typical nsLTP allergic case is a patient from southern Europe with clinical, often severe, symptoms of Rosaceae allergy, but without concomitant pollen allergy. A high degree of sensitization to mugwort or plane tree and a low sensitization to Bet v1 have been described as risk markers for nsLTP sensitization in apple allergic patients in northern Italy. In a Spanish population cherry allergy based on IgE sensitization to nsLTP was associated with plane tree and mugwort, but not with Parietaria. High homology is found between nsLTPs from different fruits and suggests that one nsLTP such as Pru p 3 from peach can be a marker for genuine Rosaceae allergy.

Summary nsLTPs (PR-14 proteins)

l Proteins stable to heat and digestion, primarily localized to the peel of l Reactions also to cooked and processed foods l Often associated with systemic and more severe reactions in addition to

the fruit/vegetable

Oral Allergy Syndrome (OAS)

l Commonly related to allergic reactions to fruit and vegetables in southern Europe

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Profilin-related plant food allergy

Sensitizing plant allergen
Prolins are small proteins in the cytoplasm of nucleated cells and they are involved in the function of the intracellular brils of the cells. Plant prolins are described as minor allergens in most pollen species and plant food allergens and show great homology and cross-reactivity even between distantly related species. The prevalence of prolin sensitization in pollen allergic patients in central and southern Europe has been estimated to 10 to 35%, but seems to be rarer in northern Europe. The prevalence increased to 55% in patient populations with multi-pollen sensitization where grass pollen sensitization is dominating.
Table 3. Some identied prolin-related plant food components (see extended list on page 24-25). [Family] Food allergen [Betulaceae] Hazelnut [Rosaceae] Almond Apple Cherry Peach Pear Plum Strawberry [Asparagaceae] Asparagus [Musaceae] Banana [Poaceae (Gramineae)] Barley Rice Wheat [Solanaceae] Bell pepper Potato Tomato [Apiaceae] Carrot Celery Parsley Prolin [Family] Food allergen [Sapindaceae] Litchi [Anacardiaceae] Mango [Cucurbitaceae] Melon Watermelon [Rutaceae] Citrus fruits [Fabaceae] Garden pea Peanut Soybean [Bromeliaceae] Pineapple [Juglandaceae] Walnut [Lamiaceae] Rape seed [Brassicaceae] Mustard [Pedaliaceae] Sesame seed [Asteraceae (Compositae)] Sunower Prolin

Cor a 2 Pru du 4 Mal d 4 Pru av 4 Pru p 4 Pyr c 4 Pru d prolin Fra a 4 Aspa o prolin Mus xp 1 Hor v 12 Ory s 12 Tri a 12 Cap a 2 Sola t prolin Lyc e 1 Dau c 4 Api g 4 Pet c 2

Lit c 1 Man i 3 Cuc m 2 Cit la prolin Cit s 2 Pis s prolin Ara h 5 Gly m 3 Ana c 1 Jug r prolin Bra n prolin Vig r prolin Ses i prolin Hel a 2

18

This might reect geographical differences in pollen exposure where birch pollen sensitization is dominating in northern Europe and grass pollen sensitization in southern Europe. Prolins are also important allergens in mugwort and Parietaria. Olive, plane tree and cypress are other important prolin sources in the Mediterranean areas and so is ragweed in US.

Clinical and diagnostic considerations

It has been proposed that the use of prolin from just one plant species is enough for testing IgE-sensitization to prolin, due to the large homology and IgE antibody crossreactivity between plant food prolins. Prolins from birch (Bet v 2) and/or timothy grass (Phl p 12) are most widely used. This extended cross-reactivity is not only seen among botanically unrelated pollens but also between pollen and food as well as between pollen and latex. The serum levels of IgE antibodies to prolins have been shown to be related to the number of positive food tests, but also to the expression of clinical symptoms. In patients with reported plant food symptoms, IgE antibodies to prolin have shown highest correlation to IgE sensitization to potato, carrot, celery, buckwheat, paprika and tomato. In some types of food allergy the prevalence of IgE-sensitizations to prolins is very high. Examples of this are tomato allergy with 44% prolin sensitization and citrus fruit allergy with up to 95% prolin sensitization. Symptoms to citrus fruits, melon, banana and/or tomato have been described as clinical markers of prolin sensitization. Prolins are, like Bet v 1 homologues, sensitive to heat and proteases and will thus primarily give rise to OAS as the clinical manifestation of food allergy. However, the most accepted opinion today is that IgE-sensitization to prolin seems to have less clinical relevance than sensitization to Bet v 1, although in some cases prolin sensitization may cause severe reactions.

Summary Profilins
l Panallergens that show great homology and cross-reactivity even between distantly related plant species l Sensitization seldom associated with clinical symptoms, but may cause demonstrable or even severe reactions in a small minority of patients (e.g. citrus fruits, melon, banana and/or tomato) l Broad plant and plant food sensitization proles may be explained by

prolin-specic IgE antibodies

19

Storage protein-related plant food allergy

Sensitizing plant allergen
The storage protein family consists of a heterogeneous group of proteins belonging to two different superfamilies; Cupins and Prolamins. They are often designated according to their sedimentation rate, 7S and 11S globulins belonging to Cupins and 2S albumins belonging to Prolamins. Storage proteins are the dominating allergens in seeds, fruit stones and kernels. The molecule structures are complex and the relation to allergy is not fully understood. IgE sensitization to storage proteins is important in peanut/soybean, tree nut, seed and cereal allergy. The chemical structure of storage proteins is commonly regarded as much more stable to heat and proteases compared to Bet v1 homologues and prolins. There are indications that the 2S albumin is the most stable molecule of the storage proteins and therefore believed to be most clinically important. Bet v 1 homologous proteins, prolins and nsLTPs are also present in nuts, but in much lower concentrations.
Table 4. Some identied storage protein-related plant food components (see extended list on page 24-25). Storage protein 2S albumin Vicilin-like Legumin-like [Family] protein protein Food allergen 7S globulin 11S globulin [Betulaceae] Hazelnut Cor a 11 Cor a 9 [Rosaceae] Almond Pru du 2S albumin Pru du Amandin Ber e 2 Ana o 2 Pis v 2, 5 Ric c 2 Storage protein 2S albumin Vicilin-like Legumin-like [Family] protein protein 7S globulin 11S globulin Food allergen [Pedaliaceae] Sesame seed Ses i 1, 2 Ses i 3 Ses i 6, 7 [Asteraceae (Compositae)] Sunower Hel a 2S albumin [Brassicaceae] Mustard Sin a 1; Bra j 1 Turnip Bra r 1 [Juglandaceae] Pecan Car i 1 Walnut Jug n 1/ Jug r 1 [Lamiaceae] Rape seed Bra n 1 Fag e 1 Sin a 2

[Lecythidaceae] Brazil nut Ber e 1 [Anacardiaceae] Cashew nut Ana o 3 Pistachio Pis v 1 Ana o 1 Pis v 3

[Euphorbiaceae] Castor bean Ric c 1, 3

Jug n 2/ Jug r 2

Jug r 4

[Fabaceae] Chick pea Cic a 2S Cic a 11S albumin globulin Garden pea Pis s 1, 2 Lentil Len c 1 Lupine Lup a Vicilin Lup a 11S globulin Peanut Ara h 2, 6, 7 Ara h 1 Ara h 3, 4 Soybean Gly m 2S Gly m Bd Gly m Glycinin albumin 28k/60k G1, G2, G4

