f422 rAra h 1 Peanut

Allergens within Food of Plant Origin

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  • Latin name: Arachis hypogaea
  • Common names: Glycinin
  • Source material: An E. coli strain carrying a cloned cDNA encoding Arachis hypogaea allergen Ara h 1.

rAra h 1
rAra h 1 from peanut (1-10).

Biological function
Trypsin inhibitor.

Mw
Approximately 57 kDa

Other allergens isolated
Peanut contains at least 32 different proteins, of which around 18 between 5 and 100 kDa have been identified as capable of binding specific IgE (11-13).

Allergens characterized to date include

  • Ara h 1, a 7S vicilin-like globulin (14).
     
  • Ara h 2, a 2S albumin, a conglutin seed storage protein, a trypsin inhibitor (15).
     
  • Ara h 3, an 11S globulin, a glycinin, a trypsin inhibitor (16).
     
  • Ara h 4, a glycinin (6).
     
  • Ara h 5, a profilin (6). 
     
  • Ara h 6, a conglutin, 2S albumin (17).
     
  • Ara h 7, a conglutin, 2S albumin(6). 
     
  • Ara h 8, a Bet v 1-homologous allergen (18).
     
  • Ara h Agglutinin (19).
     
  • Ara h LTP, a lipid transfer protein (20).
     
  • Ara h Oleosin (21).

Ara h 3 and Ara h 4 are regarded as isoforms of each other, i.e., Ara h 4 and Ara h 3 are considered to be the same allergen (16, 22).

Allergen Description

Ara h 1 is a vicilin, a member of the 7S vicilin-like globulin family (12, 14, 23-34). It is also known as Arachin. Ara h 1 is a 65 kDa protein that comprises 12% to 16% of the total protein in Peanut extracts (12) and causes sensitization from 35% to 95% of patients with Peanut allergy, depending on the population group studied (6, 10, 23, 35-40). Ara h 1 has been reported to form a stable trimeric protein (35) but upon purification of native Ara h 1 from Peanuts using only size exclusion chromatography, the allergen appeared to exist in an oligomeric structure rather than as a trimeric structure (29).

Seed storage proteins commonly comprise various groups of multiple isoforms encoded by different gene families. Arachin (11S globulin), conarachin (7S globulin) and conglutin (albumin) are the three major storage proteins in Peanut. The deduced polypeptide of Ara 1 has about 99% similarity to that of Peanut allergen Ara h 3 (28). Ara h 1 has high sequence similarity with other plant vicilins (1).

The difference in the methods of preparing Peanut as practiced in China compared with that widely used in the United States and Western countries may help explain the difference in prevalence of Peanut allergy observed in the 2 countries (41). Roasting of Peanut uses higher temperatures (150-170 degrees C) than boiling (100 degrees C) or frying (120 degrees C), and roasting has been shown to increase the allergenic property of Peanut proteins. Compared with roasted Peanut, the relative amount of Ara h 1 was reported to be reduced in fried and boiled preparations, resulting in a significant reduction of IgE-binding intensity. There was significantly less IgE binding to Ara h 2 and Ara h 3 in fried and boiled Peanut compared with that in roasted Peanut even though the protein amounts were similar in all 3 preparations (40).

Other studies have demonstrated the changes that may occur to Ara h 1 during heat processing that may play a role in the allergenicity of Ara h 1 (32, 42). Oven-roasted Peanut (177OC for 5-30 min) resulted in a level of Ara h 1 that were up to 22-fold higher than in raw Peanut (820 vs. 37 mug/ml) (43).

However, part of the difference in allergenicity may not be as a result of the heat-treatment per se but as a result of other factors. A study found that Peanut proteins of low molecular weight are found in the cooking water of Peanut. The IgE-binding capacity of the whole Peanut protein extracts prepared from boiled Peanuts was 2-fold lower than that of the extracts prepared from raw and roasted Peanut, and the proteins present in the cooking water were also recognized by IgE of Peanut-allergic patients. Although the IgE-binding capacity of purified Ara h 1 and Ara h 2 was altered by heat treatment, no significant difference in IgE immunoreactivity was observed between whole protein extracts from raw and roasted Peanut. The authors suggested that the decrease in allergenicity of boiled Peanuts results mainly from a transfer of low-molecular-weight allergens into the water during cooking (44).

