f424 Ara h 3

Summary

Ara h 3 (glycinin) is a storage protein and a cupin allergen able to withstand heat treatment and enzymatic activity. It is estimated that 97% of peanut allergy patients are sensitized to at least one of the allergens Ara h 1, 2 and 3. Individuals who are sensitized to Ara h 3 are at an increased risk for more severe symptoms and anaphylactic reactions. Polysensitization to Ara 1, 2 and 3 can help to predict the severity of reaction at challenge. The use of specific IgE to Ara h 3 in combination with Ara h 1 and 2 could be helpful to diagnose individuals with peanut allergy. Cross-reactivity of Ara h 3 has been shown with Ara h 1, other legumes and legumin tree nut allergens. 

Epidemiology

Worldwide distribution

Studies have typically reported peanut allergy prevalence rates between 1–2% in Western nations. Peanut allergy appears to be less common in Asia and other global areas, although epidemiological studies in non-Western regions have been sparse (1). Peanut allergy usually begins in childhood and persists throughout the affected individual’s lifetime however, approximately 20% of young children develop tolerance (2).

The results of a study published in 1999 found that just over half (53%) of 40 peanut-allergic patients were sensitized to Ara h 4 which is now known to be an isoform of Ara h 3, Ara h 3.02 (3, 4). In the USA, it is estimated that the prevalence is lower with just over a third of patients sensitized to Ara h 3 and 1% being monosensitized to this allergen component (5). The highest frequency of positive test results for Ara h 3 in the USA study was within the three to nine-year old group, which decreased with increasing age. Despite the lower overall prevalence of Ara h 3 sensitization in the USA, Ara h 3 is considered to be a major peanut allergen (4).

Environmental Characteristics

Source and tissue

Ara h 3 is a cupin allergen belonging to the legumin family. Legumins, also known as 11S globulins, are hexameric proteins present in the seeds of many plants (6). The allergens Ara h 1, 2 and 3 provide >30% of the total protein content of peanuts (7).

Clinical Relevance

As a storage protein, individuals who are sensitized to Ara h 3 are at an increased risk for more severe symptoms and anaphylactic reactions (8). Sensitization to peanut storage proteins Ara h 1, 2 and 3 was associated with increased quantities of airway and systemic inflammation markers compared to patients who were not sensitized to these peanut allergen components in a population of asthma sufferers (9). Food hypersensitivity symptoms were also more regularly reported by those sensitized to Ara h 1, 2 and 3 than by any other participants in the study (9).

A study found IgE was positively correlated with clinical severity and Ara h 3 in adult patients (r = 0.78, P < 0.001) but this trend was not observed in children (10). In addition, a study found that sensitization to rAra h 2 and rAra h 1 and/or rAra h 3 appeared to be predictive of more severe reactions (11). Similarly, the results of a recent study in Australia found that polysensitization to Ara 1, 2 and 3 can help to predict the severity of reaction at challenge (12).

Cross-reactive Molecules

The 11S globulin, Sin a 2, is associated with severe reactions in mustard allergic patients and has a role in cross-reactivity with 11S globulins found in tree nuts and peanuts (6).

Molecular Aspects

Biochemistry

Ara h 3 (glycinin) is a cupin allergen belonging to the legumin family (6, 13). Legumins, also known as 11S globulins, are hexameric proteins present in the seeds of many plants (6). Subunits are synthesized as a single polypeptide which is cleaved to provide an acidic and a basic polypeptide chain, linked by a disulfide bond (6). Ara h 3 has a molecular weight of 60 kDa (14).

Cupins have considerable ability to withstand heat treatment and enzymatic activity (15). Ara h 3 has a role as a storage protein in peanuts (15).

Isoforms, epitopes, antibodies

Two isoforms of Ara h 3, Ara h 3.0101 and Ara h 3.0201, and four IgE-binding epitopes have been identified (14, 16).

Research by Piersma et al. (2005) found that the acidic subunit of Ara h 3 is truncated in several places during processing, which introduces variation. The authors suggested including IgE-binding studies with peanut-derived Ara h 3 when determining the allergenicity of Ara h 3 to reflect the high degree of variation in the Ara h 3 protein structure because this is what peanut-allergic individuals encounter when consuming peanuts (17). 

Cross-reactivity

Frequent cross-reactivity is demonstrated between Ara h 3 and the other cupin allergen found in peanut, Ara h 1, with monosensitization to Ara h 1 and/or Ara h 3 being very uncommon (8).

Cross-reactivity between different legumes is due to the considerable homologies of seed storage proteins, with Ara h 3 having equivalent 11S legumin-like globulins in soya bean (Gly m glycin 1, 2 and 4), pea (Pis s 2), lupin (α-Conglutin) and the condiment, fenugreek (“Tri f 3”) (15). It has been reported that the soybean glycinin exhibits high sequence identity of 62% with peanut glycinin, Ara h 3 (18).

IgE-binding epitopes of Ara h 3 demonstrated structural homology among legumin peanut and tree nut allergens, specifically Jug r 4 of walnut, Cor a 9 of hazelnut and Ana o 2 of cashew nut, helping to explain the observed IgE-binding cross-reactivity (19).

Sin a 2, a major allergen of yellow mustard seed, was shown to share sequence identity with other allergenic 11S globulins, 27% for Ara h 3 and in addition, three epitopes in Ara h 3 were moderately conserved in Sin a 2 which could have an impact in terms of cross-reactivity (16).

Diagnostic Relevance

Disease Severity

The authors who published results from a cross-sectional study involving 222 children in Australia reported that using a combination of Ara h 1, 2 and 3 for peanut component testing could be helpful to identify patients with peanut allergy (12). An earlier study found that using the combination of Ara h 1, 2, and 3 resulted in a higher specificity (94%) when diagnosing peanut allergy in Japanese children in comparison to using IgE to Ara h 2 alone resulting in a sensitivity and specificity of 88% and 84%, respectively. However, the sensitivity of using the combination of Ara h 1, 2, and 3 was 31% (20). A study found that cosensitization to rAra h 2 and rAra h 1 and/or rAra h 3 was predictive of more severe reactions in peanut allergy (11).

Cross-Reactivity

Often, specific IgE measurements for Ara h 1 and Ara h 3 are not necessary due to the high level of cross-reactivity between them, and monosensitization to these seed storage allergen components is uncommon (8).

Compiled By

Author: RubyDuke Communications

Reviewer: Dr. Magnus Borres

Last reviewed: December 2020