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[Severe soy allergy in adults. Is there a role for specific immunotherapy?].
Abstract
An increasing number of immediate type allergies after consumption of soy products have been reported during the last years. Due to cross reactions between the main birch pollen allergen Bet v 1 and soy allergen Gly m 4, patients sensitized to birch are at special risk for soy allergy. Severe immediate type reactions to soy have also been associated with sensitizations to storage proteins Gly m 5 and Gly m 6. Therapy should include avoidance of soy products with high protein content (i.e. drinks). A limited number of studies has investigated specific immunotherapy (SIT) against birch in patients with birch-associated food allergy, namely to apple or hazel. A therapeutic effect on birch- associated food allergy was shown in some of these trials. Results are discussed controversially with regard to number of patients, study design and investigational products. A multicenter trial (BASALIT) is currently investigating the effect of SIT with 80 µg of the folded variant of recombinant Bet v 1 on birch-associated soy allergy.
... The data of the German-language anaphylaxis registry (Figure 1) depict a rather low relevance of soy allergy in childhood of 1% [22]. While the clinical relevance of cross-reactions among storage proteins is limited, cross-reactions between Bet v 1 and Gly m 4 are observed much more frequently [55,56]. Although the symptoms of pollen food syndrome to soy are usually limited to local symptoms such as oral contact urticaria, severe anaphylactic reactions can occur with rapid intake of large amounts of protein [56]. ...
... The data of the German-language anaphylaxis registry (Figure 1) depict a rather low relevance of soy allergy in childhood of 1% [22]. While the clinical relevance of cross-reactions among storage proteins is limited, cross-reactions between Bet v 1 and Gly m 4 are observed much more frequently [55,56]. Although the symptoms of pollen food syndrome to soy are usually limited to local symptoms such as oral contact urticaria, severe anaphylactic reactions can occur with rapid intake of large amounts of protein [56]. ...
Vegan diets are currently attracting a great deal of attention. However, avoiding animal-based foods restricts the diet and is associated with risks, the extent and medical implications of which are at present not sufficiently understood. Elimination diets represent the usual therapeutic long-term management in the presence of food allergy. In order to understand the risks of vegan diets and to discuss these critically from the perspective of food allergies, the expertise of a nutritionist/dietitian with expertise in this area is indispensable. This position paper deals with the incentives behind and the benefits of a plant-based diet. The knowledge required to cover macro- and micronutrient dietary requirements is presented. Using the avoidance of cow's milk as an example, the challenges of adequately meeting nutritional needs are identified and (so-called) milk alternatives are evaluated from an allergy and nutritional point of view. Finally, other plant-based (substitute) products are evaluated from the same perspective, as significant protein sources in vegan diets (e.g., legumes, nuts, and seeds) are at the same time potential and potent triggers of allergic reactions. However, the allergic potential of many substitute products cannot be fully assessed at present due to gaps in research. Wheat as the most important trigger for anaphylaxis in adults is also evaluated. Finally, the increase in ultra-processed products in the (vegan) food sector and their potential consequences for the immune system are discussed.
... In addition, there was a large number of patients who reacted to soy products. This might, among other things, be due to a study on birch pollen-associated soy allergy concurrently conducted at the Department of Dermatology, University Hospital Leipzig [22,23]. Although OAS was by far the most frequently reported clinical symptom, the majority of patients also stated to have experienced non-OAS symptoms. ...
Background:
The "Food Allergy Quality of Life Questionnaire - Adult Form" (FAQLQ-AF) is the first freely available questionnaire for the assessment of health-related quality of life (HRQL) in adults with food allergy (FA). We present validation data for the German version as well as data on HRQL in patients with birch pollen-associated FA.
Patients and methods:
The Dutch FAQLQ-AF (scale from 1-7, no impairment - maximum impairment) was translated into German. Subsequently, 73 consecutive patients with a history of birch pollen-associated FA (52 women, median age 43 years) were surveyed using questions regarding triggers and symptoms of their FA as well as questions contained in the FAQLQ-AF. Construct validity, internal consistency, and discriminative ability were analyzed.
Results:
The foods most frequently reported to elicit allergic reactions included apple (78 %), hazelnut (75 %), soy drinks (55 %), and carrot (52 %). Thirty percent of patients exclusively reported symptoms consistent with oral allergy syndrome (OAS). Sixty-four percent reported OAS combined with systemic symptoms, and only 6 % were exclusively affected by non-OAS symptoms. The German FAQLQ-AF showed good construct validity (correlation with the food allergy-independent measure: r = 0.81; p < 0.001) and excellent internal consistency (Cronbachs α = 0.98). The mean overall FAQLQ-AF score was 3.7. Women, elderly individuals, and those with multiple relevant food allergies showed a greater impairment of HRQL.
Conclusions:
The German FAQLQ-AF questionnaire is a reliable and valid tool for measuring HRQL in patients with birch pollen-associated food allergy.
... The pre-treatment was able to shift the immune response to Bet v 1 and homologue food allergens towards a Th1 phenotype, thus preventing birch pollen-related food allergy [29•]. A multicenter trial aimed at investigating the effects of immunotherapy with a folded variant of recombinant Bet v 1 at a high dose (80 μg; notably, the common commercial birch pollen extracts for injection immunotherapy contain 10-20 μg/ml of natural Bet v 1) on birch-associated soy allergy has been announced, but the results have not been published yet [30]. ...