In vitro gastric digestion was reported to result in rapid degradation of Ara h 1 into small fragments. However, gastric digestion did not affect the ability of Ara h 1 to stimulate cellular proliferation and histamine release of basophils from Peanut allergic individuals was induced to the same extent by native Ara h 1 and its digestion products. Therefore gastro-duodenal digestion fragments of Ara h 1 retain T cell stimulatory and IgE-binding and cross-linking properties of the intact protein (45). This finding is supported by an earlier study that indicated that although at least twenty-three different linear IgE-binding epitopes had been located throughout the length of the Ara h 1 protein31, that some epitopes are major binding sites resulting in significant Peanut-antibody binding even if Ara h 1 were cleaved into peptides. The cleaving-off of an N-terminal peptide from Ara h 1, which contains three allergenic epitopes of which two are major, found that Peanut-specific IgE-antigen binding occurred as a result of the epitopes that are contained in the cleaved-off peptide, implying that the peptide, or part of it, is still present in Peanuts that are consumed (14).

Other factors may play a role in heat or digestion of Ara h 1. For instance, Ara h 1 has been shown to resist proteolysis when in a trimeric configuration, a property that may contribute to its allergenicity (27). Ara h 1 and Ara h 2 were also reported to bind higher levels of IgE and were more resistant to heat and digestion by gastrointestinal enzymes once they had undergone the Maillard reaction (46). Roasted Peanut from two different sources bound IgE from patients with Peanut allergy at approximately 90-fold higher levels than the raw Peanut from the same Peanut cultivars (45).

Allergen content may vary depending on the Peanut variety and may explain the differences in the prevalence of sensitization between different population studies. For example, an accession from India had the lowest level of Ara h 1 (7.0%) whereas an accession from Nigeria had the highest level of Ara h 1 (18.5%), but the lowest level of Ara h 2 (6.2%). An accession from Zambia had the highest level of Ara h 2 (13.2%), but the lowest level of Ara h 3 (21.8%). Two accessions, 20 lines, and two Peanut cultivars (Florunner and Georgia Red) contained no or little of a 36 kDa Ara h 3 isoform, Ara h 3-im (47). Similarly, in a study of Peanut allergen expression during seed development and upon germination and seedling growth, patterns were heterogeneous depending on the specific Peanut allergen gene and the cultivars tested. Ara h 3 expression patterns among the cultivars were more variable than Ara h 1 and Ara h 2. Transcripts were tissue specific, seen in seeds, but not in leaves, flowers, or roots and were undetectable during seed germination (48).

See Peanut, f13, for further clinical information and details on Peanut allergy.

Sensitization to Peanut occurs with a high degree of heterogeneity to a number of Peanut allergens. Mono-sensitization to a single Peanut allergen is relatively rare (49).

For example, in a British study, evaluating sera of 40 Peanut-allergic individuals, of 18 allergens identified, 8 were bound by >50% of patients and the total number of bands per patient correlated significantly with challenge score and serum-IgE. The study concluded that promiscuity of IgE binding appears more important than the recognition of individual proteins (13).

Furthermore, some Peanut-allergic subjects fail to bind to either Ara h 1 or 2 suggesting that whole Peanut, rather than Ara h 1 or 2, or the use of individual Peanut allergens would be more appropriate for measuring specific-IgE responses. This also illustrates that the relative contribution of all Peanut allergens needs to be investigated (13, 36).

Between 35%-95% of Peanut-allergic individuals are sensitized to Ara h 1 (6, 10, 23, 35-40). The prevalence of sensitization to a specific Peanut allergen varies between population groups (10).

In a Dutch study children with Peanut allergy recognized predominantly Ara h2 and Ara h6, and the pattern remained stable over time. In Peanut-allergic adults, IgE was mainly directed to Ara h1 and Ara h2 (50).

Sensitization and clinical effects may occur soon after birth in breast-fed infants. In an evaluation of 23 healthy, lactating women aged 21 to 35 years, who had consumed 50 g of dry roasted Peanut, after which breast milk samples were collected at hourly intervals, Peanut protein was detected in the breast milk of 11 of 23 subjects. It was detected in 10 subjects within 2 hours of ingestion and in 1 subject within 6 hours. The median peak Peanut protein concentration in breast milk was 200 ng/ml and ranged from 120 to 430 ng/ml. Both major Peanut allergens Ara h 1 and Ara h 2 were detected (51).

