f423 rAra h 2 Peanut

Allergens within Food of Plant Origin

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  • Latin name: Arachis hypogaea
  • Common names: Conglutin
  • Source material: An E. coli strain carrying a cloned cDNA encoding Arachis hypogaea allergen Ara h 2.

rAra h 2
rAra h 2 (1-12).

Biological function
A 2S Albumin which is homologous to and functions as a trypsin inhibitor.

Mw
Approximately 17.5 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 (13-15).
 

Allergens characterized to date include

  • Ara h 1, a 7S vicilin-like globulin (16).
     
  • Ara h 2, a 2S albumin, a conglutin seed storage protein, a trypsin inhibitor (17).
     
  • Ara h 3, an 11S globulin, a glycinin, a trypsin inhibitor (18).
     
  • Ara h 4, a glycinin (2).
     
  • Ara h 5, a profilin (2).
     
  • Ara h 6, a conglutin, 2S albumin (19).
     
  • Ara h 7, a conglutin, 2S albumin (2).
     
  • Ara h 8, a Bet v 1-homologous allergen (20).
     
  • Ara h Agglutinin (21).
     
  • Ara h LTP, a lipid transfer protein (22).
     
  • Ara h Oleosin (23).

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 (18, 24).

Allergen description

Ara h 2, a 2S albumin is homologous to and functions as a trypsin inhibitor, and is related to the 2S albumin superfamily of seed storage proteins (14, 17, 25-36). It is also known as Conglutin (17). Ara h 2 contributes up to 9% of the total protein content in peanut extracts (14). Ara h 2 is a 17.5 kDa protein and has a 30% homology with 2S albumins, but appears to have the closest homology with conglutin from Lupin. It does not appear to be made up of subunits like Jug r 1 or Ber e 1 (27, 37). Ara h 2 has eight cysteine residues that could form up to four disulfide bonds (38).

Ara h 2 consists of two isoforms, namely Ara h 2.0101 and Ara h 2.0201. Ara h 2.0201 has similar but higher IgE binding than Ara h 2.0101 isoform (81% vs 77%) and contains other IgE epitopes (28, 39).

Ara h 2 is a 17.5 kDa protein that causes sensitization in >90% of patients with Peanut allergy (2-3, 26, 40-43).

Ara h 6 has homology to Ara h 2, especially in the middle part and at the C-terminal part of the protein. Almost complete inhibition of IgE-Ara h 6 interaction with Ara h 2 demonstrates that at least part of the epitopes of Ara h 6 are cross-reactive with epitopes on Ara h 2. Therefore Peanut-allergic patients recognize Ara h 6 both in vitro and in vivo to a similar extent as to that of Ara h 2 (19). However, Ara h 2 appears to be the more potent allergen, even though the two Peanut allergens share substantial cross-reactivity (30).

Ara h 2 (and the homologous Ara h 6) contains cores that are highly resistant to proteolytic digestion and to temperatures of up to 100 degrees C (30). This extreme immunological stability of the core structures of Ara h 2 provides an explanation for the persistence of the allergenic potency even after food processing (30).

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 (44). 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 (44).

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 (45).

Roasting of Peanut was shown to cause a 3.6-fold increase in trypsin inhibitory activity, i.e., they are resistant to trypsin digestion and are more likely to remain intact in the gastrointestinal tract, and functional and structural comparison of the purified Ara h 2 from roasted Peanut to native and reduced Ara h 2 from raw Peanut showed that the roasted Ara h 2 mimics the behavior of native Ara h 2 in a partially reduced form (17). Furthermore, thermal treatment of rAra h 2 in the presence of reactive carbohydrates and carbohydrate breakdown products has been shown to induce a strong increase of the IgE-binding activity (11).

Digestion of Ara h 2 with trypsin, chymotrypsin, or pepsin results in a number of relatively large fragments that are resistant to further enzymatic digestion. These peptide fragments contain intact IgE- binding epitopes and several potential enzyme cut sites that are protected from the enzymes by the compact structure of the protein. Furthermore, the resistant protein fragments contain most of the immunodominant IgE-binding eptiopes (38). Furthermore, even though IgE antibody binding capacity is reduced by protease treatment, the mediator release from functional equivalent of mast cells or basophils, and the humanized RBL cell, demonstrated that the reduction in IgE antibody binding capacity did not necessarily translate into reduced allergenic potency (30).

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 (46).

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 further 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. Ara h 2 was recognized by 71% of sera. The study concluded that promiscuity of IgE binding appears more important than the recognition of individual proteins (15).

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 (15, 41).

Greater than 75% of Peanut-allergic individuals are sensitized to Ara h 2 (2-3, 40, 49). In a Dutch study children with Peanut allergy recognized predominantly Ara h 2 and Ara h 6, and the pattern remained stable over a period of time, whereas 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 who had consumed 50 g of dry roasted Peanut, found that 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, may contain Ara h 2. A single kiss could transfer up to 88.8 mg of Peanut proteins in saliva (53).

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 (54). 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 (50).

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 (49).

A 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% (2).

Similarly, in 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 (3).

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 (40).

Recombinant Peanut allergens have been evaluated for their ability to predict the outcome of tolerance in Peanut-allergic individuals. In an American study 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) using 8 peptides representing the immunodominant sequential epitopes on Ara h 1, 2, and 3, 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. Sixty to seventy three percent of symptomatic patients recognized Ara h 2 and 87% to Ara h 3. The most striking difference in IgE binding was for Ara h 2 with 60-73% of symptomatic patients recognizing three immunodominant epitopes. For Ara h 3, 87% of symptomatic and 31% of asymptomatic patients recognized the epitope investigated. 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 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 (55).

Recombinant allergens may also play a role in the evaluation of cross-reactivity between plant families. Ara h 2 has a 30% homology with 2S albumins, but appears to have the closest homology with conglutin from Lupin (37).  Cross-reactivity may therefore occur between Ara a 2 and other foods containing 2S albumins, dependent on the degree of homology. However, cross-reactivity is not a certainty. For example, conformational analysis of the linear IgE-binding epitopes mapped on the molecular surface of Ara h 2 showed no structural homology with the corresponding regions of the walnut Jug r 1, the pecan nut Car i 1 or the Brazil nut Ber e 1 allergens. This suggests that the cross-reactivity observed between these three may depend on other ubiquitous seed storage protein allergens, namely the vicilins. However, the major IgE-binding epitope identified on the molecular surface of the walnut Jug r 1 allergen shared a pronounced structural homology with the corresponding region of the pecan nut Car i 1 allergen. The authors concluded that with the exception of Peanut, 2S albumins could thus account for the IgE-binding cross-reactivity observed between some other dietary nuts, e.g. Walnut and Pecan nut (31).

Ara h 2 has been shown to share common IgE-binding epitopes with Almond and Brazil nut allergens (8).

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 (56). 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 (57). 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 (58), and considering that the potency of allergens vary (32, 40), 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 (59).

Compiled by Dr Harris Steinman, harris@zingsolutions.com

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    60.  

2008



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