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Molecular features of food allergens

Molecular features of food allergens
Literature review current through: Jan 2024.
This topic last updated: Jan 18, 2023.

INTRODUCTION — Many of the allergen-containing protein families, and, consequently, their individual members, possess characteristic molecular features that promote allergenicity [1-5].

This topic reviews the structural and physicochemical features common to food allergens. The European Academy of Allergy and Clinical Immunology (EAACI) published the first edition of the EAACI Molecular Allergology User's Guide in May 2016 [6]. A second, revised, downloadable edition was made available in 2022 and contains a wealth of information on molecular features of allergens. The clinical features and cross-reactivity of food allergens and the pathogenesis of food allergy are discussed separately. (See "Food allergens: Clinical aspects of cross-reactivity" and "Pathogenesis of food allergy".)

A list of protein families that contain allergens can be accessed at the AllFam database of allergen families website [4]. AllFam makes use of data from the World Health Organization (WHO)/International Union of Immunological Societies (IUIS) Allergen Nomenclature database [7], which contains information on all officially recognized allergens. This information is supplemented by data from AllergenOnline. The AllFam protein family classification is based on protein definitions from the Pfam database [8].

OVERVIEW — Stability is one of several common identified properties of allergens [9]. A food allergen must possess certain structural and physicochemical properties that prevent it from being destroyed by the digestive process in order for a predisposed person to become sensitized via exposure through the gastrointestinal tract [10]. These properties ensure that enough of the protein survives in a sufficiently intact form to be taken up by the gut and to be recognized by the mucosal immune system. Processing may alter the allergenicity of food [11,12]. However, stability alone is an indication but not the final proof of the allergenic potency of a given protein [13]. Other factors and properties, such as abundance and types of immune responses induced, can play a role [9].

Food allergens must also possess the ability to induce a T helper cell type 2 (Th2) biased, allergen-specific immune response via certain structural features or biologic activities of the allergen or the association of the allergen with ligand molecules that can act as adjuvants [14]. Studies of the interaction of allergens and the innate immune system have highlighted the roles of pattern recognition receptors in initiating Th2-biased immune responses [15-17]. The interaction of invertebrate tropomyosin, a food and aeroallergen, with dectin-1 suppresses the development of type 2 immune responses by inhibiting the secretion of interleukin (IL) 33 in healthy humans [18]. A single nucleotide polymorphism in the dectin-1 gene locus results in unrestrained IL-33 release and skewing of the immune response toward a type 2 phenotype. Several members of major allergen families bind lipid ligands via hydrophobic cavities or electrostatic or hydrophobic interactions [19]. These lipids, either present in the allergen source or originating from microbial contaminations, modulate the immune response of predisposed individuals by interacting with their innate immune system.

PROTEIN STABILITY — The conformational stability of an allergenic food protein is of high importance to its allergenicity. Stability of an allergenic protein describes its ability to maintain its original and allergenic three-dimensional structure despite being exposed to heat, harsh pH changes, and proteases. The term "stability" also encompasses the ability of a protein to refold to its native or near-native conformation during cooling after heat treatment. Several structural features are related to stability including the presence of disulfide bonds, glycosylation, and rheomorphism.

Disulfide bonds — The single most important structural feature of an allergenic food protein related to its stability is the presence of disulfide bonds that are formed by pairs of cysteine residues. Intrachain disulfide bonds link segments of single-chain proteins (eg, nonspecific lipid transfer proteins [nsLTPs]) and interchain disulfide bonds link individual chains of multiple-chain proteins (eg, 2S albumins). Both types of disulfide bonds constrain the three-dimensional scaffold of a protein and protect it against denaturation by heat or protease digestion [20].

Prolamin superfamily — The prolamin superfamily is the most important protein family for plant food allergens [1]. This superfamily is characterized by the presence of a conserved cysteine skeleton [21]. Many highly disulfide-bonded members of this superfamily are notable food allergens including 2S albumins, nsLTPs, and the cereal inhibitors of trypsin and alpha-amylases. Besides the prolamin superfamily, the protein stability of several members of defense-related protein families (eg, defensins, class I and class IV chitinases, and thaumatin-like proteins [TLPs]) is also based upon the presence of a high number of disulfide bonds in their structures. Lists of allergens belonging to the various protein families can be viewed on the AllFam website [22].

