Cross-reactivity between fruit and vegetables

Vegetable foods are the most frequent cause of food allergy after the age of 5 years. The most commonly implicated foods are fruit and dried fruits, followed in Spain by legumes and fresh garden produce. In patients allergic to fruit and garden produce, multiple sensitizations to other vegetable products, whether from the same family or taxonomically unrelated, are frequent, although they do not always share the same clinical expression. Furthermore, more than 75 % of these patients are allergic to pollen, the type of pollen varying in relation to the aerobiology of the area. The basis of these associations among vegetable foods and with pollens lies in the existence of IgE antibodies against "panallergens", which determines cross-reactivity. Panallergens are proteins that are spread throughout the vegetable kingdom and are implicated in important biological functions (generally defense) and consequently their sequences and structures are highly conserved. The three best-known groups are allergens homologous to Bet v 1, profilins, and lipid transfer proteins (LTP). Allergens homologous to Bet v 1 (major birch pollen allergen) constitute a group of defense proteins (PR-10), with a molecular weight of 17 kDa, which behave as major allergens in patients from northern and central Europe with allergy to vegetables associated with birch pollen allergy. In these patients, the primary sensitization seems to be produced through the inhalation route on exposure to birch pollen. The symptomatology characteristically associated with sensitization to this family of allergens is oral allergy syndrome (OAS). Profilins are highly conserved proteins in all eukaryotic organisms and are present in pollen and a wide variety of vegetable foods. They have a molecular weight of 14 kDa and present a high degree of structural homology as well as marked cross-reactivity among one another. The presence of anti-profilin IgE broadens the spectrum of sensitizations to vegetable foods detected through skin tests and/or in vitro tests but whether it correlates with the clinical expression of food allergy is unclear.LTPs are the most commonly implicated allergens in allergy to Rosaceae fruits in patients from the Mediterranean area without birch pollen sensitization. LTPs are a family of 9kDA polypeptides, widely found in the vegetable kingdom and implicated in cuticle formation and defense against pathogens (PR-14). They are thermostable and resistant to pepsin digestion, which makes them potent food allergens and explains the frequent development of systemic symptoms (urticaria, anaphylaxis) in patients allergic to Rosaceae fruits in Spain. LTPs have also been identified in other vegetable foods and in pollens and a marked degree of cross-reactivity among them has been demonstrated, which may explain (together with profilin) the frequency of individuals sensitized to vegetable foods in the Mediterranean area.     

Plant lipid transfer proteins (LTPS): biochemical aspect in panallergen--structural and functional features, and allergenicity

Lipid transfer proteins (LTPs) are highly conserved and widely distributed throughout the plant kingdom. Several members of LTP family have been identified as relevant allergens in food and pollens. Because of their high resistance to heat treatments and enzymatic digestion, these proteins are allergenic candidates for oral route sensitisation. This review presents biochemical features, allergenicities and cross reactivities of fruit, cereal and pollen LTPs.     

Microarray based IgE detection in poly-sensitized allergic patients with suspected food allergy - an approach in four clinical cases

BackgroundComponent-resolved diagnosis and microarray technology have been recently introduced into clinical allergy practice, and may be particularly useful in poly-sensitized allergic patients.MethodsWe compare the clinical usefulness of a microarray-based IgE detection assay (ISAC^®) with skin tests and specific IgE with standard allergens (sIgE) or their monocomponents in four case reports of patients poly-sensitized to aeroallergens and food.ResultsCase 1: a woman with rhinitis, oral allergy syndrome to several fruits and anaphylaxis to cherry. Diagnostic tests supported non-specific lipid transfer proteins (nsLTPs) primary sensitization.Case 2: a woman with exercise-induced asthma, rhino-conjunctivitis and oral allergy syndrome to fresh fruits of different families. A diagnosis of primary grass and weed pollen allergy with profilin and pathogenesis-related protein family 10 (PR-10) cross-reactive food allergy was proposed.Case 3: a man with atopic eczema, asthma, rhinitis, and multiple anaphylactic episodes with cashew nuts and oral allergy syndrome to fruits. The diagnostic workup supported a primary birch pollen allergy with PR-10 and nsLTPs cross-reactive food allergy.Case 4: a woman with rhino-conjunctivitis, per-operative anaphylaxis due to latex and recent pharyngeal angio-oedema episodes. The diagnosis was a primary grass and weed pollen allergy with equivocal profilin sensitization and no obvious cross-reactivity mediated by nsLTPs sensitization.ConclusionsThe possibility to carry out multiple sIgE measurements with single protein allergens, in particular with the microarray technique, is a useful, simple and non-invasive diagnostic tool in complex poly-sensitized allergic patients.     