[Polygonaceae] Buckwheat Fag e 10/16 kDa Fag e 19 kDa

20

Clinical considerations
IgE sensitization to storage proteins in peanut/soybean, tree nuts or seeds is regarded as an important risk marker for severe systemic reactions. However, there seems to be great geographical differences. In southern Europe IgE sensitization to nsLTP is shown to be the most important allergen component for systemic reaction in hazelnut allergy, whereas 11S globulin is described as the most important in the US. LTP is not a storage protein per se, but belongs to the same superfamily (Prolamins) as 2S albumins. The 2S albumin seems to be the dominating allergen in other tree nut, seed and peanut allergies. Polysensitization to different nuts and seeds is common and is a clinical phenomenon to be aware of. The IgE sensitization to storage proteins, and the related cross-reactivity, is complex since sensitization to unrelated nuts and seeds are often seen and increases with age. IgE antibody cross-reactivity can also be seen between tree nuts and peanut, this is a new nding. In a recent study 66% of peanut allergic patients showed sensitization to tree nuts as well. The risk for clinical symptoms is related to the level of IgE sensitization and has been well documented in childhood peanut allergy. In a recent European study it was shown that all patients with proven peanut allergy were sensitized to 2S albumin (Ara h 2) and less frequently to 7S globulin (Ara h 1) and 11S globulins (Ara h 3). However, patients polysensitized to the different storage proteins had a more severe disease than those monosensitized to the 2S albumin component and they also had higher levels of peanutspecic serum IgE antibodies. The immunological and biological background for the sensitization to storage proteins is not completely understood. There is no obvious relation between sensitization to pollens and sensitization to storage proteins. In pollen sensitized patients a positive peanut test could be due to IgE antibodies to prolin, Bet v 1 or CCD, but are then often of less clinical relevance in the majority of all cases.

Diagnostic considerations
Cross-reactivity between peanuts, tree nuts and seeds is common even if they are botanically unrelated. Therefore it is often recommended that IgE antibodies to several nuts should be tested if there is a risk for severe systemic reactions. High levels of IgE antibodies to peanuts have been shown to have a high positive predictive value for clinical relevant peanut allergy in children. Food challenge tests with their clinical risks are omitted in those cases. The important clinical question is to identify patients with increased risk for systemic reaction. A history of anaphylaxis following the ingestion of peanut, sesame seed, sunower seed, mustard or tree nuts in a patient not sensitized to peach and/or other Rosaceae foods (except almond) suggests hypersensitivity to seed storage proteins. Tests based on nsLTP and different storage proteins are crucial to identify possible provoking foods for best treatment/avoidance recommendations. In peanut allergy IgE antibodies to 2S albumin (Ara h 2) seem to have a very high sensitivity and specicity to identify a clinically relevant peanut sensitization.

Summary Storage proteins

l Proteins stable to heat and digestion, primarily localized to the seed/nut/kernel l Reactions also to cooked and processed foods l Sensitization is regarded as an important risk marker for severe systemic reactions l Cross-reactivity is often seen to unrelated nuts and seeds and seems to increase with age 21

CCD-related plant food allergy

Sensitizing plant allergen
Glycoproteins in plants and in invertebrate animals carry glycans with carbohydrate determinants, which do not exist in mammals. Since these determinants function as foreign epitopes in humans they are highly immunogenic and will give rise to antibodies such as IgE. Glycoproteins can carry two basic types of glycans, i.e. N-linked and O-linked glycans. The two most studied carbohydrate determinants in allergic reactions in humans are based on a fucose or a xylose bound to N-linked glycans. This linkage is not found in mammals. The widespread presence of fucose and xylose on N-linked glycans of plants, but also of invertebrates (to less extent), explains the high degree of cross-reactivity that has been reported for carbohydrate-specic IgE antibodies. These carbohydrate determinants have been termed Cross-reactive Carbohydrate Determinants (CCDs) and the IgE antibodies are termed anti-CCD IgE. Approximately 20% of patients with allergy to pollen have IgE antibodies to pollen allergens with molecular masses higher than 30kDa. A great part of their IgE-binding is dependent on carbohydrate determinants.

Allergen A Active

Allergen B Active

Allergen C Inactive

Carbohydrate epitope Peptide epitope

Figure 4. Degranulation of mast cells require the binding of at least two epitopes to two adjacent IgE antibody molecules. This cross-linking may be achieved by two peptide epitopes, but also by one glycan and one peptide epitope (A) as well as by two glycan epitopes (B) if IgE antibodies with these specicities co-exist. However, if there is only one epitope (C), or only one IgE antibody specicity in case A, no cross-linking and thus no degranulation will occur.

22

Clinical considerations
There is an ongoing discussion about the clinical relevance of these CCD-specic IgE antibodies. At the one extreme these antibodies are claimed to be without any clinical relevance and at the other it is suggested that they can induce anaphylactic reactions. One important factor for the clinical relevance of IgE antibodies to CCD is if the allergen components are monovalent or multivalent with respect to the carbohydrate determinant. Monovalent allergen components, such as the major peanut allergen (Ara h 1), cannot cross-link anti-CCD IgE bound on mast cells and thus do not induce histamine release and clinical symptoms. However, if there also exists IgE response to other protein determinants of the CCD-monovalent component a cross-linking is possible and can give rise to histamine release (Figure 4). Therefore, when evaluating the clinical relevance of anti-CCD IgE it is important to identify the sensitizing allergen and thus the risk of concomitant IgE to protein epitopes. It has been shown that patients sensitized to grass pollen develop anti-CCD IgE that also binds to CCD monovalent peanut allergens, but does not give rise to any clinical symptoms. However, anti-CCD IgE is of clinical relevance in proteins with multiple CCD epitopes, as have been shown in allergy to tomato and celery. In conclusion, even if the clinical relevance of anti-CCD IgE has been shown in some cases most researchers agree that it has less clinical relevance than many other allergen components.

Diagnostic considerations
Since these CCD epitopes are widely distributed in plants and invertebrate animals the corresponding IgE antibodies will give rise to positive in vitro tests (cross-reactivity) to many different and unrelated plant allergens including latex, but also invertebrate animals such as bee/wasp, cockroach, mite and shellsh. When very broad allergen proles are obtained in allergy testing it can be due to anti-CCD IgE or anti-prolin IgE. Therefore it is important to investigate if CCD antibodies are present. This can be done routinely by IgE antibody testing with bromelain or horseradish peroxidase, but also by the use of a test specic to MUXF3, a common plant glycan structure. A positive in vitro test and a negative skin prick test to the same plant food allergen may indicate presence of non-cross linking CCD-specic IgE antibodies to that allergen. However, this does not exclude cross-linking to other allergens with multivalent CCD epitopes or the presence of concomitant IgE antibodies to peptide epitopes.

Summary CCDs
l CCD epitopes are widely distributed in plants and invertebrate animals l Sensitization is rarely associated with clinical symptoms, but may cause demonstrable or even severe reactions in a small minority of patients (has been proposed for celery, tomato and zucchini) l Broad allergen sensitization proles may be explained by CCD-specic IgE antibodies

23

IV. Identified food components of important plant protein families

Food allergen PR-10 protein nsLTP Prolin (Bet v 1 superfamily) 2S albumin Almond Aniseed Apple Apricot Asparagus Mal d 1 Pru ar 1 Aspa o PR-protein Pru du LTP Mal d 3 Pru du 4 Pim a 1 Storage protein Vicilin-like Legumin-like protein proteins 7S globulin 11S globulin Pru du Amandin Pru du 2S albumin

Pim a 2 Mal d 4

Pru ar 3 Aspa o 1 Aspa o prolin Pers a prolin Mus xp 1 Hor v 12 Cap a 2 Ber e 1 Fag e 10/16 kDa Fag e 19 kDa Ana o 3 Ana o 1 Ber e 2 Fag e 1 Ana o 2 Ric c 2

Avocado Banana Barley Bell pepper Hor v LTP Cap a 17 kDa

Bonnet pepper Cap ch 17 kDa Brazil nut Buckwheat Cabbage Castor bean Carrot Celery Cherry Chestnut Dau c 1 Pru av 1;Pru c 1 Cas s 1 Cashew nut Ric c LTP Dau c LTP Pru av 3 Cas s 8

