f447 Ara h 6

Summary

Ara h 6 is a conglutin seed storage protein and member of the 2S albumin family which is capable of withstanding the harsh conditions of the gastrointestinal tract. Initially, Ara h 6 was not thought to be one of the major peanut allergens but now is considered to be one of the most potent. Individuals who are sensitized to Ara h 6 are at an increased risk for more severe symptoms and anaphylactic reactions. Peanut allergy patients who are sensitized to Ara h 6 are frequently also sensitized to Ara h 2 however, in rare cases, Ara h 6 sensitization without Ara h 2 sensitization may cause severe reactions to peanut. Using IgE specific to Ara h 2 and 6 can help to diagnose peanut allergy. Similarities in physicochemical properties to known IgE epitopes of 2S albumins could account for clinically observed cross-sensitivity between peanuts and tree nuts.

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).

In a study involving 30 peanut-allergic individuals, the majority of patients with a positive skin prick test (SPT) were sensitized to Ara h 2 (83%, n=25) and Ara h 6 (87%, n=26) (3). A UK study found that 84% (42/50) were sensitized to Ara h 2 and 6 (4). This is in agreement with an earlier study which concluded that Ara h 2 and 6 were the most frequently recognized major peanut allergens in children (5). A review by van der Valk et al. (2016) summarized the prevalence of cosensitization of Ara h 2 and 6 which ranged from 0 to 90% (e.g. 0, 45, 59, 71, 73, 74, 80, 90%) and monosensitization to Ara h 6 was uncommon (6).

Environmental Characteristics

Source and tissue

Ara h 6 is a member of the 2S albumin family and therefore belongs to the prolamine protein superfamily (7). 2S albumins are found in the seeds of many mono- and dicotyledon plants where they provide amino acids for growing seedlings and have a role in pathogen defense (8, 9). 

Clinical Relevance

Typical clinical symptoms of peanut allergy range from angioedema, urticaria, nausea, abdominal pain, vomiting, wheezing, and breathlessness which usually occur soon after peanut ingestion (10). Since Ara h 6 is a storage protein, individuals who are sensitized to this component are at an increased risk for more severe symptoms and anaphylactic reactions (11). Ara h 2 and Ara h 6 are considered to be the most potent peanut allergens (12) although compared to Ara h 1, 2 and 3, Ara h 6 was identified as a major peanut allergen more recently (4). Kukkonen et al. (2015) found that all of the severely peanut-allergic patients in their study were sensitized to Ara h 2 or 6 (13).

In rare cases, Ara h 6 sensitization may occur without Ara h 2 and this could cause a severe reaction to peanut (14). A 15-year-old boy with a history of anaphylaxis was sensitized to Ara h 8 but not to Ara h 1, 2 or 3. During an open challenge to peanut, he experienced gastrointestinal and respiratory signs, and therefore treatment was provided (14). IgE blood testing revealed a doubling of IgE antibody concentration to peanut compared to a sample nine months earlier. With barely detectable levels of IgE antibody to Ara h 2 and 9, this prompted the analysis of Ara h 6 IgE sensitization and demonstrated a large sensitization despite a very modest level of IgE to Ara h 2 (14).

Cross-reactive Molecules

Similarities in physicochemical properties to known IgE epitopes of 2S albumins could account for clinically observed cross-sensitivity between peanuts and tree nuts (15).

Molecular Aspects

Biochemistry

Ara 6 is a 15 kDa conglutin seed storage protein belonging to the 2S albumin family (16). Ara h 2 and Ara h 6 share 59% of their amino acid sequence identity (9). 2S albumins are thought to sensitize directly in the gastrointestinal tract which is possible despite the harsh conditions due to the high stability of their intrinsic protein structure, consisting of a well-conserved skeleton of cysteine residues (17).

The structure of Ara h 6 is critical in terms of its allergenic potential because disruption of the disulphide bonds alters the IgE binding capacity (9). Heat denaturation has been shown to increase allergenicity of Ara h 6 in mice (8). A study reported that only when Ara h 6 was subjected to autoclaving did it show signs of denaturation and a decrease in IgE-binding potency (18).

Isoforms, epitopes, antibodies

Currently, one isoform of Ara h 6 has been identified, Ara h 6.0101 (16). Five of seven IgE-binding linear epitopes of Ara h 2 share 70–93% homology to similar regions of Ara h 6 (19). Otsu et al. (2014) hypothesized that Ara h 6 is more tightly folded compared to Ara h 2, making conformational IgE-binding epitopes less cross-reactive than the highly homologous linear epitopes (19, 20).

Diagnostic Relevance

Disease Severity

Hemmings et al. (2020) found that Ara h 2 and 6 specific IgE provided the greatest accuracy to diagnose peanut allergy which is in agreement with results from an earlier double-blind placebo-controlled study and an oral food challenge study in the Mediterranean region (4, 13, 21). However, variation has been shown in IgE cross-reactivity between Ara h 2 and 6 and therefore using a mixture of these two 2S albumins may improve diagnostic performance when trying to determine the severity of allergic symptoms (12). Although Ara h 6 monosensitization has been reported as uncommon, a study in Iceland demonstrated that two of six peanut-allergic patients who were Ara h 2 negative were monosensitized to Ara h 6 (22). 

Compiled By

Author: RubyDuke Communications

Reviewer: Dr. Magnus Borres

Last reviewed: December 2020