2S albumins – The 2S albumins are a major group of seed storage proteins that are present in seeds, tree nuts, and legumes. Although quite diverse, 2S albumins share a disulfide linked core and similar physicochemical properties that contribute to the observed co-allergy among peanuts, tree nuts, and sesame [23]. These compact molecules exhibit high thermostability and resistance to extreme pH values and proteolysis due to the presence of four conserved disulfide bonds. This stability was demonstrated for various 2S albumins from seeds, nuts, and legumes including mustard seed [24], rapeseed [25], sesame seed [26], sunflower seed [27], Brazil nut [27-29], and peanut [30,31]. As an example, a study confirmed that Sin a 1, the allergenic 2S albumin of mustard seeds, possessed resistance to alpha-chymotrypsin digestion, heat denaturation, and insensitivity to pH variations and the presence of salts [32].

Cor a 14, the 2S albumin from hazelnut, has been described as a high-risk marker for severe hazelnut allergy [33]. Cor a 14 purified from raw hazelnuts was resistant to proteolytic degradation and required temperatures of more than 80°C to start unfolding [34]. Native and heat-treated Cor a 14 was recognized by sera from hazelnut-allergic patients. However, denaturation of the allergen led to reduced immunoglobulin E (IgE) binding. The digestion of hazelnut flour according to the Infogest international consensus in vitro digestion method [35] revealed that a narrow range of peptides close to the C-terminus of Cor a 14 was released, while the core structure of disulfide-bonded alpha-helices remained intact [36]. Cor a 14 was also shown to retain its IgE-binding capacity after hot air or infrared roasting at 140°C, while roasting at 170°C caused a reduction in IgE binding [37].

Pin p 1, the 2S albumin from pine nuts, was heat stable for 120 minutes at 100°C and still possessed a robust capacity to inhibit IgE binding to whole pine nut extract [38] despite exposure of the major five IgE epitopes, including three located within loop regions, on the protein's surface [39].

Mass spectrometric analysis of allergens in roasted walnuts revealed that the 2S albumin Jug r 1 only underwent minor changes in solubility following heat treatments up to 180°C for 20 minutes, a characteristic attributed to its disulfide-stabilized scaffold [40]. In general, walnut proteins are relatively stable under certain thermal processing conditions, and IgE reactivity remains present even when insoluble aggregates are formed [41].

The 2S albumin from pecan (Carya illinoinensis) was resistant to digestion by pepsin in simulated gastric fluid and comparatively stable to proteolysis by trypsin and pancreatin in simulated intestinal fluid [42]. Moreover, digestion of Car i 1 generated different proteolysis-resistant peptides that bound IgE from pecan-allergic individuals.

The grain-like seeds of Tartary buckwheat (Fagopyrum tataricum), one of the two cultivated buckwheat species, are an important functional food. The seeds contain Fag t 2, a member of the 2S albumin family that was characterized as highly stable to pepsin digestion and thermal denaturation [43].

The soybean 2S albumin Gly m 8 possesses an extraordinary stability and solubility, which allows its extraction even from processed complex matrices. A sandwich enzyme-linked immunosorbent assay (ELISA) was developed based upon these molecular characteristics that allowed the tracking of Gly m 8 in processed foods [44].

Ground raw peanuts were subjected to in vitro simulated oral and gastric digestion mimicking physiologic conditions [45]. Ara h 2 and 6, 2S albumins and major allergens of peanut, remained mostly intact. In addition, short digestion-resistant peptides released by gastric digestion of Ara h 2 and 6 were highly potent in binding patients' IgE, illustrating their clinical relevance. Subjecting coarse peanut powder to in vitro oral, gastric, duodenal, and intestinal digestion resulted in generation of Ara h 2 and 6 protein fragments only slightly smaller than the intact proteins and release of a number of immunoreactive peptides [46]. Intact Ara h 6 and posttranslationally cleaved Ara h 6 that consists of two chains held together by disulfide bonds are found in peanuts at similar levels [47]. No differences in IgE binding were reported. While harsh conditions are required to denature both Ara h 6 forms and to significantly reduce their IgE-binding capacity, the cleaved form is more resistant to denaturation [48]. Ara h 2 and Ara h 6 survive digestion and remain immunologically intact in breast milk [49].