Peanut is a very potent allergen and exposure to this allergen through saliva via kissing and utensils may cause local and systemic allergic reactions and saliva has been shown to contain up to 1110 mg/ml Ara h 1 (52), and by extrapolation, a single kiss could transfer up to 88.8 mg of Peanut proteins in saliva (53). A study evaluating the persistence in saliva after ingestion of Peanut butter and following mouth cleansing interventions, found that salivary Ara h 1 varied considerably immediately after ingestion, but included levels expected to invoke reactions (as much as 40 microg/mL). Most subjects with detectable Peanut after a meal had undetectable levels by 1 hour with no interventions. But Ara h 1 remained detectable in approximately 40% of samples (though typically below thresholds reported to induce reactions). The study concluded that patients with Peanut allergy require counseling regarding risks of kissing or sharing utensils, even if partners have brushed teeth or chewed gum (51).

A Dutch study investigated the relevance of Peanut allergens in 32 adult Peanut-allergic patients by in vitro, ex vivo and in vivo assays. Ara h 2 was reported as the most frequently recognized allergen (81%) (26/32) in skin-specific IgE evaluation and induced basophil degranulation at low concentrations, followed by Ara h 1 (44%) then Ara h 3 (37.5%). Ara h 2 was also deemed more potent eliciting reactions at 100-fold lower concentrations than Ara h 1 and 3 as analyzed by skin specific IgE testing and basophil histamine release. Besides these three allergens evaluated for, proteins smaller than 15 kDa were also identified as binding IgE in the majority of the patients (20/32). The study concluded that in this group of patients, Ara h2 was the most important Peanut allergen (40). In a more recent Dutch study examining the IgE reactivity to major Peanut allergens in 20 Peanut-allergic children at two subsequent time-points, before DBPCFC, all 20 Peanut-allergic children were shown to have specific IgE to Ara h 2, 16 to Ara h 6, and 10 to both Ara h 1 and Ara h 3. After 20 months, Peanut-specific IgE levels and the individual recognition of major allergens were comparable with the levels and recognition before challenge. Skin specific IgE was detected to Ara h 2 and Ara h 6 in most children, whereas for Ara h 1 and Ara h 3 in approximately 50% of the children. No parameters could be related to the severity of Peanut allergy (49).

The availability of recombinant Peanut allergens has resulted in a greater ability to assess the sensitization and clinical profiles of individual Peanut allergens in different population groups. This is illustrated by a number of studies.

In an evaluation of recombinant allergens, Ara h 1, Ara h 2, and Ara h 3, using sera of 77 American Peanut-allergic patients, seven different patterns of sensitization were identified. The majority of patients (97%) had specific IgE to at least one of the recombinant allergens (Ara h 1, Ara h 2, and Ara h 3), and 77%, 75% and 77% recognized rAra h1, rAra h 2 and rAra h 3 respectively. High epitope diversity was found in patients with a history of more severe allergic reactions (48).

European study evaluating sera from 40 patients for sensitization to six recombinant Peanut allergens, showed 14 individual recognition patterns. Of the sera, Ara h 1 was recognized by 65%, Ara h 2 by 85%, Ara h 4 by 53%, Ara h 5 by 13%, Ara h 6 by 38% and Ara h 7 by 43% (6).

Similarly, a French and American study aimed at evaluating the diagnostic value of the 3 major recombinant Peanut allergens utilizing skin and serum specific IgE determination in 30 Peanut-allergic patients. All patients with Peanut allergy demonstrated skin specific IgE to rAra h 2; 40% reacted with rAra h 1 and 27% with rAra h 3. Monosensitization to rAra h 2 was observed in 53% of patients. Levels of specific IgE did not correlate with the disease severity. However, patients with monosensitization to rAra h 2 had a significantly lower severity score than polysensitized subjects and a lower level of specific IgE against Peanut extract and rAra h 2. Cosensitization to rAra h 2 and rAra h 1 and/or rAra h 3 appeared to be predictive of more severe reactions (10).

A more recent Dutch study investigated whether a sensitization to individual allergens Ara h 1, Ara h 2, Ara h 3 and Ara h 6 could be correlated with clinical severity. Purified Peanut allergens were utilized for skin and serum specific-IgE evaluation in 30 patients. The majority of patients were found to have specific IgE to Ara h 2 (25/30, 83%) and Ara h 6 (26/30, 87%). Sixteen patients (53%) were sensitized to Ara h 1 and 15 patients (50%) to Ara h 3. All patients with skin specific IgE for Ara h 1 and/or Ara h 3 were also sensitized to Ara h 2 and/or Ara h 6. Patients with severe symptoms had a higher skin specific IgE response to Ara h 2 and Ara h 6 at low concentrations (0.1 mug/ml) and to Ara h 1 and Ara h 3 at higher concentrations (100 mug/ml) compared with patients with mild symptoms. Patients with more severe symptoms also recognized a greater number of allergens and showed a higher cumulative skin specific IgE response than with patients with mild symptoms. Ara h 2 and Ara h 6 appeared to be more potent than Ara h 1 and Ara h 3. Both skin specific IgE reactivity to low concentrations of Ara h 2 and Ara h 6 and to higher concentrations of Ara h 1 and Ara h 3 were shown to be indicative of severe symptoms (24).