Biology of weed pollen allergens

Weeds represent a heterogeneous group of plants, usually defined by no commercial or aesthetic value. Important allergenic weeds belong to the plant families Asteraceae, Amaranthaceae, Urticaceae, Euphorbiaceae, and Plantaginaceae. Major allergens from ragweed, mugwort, feverfew, pellitory, goosefoot, Russian thistle, plantain, and Mercurialis pollen have been characterized to varying degrees. Four major families of proteins seem to be the major cause of allergic reactions to weed pollen: the ragweed Amb a 1 family of pectate lyases; the defensin-like Art v 1 family from mugwort, feverfew, and probably also from sunflower; the Ole e 1-like allergens Pla l 1 from plantain and Che a 1 from goosefoot; and the nonspecific lipid transfer proteins Par j 1 and Par j 2 from pellitory. As described for other pollens, weed pollen also contains the panallergens profilin and calcium-binding proteins, which are responsible for extensive cross-reactivity among pollensensitized patients.     

The Role of Lipid Transfer Proteins in Allergic Diseases

Nonspecific lipid transfer proteins (LTPs) are important allergens in fruits, vegetables, nuts, pollen, and latex. Despite their wide distribution throughout the plant kingdom, their clinical relevance is largely confined to the Mediterranean area. As they can sensitize via the gastrointestinal tract, LPTs are considered true food allergens, and IgE reactivity to LTPs is often associated with severe systemic symptoms. Although Pru p 3 represents the predominant LTP in terms of patients’ IgE recognition, the contribution of pollen LTPs in primary sensitization cannot be ruled out. Due to structural homology, LTPs from different allergen sources are generally IgE cross-reactive. However, sensitization profiles among allergic patients are extremely heterogeneous, and individual cross-reactivity patterns can be restricted to a single LTP or encompass many different LTPs. Molecule-based approaches in allergy research and diagnosis are important for better understanding of LTP allergy and could assist clinicians with providing adequate patient-tailored advice.     

Can any protein become an allergen?

Allergens of plant and animal foods and pollen belong to a highly restricted number of protein families. The AllFam Database (http://www.meduniwien.ac.at/allergens/allfam/) provides regularly updated lists of protein families that contain allergens. At present, 2% of the 9318 protein families defined by the Pfam Database (http://pfam.sanger.ac.uk/) contain allergens. Related protein families can be grouped into superfamilies placing allergenic proteins in an evolutionary context. With the exception of the prolamin superfamily, allergenic plant proteins are found in few member families of their respective superfamilies. This might indicate that allergenicity emerged rather infrequently in a very limited number of protein families. Moreover, most members of a given protein family seem to be non-allergenic. In contrast to plant allergens, the allergenicity of animal food allergens seems to be dependent on the degree of identity to a human homologue. The closer a potential animal allergen is to a human protein, the less likely it is to act as allergen.     

