The importance of the 2S albumins for allergenicity and cross-reactivity of peanuts, tree nuts, and sesame seeds

Abstract

Allergies to peanuts, tree nuts, and sesame seeds are among the most important food-related causes of anaphylaxis. Important clinical questions include: Why is there a variable occurrence of coallergy among these foods and Is this immunologically mediated? The clinical and immunologic data summarized here suggest an immunologic basis for these coallergies that is based on similarities among the 2S albumins. Data from component resolved diagnostics have highlighted the relationship between IgE binding to these allergens and the presence of IgE-mediated food allergy. Furthermore, in vitro and in vivo experiments provide strong evidence that the 2S albumins are the most important allergens in peanuts for inducing an allergic effector response. Although the 2S albumins are diverse, they have a common disulfide-linked core with similar physicochemical properties that make them prime candidates to explain much of the observed coallergy among peanuts, tree nuts, and sesame seeds. The well-established frequency of cashew and pistachio nut coallergy (64%-100%) highlights how the structural similarities among their 2S albumins may account for observed clinical cross-reactivity. A complete understanding of the physicochemical properties of the 2S albumins in peanuts, tree nuts, and sesame seeds will enhance our ability to diagnose, treat, and ultimately prevent these allergies.

Keywords: 2S albumins; IgE; Peanuts; food allergy; tree nuts.

Conflict of interest statement

Conflict of Interest Statement: SCD, KN, WB, XC and CHS have received grant support from the National Institutes of Health. SA and AK have no relevant conflicts of interest. In addition, SCD reports grant support from Genentech, Inc., is a member of the Medical Expert Panel, Department of Health and Human Services, Division of Vaccine Injury Compensation and serves on an advisory board and/or is a consultant for Allakos, CSL Behring, BioCryst, Grifols and UKKO. SK is consultant for DBV Technologies. KCN reports grants from the Food Allergy Research & Education (FARE), End Allergies Together (EAT), Allergenis, and Ukko Pharma. She is involved in Clinical trials with Regeneron, Genentech, AImmune Therapeutics, DBV Technologies, AnaptysBio, Adare Pharmaceuticals, and Stallergenes-Greer, Novartis, Sanofi, Astellas and Nestle. She is a Data and Safety Monitoring Board member at Novartis and NHLBI. She cofounded BeforeBrands, Alladapt, ForTra, and Iggenix and is a Director of FARE and World Health Organization (WAO) Center of Excellence. She has received personal fees from Regeneron, Astrazeneca, ImmuneWorks, and Cour Pharmaceuticals.

Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Figures

FIG 1.. PD-graph of the central region of 2S albumins from peanut, tree nuts and sesame seeds.

PD-graph is a program that automatically calculates and graphically portrays the pairwise property distances (PD) between unaligned sequences supplied in Fasta format as a text file. Lower PD indicates higher sequence similarity. The program is available from Github (https://github.com/bjmnbraun/DGraph). Consistent with observed clinical studies, walnut/pecan (Jug r 1, Jug n 1, Car i 1) and pistachio/cashew (Pis v 1, Ana o 3) share extensive common sequences. Pine nut (Pin p 1) is an outlier, consistent with the low number of cross-reactions observed. The 3 peanut allergens (Ara h 2, Ara h 6 and Ara h 7) are most similar to each other, with greater distance to all of the tree nuts and sesame seeds. See Table 4 for allergen source and sequence. Allergen names have been shortened to comply with FASTA header format, which does not permit spaces. The scale (left) relates the line density to the property distance (PD) between pairs (lower PD= higher similarity in PCPs).

FIG 2.. The structural folds of Ara h 2 and Ber e 1.

A) Crystal structure of Ara h 2 (PDB id: 3OB4) and B) NMR structure of Ber e 1 (PDB id. 2LVF) showing the secondary structure elements (Helices H1-H5) conserved in the 2S albumins. The unstructured (disordered) loop characteristic of Ara h 2 is shown as a dotted line to the right connecting H2 and H3. The four disulphide bonds connecting helix H1/H4, H3/H5, H3/H4 and H4 and the C-terminal of the protein are shown in yellow.

FIG 2.. The structural folds of Ara h 2 and Ber e 1.

A) Crystal structure of Ara h 2 (PDB id: 3OB4) and B) NMR structure of Ber e 1 (PDB id. 2LVF) showing the secondary structure elements (Helices H1-H5) conserved in the 2S albumins. The unstructured (disordered) loop characteristic of Ara h 2 is shown as a dotted line to the right connecting H2 and H3. The four disulphide bonds connecting helix H1/H4, H3/H5, H3/H4 and H4 and the C-terminal of the protein are shown in yellow.

FIG 3.. Potential conformational epitopes shared by Ana o 3 and Pis v 1

A) Mapping of four linear epitopes on the Ana o 3 structure. The 3D model of Ana o 3 was generated using the NMR structure Ber e 1 as a template. The four linear IgE epitopes of Ana o 3 as identified in, are highlighted in colors. B) Conserved residues between Ana o 3 and Pis v 1, identified in the alignment of the sequences (Fig E1) are mapped on the surface of the 3D model of Ana o 3. This representation shows a large surface exposed area (blue), indicated by a dashed oval. This conserved region overlaps to a large extent with the linear epitopes in helix 1 and helix 3 of Ana o 3. C) and D) Structurally similar surface patches of Ana o 3 (red) and Pis v 1 (green). A common surface patch of Ana o 3 and Pis v 1 was found by Cross-react with a high similarity score of 0.90. The surface patch in Ana o 3 is centered at residue Q47; its best counterpart in Pis v 1 was found at the equivalent residue Q54 of Pis v 1. Residue Q47 is also labeled in A). This surface patch could be part of a conformational epitope responsible for the clinical observed cross-reactivity between CN and Pis v 1.