Comparisons of Allergenic and Metazoan Parasite Proteins: Allergy the Price of Immunity

Abstract

Allergic reactions can be considered as maladaptive IgE immune responses towards environmental antigens. Intriguingly, these mechanisms are observed to be very similar to those implicated in the acquisition of an important degree of immunity against metazoan parasites (helminths and arthropods) in mammalian hosts. Based on the hypothesis that IgE-mediated immune responses evolved in mammals to provide extra protection against metazoan parasites rather than to cause allergy, we predict that the environmental allergens will share key properties with the metazoan parasite antigens that are specifically targeted by IgE in infected human populations. We seek to test this prediction by examining if significant similarity exists between molecular features of allergens and helminth proteins that induce an IgE response in the human host. By employing various computational approaches, 2712 unique protein molecules that are known IgE antigens were searched against a dataset of proteins from helminths and parasitic arthropods, resulting in a comprehensive list of 2445 parasite proteins that show significant similarity through sequence and structure with allergenic proteins. Nearly half of these parasite proteins from 31 species fall within the 10 most abundant allergenic protein domain families (EF-hand, Tropomyosin, CAP, Profilin, Lipocalin, Trypsin-like serine protease, Cupin, BetV1, Expansin and Prolamin). We identified epitopic-like regions in 206 parasite proteins and present the first example of a plant protein (BetV1) that is the commonest allergen in pollen in a worm, and confirming it as the target of IgE in schistosomiasis infected humans. The identification of significant similarity, inclusive of the epitopic regions, between allergens and helminth proteins against which IgE is an observed marker of protective immunity explains the 'off-target' effects of the IgE-mediated immune system in allergy. All these findings can impact the discovery and design of molecules used in immunotherapy of allergic conditions.

Fig 1. Flowchart depicting the workflow involved in the present analysis.

Fig 2. The distribution of protein molecule entries (dark gray bars) listed in the Allergome database across different species (light gray bars) by taxonomic grouping (Bacteria, Fungi, Plants and Metazoan).

Fig 3. Distribution of allergenic molecules retrieved from Allergome database across Pfam domain families.

Number of Pfam domain families with no allergenic members have also been represented. The Y-axis is scaled logarithmically (base 10), however true values are represented.

Fig 4. Pfam domain families that are highly populated with allergenic protein sequences.

Protein domain families considered for this analysis are highlighted in the box based on the families presented in the article co-authored by Fitzsimmons and Dunne [21].

Fig 5

A. Sequence alignment of the epitopic region from Atlantic salmon (Salmo salar) allergenic parvalbumin-like 1 protein (UniProt accession: B5DH17) and predicted epitopic-like region from worm Schistosoma japonicum (UniProt accession: Q5C262). B. Superposition of the 3D structural model of salmon parvalbumin-like 1 protein (colored in green) and EF hand domain of the Schistosoma japonicum protein (in cyan). Epitope (allergen) and predicted epitopic-like regions (parasite protein) are depicted in the box.

Fig 6

A. Sequence alignment of the epitopic region from profilin protein (allergenic) from Betula pendula (European white birch) (UniProt accession: P25816) and predicted epitopic-like region from the worm Ascaris lumbricoides (UniProt accession: F1LGV9). B. Superposition of the 3D structure of plant allergenic protein (PDB accession: 1CQA) (colored in green) and the 3D structural model of profilin protein from the worm Ascaris lumbricoides (in cyan). Epitope (allergen) and predicted epitopic-like regions (parasite protein) are depicted in the box.

Fig 7

A. Superposition of the 3D structure of timothy grass Phl p 1 (PDB accession: 1N10) (in green) and the 3D structural model of mite protein (in cyan). Epitope (allergen) and predicted epitopic-like regions (parasite protein) are depicted in the box. B. Sequence alignment of the epitopic region from Phleum pratense ‘Phl p 1’, a major timothy grass pollen allergen (UniProt accession: P43213) and predicted epitopic-like region from Mite group 2 allergen ‘Pso o 2’ protein (UniProt accession: Q965E2) from Psoroptes ovis.

Fig 8. Magnitudes of specific IgE, IgG4 and IgG1 responses to S. mansoni Bet v 1-like protein, SmBv1L, in a population of 222 individuals infected with S. mansoni, dotted lines indicate threshold of magnitude for a response.

Data were normalized for expression on a log scale by the addition of constants so as to include zero values.

Fig 9. Venn diagram showing the distribution of Ab isotype responses to SmBv1L within IgG1, IgG4 and IgE responders in a population of 222 individuals endemically infected with S. mansoni.