Gibberellin-regulated protein allergy: Clinical features and cross-reactivity

Gibberellin-regulated proteins (GRPs)/GASA proteins are members of cysteine-rich antimicrobial peptide families and are conserved in a broad range of plants. Some GRPs in fruits and pollens have been identified as allergens including peach Pru p 7, Japanese apricot Pru m 7, orange Cit s 7, pomegranate Pun g 7, and cypress pollen GRP. The clinical features of fruit-derived GRP allergies frequently include systemic reactions, multiple fruit allergies regardless of plant kingdom classifications and, less frequently, cofactor-dependence. Multiple fruit allergies might be related to cross-reactivity between GRPs. Clinical cross-reactivity, at least between the four fruit-derived GRPs, has been proven. In addition, GRP allergy induces peculiar clinical symptoms, such as laryngeal tightness and facial swelling, especially eyelid edema, which was proposed to be a predictive factor for Pru p 7 allergy. Fruit-derived GRPs have an unusually high content of cysteine, resulting in high stability to heat and resistance to digestive enzymes. Therefore, GRPs are considered “true” food allergens that induce severe allergic reactions. As an alternative mechanism of fruit-derived GRP allergies, cross-reactivity between fruit GRP and cypress pollen GRP, which might play a role as a sensitizer, is suspected. Taken together, these characteristics indicate GRPs are clinically relevant plant allergens.This review article summarizes our current knowledge of the clinical features and important aspects of GRP sensitization and allergy.     

B cell Biology: An Overview

As investigations into the innate immune responses that lead to allergic sensitization become better defined, there is a need to determine how allergens could interact with pattern recognition receptors that bind non-proteinaceous moieties. Many important allergens are not covalently bound to lipid or carbohydrate, but have structures belonging to lipid, glycan and glycolipid-binding families. These include ML-domain proteins, lipopolysaccharide-binding/cell permeability-increasing proteins, von Ebner gland lipocalins, salivary lipocalins/major urinary proteins, plant pathogenesis-related proteins PR-5 and -10, uteroglobins, non-specific lipid transfer proteins, large lipid transfer proteins and proteins with chitin and other carbohydrate-binding modules. The binding expected is overviewed with regard to importance of the allergens and their ability to elicit responses proposed from experimental models. The evidence compiled showing that allergens from the same source sensitize for different types of adaptive immune responses supports the concept that individual allergens within these sources have their own distinctive interactions with innate immunity.     

Allergic reaction after ingestion of orange blossom pollen.

A 31-year-old atopic subject with allergic rhinoconjunctivitis with sensitization to several pollens, presented with urticaria and angioedema after ingestion of orange blossom pollen (Citrus sinensis). A positive skin prick test for orange blossom pollen extract (BIAL-Aristegui, Bilbao, Spain) at a concentration of 1.2 mg/ml was obtained. Serum specific IgE antibodies to orange blossom pollen were shown (Unicap Pharmacia System, Uppsala, Sweeden). A conjunctival provocation test was negative with orange blossom pollen extract dilutions of 1:1000, 1:100 and 1:10 w/v. We describe a patient with an IgE-mediated reaction caused by hypersensitivity to orange blossom pollen. Although the pollen is an aeroallergen and the way of sensitization and entrance is the airway, and therefore the symptoms appear in this location, when contact is through some other route such as the digestive tract, it is also able to sensitize reporting urticaria and angioedema like in our case, instead of respiratory symptoms.     

Are there any links between Hop Japanese pollen and other weed pollens or food allergens on skin prick tests?

Recent investigations suggest that the importance of Hop Japanese pollen, which has been known as one of the major causative weed pollens, is increasing in this country. There have been few data dealing with the allergenic relationship between Hop J pollen and other food or inhalant allergens. Among 2909 patients who visited the Allergy Clinic of Ajou University Hospital, Suwon, Korea, 471 patients sensitized to Hop J, mugwort, or ragweed pollens on skin-prick test were enrolled. Positive rates to common inhalant or food allergens and their allergenic relationships with other pollens or food allergens were analyzed based upon skin-prick test results. The positive rates to sunflower, fat hen, nettle, grass (Bermuda, Orchard) and tree (alder, birch, and poplar) pollen were significantly higher in those sensitized to Hop J pollen than in those of negative responders (p < 0.05, respectively). No significant associations were noted with ragweed or mugwort pollen (p > 0.05, respectively). In regard to food-related allergens, an association was noted between Hop (Humulus lupulus) or celery allergens in those sensitized to Hop J pollen (p < 0.05, respectively). Hop J pollen may have possible links with celery, Hop, and sunflower pollens on skin-prick test. Further in vitro investigations will be needed to evaluate the possibility of cross-reacting components between them.     

