f458 Ara h 18

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 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 and persists throughout the affected individual’s lifetime (4); however, approximately 20% of young children develop tolerance (5).

In a study with 124 individuals, which 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), 35 samples (28%) 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 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 sensitization to severe clinical symptoms, 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 (8, 9).

Cyclophilins are highly cross-reactive. Cross-reactive pollen sensitization may cause a positive test result to peanut despite the absence of a 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 (8).

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 (Fig. 1) (7). However, their heat stability has not yet been elucidated. Inhibition results using grass pollen extract showed that Ara h 18 is probably not a primary sensitizer, but a cross-reactive determinant (1). 

Figure 1: Increased risk for severe symptoms and anaphylactic reactions from left to right (7).

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 (10).  

Molecular Aspects

Biochemistry

At the time of writing, 17 peanut allergens have been identified (7).

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). 

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).

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. Merce Tena-Campos

Reviewer: Dr. Merima Mehic Chaveton & Ulrica G. Olsson

Last reviewed: 2023-07-17