Bra o 3 Ric c 1, 3

Dau c 4 Api g 4 Pru av 4 Cas s prolin Cic a 2S albumin Cic a 11S globulin

Api g 1

Chick pea Citrus fruits Coriander Cumin

Cit s 3;Cit l 3; Cit s 2 Cit r 3 Coc n prolin Coc n 29kDa Cor s 2 Cuc s prolin Cum c 2 Pis s prolin Cor a 2 Pis s 1, 2 Cor a 11 Len c 1 Cor a 9

Coconut Cor s 1 Cum c 1 Cucumber Garden pea Grape Hazelnut Kiwi Cor a 1 Cor a 8

Vit v 1 Act d prolin

Act d 8;Act c 8

Lentil Lettuce Litchi

Lac s 1 Lit c 1 Lup a 11S globulin

Lupine Lup a Vicilin Maize 24 Zea m 14

IV. Identified food components of important plant protein families

Food allergen PR-10 protein nsLTP Prolin (Bet v 1 superfamily) 2S albumin Mango Melon Mung bean Man i 14 kDa Cuc m 3 Vig r 1 All c LTP Pet c LTP Pru p 3 Ara h 9 Pyr c 3 Storage protein Vicilin-like Legumin-like protein proteins 7S globulin 11S globulin Man i 3 Cuc m 2 Vig r prolin Sin a 1; Bra j 1 Sin a 2 All c prolin Pet c 2 Pru p 4 Ara h 5 Ara h 2, 6, 7 Car i 1 Ara h 1 Ara h 3, 4 Pyr c 4 Dio k prolin Ana c 1 Pis v 1 Pis v 3 Pis v 2, 5 Pru d prolin Pap s prolin Sola t prolin Cuc ma prolin, Cuc ma 13 kDa Bra n 1

Mustard Onion Parsley Peach Peanut Pear Persimmon Pet c 1 Pru p 1 Ara h 8 Pyr c 1

Pecan Dio k 17kDa Pineapple Plum Poppy seed Potato Pru d 3

Pistachio Pap s 17 kDa STH-2/STH-21

Pumpkin Rape seed Raspberry Rub i 1 Rice

Bra n LTP Bra n prolin Ory s LTP

Rub i 3 Ory s 12 Cro s 2 Ses i prolin Ses i 1, 2 Ses i 3 Ses i 6, 7 Gly m 2S Gly m Bd28k/60k Gly m Glycinin albumin G1, G2, G4

Saffron Sesame seed

Soybean Gly m 4 Gly m 3 Spelt Strawberry Fra a 1 Tri s LTP Spinach Fra a 3 Hel a 3 Lyc e 3 Jug r 3 Tri a 14 Sunower Tomato Turnip Walnut Wheat

Spi o prolin Fra a 4 Hel a 2 Hel a 2S albumin Bra r 1 Jug n 1/Jug r 1 Jug n 2/Jug r 2 Jug r 4 Lyc e 1 Jug r prolin Cit la prolin Tri a 12 Cuc p prolin

Bra r LTP

Watermelon Zucchini

25

References
Recent reviews related to Plant Food Allergy
1. Zuidmeer L, van Ree R. Lipid transfer protein allergy: primary food allergy or pollen/food syndrome in some cases. Curr Opin Allergy Clin Immunol. 2007;7:269-73. 2. Richard C, Leduc V, Battais F. Plant lipid transfer proteins (LTPS): biochemical aspect in panallergen--structural and functional features, and allergenicity. Allerg Immunol (Paris). 2007;39:76-84. 3. Wopfner N, Dissertori O, Ferreira F, Lackner P . Calcium-binding proteins and their role in allergic diseases. Immunol Allergy Clin North Am. 2007;27:29-44. 4. Bohle B. The impact of pollen-related food allergens on pollen allergy. Allergy. 2007;62:3-10. 5. Salcedo G, Sanchez-Monge R, Barber D, Diaz-Perales A. Plant non-specic lipid transfer proteins: an interface between plant defence and human allergy. Biochim Biophys Acta. 2007;1771:781-91. 6. Marion D, Bakan B, Elmorjani K. Plant lipid binding proteins: properties and applications. Biotechnol Adv. 2007;25:195-7. 7. Altmann F. The role of protein glycosylation in allergy. Int Arch Allergy Immunol. 2007;142:99-115. 8. Egger M, Mutschlechner S, Wopfner N, Gadermaier G, Briza P , Ferreira F. Pollen-food syndromes associated with weed pollinosis: an update from the molecular point of view. Allergy. 2006;61:461-76. 9. Breiteneder H, Clare Mills EN. Plant food allergens--structural and functional aspects of allergenicity. Biotechnol Adv. 2005;23:395-9. 10. Gangur V, Kelly C, Navuluri L. Sesame allergy: a growing food allergy of global proportions? Ann Allergy Asthma Immunol. 2005;95:4-11. 11. Breiteneder H, Mills C. Nonspecic lipid-transfer proteins in plant foods and pollens: an important allergen class. Curr Opin Allergy Clin Immunol. 2005;5:275-9. 12. Breiteneder H, Mills EN. Molecular properties of food allergens. J Allergy Clin Immunol. 2005;115:14-23. 13. Malandain H. IgE-reactive carbohydrate epitopes--classication, cross-reactivity, and clinical impact. Allerg Immunol (Paris). 2005;37:122-8. 14. Salcedo G, Sanchez-Monge R, Diaz-Perales A, Garcia-Casado G, Barber D. Plant non-specic lipid transfer proteins as food and pollen allergens. Clin Exp Allergy. 2004;34:1336-41. 15. Mothes N, Horak F, Valenta R. Transition from a botanical to a molecular classication in tree pollen allergy: implications for diagnosis and therapy. Int Arch Allergy Immunol. 2004;135:357-73. 16. Mills EN, Jenkins JA, Alcocer MJ, Shewry PR. Structural, biological, and evolutionary relationships of plant food allergens sensitizing via the gastrointestinal tract. Crit Rev Food Sci Nutr. 2004;44:379-407. 17. Breiteneder H, Radauer C. A classication of plant food allergens. J Allergy Clin Immunol. 2004;113:821-30. 18. Roux KH, Teuber SS, Sathe SK. Tree nut allergens. Int Arch Allergy Immunol. 2003;131:234-44. 19. Wagner S, Breiteneder H. The latex-fruit syndrome. Biochem Soc Trans. 2002;30:935-40. 20. Hoffmann-Sommergruber K. Pathogenesis-related (PR)-proteins identied as allergens. Biochem Soc Trans. 2002;30:930-5. 21. Shewry PR, Beaudoin F, Jenkins J, Grifths-Jones S, Mills EN. Plant protein families and their relationships to food allergy. Biochem Soc Trans. 2002 ;30:906-10. 22. van Ree R. Clinical importance of non-specic lipid transfer proteins as food allergens. Biochem Soc Trans. 2002;30:910-3. 23. Yagami T. Allergies to cross-reactive plant proteins. Latex-fruit syndrome is comparable with pollen-food allergy syndrome. Int Arch Allergy Immunol. 2002;128:271-9. 24. Vieths S, Scheurer S, Ballmer-Weber B. Current understanding of cross-reactivity of food allergens and pollen. Ann N Y Acad Sci. 2002;964:47-68. 25. Midoro-Horiuti T, Brooks EG, Goldblum RM. Pathogenesis-related proteins of plants as allergens. Ann Allergy Asthma Immunol. 2001;87:261-71. 26. Sicherer SH. Clinical implications of cross-reactive food allergens. J Allergy Clin Immunol. 2001;108:881-90. 27. Aalberse RC, Akkerdaas J, van Ree R. Cross-reactivity of IgE antibodies to allergens. Allergy. 2001;56:478-90. 28. Pastorello EA, Pompei C, Pravettoni V, Brenna O, Farioli L, Trambaioli C, Conti A. Lipid transfer proteins and 2S albumins as allergens. Allergy. 2001;56 Suppl 67:45-7. Review. 29. Salcedo G, Diaz-Perales A, Sanchez-Monge R. The role of plant panallergens in sensitization to natural rubber latex. Curr Opin Allergy Clin Immunol. 2001;1:177-83. 30. Breiteneder H, Ebner C. Molecular and biochemical classication of plant-derived food allergens. J Allergy Clin Immunol. 2000;106:27-36. 31. Caballero T, Martin-Esteban M. Association between pollen hypersensitivity and edible vegetable allergy: a review. J Investig Allergol Clin Immunol. 1998;8:6-16.