nsLTPs – These proteins are structurally related to the 2S albumins. They play a role in plant defense mechanisms against bacteria and fungi and possibly in the assembly of protective lipid layers, such as cutin, on exposed surfaces. Two subfamilies of nsLTPs with a molecular mass of 9 kDa (nsLTP1) and 7 kDa (nsLTP2) have been described [50]. These proteins are composed of four alpha-helices stabilized by four disulfide bonds and are resistant to proteolysis, harsh pH changes, and thermal treatments [51]. They are able to refold to their native structure on cooling. nsLTPs can survive conditions in the digestive tract as fully IgE-reactive molecules that retain the ability to trigger mast cells [52]. All allergenic nsLTPs are, to varying degrees, resistant to heat and digestion [53].

The nsLTP1 found in peach is the major peach allergen, Pru p 3, and it is highly resistant to digestion by pepsin [54]. Natural Pru p 3 purified from peach skin is heat stable under acidic conditions, returning to its natural state upon cooling [55]. Natural purified Pru ar 3, an nsLTP1 from apricots, was found to have a resistance of 9 percent to proteolytic degradation when subjected to gastrointestinal digestion [56]. This resistance was much lower than the one found for the peach nsLTP1 (35 percent) and might explain the lower allergenicity of Pru ar 3. Tri a 14, an nsLTP1 from wheat berries, displays high resistance to heat and digestive proteolysis, comparable with that of Pru p 3 [57]. Likewise, Cor a 8, an nsLTP1 from hazelnut, is stable at low pH and refolds after thermal denaturation [58].

The IgE-binding capacity of the corn nsLTP1, Zea m 14, remains unchanged after thermal treatments, even though its secondary structure is altered [59]. Similarly, the cherry nsLTP1, Pru av 3, shows a high resistance to digestion by pepsin, and its IgE reactivity is not diminished after thermal processing [60]. Heat stability has also been reported for the allergenic nsLTP1, Cor a 8, from hazelnut [61,62]. Sola l 3 is an nsLTP1 present in the epicarp of tomatoes (Solanum lycopersicum). The biochemical characterization of recombinant Sola l 3, expressed in Escherichia coli, revealed its stability to thermal denaturation [63]. Although heating induced changes in the secondary structure of Sola l 3, cooling of the protein resulted in a complete recovery of its native conformation. This is in agreement with studies reporting the involvement of nsLTPs in allergic reaction and anaphylaxis to processed tomato products [64,65]. Tomato fruits possess three different nsLTPs [53]. In addition to the tomato peel/pulp nsLTP1 Sola l 3, the nsLTP1 Sola s 7 and the nsLTP2 Sola l 6 are present in tomato seeds. Sola l 7 showed the highest stability to in vitro digestion and was able to activate basophils after digestion [53].

Api g 6, an nsLTP2 from celery root, represents the first well-characterized allergen from the second subfamily of nsLTPs [66]. Api g 6 was shown to possess a very high thermal stability (Tm >90°C) and high resistance to gastrointestinal digestion. The nsLTP1 from durum wheat (Triticum durum) was shown to be highly resistant to gastroduodenal hydrolysis when cooked durum wheat pasta was digested using a harmonized in vitro static model of oral-gastro-duodenal digestion [67].