Allergen-specific immunotherapy is the only treatment able to change the natural history of either respiratory or hymenoptera venom allergy. From an immunological point of view, there is no reason to believe that its clinical effects should be different in food allergies. However, due to the high prevalence of adverse events that accompanied the first attempts of injection immunotherapy with food extracts some 20 years ago, such treatment is presently non-available although a thoroughly standardized food extract for injection immunotherapy should theoretically not expose the patients to higher risks than airborne allergen extracts or venoms. Allergen-specific immunotherapy with birch pollen extract is an interesting model to investigate the effects of the treatment on plant-food allergies that occur as a consequence of cross-reactivity with the major allergen, Bet v 1. Although the interest for this field has partly settled during the last years, the available data suggest that an adequate dose of the birch pollen major allergen, Bet v 1, particularly if administered subcutaneously, is able reduce secondary plant food allergy also, although doses needed to exert such effect are probably higher than those required to reduce respiratory symptoms. The administration of higher doses of the major allergen without an increase of the risk of adverse reactions should be possible if modified hypoallergenic molecules obtained either by genetic engineering or chemical treatments are used.
Background:
Conflicting results exist on the effect of allergen immunotherapy (AIT) on pollen related food allergy. We aimed to investigate the efficacy of one year AIT with the folding variant (FV) of recombinant (r) Bet v 1 on birch related soy allergy.
Methods:
Out of 138 subjects with Bet v 1 sensitization, 82 were positive at double blind placebo controlled food challenge (DBPCFC) with soy. 56/82 were randomized 2:1 (active: placebo). Per protocol population (PPP) had received >150μg of allergen or placebo preparation.
Outcome measures:
lowest observed adverse effect levels (LOAEL), post interventional occurrence of objective signs (objS) at any dose level, sIgE/IgG4 against Bet v 1 and Gly m 4. Between-group changes were investigated (ANCOVA, Mann-Whitney-U-, Fisher exact test).
Results:
Baseline characteristics including LOAELs were comparable in both groups with objS and subjS occurring in 82% and 95% of active (n=38) versus 78% and 83% of placebo group (n=18). After AIT, objS occurred in 24% and 47%, respectively. LOAEL group differences showed a beneficial tendency (p=0.081) for LOAELobjective in PPP (30 verum, 15 placebo). sIgG4 raised only in active group (Bet v 1: p=0.054, Gly m 4: p=0.037), no relevant changes occurred for sIgE. Only 56% of the intended sample size was recruited.
Conclusion:
For the first time, we present data on the effect of rBet v 1-FV on birch related soy allergy. rBet v 1-FV AIT induced significant immunogenic effects. Clinical assessment showed a tendency in favor of the active group but did not reach statistical significance. This article is protected by copyright. All rights reserved.
Background
Multicentre trials investigating food allergies by double blind placebo controlled food challenges (DBPCFC) need standardized procedures, challenge meals and evaluation criteria. We aimed at developing a standardized approach for identifying patients with birch related soy allergy by means of DBPCFC to soy, including determination of threshold levels, in a multicentre setting. Methods
Microbiologically stable soy challenge meals were composed of protein isolate with consistent Gly m 4 levels. Patients sensitized to main birch allergen Bet v 1 and concomitant sensitization to its soy homologue Gly m 4 underwent DBPCFC. Outcome was defined according to presence and/or absence of ten objective signs and intensity of eight subjective symptoms as measured by visual analogue scale (VAS). Results138 adult subjects (63.8% female, mean age 38 years) underwent DBPCFC. Challenge meals and defined evaluation criteria showed good applicability in all centres involved. 45.7% presented with objective signs and 65.2% with subjective symptoms at soy challenge. Placebo challenge meals elicited non-cardiovascular objective signs in 11.6%. In 82 (59.4%) subjects DBPCFC was judged as positive. 70.7% of DPBCFC+ showed objective signs and 85.4% subjective symptoms at soy challenge. Subjective symptoms to soy challenge meal in DBPCFC+ subjects started at significantly lower dose levels than objective signs (p < 0.001). Median cumulative eliciting doses for first objective signs in DBPCFC+ subjects were 4.7 g [0.7–24.7] and 0.7 g [0.2–4.7] total soy protein for first subjective symptoms (p = 0.01). Conclusions
We present the hitherto largest group of adults with Bet v 1 and Gly m 4 sensitization being investigated by DBPCFC. In this type of food allergy evaluation of DBPCFC outcome should not only include monitoring of objective signs but also scoring of subjective symptoms. Our data may contribute to standardize DBPCFC in pollen-related food allergy in multicentre settings. Trial registrationEudraCT: 2009-011737-27.
Zusammenfassung
Hintergrund
: Der „Food Allergy Quality of Life Questionnaire – Adult Form“ (FAQLQ‐AF) ist der erste frei verfügbare Fragebogen zur Erfassung der gesundheitsbezogenen Lebensqualität (health‐related quality of life; HRQL) bei Erwachsenen mit Nahrungsmittelallergie (NMA). Wir präsentieren Daten zur Validierung der deutschsprachigen Version sowie zur HRQL bei Patienten mit birkenpollenassoziierter NMA.
Patienten und Methodik
: Die niederländische Version des FAQLQ‐AF (Skala 1–7, kein – extremer Einfluss) wurde ins Deutsche übersetzt. Dreiundsiebzig Patienten mit anamnestisch vorhandener birkenpollenassoziierter NMA (52 Frauen, medianes Alter 43 Jahre) beantworteten Fragen zu Auslösern und Symptomen der NMA sowie den FAQLQ‐AF. Konstruktvalidität, diskriminative Validität sowie interne Konsistenz des FAQLQ‐AF wurden gemessen.