Food Allergy and Atopic Dermatitis: How Are They Connected?

Food allergy predominantly affects children rather than adults with atopic dermatitis (AD). Early food sensitization has been found to be significantly associated with AD. Three different patterns of clinical reactions to food allergens in AD patients have been identified: 1) immediate-type symptoms, 2) isolated eczematous late-type reactions, and 3) combined reactions. Whereas in children, allergens from cow’s milk, hen’s egg, soy, wheat, fish, peanut, or tree nuts are primarily responsible for allergic reactions, birch pollen–related food allergens seem to play a major role in adolescent and adults with AD in Central and Northern Europe. Defects in the epidermal barrier function seem to facilitate the development of sensitization to allergens following epicutaneous exposure. The relevance of defects in the gut barrier as well as genetic characteristics associated with an increased risk of food allergy remain to be further investigated. Many studies focus on sufficient strategies of prevention, which actually include breastfeeding or feeding with hydrolyzed formula during the first 4 months of life.     

LTP allergy/sensitization in a pediatric population

Plant lipid transfer proteins (LTPs) are widespread plant food allergens, highly resistant to food processing and to the gastrointestinal environment, which have been described as the most common food allergens in the Mediterranean area. LTP allergy is widely described in adults, but it represents an emerging allergen also in the pediatric population. Little is known about the real prevalence and the clinical features of this allergy in children and it still often remains underdiagnosed in these patients.An early identification and a deeper knowledge of this allergy in childhood can avoid severe systemic reactions and improve the child's quality of life. Pediatricians should always consider the possibility of LTP involvement in cases of plant-derived food allergy.     

Devenir des allergènes dans le tube digestif

Mechanisms by which food allergens sensitize atopic individuals still remain unclear. However, most of them are thought to sensitize via the gastrointestinal tract. Due to the very acidic conditions in the stomach and the intense proteolysis occurring in the stomach and in the intestine, only small amounts of intact or immunologically active proteins are taken up by the gut mucosa. This suggested that food allergens are, at least partially, resistant to gastro-duodenal digestion in order to be able to sensitize the mucosal immune system. As a result, several in vitro models have been developed to evaluate the stability of potential allergens to digestion. Indeed, resistance to digestion is part of the premarketing allergenicity assessment of newly expressed proteins in genetically modified crops. However, some food allergens are rapidly and extensively degraded during digestion, whereas some other food proteins that are resistant to digestion are not allergenic. It has been shown that degradation products, i.e. peptide fragments of various sizes, produced during the digestion of a protein may keep (part of) the allergenicity of the native protein. In addition, other factors may interact as to make a food protein an allergen, such as the structure and composition of the food matrix, technologic processing including cooking of the whole food that contains the allergens. Some studies also suggested that the biological property of a protein to be an allergen can influence its mode and route of transport across the intestinal epithelial barrier, which may have a profound impact on the immune responses thus generated. It is noteworthy that a pregastric absorption also occurs, i.e. in the oral cavity, which explains the occurrence of symptoms few minutes after ingestion of food allergens.     

Double-blind, placebo-controlled evaluation of grass pollen specific immunotherapy with oral drops administered sublingually or supralingually

Forty-one patients suffering from grass pollen allergy underwent specific immunotherapy with standardized allergen extract consisting of six grass pollens (H-Al per os) administered either sublingually or supralingually for one year. In order to investigate clinical and immunological changes induced by the administration of allergens via the oral mucosa, the double-blind, placebo-controlled, randomized design of the trial with 30 other patients enrolled in placebo groups was applied. Specific immunotherapy with oral drops administered sublingually or supralingually was performed in the same way, keeping the drops under or on the tongue, respectively, for 1-2min before swallowing them; at the end of the trial the cumulative dose of the allergen was almost 20 times higher than that of the subcutaneous therapy with corresponding allergen preparation. Data about symptoms scores and drugs intake during grass pollen season, as well as skin reactivity, levels of specific IgG and IgE antibodies, before the study and after the study's completion, were obtained. It was found that both routes of administration are effective according to subjective clinical parameters and drug consumption, with a highly significant reduction of symptoms and drug intake favoring sublingual administration where a reduction of more than 60% was achieved. Only sublingual active group showed a significant increase in Dactylis glomerata-specific IgG serum levels. Adverse effects were limited to a small number of generally mild local and/or systemic reactions. The results suggest that the administration of allergens via the oral mucosa is safe and clinically effective, favoring the sublingual rather than supralingual route.     