Alpha-amylase/trypsin inhibitors (AATIs) – AATIs are restricted to the seed storage tissues (endosperm) of cereal grasses. This family of inhibitors, which includes trypsin inhibitors, alpha-amylase inhibitors, and bifunctional trypsin/alpha-amylase inhibitors, is mainly active against digestive enzymes of insects that feed on stored cereal grains. AATIs consist of four to five alpha-helices and a short antiparallel beta sheet tightly held together by four to five intrachain disulfide bridges. AATIs have the capacity not only to sensitize by inhalation but also by ingestion [68]. AATIs from wheat have been identified as strong activators of innate immune responses in monocytes, macrophages, and dendritic cells by engaging the Toll-like receptor 4, myeloid differentiation protein 2/lymphocyte antigen 86, and cluster of differentiation 14 (TLR4-MD2-CD14) complex and eliciting proinflammatory cytokines [69]. Wheat AATIs were also reported to exacerbate allergen-specific T cell proliferation and cytokine production, thus acting as adjuvants of allergy [70].

IgE epitopes of the dimeric wheat AATI 0.19 (Tri a 28) were detectable after up to 120 minutes of simulated gastric fluid digestion in emulsifying conditions. Intramolecular disulfide bonds and, in particular, emulsification were found to be crucial factors for protein stability [71]. However, the overall effect of baking during wheat sourdough bread making had a greater effect on the abundance of the trimeric AATI Tri a 30 than fermentation conditions [72].

Defensins — Defensins are small (<10 kDa), cysteine-rich (forming three to six disulfide bonds), cationic peptides that are mostly involved in host defense. The defensins belong to two superfamilies and have evolved from two independent origins [73]. Defensins from animal, plant, and fungal species are classified into cis- or trans-defensins [74].

Defensins from plants belong to the cis-defensin superfamily and are produced by all species of plants [75]. These defensins represent major components of the innate immune system of plants and have various biologic functions including antibacterial and antifungal activities and lipid binding. Plant defensins contain 45 to 54 amino acid residues. Although the defensin structure is highly conserved, their amino acid sequences are highly variable with the exception of the conserved cysteine residues. Their three-dimensional structure is stabilized by four disulfide bridges formed by eight strictly conserved cysteine residues. The disulfide bonds are responsible for the stability of defensins to pH changes, proteolysis, and extreme temperature changes.

Two groups of peanut defensins, Ara h 12 and Ara h 13, which react in particular with IgE from patients with severe peanut allergy, were isolated from lipophilic extracts of roasted peanuts [76]. They possessed four disulfide bonds and formed dimers under natural conditions. The defensin Api g 7, a plant food allergen present in celery roots, also possesses the conserved eight cysteine residues [77].

Thaumatin-like proteins — TLPs belong to the family five of pathogenesis-related proteins. TLPs are involved in the resistance and response to fungal pathogens by inhibiting hyphal growth. The conformation of TLPs is stabilized by eight disulfide bonds [78]. This extensive disulfide cross-linking renders zeamatin, a TLP from corn, highly resistant to proteolysis [79].

Allergenic TLPs have been identified in various fruits, including Mal d 2 from apple [80,81], Mus a 4 from banana [82], Pru av 2 from cherry [83], Act d 2 from kiwi [84,85], Vit v TLP from grape [86], Pru p 2 from peach [87], Lac s TLP from lettuce [88], and Man z TLP from sapodilla plum [89]. Grape TLPs are produced by the plant during ripening of the berry. They persist during the entire vinification process and are among the major proteins present in wine [90]. Mal d 2, the TLP from apple, possesses remarkable stability to proteolysis and thermal treatments [81]. The allergen retains its full IgE-binding capacity after two hours each of gastric and duodenal digestion. The heat-induced denaturation of the allergenic TLP from kiwi fruit, Act d 2, under acidic conditions is fully reversible, and IgE binding to this allergen is detectable in processed food products [85]. Ole e 13, the TLP from raw olives, loses its allergenicity due to the routine, prolonged maceration treatment of raw olives with sodium hydroxide (NaOH) [91]. This finding offers an explanation as to why there are only a low number of patients who are allergic to this highly consumed fruit. Mealworms, which are edible for humans and are processed into food items, contain a constitutively expressed thaumatin-like protein [92].