Ergebnisse
: Häufigste auslösende Nahrungsmittel waren: Äpfel (78 %), Haselnüsse (75 %), Sojadrinks (55 %) und Karotten (52 %). Ausschließlich ein orales Allergiesyndrom (OAS) gaben 30 % an, 64 % ein OAS mit weiteren Symptomen, 6 % nur weitere Nicht‐OAS‐Symptome. Der deutschsprachige FAQLQ‐AF zeigte eine sehr gute Konstruktvalidität (Korrelation mit food allergy independent measure [FAIM]: r = 0,81; p < 0,001) und eine exzellente interne Konsistenz (Cronbachs α = 0,98). Der mittlere FAQL‐AF Gesamtwert lag bei 3,7 (± 1,6). Der deutschsprachige FAQLQ‐AF zeigte bei Frauen, älteren Patienten und solchen mit vielfältigen relevanten Nahrungsmittelallergenen eine stärkere Beeinträchtigung der HRQL.
Schlussfolgerung
: Der deutschsprachige FAQLQ‐AF ist ein zuverlässiges und valides Messinstrument um die HRQL bei Patienten mit birkenpollenassoziierter NMA zu messen.
Isoflavones first came to the attention of the scientific community in the 1940s because of fertility problems observed in sheep grazing on a type of isoflavone-rich clover. It was not until the 1990s, largely because of research sponsored by the U.S. National Cancer Institute, that the role of soy foods in disease prevention began to receive widespread attention. Subsequently, isoflavones and soy foods were being studied for their ability to alleviate hot flashes and inhibit bone loss in postmenopausal women. In 1995, soy protein attracted worldwide attention for its ability to lower cholesterol. At that same time, isoflavones began to be widely discussed as potential alternatives to conventional hormone therapy. There are other aspects about soy isoflavones to investigate that have been less studied. These are the psychotropic effects on anxiety, depression, and cognitive symptoms in menopausal women. The few studies that were found regarding the antidepressant effects of soy concluded that the administration of soybean could act as an alternative to estrogens in the treatment of depressive disorders during menopause. There were very few studies about soy in menopausal anxiety symptoms and cognitive symptoms. More studies are necessary in human beings with the goal of elucidating the role of soy in cognition in menopausal women. This chapter is a brief overview based on evidence from the past decade about the use of soy isoflavones in the treatment of the menopausal psychological symptoms.
Component-resolved diagnostics (CRD) utilize purified native or recombinant allergens to detect IgE sensitivity to individual allergen molecules and have become of growing importance in clinical investigation of IgE-mediated allergies. This overview updates current developments of CRD, including multiarray test systems. Cross-reactions between allergens of known allergen families (i.e. to Bet v 1 homologues) are emphasised. In pollinosis as well as in allergy to hymenoptera venoms or to food, CRD allows to some extent discrimination between clinically significant and irrelevant sIgE results and the establishing of sensitisation patterns with particular prognostic outcomes (i.e. sensitisations to storage proteins which correlate with clinically severe reactions in peanut allergy). Further promising improvements in diagnostics are expected from additional, not yet commercially available, recombinant allergen diagnostics identifying particular molecules of risk. Overall, CRD may decrease the need for provocation testing and may also improve the specificity of allergen-specific immunotherapy.
To date no studies have compared generic health-related quality of life (HRQL) of food allergic patients from childhood to adulthood with that of the general population or patients with other chronic diseases. The aim of this study was to compare generic HRQL of food allergic patients with the general population and other diseases.
Generic HRQL questionnaires (CHQ-CF87 and RAND-36) were completed by 79 children, 74 adolescents and 72 adults with food allergy. The generic HRQL scores were compared with scores from published studies on the general population and patients with asthma, irritable bowel syndrome (IBS), diabetes mellitus (DM) and rheumatoid arthritis (RA).
Food allergic children and adolescents reported fewer limitations in school work due to behavioural problems (P < or = 0.013), but food allergic adolescents and adults reported more pain (P = 0.020), poorer overall health (P < 0.001), more limitations in social activities (P < 0.001) and less vitality (P = 0.002) than individuals from the general population. Food allergic patients reported poorer generic HRQL than patients with DM, but better generic HRQL than patients with RA, asthma and IBS.
HRQL is impaired in food allergic adolescents and adults, compared to the general population, and it is intermediate in magnitude between DM and RA, asthma and IBS. Children show the least impact on generic HRQL from food allergy.
Food allergy may be life-threatening, and patients affected need to receive accurate diagnoses and treatment. Hazelnut has often been implicated as responsible for allergic reactions, and trace quantities can induce systemic reactions.
The aim of this study was to evaluate the efficacy and tolerance of sublingual immunotherapy with a standardized hazelnut extract in patients allergic to hazelnut.
This was a randomized, double-blind, placebo-controlled study. Inclusion criteria were a history of hazelnut allergy and positive skin prick test and double-blind placebo-controlled food challenge results. Patients were then randomly assigned into 2 treatment groups (hazelnut immunotherapy or placebo). Efficacy was assessed by double-blind, placebo-controlled food challenge after 8 to 12 weeks of treatment. Blood samples were drawn for measurement of specific IgE, IgG(4), and serum cytokines before and after treatment.