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References related to PR-10 proteins (Bet v 1 homologues)

1. Ballmer-Weber BK, Holzhauser T, Scibilia J, Mittag D, Zisa G, Ortolani C, Oesterballe M, Poulsen LK, Vieths S, Bindslev-Jensen C. Clinical characteristics of soybean allergy in Europe: a double-blind, placebo-controlled food challenge study. J Allergy Clin Immunol. 2007;119:1489-96. 2. Bohle B. The impact of pollen-related food allergens on pollen allergy. Allergy. 2007;62:3-10. Review. 3. Moverare R, Kosunen TU, Haahtela T. Change in the pattern of IgE reactivity to timothy grass and birch pollen allergens over a 20-year period. J Investig Allergol Clin Immunol. 2006;16:274-8. 4. Fernandez-Rivas M, Bolhaar S, Gonzalez-Mancebo E, Asero R, van Leeuwen A, Bohle B, Ma Y, Ebner C, Rigby N, Sancho AI, Miles S, Zuidmeer L, Knulst A, Breiteneder H, Mills C, Hoffmann-Sommergruber K, van Ree R. Apple allergy across Europe: how allergen sensitization proles determine the clinical expression of allergies to plant foods. J Allergy Clin Immunol. 2006;118:481-8. 5. Bohle B, Zwolfer B, Heratizadeh A, Jahn-Schmid B, Antonia YD, Alter M, Keller W, Zuidmeer L, van Ree R, Werfel T, Ebner C. Cooking birch pollen-related food: divergent consequences for IgE- and T cell-mediated reactivity in vitro and in vivo. J Allergy Clin Immunol. 2006;118:242-9. 6. Asero R, Marzban G, Martinelli A, Zaccarini M, Machado ML. Search for low-allergenic apple cultivars for birch-pollen-allergic patients: is there a correlation between in vitro assays and patient response? Allerg Immunol (Paris). 2006;38:94-8. 7. Moreno-Ancillo A, Gil-Adrados AC, Cosmes PM, Dominguez-Noche C, Pineda F. Role of Dau c 1 in three different patterns of carrotinduced asthma. Allergol Immunopathol (Madr). 2006;34:116-20. 8. Cudowska B, Kaczmarski M, Restani P . Immunoblotting in the diagnosis of cross-reactivity in children allergic to birch. Rocz Akad Med Bialymst. 2005;50:268-73. 9. Schimek EM, Zwolfer B, Briza P , Jahn-Schmid B, Vogel L, Vieths S, Ebner C, Bohle B. Gastrointestinal digestion of Bet v 1homologous food allergens destroys their mediator-releasing, but not T cell-activating, capacity. J Allergy Clin Immunol. 2005;116:1327-33. 10. Bohle B, Radakovics A, Luttkopf D, Jahn-Schmid B, Vieths S, Ebner C. Characterization of the T cell response to the major hazelnut allergen, Cor a 1.04: evidence for a relevant T cell epitope not cross-reactive with homologous pollen allergens. Clin Exp Allergy. 2005;35:1392-9. 11. Mittag D, Batori V, Neudecker P , Wiche R, Friis EP , Ballmer-Weber BK, Vieths S, Roggen EL. A novel approach for investigation of specic and cross-reactive IgE epitopes on Bet v 1 and homologous food allergens in individual patients. Mol Immunol. 2006;43:268-78. 12. Mittag D, Vieths S, Vogel L, Wagner-Loew D, Starke A, Hunziker P , Becker WM, Ballmer-Weber BK. Birch pollen-related food allergy to legumes: identication and characterization of the Bet v 1 homologue in mungbean (Vigna radiata), Vig r 1. 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References related to nsLTPs (PR-14 proteins)

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Allergy to nonspecic lipid transfer proteins in Rosaceae: a comparative study of different in vivo diagnostic methods. Ann Allergy Asthma Immunol. 2001;87:68-71. 49. Asero R, Mistrello G, Roncarolo D, Amato S, van Ree R. A case of allergy to beer showing cross-reactivity between lipid transfer proteins. Ann Allergy Asthma Immunol. 2001;87:65-7. 50. Pastorello EA, Farioli L, Pravettoni V, Giuffrida MG, Ortolani C, Fortunato D, Trambaioli C, Scibola E, Calamari AM, Robino AM, Conti A. Characterization of the major allergen of plum as a lipid transfer protein. J Chromatogr B Biomed Sci Appl. 2001;756:95-103. 51. Conti A, Fortunato D, Ortolani C, Giuffrida MG, Pravettoni V, Napolitano L, Farioli L, Perono Garoffo L, Trambaioli C, Pastorello EA. Determination of the primary structure of two lipid transfer proteins from apricot (Prunus armeniaca). J Chromatogr B Biomed Sci Appl. 2001;756:123-9. 52. Asero R, Mistrello G, Roncarolo D, de Vries SC, Gautier MF, Ciurana CL, Verbeek E, Mohammadi T, Knul-Brettlova V, Akkerdaas JH, Bulder I, Aalberse RC, van Ree R. Lipid transfer protein: a pan-allergen in plant-derived foods that is highly resistant to pepsin digestion. Int Arch Allergy Immunol. 2001;124:67-9. 53. Scheurer S, Pastorello EA, Wangorsch A, Kastner M, Haustein D, Vieths S. Recombinant allergens Pru av 1 and Pru av 4 and a newly identied lipid transfer protein in the in vitro diagnosis of cherry allergy. J Allergy Clin Immunol. 2001;107:724-31. 54. Pastorello EA, Farioli L, Pravettoni V, Ispano M, Scibola E, Trambaioli C, Giuffrida MG, Ansaloni R, Godovac-Zimmermann J, Conti A, Fortunato D, Ortolani C. The maize major allergen, which is responsible for food-induced allergic reactions, is a lipid transfer protein. J Allergy Clin Immunol. 2000;106:744-51. 55. 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References related to Profilins

1. Lopez-Torrejon G, Diaz-Perales A, Rodriguez J, Sanchez-Monge R, Crespo JF, Salcedo G, Pacios LF. An experimental and modelingbased approach to locate IgE epitopes of plant prolin allergens. J Allergy Clin Immunol. 2007;119:1481-8. 2. Gamboa PM, Caceres O, Antepara I, Sanchez-Monge R, Ahrazem O, Salcedo G, Barber D, Lombardero M, Sanz ML. Two different proles of peach allergy in the north of Spain. Allergy. 2007;62:408-14. 3. Ma Y, Zuidmeer L, Bohle B, Bolhaar ST, Gadermaier G, Gonzalez-Mancebo E, Fernandez-Rivas M, Knulst AC, Himly M, Asero R, Ebner C, van Ree R, Ferreira F, Breiteneder H, Hoffmann-Sommergruber K. Characterization of recombinant Mal d 4 and its application for component-resolved diagnosis of apple allergy. Clin Exp Allergy. 200;36:1087-96.