Chitinases — Chitinases form a large group of enzymes that degrade the polymer chitin, a structural component of insect exoskeletons and fungal cell walls. Allergenic chitinases are found in fruits but also in edible insects [93]. Although there are at least five structural classes of chitinases, class I contains most of the chitinases identified as allergens in plants and plant foods [94]. Class I chitinases possess an N-terminal cysteine-rich domain. This highly conserved so-called hevein domain binds chitin and is stabilized by four disulfide bridges. The main IgE-binding epitopes are located in this domain [95]. Pers a 1, the allergenic class I chitinase from avocado, retains its ability to produce positive skin prick tests after gastric digestion [96]. Class IV chitinases also possess a disulfide-stabilized N-terminal chitin-binding domain, and, like class I chitinases, their catalytic chitinase domains are stabilized by three disulfide bonds [94]. Zea m 8, a class IV chitinase from corn, survives food-processing procedures and the gastric environment due to its resistance to elevated temperatures and to low pH [97]. Silkworm pupae are a nutrient-rich food that are consumed regularly in China and may be adopted as food in Western countries. An allergenic chitinase was described in silkworm (Bombyx mori) pupae [98,99]. Hence challenges associated with the consumption of insects include the careful evaluation of the presence of allergens such as chitinases [100]. Oil-fried or water-boiled pupae retain their allergenicity and can cause anaphylaxis [101].

Other allergens with disulfide bonds — The allergenic soybean Kunitz trypsin inhibitor is resistant to thermal and proteolytic denaturation [102]. Kiwellin (Act d 5) is an important kiwi allergen that contains an N-terminal cysteine-rich domain [103]. It is one of the three most abundant proteins present in kiwi fruit.

Glycosylation — N-glycosylation is a major modification of proteins in plant cells that occurs during their passage through the endoplasmic reticulum. Glycosylation affects the biologic properties of proteins. The correct glycosylation of proteins plays a pivotal role in their folding [104] and increases their thermal and proteolytic stability [105-107].

The immunologic activity and relevance of IgE antibodies directed to carbohydrate epitopes has been a matter of debate since the discovery of N-glycan-specific IgE [108]. Approximately 20 percent or more of allergic patients generate specific antiglycan IgE. Although IgE-binding glycoproteins are widespread in pollens, foods, and insect venoms, their cross-reactive carbohydrate determinants (CCDs) do not appear to cause clinical symptoms in most patients [109]. One exception is the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). Alpha-gal-specific IgE antibodies bind to a variety of mammalian allergens and are associated with delayed anaphylaxis after eating mammalian meat [110-115].

The 7S seed storage globulins are frequently glycosylated, with one or two N-linked glycosylation sites located in the C-terminal domain. Soybean Gly m 5 is an allergenic seed storage protein that consists of homo- and heterotrimers of three subunits, namely alpha, alpha', and beta. All three individual subunits are glycosylated on all potential glycosylation sites [116]. In simulated gastrointestinal digestion assays, deglycosylated Gly m 5 was completely degraded, while alpha and beta subunits of the Gly m 5 glycoprotein partially survived the process of digestion [117]. The allergen Ara h 1, the 7S globulin of peanut, possesses one consensus N-glycosylation site. The glycan moieties attached to Ara h 1 are a heterogeneous mixture of N-glycans [118]. Vicilin (Pis s 1) and convicilin (Pis s 2), both 7S globulins, are potential major allergens from pea seeds. Proteolytic fragments from vicilin are relevant IgE-binding pea components [119]. N-glycosylation of the 7S globulin of pea increases its stability and resistance to chemical denaturation [120].

Sola l 2, an allergenic beta-fructofuranosidase with four glycosylation sites, was reported to trigger the degranulation of human basophils, and this process was mediated by the glycan structure of the Sol l 2 [121,122]. The carbohydrate moiety of Act d 2, a clinically relevant allergenic TLP from kiwi, was shown to play a significant role in the sensitization process by activating antigen-presenting cells and triggering a proinflammatory response [123]. Once the allergy is established, symptoms are primarily induced by the protein portion of the allergen, and involvement of the N-glycan portion is negligible.