Twenty-three patients were enrolled and divided into 2 treatment groups. Twenty-two patients reached the planned maximum dose at 4 days. Systemic reactions were observed in only 0.2% of the total doses administered. Mean hazelnut quantity provoking objective symptoms increased from 2.29 g to 11.56 g (P = .02; active group) versus 3.49 g to 4.14 g (placebo; NS). Moreover, almost 50% of patients who underwent active treatment reached the highest dose (20 g), but only 9% in the placebo. Laboratory data showed an increase in IgG(4) and IL-10 levels after immunotherapy in only the active group.
Our data confirm significant increases in tolerance to hazelnut after sublingual immunotherapy as assessed by double-blind, placebo-controlled food challenge, and good tolerance to this treatment.
Birch pollen-specific immunotherapy (SIT) decreases allergy to foods containing birch pollen-homologous allergens. Cross-reactivity was also observed between plane tree pollen and some vegetable foods.
The aim of this study was to evaluate the outgrowing of food allergy by patients suffering from vegetable food allergy associated with plane tree pollinosis (rhinoconjunctivitis and/or asthma) during plane tree pollen SIT.
An observational and prospective study was conducted in 16 adult patients suffering from vegetable food allergy (hazelnut, walnut, lettuce, peach and cherry) and from plane tree pollinosis receiving plane tree pollen SIT for 1 year. Open oral challenges with the implicated food were performed before and after SIT. Blood samples were drawn for measurement of pollen- and food-specific IgE and IgG4 before and after treatment.
Plane tree SIT resulted in a significant decrease in food allergy, since the mean food quantity provoking objective symptoms increased from 2.19 to 13.74 g (p < 0.05), and 6 of the 11 patients tolerated the highest level (25 g) of the challenged food after plane tree SIT. Laboratory data also showed a decrease in IgE levels and an increase in IgG4 levels after immunotherapy.
SIT with plane tree pollen has a positive impact on food allergy in plane tree pollen-allergic subjects.
Health properties and uses of soybean, as well as the different chemical and botanical characteristics of this legume are shown in this review. Soybean represents an excellent source of high quality protein, it has a low content in saturated fat, it contains a great amount of dietary fibre and its isoflavone content makes it singular among other legumes. Many researches have been carried out into the benefits of legumes: chickpeas, beans, lentils and soy, among others, but characterization and positive health effects of soybeans have been recently studied. The interest in this legume has increased because of its functional components. Most of the studies have been focused on soybean protein as a possible source of prevention against cardiovascular disease. This positive effect may be due to a decrease in serum cholesterol concentrations. In addition, there are many studies on isoflavones, non-nutritive substances, associated with prevention and treatment of different chronic diseases. Moreover, some studies have shown the health properties of soy dietary fibre. Therefore, it would be interesting to consider the replacement of animal based foods for soybean foods in order to obtain some nutritional benefits.
Since 1981, 26 outbreaks of asthma have been detected in the city of Barcelona. The geographic clustering of cases close to the harbor led us to consider the harbor as the probable source of the outbreaks. We therefore studied the association between the unloading of 26 products from ships in the harbor and outbreaks of asthma in 1985 and 1986. All 13 asthma-epidemic days in these two years coincided with the unloading of soybeans (lower 95 percent confidence limit of the risk ratio, 7.2). Of the remaining 25 products, only the unloading of wheat was related to the epidemics of asthma, although when adjusted for the unloading of soybeans the relation was not statistically significant. High-pressure areas and mild southeasterly to southwesterly winds, which favored the movement of air from the harbor to the city, were registered on all epidemic days. Particles of starch and episperm cells that were recovered from air samplers placed in the city had morphologic characteristics identical to those of soybean particles. Furthermore, the lack of bag filters at the top of one of the harbor silos into which soybeans were unloaded allowed the release of soybean dust into the air. We conclude that these outbreaks of asthma in Barcelona were caused by the inhalation of soybean dust released during the unloading of soybeans at the city harbor.
Component-resolved diagnostics (CRD) have become of growing importance in clinical investigation of IgE-mediated allergies. This review updates the current use of CRD in respiratory allergies (e. g. to pollen, animal dander, mites, latex), as well as in allergies to hymenoptera venom or in food allergies to plants (e. g. Bet v 1 homologues, lipid transfer proteins, storage proteins) or to animal-derived food allergens (e. g. milk, meat, fish). CRD may help to elucidate the clinical relevance of an allergic sensitization. In some cases, CRD may also be useful in predicting either severity of clinical reactions or the therapeutic effect of specific immunotherapy.
Although peanut and soybean proteins share extensive amino acid sequence homology, the incidence and severity of allergic reactions to soy are much less than those to peanut. Soybeans are rich in anti-inflammatory isoflavones and are the most common source of isoflavones in the human food supply.
We hypothesized that the active isoflavones in the gut milieu are capable of modulating immune responses to dietary antigens by regulating dendritic cell (DC) function.
We tested this hypothesis in a murine model of peanut allergy and in human monocyte-derived dendritic cells (MDDCs). C3H/HeJ mice were fed a diet containing genistein and daidzein. The mice were sensitized and challenged with peanut, and the anaphylactic symptoms were compared with those of mice fed a soy-free diet. Human MDDCs were activated with cholera toxin in the presence of isoflavones. The surface expression of DC activation markers and DC-mediated effector functions were analyzed by means of flow cytometry.
Dietary isoflavones significantly reduced the anaphylactic symptoms and mast cell degranulation in vivo after peanut challenge. Serum peanut-specific antibodies were markedly reduced in mice fed the isoflavone diet. Isoflavones inhibited cholera toxin-induced DC maturation in the mesenteric lymph nodes and human MDDCs and subsequent DC-mediated CD4(+) T-cell function in vitro.