Improving pollen immunotherapy: minor allergens and panallergens

Multiple sensitizations to pollens are common clinical situations in Spain, and alter the efficacy of allergen-specific immunotherapy. We now know that optimization of the diagnosis is required to define the best suited treatment for each patient. All pollen allergens belong to 29 families of proteins - the most abundant being the expansins, prophyllins and polcalcins. The ubiquitous nature of proteins such as the prophyllins and polcalcins defines them as panallergens, and explains the cross-reactivity that is erroneously interpreted by clinicians as constituting multi-sensitization. Other families of allergens, such as the calcium transporting proteins (LTPs) are more restricted, but are associated to severe types of allergic disease - this being particularly useful to decide upon the indication of immunotherapy. Although recombinant allergens can be produced for in vitro diagnostic purposes, current legislation only allows the use of natural proteins for immunotherapy. However, the same technology can be applied to the study of extracts for vaccines, and it seems that allergen quantification by the manufacturers is a no return trip which clinicians are obliged to follow.     

Allergènes alimentaires croisant avec les allergènes des pollens

The range of pollen-food cross-reactions has increased over the past decade, the clinical pictures are more clear with respect to the allergens concerned, and the molecular basis for some of them have been determined. Diagnostic methods include skin tests, assays for specific IgE, and open and double blind oral provocation tests. Investigation of allergic cross-reactions, first based solely on immunological inhibition techniques using natural allergen extracts, have benefited from molecular biology. Many allergens homologous with pollen allergens have been sequenced and the three dimensional structure of Pru av 1 has been determined, allowing studies on a sub-molecular scale. Allergen cross-reactions between pollen and food, for which the clinical relevance is well established, involve allergens of the Bet v 1 and Bet v 2 families. These allergens are present in numerous edible fruits and vegetables. Identity with the Bet v 1 sequence varies from 38 to 67%, being closest for the profilins (70-80%). Cross sensitization with Bet v 1 and profilins, although particularly frequent, may be silent clinically. Other candidate molecules involved in cross-reactions between pollen and food allergens are Bet v 6, a minor birch allergen, the lipotransferases found in some of the compositae, and the 1,3-β-glucanases corresponding to a major olive allergen. The significance of the detection of specific IgE directed against carbohydrate determinants remains to be investigated. A major problem for the clinician is the absence of clinical significance of cross-reactivity that has been demonstrated in vitro and in vivo.     

Why can patients with baker's asthma tolerate wheat flour ingestion? Is wheat pollen allergy relevant?

Diagnosis in patients sensitised to multiple pollens is difficult due to the relationship between pollen and food allergens. Misdiagnosis is often a cause for unsuccessful specific immunotherapy. Wheat is a potent allergen source and is one of the causes of baker's asthma, food and pollen allergy. Recently, we have performed a study on pollen sensitisation in our area, where cereal crops are very important. The clinical data from 19718 patients reviewed showed that grass pollen was the main source of clinical symptoms (6369 patients, 32.30% of asthmatics). However, wheat and cereal crop pollen showed very low prevalence. On the other hand, patients with wheat flour allergy after ingestion and/or with baker's asthma were not sensitised to wheat pollen, despite it containing some common allergens. In the same way, all our asthmatic bakers (135 patients) tolerated the ingestion of bread. Here we try to explain the reason for these surprising observations.     