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 4. Radauer C, Willerroider M, Fuchs H, Hoffmann-Sommergruber K, Thalhamer J, Ferreira F, Scheiner O, Breiteneder H. Cross-reactive and species-specic immunoglobulin E epitopes of plant prolins: an experimental and structure-based analysis. Clin Exp Allergy. 2006;36:920-9. 5. Compes E, Hernandez E, Quirce S, Palomares O, Rodriguez R, Cuesta J, Sastre J, Villalba M. Hypersensitivity to black locust (Robinia pseudoacacia) pollen: allergy mirages. Ann Allergy Asthma Immunol. 2006;96:586-92. 6. Zuidmeer L, Salentijn E, Rivas MF, Mancebo EG, Asero R, Matos CI, Pelgrom KT, Gilissen LJ, van Ree R.The role of prolin and lipid transfer protein in strawberry allergy in the Mediterranean area. Clin Exp Allergy. 2006;36:666-75. 7. Crespo JF, Retzek M, Foetisch K, Sierra-Maestro E, Cid-Sanchez AB, Pascual CY, Conti A, Feliu A, Rodriguez J, Vieths S, Scheurer S. Germin-like protein Cit s 1 and prolin Cit s 2 are major allergens in orange (Citrus sinensis) fruits. Mol Nutr Food Res. 2006;50:282-90. 8. Lopez-Torrejon G, Ibanez MD, Ahrazem O, Sanchez-Monge R, Sastre J, Lombardero M, Barber D, Salcedo G. Isolation, cloning and allergenic reactivity of natural prolin Cit s 2, a major orange allergen. Allergy. 2005;60:1424-9. 9. Sankian M, Varasteh A, Pazouki N, Mahmoudi M. Sequence homology: a poor predictive value for prolins cross-reactivity. Clin Mol Allergy. 2005;3:13. 10. Lopez-Torrejon G, Crespo JF, Sanchez-Monge R, Sanchez-Jimenez M, Alvarez J, Rodriguez J, Salcedo G. Allergenic reactivity of the melon prolin Cuc m 2 and its identication as major allergen. Clin Exp Allergy. 2005;35:1065-72. 11. Asturias JA, Ibarrola I, Fernandez J, Arilla MC, Gonzalez-Rioja R, Martinez A. Pho d 2, a major allergen from date palm pollen, is a prolin: cloning, sequencing, and immunoglobulin E cross-reactivity with other prolins. Clin Exp Allergy. 2005;35:374-81. 12. Enrique E, Alonso R, Bartolome B, San Miguel-Moncin M, Bartra J, Fernandez-Parra B, Tella R, Asturias JA, Ibarrola I, Martinez A, CisteroBahima A. IgE reactivity to prolin in Platanus acerifolia pollen-sensitized subjects withplant-derived food allergy. J Investig Allergol Clin Immunol. 2004;14:335-42. 13. Ghunaim N, Gronlund H, Kronqvist M, Gronneberg R, Soderstrom L, Ahlstedt S, van Hage-Hamsten M. Antibody proles and self-reported symptoms to pollen-related food allergens in grass pollen-allergic patients from northern Europe. Allergy. 2005;60:185-91. 14. Cudowska B, Kaczmarski M. Diagnostic value of birch recombinant allergens (rBet v 1, prolin rBet v 2) in children with pollenrelated food allergy. Rocz Akad Med Bialymst. 2004;49:111-5. 15. Wagner S, Radauer C, Hafner C, Fuchs H, Jensen-Jarolim E, Wuthrich B, Scheiner O, Breiteneder H. Characterization of cross-reactive bell pepper allergens involved in the latex-fruit syndrome. Clin Exp Allergy. 2004;34:1739-46. 16. Scheurer S, Lauer I, Foetisch K, San Miguel Moncin M, Retzek M, Hartz C, Enrique E, Lidholm J, Cistero-Bahima A, Vieths S. Strong allergenicity of Pru av 3, the lipid transfer protein from cherry, is related to high stability against thermal processing and digestion. J Allergy Clin Immunol. 2004;114:900-7. 17. Barderas R, Villalba M, Rodriguez R. Recombinant expression, purication and cross-reactivity of chenopod prolin: rChe a 2 as a good marker for prolin sensitization. Biol Chem. 2004;385:731-7. 18. Barderas R, Villalba M, Pascual CY, Batanero E, Rodriguez R. Prolin (Che a 2) and polcalcin (Che a 3) are relevant allergens of Chenopodium album pollen: isolation, amino acid sequences, and immunologic properties. J Allergy Clin Immunol. 2004;113:1192-8. 19. Westphal S, Kempf W, Foetisch K, Retzek M, Vieths S, Scheurer S. Tomato prolin Lyc e 1: IgE cross-reactivity and allergenic potency. Allergy. 2004;59:526-32. 20. Asero R, Mistrello G, Roncarolo D, Amato S. Parietaria prolin shows only limited cross-reactivity with birch and grass prolins. Int Arch Allergy Immunol. 2004;133:121-4.. 21. Ebo DG, Hagendorens MM, Bridts CH, De Clerck LS, Stevens WJ. Sensitization to cross-reactive carbohydrate determinants and the ubiquitous protein prolin: mimickers of allergy. Clin Exp Allergy. 2004;34:137-44. 22. De Amici M, Mosca M, Vignini M, Quaglini S, Moratti R. Recombinant birch allergens (Bet v 1 and Bet v 2) and the oral allergy syndrome in patients allergic to birch pollen .Ann Allergy Asthma Immunol. 2003;91:490-2. 23. Fernandez-Rivas M, Gonzalez-Mancebo E, Rodriguez-Perez R, Benito C, Sanchez-Monge R, Salcedo G, Alonso MD, Rosado A, Tejedor MA, Vila C, Casas ML. Clinically relevant peach allergy is related to peach lipid transfer protein, Prup 3, in the Spanish population. J Allergy Clin Immunol. 2003;112:789-95. 24. Mari A, Wallner M, Ferreira F. Fagales pollen sensitization in a birch-free area: a respiratory cohort survey using Fagales pollen extracts and birch recombinant allergens (rBet v 1, rBet v 2, rBet v 4). Clin Exp Allergy. 2003;33:1419-28. 25. Willerroider M, Fuchs H, Ballmer-Weber BK, Focke M, Susani M, Thalhamer J, Ferreira F, Wuthrich B, Scheiner O, Breiteneder H, HoffmannSommergruber K. Cloning and molecular and immunological characterisation of two new food allergens, Cap a 2 and Lyc e 1, prolins from bell pepper (Capsicum annuum) and Tomato (Lycopersicon esculentum). Int Arch Allergy Immunol. 2003;131:245-55. 26. Rossi RE, Monasterolo G, Monasterolo S. Detection of specic IgE antibodies in the sera of patients allergic to birch pollen using recombinant allergens Bet v 1, Bet v 2, Bet v 4: evaluation of different IgE reactivity proles. Allergy. 2003;58:929-32. 27. Asero R, Mistrello G, Roncarolo D, Amato S, Zanoni D, Barocci F, Caldironi G. Detection of clinical markers of sensitization to prolin in patients allergic to plant-derived foods. J Allergy Clin Immunol. 2003;112:427-32. 28. Rodriguez-Perez R, Fernandez-Rivas M, Gonzalez-Mancebo E, Sanchez-Monge R, Diaz-Perales A, Salcedo G. Peach prolin: cloning, heterologous expression and cross-reactivity with Bet v 2. Allergy. 2003;58:635-40. 29. Rodriguez-Perez R, Crespo JF, Rodriguez J, Salcedo G. Prolin is a relevant melon allergen susceptible to pepsin digestion in patients with oral allergy syndrome. J Allergy Clin Immunol. 2003;111:634-9. 30. Diaz-Perales A, Tabar AI, Sanchez-Monge R, Garcia BE, Gomez B, Barber D, Salcedo G. Characterization of asparagus allergens: a relevant role of lipid transfer proteins. J Allergy Clin Immunol. 2002;110:790-6.