These data suggest that dietary isoflavones suppress allergic sensitization and protect against peanut allergy in vivo. Dietary supplementation of soybean isoflavones could be a novel strategy to prevent the development of allergic reactions to food.
Exposure to soy antigens has been associated with asthma in community outbreaks and in some workplaces. Recently, 135 soy flake processing workers (SPWs) in a Tennessee facility were evaluated for immune reactivity to soy. Allergic sensitization to soy was common and was five times more prevalent than in health care worker controls (HCWs) with no known soy exposure.
To characterize sensitization to soy allergens in SPWs.
Sera that were positive to soy ImmunoCAP (n=27) were tested in IgE immunoblots. Wild-type (WT) and transgenic (TG) antigens were sequenced using nanoscale Ultra-Performance Liquid Chromatography Tandem Mass Spectrometry (nanoUPLC MS/MS). IgE reactivity towards 5-enolpyruvylshikimate-3-phosphate synthase (CP4-EPSP), a protein found in TG soy, was additionally investigated. De-identified sera from 50 HCWs were used as a control.
Immunoblotting of WT and TG soy flake extracts revealed IgE against multiple soy antigens with reactivity towards 48, 54, and 62 kDa bands being the most common. The prominent proteins that bound SPW IgE were identified by nanoUPLC MS/MS analysis to be the high molecular weight soybean storage proteins, β-conglycinin (Gly m 5), and Glycinin (Gly m 6). No specific IgE reactivity could be detected to lower molecular weight soy allergens, Gly m 1 and Gly m 2, in soybean hull (SH) extracts. IgE reactivity was comparable between WT and TG extracts; however, IgE antibodies to CP4-EPSP could not be detected.
SPWs with specific IgE to soy reacted most commonly with higher molecular weight soybean storage proteins compared with the lower molecular weight SH allergens identified in community asthma studies. IgE reactivity was comparable between WT and TG soy extracts, while no IgE reactivity to CP4-EPSP was observed. High molecular weight soybean storage allergens, Gly m 5 and Gly m 6, may be respiratory sensitizers in occupational exposed SPWs.
Food-dependent exercise-induced anaphylaxis (FDEIA) due to soybeans is a rare disorder. The allergen responsible for FDEIA due to soybeans has not yet been determined.
We characterized the clinical features of a patient with FDEIA due to tofu, who was well tolerant to drinking soy milk. We then sought to identify the responsible soybean allergen(s) in that patient. We further studied whether different stabilities of the allergen(s) to pepsin digestion between two soybean products are related to their clinical allergenicity.
Skin prick tests and provocation tests using soybean products were performed to detect the responsible food and other factors that induced the allergic symptoms. Specific IgE to various soybean allergens were examined by ImmunoCAP, ELISA and protein microarray assays. Immunoblotting for soybeans and soybean products using the patient's serum was also performed. Soybean products were serially digested by pepsin to disclose the stability of the allergens.
Provocation with ingestion of tofu and exercise induced the allergic symptoms, while ingestion of soy milk and exercise did not. Immunoblot analysis, ELISA and protein microarray assay revealed that beta-conglycinin mainly reacts with IgE antibodies in the patient's serum. By immunoblot analysis, beta-conglycinin in soy milk completely disappeared after pepsin digestion within 20 min, whereas beta-conglycinin in tofu was almost intact after more than 120 min of pepsin digestion.
We identified beta-conglycinin as the causative allergen in a patient with FDEIA induced by tofu. The difference in resistance to pepsin digestion between tofu and soy milk suggests that the presence of undigested allergens in the digestive tract is a prerequisite for the development of FDEIA.
Soybean is considered an important allergenic food, but published data on soybean allergens are controversial.
We sought to identify relevant soybean allergens and correlate the IgE-binding pattern to clinical characteristics in European patients with confirmed soy allergy.
IgE-reactive proteins were identified from a soybean cDNA expression library, purified from natural soybean source, or expressed in Escherichia coli. The IgE reactivity in 30 sera from subjects with a positive double-blind, placebo-controlled soybean challenge (n = 25) or a convincing history of anaphylaxis to soy (n = 5) was analyzed by ELISA or CAP-FEIA.
All subunits of Gly m 5 (beta-conglycinin) and Gly m 6 (glycinin) were IgE-reactive: 53% (16/30) of the study subjects had specific IgE to at least 1 major storage protein, 43% (13/30) to Gly m 5 , and 36% (11/30) to Gly m 6. Gly m 5 was IgE-reactive in 5 of 5 and Gly m 6 in 3 of 5 children. IgE-binding to Gly m 5 or Gly m 6 was found in 86% (6/7) subjects with anaphylaxis to soy and in 55% (6/11) of subjects with moderate but only 33% (4/12) of subjects with mild soy-related symptoms. The odds ratio (P < .05) for severe versus mild allergic reactions in subjects with specific IgE to Gly m 5 or Gly m6 was 12/1.
Sensitization to the soybean allergens Gly m 5 or Gly m 6 is potentially indicative for severe allergic reactions to soy.