Clinical profile of a Mediterranean population sensitised to date palm pollen (Phoenix dactylifera). A retrospective study

BackgroundDate palm pollen allergy is frequently associated with polysensitisation. Observational studies have suggested that date-palm-sensitised individuals could be included in a distinct group of polysensitised patients. The objectives of the study were to analyse the clinical characteristics of a group of patients diagnosed of date-palm pollen allergy and to compare them with pollen allergic patients without date-palm sensitisation.MethodsForty-eight palm-pollen sensitised individuals were classified as Group A. A control group of 48 patients sensitised to pollens but without palm-pollen allergy were included as Group B. All individuals were skin prick tested with a common battery of aeroallergens. Information about age, sex, family history of atopy, respiratory symptoms, food allergy and sensitisation to other pollens were considered variables of the study. Specific IgE and the allergogram to date-palm pollen were determined in a subgroup of Group A.ResultsSignificant differences in the family history of atopy and number of sensitisations were observed. Both parameters were significantly higher in Group A. Group A showed high prevalence of asthma and higher level of sensitisation to foods (p < 0.05). Significant differences were obtained for sensitisation to epithelia and pollens. Pho d 2 was the most commonly recognised allergen (83.3%) in the palm-pollen allergic group.ConclusionsDate-palm pollen allergic patients constitute a homogeneous group characterised for showing bronchial asthma, sensitisation to food allergens and polysensitisation. These results suggest that the reasons for sensitisation to date-palm pollen remain to be elucidated, but could relate to the existence of as yet non-identified pan-allergens.     

Diagnostic usefulness of component-resolved diagnosis by skin prick tests and specific IgE to single allergen components in children with allergy to fruits and vegetables

IntroductionThe accurate identification of sensitizing proteins in patients allergic to plant-derived foods is extremely important, allowing a correct dietary advice. We aimed to evaluate the diagnostic usefulness of skin prick tests (SPT) and specific IgE (sIgE) with single molecular allergen components in children with allergy to fruits and vegetables.MethodsTwenty children underwent SPT with a palm profilin (Pho d 2, 50 μg/mL); a Mal d 1-enriched apple extract (2 μg/mL) (PR-10 allergen); and a peach Lipid Transfer Protein (LTP) (Pru p 3, 30 μg/mL). Detection of sIgE to rBet v 1, rBet v 2, Phl p 12 and Pru p 3 was also measured.ResultsAllergy to multiple fruits and vegetables was observed in 11 (55%) children. Sensitization by SPT to Pho d 2, Mal d 1, and Pru p 3 occurred in 5, 7, and 8 cases, respectively. LTP sensitization appeared to be associated with peach allergy but not with severe reactions, and profilins sensitization to melon and tomato allergy. Kiwi sensitization (12 cases), the plant-derived food that caused more allergic reactions, seemed mostly species-specific. The concordance of SPT extracts and sIgE to the corresponding pan-allergens was high for profilins (k = 0.857) and LTP (k = 0.706), while for PR-10 allergens it was absent (k = 0.079).ConclusionsPan-allergen sensitization in children with allergy to fruits and vegetables was common and often multiple. There was no association of severe reactions to LTP sensitization. The introduction of routine SPT to pan-allergens can be a simple and feasible way of improving diagnostic and therapeutic efficacy.     

Food Allergies Caused by Allergenic Lipid Transfer Proteins: What Is behind the Geographic Restriction?

Purpose of Review

To critically examine evidence suggesting that food allergy induced by lipid transfer proteins (LTPs) follows a geographic pattern.

Recent Findings

LTP syndrome remains most common in the Mediterranean basin, with a clear gradient seen in prevalence of LTP sensitization between northern and southern Europe. We hypothesize that high levels of birch pollen seem to protect against LTP allergy, as these higher levels correlate with a lower prevalence of LTP hypersensitivity. Nevertheless, LTP food allergy cases still appear in areas having a high environmental level of birch pollen.

Summary

Food allergy caused by LTP may be related to (1) primary sensitization to a food LTP allergen in the absence of pollinosis, (2) primary sensitization to LTP from a pollen source, and (3) co-sensitization to LTP from pollen and food.