Summary
Ara h 18 is a newly discovered peanut allergen component from the cyclophilin protein family with a molecular mass of 18.2 kDa [1]. Biochemically, members of the cyclophilin protein family have the enzymatic function of peptidyl-prolyl cis-trans isomerases and are known for their high-affinity binding to the immunosuppressive agent cyclosporine A [2]. Cyclophilins are highly conserved and have been reported as IgE binding proteins in grass, tree, and weed pollen, several plant foods such as peanut, carrot, pumpkin, and tomato, as well as in several fungi and house dust mites [1], and are officially recognized allergens in several of those allergen sources [3].
Epidemiology
Worldwide distribution
Peanuts are consumed across the world and according to literature, peanut allergy affects approximately 2% of the population in Western nations, with data suggesting an increasing prevalence and incidence [4]. Peanut allergy usually begins in childhood, with 22% acquiring tolerance by age 4, 27% by age 12 and persisting throughout the affected individual’s lifetime in a majority of patients [4, 5].
In a study with 109 individuals, who were IgE positive to peanut but had a negative result (<0.35 kUA/l) to all peanut components available for specific IgE testing in clinical routine (Ara h 1-3, 6, 8-9) and showed grass pollen cross-reactivity, 35 samples (32%) were found to have IgE to Ara h 18, with a median level among positives of 10.6 kUA/l. While Ara h 18 was comparable to profilin (36%) regarding prevalence and magnitude of sensitization in this population, 13 of the samples were uniquely positive to Ara h 18 [1].
Environmental Characteristics
Source and tissue
Ara h 18 is a cyclophilin protein peanut allergen component.
The peanut (Arachis hypogaea) belongs to the legume family (Leguminosae) (6).
Clinical Relevance
The clinical patterns of peanut allergy, from asymptomatic sensitization to severe clinical manifestations, depend on the exposure routes and the physicochemical properties of the involved peanut proteins [7].
Primary sensitization to peanut is generally characterized by sensitization to the storage proteins Ara h 1, Ara h 2, Ara h 3 and/or Ara h 6 and sensitization to these components is often associated with severe allergic symptoms to peanut [7-10].
Plant cyclophilins are highly cross-reactive [11]. Cross-reactive pollen sensitization may cause a positive test result to peanut despite the absence of primary peanut sensitization. Individuals with IgE antibodies only to pollen-associated targets are considered to have a low risk of a severe reaction to peanut [10].
Disease severity
Cyclophilins could carry a risk of severe symptoms and reactions, similar to Lipid Transfer Proteins (LTPs) and defensins, but lower than oleosins and storage proteins. Inhibition results using grass pollen extract showed that Ara h 18 is probably not a primary sensitizer, but a cross-reactive determinant [1, 7].
In an Italian multicentric cohort of 253 pediatric patients with seasonal allergic rhinoconjunctivitis and birch pollen sensitization, IgE to Bet v 7, a cyclophilin with high cross-reactivity to Ara h 18, was found in 43 (17%) patients. Ten of the 43 patients were apparently monosensitized to Bet v 7. In this cohort, a significant association of Bet v 7 sensitization with oral allergy syndrome (OAS) and asthma was found in univariate analysis. However, adjusting on sensitization to other pollen-food cross-reactive allergens (Bet v 1, profilin, and LTP) resulted in the loss of significance for Bet v 7 association. Finally, among the 10 patients with seasonal rhinoconjunctivitis apparently monosensitized to Bet v 7, none suffered from OAS, but seven were asthmatic [12].
Cross-reactive molecules
Cyclophilins are highly conserved proteins and extensive immunological cross-reactivity has been demonstrated between cyclophilins from different sources. Ara h 18 has a high sequence similarity to pollen cyclophilins from birch, olive and periwinkle [1]. Sequence identity has been shown to correlate with immunological cross-reactivity and might have implications in the clinic [13, 14]. However, functional data are not yet available regarding the ability of cyclophilins, such as Ara h 18, to induce IgE-mediated activation and degranulation of mast cells and/or basophils [1, 12].
Molecular Aspects
Biochemistry
At the time of writing, 18 peanut allergens have been officially recognized [3].
Ara h 18 has a molecular mass of 18.2 kDa and is a cyclophilin protein [1]. Biochemically, members of the cyclophilin protein family have the enzymatic function of peptidyl-prolyl cis-trans isomerases and are known for their high-affinity binding to the immunosuppressive agent cyclosporine A [2]. They have a folded protein structure with a hydrophobic core, composed of four antiparallel beta-sheets, closely packed with four additional beta-sheets and two alpha-helices [11]. Ara h 18 heat stability has not yet been elucidated. .
Cross-reactivity due to structural similarity
Ara h 18 is 88-91 % identical to cyclophilins in birch (Bet v 7), olive (Ole e 15) and periwinkle (Cat r 1) pollen [1, 12, 14].
Diagnostic Relevance
Ara h 18 is unlikely to be a primary sensitizer, but a cross-reactive determinant, binding IgE antibodies elicited by sensitization to another common allergen source, such as pollen. Ara h 18 may be helpful in explaining a positive peanut sensitization test result in the absence of IgE to currently available peanut components, which may elicit unjustified anxiety and unnecessary dietary avoidance/restriction [1].
Compiled By
Author: Dr. Joana Vitte
Reviewer: Dr. Michael Spangfort
Last reviewed: 2024-12-17