Twenty patients suffering from birch pollen allergy received two or three courses of immunotherapy in successive years. In 9 patients, the fruit allergy improved; 4 patients reported no improvement. In 3 patients, the fruit allergy developed after beginning the immunotherapy. At the end of the 3 years, 16 of these patients were allergic to fruit, 13 of them to apple. After each preseasonal course of immunotherapy with tree pollen extract, a temporal and parallel increase in the titers of IgE antibodies to birch pollen allergens and apple allergens were observed. In contrast, only the titers of birch pollen allergen specific IgG and IgG4 increased, whereas apple allergen specific IgG and IgG4 did not, or only very slightly. In Western blot studies, IgG4 antibodies bound to more components of apple extract than birch pollen extract. On the average, IgG4 antibodies recognize more components of apple and birch pollen extracts than do IgE antibodies. In histamine release studies, the sensitivity of washed leukocytes to birch pollen extract decreased significantly during the observation time. However, the difference between apple extract-induced histamine release before and after immunotherapy was not significant. None of the immunological parameters investigated here correlate well with severity or prognosis of the fruit (apple) allergy. The clinical improvement of pollinosis was associated with a rise in birch pollen specific IgG4 antibody titers and a decrease of allergen-induced histamine liberation. Beside improvement of the fruit allergy in 56% of the cases, the courses of apple specific IgE and IgG4 antibody titers seem to indicate a slight sensitization against apple allergens.
Most patients with birch pollen allergy report oral allergy symptoms after eating fresh apples and other vegetable foods. Major birch pollen and apple allergens, Bet v 1 and Mal d 1, are highly homologous; as a consequence, pollen-specific immunotherapy (SIT) might be expected to improve apple hypersensitivity.
To evaluate the clinical and immunological effects of birch pollen SIT on oral allergy syndrome (OAS) induced by apples.
A prospective study carried out in 49 birch pollen-sensitive patients with apple-induced OAS who received injection immunotherapy for 12, 24, or 36 months. Twenty-six patients not submitted to SIT and followed up for 12-48 months were used as controls. Both SPT and open oral challenges with fresh golden delicious apple were performed, as well as specific IgE measurements, before and after SIT.
Forty-one patients (84%) vs no control (0%) reported a significant reduction (50-95%) or a total disappearance (100%) of OAS symptoms after SIT (P < 0. 001). Similar responses were observed in patients treated for 12, 24, or 36 months. SIT also induced a marked reduction in skin reactivity against fresh apple in 43 patients (88%). The effect of SIT was inversely related with baseline skin reactivity: 50% and 8% patients with a weakly or strongly positive baseline apple skin prick tests (SPT), respectively, did not report changes in OAS severity after SIT (P < 0.01). In contrast, baseline birch pollen-specific or apple-specific IgE antibodies levels did not influence SIT effectiveness on OAS. SIT induced a marked decrease in birch pollen-specific IgE levels (P < 0.001), whereas apple-specific IgE showed an unexpected variability (reduction in 21%, no change in 43%, increase in 38%). No control subject reported a reduction in OAS severity or showed a decrease in skin reactivity at follow-up (P < 0.001).
SIT with birch pollen extracts effectively reduces clinical apple sensitivity and skin reactivity in most cases after only 1 year of treatment; these effects are not paralleled by a similar reduction in apple-specific IgE. These findings suggest a decrease in activability of effector cells as the mechanism underlying clinical benefit.
Anaphylactic reactions to soy products have been attributed to stable class 1 food allergens.
IgE- mediated reactions to a soy-containing dietary food product in patients allergic to birch pollen were investigated.
Detailed case histories were taken from 20 patients. Their sera were analyzed for IgE (UniCAP) specific for birch, grass, mugwort, the recombinant birch allergens rBet v 1 and rBet v2, and soy protein. Extracts from birch pollen, soy isolate, rBet v 1, and the recombinant PR-10 soy protein rSAM22 were coupled to paper disks or nitrocellulose for IgE measurements (enzyme allergosorbent test) or Western blot analysis. Enzyme allergosorbent testing, Western blot inhibition, and histamine release studies were performed with the same allergens.
Most patients (17/20) experienced facial, oropharyngeal, and/or systemic allergic symptoms within 20 minutes after ingesting the soy product for the first time. Birch pollen allergy (16/20) was common, along with oral allergy syndrome to apple (12/20) or hazelnut (11/20). IgE levels to birch and Bet v 1 but not to other inhalants were high in 18 of 20 patients. Significant IgE binding to rSAM22 occurred in 17 of 20 patients. Blot experiments with the soy isolate revealed IgE-binding bands at 17 kd (15/20), 22 kd (1/20), and 35 to 38 kd (2/20); the former was inhibited by preincubation of the sera with rBet v 1 or rSAM22. Birch extract and soy isolate, rBet v 1, and rSAM22 induced dose-dependent histamine release in the nanomolar range.
Immediate-type allergic symptoms in patients with birch pollen allergy after ingestion of soy protein-containing food items can result from cross-reactivity of Bet v 1 -specific IgE to homologous pathogenesis-related proteins, particularly the PR-10 protein SAM22.
Recent studies showed that injection specific immunotherapy (SIT) with birch pollen extract greatly reduces or cures the associated apple allergy in a large proportion of birch pollen-allergic patients. However, the long-term efficacy of SIT for apple allergy has not been assessed.
To evaluate the duration of the effect of injection SIT with birch pollen extract on apple allergy in birch pollen-allergic patients.
Thirty birch pollen-allergic patients showing both the clinical disappearance of apple allergy and a negative SPT with fresh apple at the end of their injection SIT course were followed-up at 12-month intervals from 6 months after SIT was stopped. Apple tolerance as well as SPT was assessed on all occasions. Fifty-seven birch pollen-allergic subjects without apple allergy and not submitted to SIT regularly followed-up for the onset of oral allergy syndrome (OAS) were used as controls.