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IgE reactivity to prolin in pollen-sensitized subjects with adverse reactions to banana and pineapple. Int Arch Allergy Immunol. 2002;128:105-14. 36. Niederberger V, Purohit A, Oster JP , Spitzauer S, Valenta R, Pauli G. The allergen prole of ash (Fraxinus excelsior) pollen: crossreactivity with allergens from various plant species. Clin Exp Allergy. 2002;32:933-41. 37. Kwaasi AA, Har HA, Parhar RS, Saleh S, Collison KS, Panzani RC, Al-Sedairy ST, Al-Mohanna FA. Cross-reactivities between date palm (Phoenix dactylifera L.) polypeptides and foods implicated in the oral allergy syndrome. Allergy. 2002;57:508-18. 38. Ballmer-Weber BK, Hoffmann A, Wuthrich B, Luttkopf D, Pompei C, Wangorsch A, Kastner M, Vieths S. Inuence of food processing on the allergenicity of celery: DBPCFC with celery spice and cooked celery in patients with celery allergy. Allergy. 2002;57:228-35. 39. Ballmer-Weber BK, Wuthrich B, Wangorsch A, Fotisch K, Altmann F, Vieths S. Carrot allergy: double-blinded, placebo-controlled food challenge and identication of allergens. J Allergy Clin Immunol. 2001;108:301-7. 40. Ganglberger E, Radauer C, Wagner S, Riordain G, Beezhold DH, Brehler R, Niggemann B, Scheiner O, Jensen-Jarolim E, Breiteneder H. Hev b 8, the Hevea brasiliensis latex prolin, is a cross-reactive allergen of latex, plant foods and pollen. Int Arch Allergy Immunol. 2001;125:216-27. 41. Benitez D, Garcia-Ortega P , Picado C, Mila J, Vives J, Martinez J, Vilella R. Specic immune response to Phleum pratense plant prolin in atopic patients and control subjects. Allergol Immunopathol (Madr). 2001;29:9-15. 42. Scheurer S, Wangorsch A, Nerkamp J, Skov PS, Ballmer-Weber B, Wuthrich B, Haustein D, Vieths S. Cross-reactivity within the prolin panallergen family investigated by comparison of recombinant prolins from pear (Pyr c 4), cherry (Pru av 4) andcelery (Api g 4) with birch pollen prolin Bet v 2. J Chromatogr B Biomed Sci Appl. 2001;756:315-25. 43. Mari A. Multiple pollen sensitization: a molecular approach to the diagnosis. Int Arch Allergy Immunol. 2001;125:57-65. 44. Asero R, Mistrello G, Roncarolo D, de Vries SC, Gautier MF, Ciurana CL, Verbeek E, Mohammadi T, Knul-Brettlova V, Akkerdaas JH, Bulder I, Aalberse RC, van Ree R. Lipid transfer protein: a pan-allergen in plant-derived foods that is highly resistant to pepsin digestion. Int Arch Allergy Immunol. 2001;124:67-9. 45. Anliker MD, Reindl J, Vieths S, Wuthrich B. Allergy caused by ingestion of persimmon (Diospyros kaki): detection of specic IgE and cross-reactivity to prolin and carbohydrate determinants. J Allergy Clin Immunol. 2001;107:718-23. 46. Hemmer W, Focke M, Wantke F, Gotz M, Jarisch R, Jager S, Gotz M. Ash (Fraxinus excelsior)-pollen allergy in central Europe: specic role of pollen panallergens and the major allergen of ash pollen, Fra e 1. Allergy. 2000;55:923-30. 47. Luttkopf D, Ballmer-Weber BK, Wuthrich B, Vieths S. Celery allergens in patients with positive double-blind placebo-controlled food challenge. J Allergy Clin Immunol. 2000;106:390-9. 48. Scheurer S, Wangorsch A, Haustein D, Vieths S. Cloning of the minor allergen Api g 4 prolin from celery (Apium graveolens) andits cross-reactivity with birch pollen prolin Bet v 2. Clin Exp Allergy. 2000;30:962-71. 49. Ganglberger E, Radauer C, Grimm R, Hoffmann-Sommergruber K, Breiteneder H, Scheiner O, Jensen-Jarolim E. N-terminal sequences of high molecular weight allergens from celery tuber. Clin Exp Allergy. 2000;30:566-70. 50. Diez-Gomez ML, Quirce S, Cuevas M, Sanchez-Fernandez C, Baz G, Moradiellos FJ, Martinez A. Fruit-pollen-latex cross-reactivity: implication of prolin (Bet v 2). Allergy. 1999;54:951-61. 51. Jensen-Jarolim E, Gerstmayer G, Kraft D, Scheiner O, Ebner H, Ebner C. Serological characterization of allergens in poppy seeds. Clin Exp Allergy. 1999;29:1075-9. 52. 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 58. Jensen-Jarolim E, Santner B, Leitner A, Grimm R, Scheiner O, Ebner C, Breiteneder H. Bell peppers (Capsicum annuum) express allergens (prolin, pathogenesis-related protein P23 and Bet v 1) depending on the horticultural strain. Int Arch Allergy Immunol. 1998;116:103-9. 59. Rudeschko O, Fahlbusch B, Steurich F, Schlenvoigt G, Jager L. Kiwi allergens and their cross-reactivity with birch, rye, timothy, and mugwort pollen. J Investig Allergol Clin Immunol. 1998;8:78-84. 60. Vallverdu A, Asturias JA, Arilla MC, Gomez-Bayon N, Martinez A, Martinez J, Palacios R. Characterization of recombinant Mercurialis annua major allergen Mer a 1 (prolin). J Allergy Clin Immunol. 1998;101:363-70. 61. Niederberger V, Laffer S, Froschl R, Kraft D, Rumpold H, Kapiotis S, Valenta R, Spitzauer S. IgE antibodies to recombinant pollen allergens (Phl p 1, Phl p 2, Phl p 5, and Bet v 2) account for a high percentage of grass pollen-specic IgE. J Allergy Clin Immunol. 1998;101:258-64. 62. Hirschwehr R, Heppner C, Spitzauer S, Sperr WR, Valent P , Berger U, Horak F, Jager S, Kraft D, Valenta R. Identication of common allergenic structures in mugwort and ragweed pollen. J Allergy Clin Immunol. 1998;10:196-206. 63. Leitner A, Jensen-Jarolim E, Grimm R, Wuthrich B, Ebner H, Scheiner O, Kraft D, Ebner C. Allergens in pepper and paprika. Immunologic investigation of the celery-birch-mugwort-spice syndrome. Allergy. 1998;53:36-41. 64. Fernandez-Rivas M, van Ree R, Cuevas M. Allergy to Rosaceae fruits without related pollinosis. J Allergy Clin Immunol. 1997;100:728-33. 65. Jensen-Jarolim E, Leitner A, Hirschwehr R, Kraft D, Wuthrich B, Scheiner O, Graf J, Ebner C. Characterization of allergens in Apiaceae spices: anise, fennel, coriander and cumin. Clin Exp Allergy. 1997;27:1299-306. 66. Asturias JA, Arilla MC, Gomez-Bayon N, Martinez J, Martinez A, Palacios R. Cloning and expression of the panallergen prolin and the major allergen (Ole e 1) from olive tree pollen. J Allergy Clin Immunol. 1997;100:365-72. 67. Fuchs T, Spitzauer S, Vente C, Hevler J, Kapiotis S, Rumpold H, Kraft D, Valenta R. Natural latex, grass pollen, and weed pollen share IgE epitopes. J Allergy Clin Immunol.1997;100:356-64. 68. Elfman L, Svensson M, Lidholm J, Pauli G, Valenta R. Different proles in specic IgE to rBet v 1 and rBet v 2 in patients allergic to birch pollen from six countries. Int Arch Allergy Immunol. 1997;113:249-51. 69. Rossi RE, Monasterolo G, Operti D, Corsi M. Evaluation of recombinant allergens Bet v 1 and Bet v 2 (prolin) by Pharmacia CAP system in patients with pollen-related allergy to birch and apple. Allergy. 1996;51:940-5. 70. Bauer L, Ebner C, Hirschwehr R, Wuthrich B, Pichler C, Fritsch R, Scheiner O, Kraft D. IgE cross-reactivity between birch pollen, mugwort pollen and celery is due to at least three distinct cross-reacting allergens: immunoblot investigation of the birchmugwort-celery syndrome. Clin Exp Allergy. 1996;26:1161-70. 71. Laffer S, Spitzauer S, Susani M, Pairleitner H, Schweiger C, Gronlund H, Menz G, Pauli G, Ishii T, Nolte H, Ebner C, Sehon AH, Kraft D, Eichler HG, Valenta R. Comparison of recombinant timothy grass pollen allergens with natural extract for diagnosis of grass pollen allergy in different populations. J Allergy Clin Immunol. 1996;98:652-8. 72. Pauli G, Oster JP , Deviller P , Heiss S, Bessot JC, Susani M, Ferreira F, Kraft D, Valenta R. Skin testing with recombinant allergens rBet v 1 and birch prolin, rBet v 2:diagnostic value for birch pollen and associated allergies. J Allergy Clin Immunol. 1996;97:1100-9. 73. Eng PA, Yman L, Maaninen E, Wuthrich B. Inhalant allergy to fresh asparagus. Clin Exp Allergy. 1996;26:330-4. 74. Fah J, Wuthrich B, Vieths S. Anaphylactic reaction to lychee fruit: evidence for sensitization to prolin. Clin Exp Allergy. 1995;25:1018-23. 75. Ebner C, Hirschwehr R, Bauer L, Breiteneder H, Valenta R, Ebner H, Kraft D, Scheiner O. Identication of allergens in fruits and vegetables: IgE cross-reactivities with the important birch pollen allergens Bet v 1 and Bet v 2 (birch prolin). J Allergy Clin Immunol. 1995;95:962-9. 76. Vallier P , Balland S, Harf R, Valenta R, Deviller P . Identication of prolin as an IgE-binding component in latex from Hevea brasiliensis: clinical implications. Clin Exp Allergy. 1995;25:332-9. 77. van Ree R, Fernandez-Rivas M, Cuevas M, van Wijngaarden M, Aalberse RC. Pollen-related allergy to peach and apple: an important role for prolin. J Allergy Clin Immunol. 1995;95:726-34. 78. Valenta R, Duchene M, Ebner C, Valent P , Sillaber C, Deviller P , Ferreira F, Tejkl M, Edelmann H, Kraft D, et al. Prolins constitute a novel family of functional plant pan-allergens. J Exp Med. 1992;175:377-85. 79. Valenta R, Vrtala S, Ebner C, Kraft D, Scheiner O. Diagnosis of grass pollen allergy with recombinant timothy grass (Phleum pratense) pollen allergens. Int Arch Allergy Immunol. 1992;97:287-94.