Recombinant Peanut allergens have been evaluated for their ability to predict the outcome of tolerance in Peanut-allergic individuals. An American study was performed using sera from 15 patients with symptomatic Peanut allergy and 16 patients who were sensitized but tolerant (of which 10 of these 16 patients had "outgrown" their allergy) investigated 8 peptides representing the immunodominant sequential epitopes on Ara h 1, 2, and 3. It was found that regardless of their Peanut-specific IgE levels, most patients with symptomatic Peanut allergy showed IgE binding to the 3 immunodominant epitopes on Ara h 2. In contrast, each of these epitopes was recognized by < 10% of the tolerant patients. Tolerant patients did not recognize 2 immunodominant epitopes on Ara h 1. At least 93% of symptomatic, but only 12.5% of tolerant patients, recognized 1 of these "predictive" epitopes on Ara h 1 or Ara h 2. With up to 50% of patients with Peanut-specific IgE levels below suggested diagnostic decision levels still being clinically reactive, oral food challenges could be avoided in approximately 90% of these patients through the determination of peptide-specific IgE. This study analyzed only selected allergen epitopes rather than whole proteins (54).

Recombinant allergens may also play a role in the evaluation of cross-reactivity between plant families. Ara h 1 is a vicilin, a member of the 7S vicilin-like globulin family, and therefore cross-reactivity between Ara h 1 and other vicilins is likely (4). For example, the vicilin allergen Ara h 1 accounts for the IgE-binding cross-reactivity commonly observed between the vicilin allergens from edible legume seeds such as Lentil (Len c 1) and Pea (Pis s 1) (30). In a study of 3 patients with a history of anaphylaxis to Pea who subsequently had symptoms after ingestion of Peanut, all were shown to have skin and serum specific IgE for Pea and Peanut. Immunoblotting demonstrated strong IgE binding mainly to vicilin in Pea and exclusively to Ara h 1 in Peanut. However, inhibition studies with both crude and purified proteins showed that IgE binding to Peanut could be inhibited by Pea but not or only partially the other way around. The study therefore confirmed that clinically relevant cross-reactivity between Pea and Peanut occurs and as a result of vicilin homologues (55).

Assessment of isoforms of the Lentil vicilin allergen, Len c 1.02, has been demonstrated to have a greater than 50% identity with Ara h 1 and Soybean conglutinin subunits (56). A protein of Lupine, a beta-conglutin precursor, was shown to be significantly homologous to Ara h 1 (57). Lupine has become a significant allergen as a result of its large-scale introduction into processed foods and frequent cross-reactions with other members of the legume family (57).

Nonetheless, cross-reactivity between vicilin proteins are not a certainty: although Cashew and Peanut vicilins share 27% identity, they do not share linear epitopes, and hence do not appear to be cross-reactive in spite of other similarities such as the presence of multiple linear IgE binding epitopes, a lack of any common primary structural characteristics of the linear IgE binding epitopes, positional overlap of some of the IgE binding epitopes, and the presence of immunodominant IgE binding epitopes (58).

One known IgE-binding epitope of Ara h 1 has been shown to have an 80% homology with the corresponding area of Ses i 3, a Sesame seed protein to which 75% of the Sesame-allergic patients are sensitized to (59).

Diagnostic methods e.g., skin and serum specific IgE, etc., are based on natural Peanut extracts that contain both allergenic and non-allergenic proteins. A great variability and difficulty of standardization exists because the extract composition depends on the origin of raw material and extraction, purification and storage procedures (60). Recombinant allergens leads to standardized reagents that are biochemically characterized and therefore results that are comparable. Furthermore, recombinant allergens produced in E coli lack cross reactive carbohydrate determinants (CCDs), which increases diagnostic specificity (61). As the amount of Ara h 1 and Ara h 3 in Peanut can vary or be higher than Ara 2 and Ara h 6 (62), and considering that the potency of allergens vary (24-25), utilizing recombinant allergens may allow more precise measurement and evaluation of IgE responses in certain instances, in particular for more-appropriate diagnoses when used in Component Resolved Diagnosis (CRD), for exploring cross-reactivity, and for immunotherapy (63).

Compiled by Dr Harris Steinman, harris@zingsolutions.com

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2007



Further Reading