The overall prevalence of OAS after 30 months of follow-up did not differ between patients and controls. Although most patients became re-sensitized to apple by SPT over time, >50% of them were still able to tolerate eating the fruit at the 30-month follow-up visit.
Although most patients show a 'natural', gradual propensity to apple re-sensitization (a consequence of prolonged and repeated inhalation of birch pollen responsible for primary sensitization?), the clinical effects of injection SIT on food allergy seem rather long lasting.
Allergic reactions to legumes are generally thought to be acquired by means of primary sensitization through the gastrointestinal tract. Recently, Gly m 4 (starvation-associated message 22), a Bet v 1-related pathogenesis-related protein 10 from soy, was suggested to be an allergen in patients with allergic reactions to a dietary product containing a soy protein isolate.
We sought to evaluate the clinical relevance of Gly m 4 in subjects allergic to birch pollen with soy allergy and to assess the risk for subjects allergic to birch pollen to acquire soy allergy.
Twenty-two patients allergic to birch pollen with soy allergy confirmed by means of positive double-blind, placebo-controlled food challenge results (n = 16) or a convincing history (n = 6) were investigated for IgE reactivity to birch pollen and soy allergens by using the Pharmacia CAP system and immunoblot analysis. Cross-reactivity was assessed by means of enzyme allergosorbent test inhibition. Ninety-four patients with birch pollen allergy were interviewed to assess soy tolerance and screened for IgE reactivity to Gly m 4 by means of immunoblotting. The Gly m 4 content in soy foods and soybean varieties was investigated by means of quantitative evaluation of immunoblots.
During double-blind, placebo-controlled food challenge, 10 patients experienced symptoms localized to the oral cavity, and 6 patients had a more severe reaction. CAP analysis revealed Gly m 4-specific IgE in 96% (21/22) of the patients. All patients had Bet v 1-specific IgE antibodies, and 23% (5/22) had positive Bet v 2 results. In IgE immunoblotting 25% (6/22) of the patients recognized soy profilin (Gly m 3), and 64% (14/22) recognized other soy proteins. IgE binding to soy was at least 80% inhibited by birch pollen and 60% inhibited by rGly m 4 in 9 of 11 sera tested. Seventy-one percent (67/94) of highly Bet v 1-sensitized patients with birch pollen allergy were sensitized to Gly m 4, and 9 (9.6%) of those patients reported soy allergy. The Gly m 4 content in soy products ranged between 0 and 70 ppm (milligrams per kilogram).
Our results confirm that soybean is another birch pollen-related allergenic food. Gly m 4 is the major soy allergen for patients allergic to birch pollen with soy allergy. The content of Gly m 4 in soy food products strongly depends on the degree of food processing.
The effect of birch-pollen immunotherapy (IT) on cross-reactive food allergies is controversial.
The aim of this study was to investigate the effect of birch-pollen IT on apple allergy and to evaluate recombinant allergens and double-blind placebo-controlled food challenges (DBPCFCs) as monitoring tools.
Twenty-five adult birch-pollen- and apple-allergic patients were randomly divided into two groups, either receiving birch-pollen IT or symptomatic drugs only. IgE and IgG4 antibodies against birch pollen, apple, natural Bet v 1 and Mal d 1 were measured. In addition, skin prick tests (SPT) were performed using recombinant Bet v 1 (rBet v 1) and Mal d 1 (rMal d 1). Clinical outcome was evaluated by DBPCFC. CD4(+)CD25(+) regulatory T cells (Tregs) were isolated from peripheral blood and tested in functional assays.
Birch-pollen IT resulted in a significant decrease of SPT reactivity for rBet v 1 (30-fold) and rMal d 1 (10-fold) already after 3 months. IgG4 antibodies were potently induced against Bet v 1, displaying cross-reactivity to Mal d 1. Visual analogue scale scores decreased >10-fold in 9/13 patients of the IT group, with three patients converting to negative. In the control group, no decrease was observed. Birch-pollen IT did not lead to detectable changes in the number or function of the CD4(+)CD25(+) Tregs.
This trial supports the claims that birch-pollen IT also decreases allergy to foods containing Bet v 1-homologous allergens. Recombinant allergens and DBPCFCs have proven to be useful tools for monitoring the effect of birch-pollen IT on linked food allergies.
The efficacy of specific immunotherapy (SIT) in pollen allergy is well established. However, its effect on pollen associated food allergy particularly the oral allergy syndrome (OAS) is not definitely ascertained.
The purpose of this controlled prospective study was to investigate whether SIT with tree pollen, mainly birch, has an effect on OAS induced by apple or hazelnut in birch pollen-allergic individuals.
Twenty-seven birch pollen-allergic subjects with OAS induced by apple or hazelnut underwent open oral provocation tests (OPT) with increasing doses (1 to 128 g) of fresh apple or ground hazelnut 1 year apart. Fifteen of 27 subjects were treated with SIT and 12 were not. Skin-prick test with birch pollen, apple and hazelnut, and specific serum IgE, IgG and IgG4 to rBet v 1, apple and hazelnut were determined.
Thirteen of 15 (87%) SIT-treated subjects could eat significantly (P <0.001) more of apple or hazelnut without any symptoms/signs. The average tolerated quantity increased from 12.6 to 32.6 g apple after 1 year in this group. In contrast, only one of 12 (8%) individuals without SIT was able to consume a higher amount without symptoms. On evaluating laboratory parameters, only IgG4 antibodies to rBet v 1 were found to be significantly (P <0.01) increased in the SIT-treated group after 1 year.