References related to Storage Proteins

1. Choi SY, Sohn JH, Lee YW, Lee EK, Hong CS, Park JW. Application of the 16-kDa buckwheat 2 S storage albumin protein for diagnosis of clinical reactivity. Ann Allergy Asthma Immunol. 2007;99:254-60. 2. Flinterman AE, van Hoffen E, den Hartog Jager CF, Koppelman S, Pasmans SG, Hoekstra MO, Bruijnzeel-Koomen CA, Knulst AC, Knol EF. Children with peanut allergy recognize predominantly Ara h2 and Ara h6, which remains stable over time. Clin Exp Allergy. 2007;37:1221-8. 3. McDermott RA, Portereld HS, El Mezayen R, Burks AW, Pons L, Schlichting DG, Solomon B, Redzic JS, Harbeck RJ, Duncan MW, Hansen KC, Dreskin SC. Contribution of Ara h 2 to peanut-specic, immunoglobulin E-mediated, cell activation. Clin Exp Allergy. 2007;37:752-63.

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 4. Nolan RC, Richmond P , Prescott SL, Mallon DF, Gong G, Franzmann AM, Naidoo R, Loh RK. Skin prick testing predicts peanut challenge outcome in previously allergic or sensitized children with low serum peanut-specic IgE antibody concentration. Pediatr Allergy Immunol. 2007;18:224-30. 5. Wainstein BK, Yee A, Jelley D, Ziegler M, Ziegler JB. Combining skin prick, immediate skin application and specic-IgE testing in the diagnosis of peanut allergy in children. Pediatr Allergy Immunol. 2007;18:231-9. 6. de Leon MP , Drew AC, Glaspole IN, Suphioglu C, OHehir RE, Rolland JM. IgE cross-reactivity between the major peanut allergen Ara h 2 and tree nut allergens. Mol Immunol. 2007;44:463-71. 7. Peeters KA, Koppelman SJ, van Hoffen E, van der Tas CW, den Hartog Jager CF, Penninks AH, Hee SL, Bruijnzeel-Koomen CA, Knol EF, Knulst AC. Does skin prick test reactivity to puried allergens correlate with clinical severity of peanut allergy? Clin Exp Allergy. 2007;37:108-15. 8. Andersson K, Ballmer-Weber BK, Cistero-Bahima A, Ostling J, Lauer I, Vieths S, Lidholm J. Enhancement of hazelnut extract for IgE testing by recombinant allergen spiking. Allergy. 2007;62:897-904. 9. Benito C, Gonzalez-Mancebo E, de Durana MD, Tolon RM, Fernandez-Rivas M. Identication of a 7S globulin as a novel coconut allergen. Ann Allergy Asthma Immunol. 2007;98:580-4. 10. Wallowitz ML, Chen RJ, Tzen JT, Teuber SS. Ses i 6, the sesame 11S globulin, can activate basophils and shows cross-reactivity with walnut in vitro. Clin Exp Allergy. 2007;37:929-38. 11. Astier C, Morisset M, Roitel O, Codreanu F, Jacquenet S, Franck P , Ogier V, Petit N, Proust B, Moneret-Vautrin DA, Burks AW, Bihain B, Sampson HA, Kanny G. Predictive value of skin prick tests using recombinant allergens for diagnosis of peanut allergy. J Allergy Clin Immunol. 2006;118:250-6. 12. Lin J, Shewry PR, Archer DB, Beyer K, Niggemann B, Haas H, Wilson P , Alcocer MJ. The potential allergenicity of two 2S albumins from soybean (Glycine max): a protein microarray approach. Int Arch Allergy Immunol. 2006;141:91-102. 13. Leduc V, Moneret-Vautrin DA, Tzen JT, Morisset M, Guerin L, Kanny G. Identication of oleosins as major allergens in sesame seed allergic patients. Allergy. 2006;61:349-56. 14. de Leon MP , Drew AC, Glaspole IN, Suphioglu C, Rolland JM, OHehir RE. Functional analysis of cross-reactive immunoglobulin E antibodies: peanut-specic immunoglobulin E sensitizes basophils to tree nut allergens. Clin Exp Allergy. 2005;35:1056-64. 15. Roberts G, Lack G. Diagnosing peanut allergy with skin prick and specic IgE testing. J Allergy Clin Immunol. 2005;115:1291-6. 16. Palomares O, Cuesta-Herranz J, Vereda A, Sirvent S, Villalba M, Rodriguez R. Isolation and identication of an 11S globulin as a new major allergen in mustard seeds. Ann Allergy Asthma Immunol. 2005;94:586-92. 17. Robotham JM, Wang F, Seamon V, Teuber SS, Sathe SK, Sampson HA, Beyer K, Seavy M, Roux KH. Ana o 3, an important cashew nut (Anacardium occidentale L.) allergen of the 2S albumin family. J Allergy Clin Immunol. 2005;115:1284-90. 18. Palomares O, Cuesta-Herranz J, Rodriguez R, Villalba M. A recombinant precursor of the mustard allergen Sin a 1 retains the biochemical and immunological features of the heterodimeric native protein. Int Arch Allergy Immunol. 2005;137:18-26. 19. Mittag D, Akkerdaas J, Ballmer-Weber BK, Vogel L, Wensing M, Becker WM, Koppelman SJ, Knulst AC, Helbling A, Hee SL, Van Ree R, Vieths S. Ara h 8, a Bet v 1-homologous allergen from peanut, is a major allergen in patients with combined birch pollen and peanut allergy. J Allergy Clin Immunol. 2004;114:1410-7. 20. Koppelman SJ, Wensing M, Ertmann M, Knulst AC, Knol EF. Relevance of Ara h1, Ara h2 and Ara h3 in peanut-allergic patients, as determined by immunoglobulin E Western blotting, basophil-histamine release and intracutaneous testing: Ara h2 is the most important peanut allergen. Clin Exp Allergy. 2004;34:583-90. 21. Comstock SS, McGranahan G, Peterson WR, Teuber SS. Extensive in vitro cross-reactivity to seed storage proteins is present among walnut (Juglans) cultivars and species. Clin Exp Allergy. 2004;34:1583-90. 22. Wensing M, Knulst AC, Piersma S, OKane F, Knol EF, Koppelman SJ. Patients with anaphylaxis to pea can have peanut allergy caused by cross-reactive IgE to vicilin (Ara h 1). J Allergy Clin Immunol. 2003;111:420-4. 23. Lopez-Torrejon G, Salcedo G, Martin-Esteban M, Diaz-Perales A, Pascual CY, Sanchez-Monge R. Len c 1, a major allergen and vicilin from lentil seeds: protein isolation and cDNA cloning. J Allergy Clin Immunol. 2003;112:1208-15. 24. Wang F, Robotham JM, Teuber SS, Sathe SK, Roux KH. Ana o 2, a major cashew (Anacardium occidentale L.) nut allergen of the legumin family. Int Arch Allergy Immunol. 2003;132:27-39. 25. Ranc F, Abbal M, Lauwers-Cancs V. Improved screening for peanut allergy by the combined use of skin prick tests and specic IgE assays. J Allergy Clin Immunol. 2002 ;109:1027-33. 26. Teuber SS, Sathe SK, Peterson WR, Roux KH. Characterization of the soluble allergenic proteins of cashew nut (Anacardium occidentale L.). J Agric Food Chem. 2002;50:6543-9. 27. Beyer K, Grishina G, Bardina L, Grishin A, Sampson HA. Identication of an 11S globulin as a major hazelnut food allergen in hazelnut-induced systemic reactions. J Allergy Clin Immunol. 2002;110:517-23. 28. Wang F, Robotham JM, Teuber SS, Tawde P , Sathe SK, Roux KH. Ana o 1, a cashew (Anacardium occidental) allergen of the vicilin seed storage protein family. J Allergy Clin Immunol. 2002;110:160-6. 29. Beyer K, Bardina L, Grishina G, Sampson HA. 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 32. Beardslee TA, Zeece MG, Sarath G, Markwell JP . Soybean glycinin G1 acidic chain shares IgE epitopes with peanut allergen Ara h 3. Int Arch Allergy Immunol. 2000;123:299-307. 33. Helm RM, Cockrell G, Connaughton C, Sampson HA, Bannon GA, Beilinson V, Livingstone D, Nielsen NC, Burks AW. A soybean G2 glycinin allergen. 1. Identication and characterization. Int Arch Allergy Immunol. 2000;123:205-12. 34. Kelly JD, Hee SL. 2S methionine-rich protein (SSA) from sunower seed is an IgE-binding protein. Allergy. 2000;55(6):556-60. 35. Seppala U, Alenius H, Turjanmaa K, Reunala T, Palosuo T, Kalkkinen N. Identication of patatin as a novel allergen for children with positive skin prick test responses to raw potato. J Allergy Clin Immunol. 1999;103:165-71. 36. Monsalve RI, Gonzalez de la Pena MA, Lopez-Otin C, Fiandor A, Fernandez C, Villalba M, Rodriguez R. Detection, isolation and complete amino acid sequence of an aeroallergenic protein from rapeseed our. Clin Exp Allergy. 1997;27:833-41. 37. Bartolome B, Mendez JD, Armentia A, Vallverdu A, Palacios R. Allergens from Brazil nut: immunochemical characterization. Allergol Immunopathol (Madr). 1997;25:135-44. 38. Varjonen E, Bjorksten F, Savolainen J. Stability of cereal allergens. Clin Exp Allergy. 1996;26:436-43.

References related to CCDs

1. Jin C, Hantusch B, Hemmer W, Stadlmann J, Altmann F. Afnity of IgE and IgG against cross-reactive carbohydrate determinants on plant and insect glycoproteins. J Allergy Clin Immunol. 2008;121:185-90. 2. Malandain H, Giroux F, Cano Y. The inuence of carbohydrate structures present in common allergen sources on specic IgE results. Eur Ann Allergy Clin Immunol. 2007;39:216-20. 3. Mahler V, Gutgesell C, Valenta R, Fuchs T. Natural rubber latex and hymenoptera venoms share ImmunoglobinE-epitopes accounting for cross-reactive carbohydrate determinants. Clin Exp Allergy. 2006;36:1446-56. 4. Jappe U, Raulf-Heimsoth M, Hoffmann M, Burow G, Hubsch-Muller C, Enk A. In vitro hymenoptera venom allergy diagnosis: improved by screening for cross-reactive carbohydrate determinants and reciprocal inhibition. Allergy. 2006;61:1220-9. 5. Ballmer-Weber BK, Wangorsch A, Bohle B, Kaul S, Kundig T, Fotisch K, van Ree R, Vieths S. Component-resolved in vitro diagnosis in carrot allergy: does the use of recombinant carrot allergens improve the reliability of the diagnostic procedure? Clin Exp Allergy. 2005;35:970-8. 6. Kochuyt AM, Van Hoeyveld EM, Stevens EA. Prevalence and clinical relevance of specic immunoglobulin E to pollen caused by sting- induced specic immunoglobulin E to cross-reacting carbohydrate determinants in Hymenoptera venoms. Clin Exp Allergy. 2005;35:441-7. 7. Malandain H. Widening sensitization spectrum through carbohydrate panepitopes--a hypothesis. Allerg Immunol (Paris). 2004;36:297-9. 8. Ebo DG, Hagendorens MM, Bridts CH, De Clerck LS, Stevens WJ. Sensitization to cross-reactive carbohydrate determinants and the ubiquitous protein prolin: mimickers of allergy. Clin Exp Allergy. 2004;34:137-44. 9. Foetisch K, Westphal S, Lauer I, Retzek M, Altmann F, Kolarich D, Scheurer S, Vieths S. Biological activity of IgE specic for crossreactive carbohydrate determinants. J Allergy Clin Immunol. 2003;111:889-96. 10. Vieths S, Luttkopf D, Reindl J, Anliker MD, Wuthrich B, Ballmer-Weber BK. Allergens in celery and zucchini. Allergy. 2002;57 Suppl 72:100-5. 11. Ballmer-Weber BK, Hoffmann A, Wuthrich B, Luttkopf D, Pompei C, Wangorsch A, Kastner M, Vieths S. Inuence of food processing on the allergenicity of celery: DBPCFC with celery spice and cooked celery in patients with celery allergy. Allergy. 2002;57:228-35. 12. Luttkopf D, Ballmer-Weber BK, Wuthrich B, Vieths S. Celery allergens in patients with positive double-blind placebo-controlled food challenge. J Allergy Clin Immunol. 2000;106:390-9. 13. Fotisch K, Altmann F, Haustein D, Vieths S. Involvement of carbohydrate epitopes in the IgE response of celery-allergic patients. Int Arch Allergy Immunol. 1999;120:30-42. 14. Fotisch K, Fah J, Wuthrich B, Altmann F, Haustein D, Vieths S. IgE antibodies specic for carbohydrates in a patient allergic to gum Arabic (Acacia senegal). Allergy. 1998;53:1043-51. 15. van der Veen MJ, van Ree R, Aalberse RC, Akkerdaas J, Koppelman SJ, Jansen HM, van der Zee JS. Poor biologic activity of crossreactive IgE directed to carbohydrate determinants of glycoproteins. J Allergy Clin Immunol. 1997;100:327-34.

Allergen database references

1. International Union of Immunological Societies (IUIS) Allergen Nomenclature Sub-Committee http://www.allergen.org/Allergen.aspx 2. Allergome http://www.allergome.org 3. AllFam http://www.meduniwien.ac.at/allergens/allfam

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