The study shows that SIT with extracts containing birch pollen has a positive impact on OAS to apple or hazelnut in birch pollen-allergic individuals. In spite of this outcome, the amount of apple/hazelnut tolerated is still small. Thus, the effect of SIT on the patients' management of OAS remains limited.
Conflicting results concerning the effect of specific pollen immunotherapy (SIT) on allergy to plant foods have been reported. The aim of this study was to investigate the effect of SIT using a birch pollen extract on food allergy with focus on allergy to apple. Seventy-four birch pollen-allergic patients were included in a double-blind, double-dummy, and placebo-controlled comparison of sublingual-swallow (SLIT) and subcutaneous (SCIT) administration of a birch pollen extract. Sixty-nine percent of these patients reported allergy to apple. The clinical reactivity to apple was evaluated by open oral challenges with fresh apple and a questionnaire. The immunoglobulin E (IgE)-reactivity was assessed by skin prick test (SPT), specific IgE, and leukocyte histamine release (HR). Forty patients were included in the final evaluation of the effect of SIT. The challenges were positive in 9 (SCIT), 6 (SLIT), and 8 (placebo) patients after treatment compared to 10, 4, and 10 patients, respectively, before SIT. The symptom scores to apple during challenges decreased in all groups, but only significantly in the placebo group (p = 0.03). As evaluated by the questionnaire, the severity of food allergy in general did not change and there were no differences between the groups. In spite of a significant effect on seasonal hay fever symptoms and use of medication and decrease in IgE-reactivity, SIT was not accompanied by a significant decrease in the severity of allergy to apple compared to placebo. Therefore, oral allergy syndrome (OAS) to apple should not be considered as a main criterion for selecting patients for birch pollen immunotherapy at present.
Cross-reactivity between the major birch pollen allergen, Bet v 1, and the apple protein, Mal d 1, frequently causes food allergy.
To investigate the effects of successful sublingual immunotherapy (SLIT) with birch pollen extract on apple allergy and the immune response to Bet v 1 and Mal d 1.
Before and after 1 year of SLIT, Bet v 1-sensitized patients with oral allergy syndrome to apple underwent nasal challenges with birch pollen and double-blind placebo-controlled food challenges with apple. Bet v 1-specific and Mal d 1-specific serum antibody levels and proliferation in PBMCs and allergen-specific T-cell lines (TCLs) were determined. Bet v 1-specific TCLs were mapped for T-cell epitopes.
In 9 patients with improved nasal provocation scores to birch pollen, apple-induced oral allergy syndrome was not significantly reduced. Bet v 1-specific IgE and IgG(4) levels significantly increased. Bet v 1-specific T-cell responses to all epitopes and those cross-reactive with Mal d 1 significantly decreased. However, neither Mal d 1-specific IgE and IgG(4) levels nor Mal d 1-induced T-cell proliferation changed significantly. In contrast, Mal d 1-specific TCLs showed increased responses to Mal d 1 after 1 year of SLIT.
This longitudinal study indicates that pollen SLIT does not efficiently alter the immune response to pollen-related food allergens, which may explain why pollen-associated food allergy is frequently not ameliorated by pollen immunotherapy even if respiratory symptoms significantly improve.
SLIT with birch pollen may have no clinical effect on associated apple allergy.
Soybean is a relevant allergenic food, but little is known about individual threshold doses in soy allergy.
We sought to determine the clinical characteristics of soy allergy in Europe, including a dose-response curve.
Patients with a history of soy allergy underwent a titrated, double-blind, placebo-controlled food challenge. A statistical model was used to calculate the risk of allergic consumers to experience an allergic reaction to soy. Sera were analyzed for specific IgE to soy, peanut, Bet v 1, and Gly m 4.
All patients but one responded primarily with subjective symptoms to the challenge followed by objective symptoms in 11 subjects, ranging from rhinitis up to a decrease in blood pressure. Cumulative threshold doses for allergic reactions ranged from 10 mg to 50 g for subjective symptoms and from 454 mg to 50 g for objective symptoms. The pattern of IgE reactivity against proteins with molecular weights of between approximately 10 and 70 kd was highly individual among the patients and did not correlate with the severity of symptoms.
When data are fitted by using a normal distribution statistical model, they predict that 1% of patients with soy allergy would react subjectively and objectively with 0.21 and 37.2 mg of soy protein, respectively.
Both the clinical and immunologic basis of soy allergy in Europe are highly complex, which affects the diagnosis of soy allergy and the advice given to patients with soy allergy in regard to risk management.
The purpose of this paper is to review and discuss studies on soy allergy.
In Central Europe soy is a clinically relevant birch pollen-related allergenic food. Crossreaction is mediated by a Bet v 1 homologous protein, Gly m 4. Additionally, birch pollen allergic patients might acquire through Bet v 1 sensitization allergies to mungbean or peanut, in which Vig r 1 and Ara h 8 are the main cross-reactive allergens. Threshold doses in soy allergic individuals range from 10 mg to 50 g of soy and are more than one order of magnitude higher than in peanut allergy. No evidence was found for increased allergenicity of genetically modified soybeans.
In Europe, both primary and pollen-related food allergy exist. The diagnosis of legume allergy in birch pollen-sensitized patients should not be excluded on a negative IgE testing to legume extracts. Bet v 1 related allergens are often underrepresented in extracts. Gly m 4 from soy and Ara h 8 from peanut are nowadays commercially available and are recommended in birch pollen allergic patients with suspicion of soy or peanut allergy, but negative extract-based diagnostic tests to screen for IgE specific to these recombinant allergens.