Intrinsically disordered proteins — Intrinsically disordered proteins (IDPs) are a class of functional proteins or protein regions that contain smaller or larger highly dynamic fragments. Some proteins are even characterized by a complete lack of ordered structure under physiologic conditions [124]. IDPs have been called many names in the past, among them the term "rheomorphic proteins" [125,126]. Such proteins are dynamic. They adopt various secondary structures that are in equilibrium with each other. They resemble unfolded, denatured, or partially folded proteins. Consequently, rheomorphic proteins do not undergo sharp transitions from one conformational state to another on heating and thus possess many potential thermostable epitopes [127]. Heat stability was observed for several IDPs, including caseins (Bos d 9 through 12), major cow's milk allergens, for which the term rheomorphic was first used [126,128]. An in silico study identified intrinsically disordered regions in allergens to a higher degree than in nonallergenic proteins [129].

Based upon its heat stability, flexibility, and lack of secondary structure elements, Man e 5, a food allergen from manioc (Manihot esculenta), was determined an IDP [130]. Beta parvalbumins are major fish allergens. The parvalbumin beta 1 from coho salmon was found to display a markedly disorganized secondary structure and lack of rigid tertiary structure in its apo-state [131]. This instability appeared to be a hallmark of the elevated calcium affinity of the protein. The apo-state of pike alpha and beta parvalbumins were also shown to belong to the family of IDPs [132]. ENEA (amino acid code letters for the first four amino acids in the protein: glutamic acid [E], asparagine [N], glutamic acid [E], alanine [A]) is an allergen from peach and apricot that cross-reacts with the Hev b 5 allergen from Hevea brasiliensis latex [133]. Similarly to Hev b 5 and to Man e 5, the structural characterization indicated that ENEA is an intrinsically disordered protein.

Another group of IDPs are the cereal seed storage prolamins, members of the prolamin superfamily. These proteins possess remnants of the original conserved cysteine skeleton of the prolamin superfamily, as found in the 2S albumins, nsLTPs, and alpha-amylase/trypsin inhibitors, that has been disrupted by the insertion of a central domain consisting of repeated sequences of varying lengths, depending on the type of cereal prolamin [134]. These repetitive sequences adopt rapidly interconverting beta-turn and beta-sheet secondary structures that tend to form aggregates linked by intermolecular beta sheets [135]. The formation of such structures renders the seed storage prolamins rather insoluble, although they are hydrophilic and bind water avidly. Cereal prolamins do not possess a compact globular structure and thus do not undergo a distinct transition from a native to denatured state when exposed to heat.

Repetitive structures — Highly repetitive linear epitopes are to some degree unaffected by heat denaturation and partial proteolysis. Tropomyosins are a family of closely related proteins present in muscle and nonmuscle cells [136]. Tropomyosins contain a seven amino acid residue ("heptad") repeat [137]. Most tropomyosins have an unbroken series of 40 continuous heptads. Tropomyosins, major seafood allergens of crustaceans and mollusks, are heat stable and cross-reactive. Extracts from boiled Penaeus indicus shrimp were found to contain the allergenic tropomyosin Pen i 1, with unaltered allergenicity [138].

While invertebrate tropomyosins are well associated with food allergy, vertebrate tropomyosins do not elicit allergy or cross-reactivity despite their high sequence identities and structural similarities with invertebrate homologs. However, tropomyosin from Penaeus aztecus (Pen a 1) was more stable to thermal denaturation and proteolysis than porcine (Sus scrofa) tropomyosin [139]. Heat-denatured Pen j 1, an allergenic tropomyosin from Marsupenaeus japonicus prawns, was shown to refold upon cooling and to maintain its antigenicity following the heat treatment [140]. While sequence-based methods could not discriminate allergenic from nonallergenic tropomyosins, molecular dynamics simulations uncovered differences in the global structural flexibility and resultant susceptibility to proteolysis between allergenic and nonallergenic tropomyosins [139].

Repetitive structures are also a characteristic feature of many IDPs. Cereal seed storage prolamins probably exhibit the most degenerate repetitive sequences. These are based upon several different short motifs that are rich in proline and glutamine and range from four to eight residues in length [141].

INTERACTION WITH MEMBRANES AND OTHER LIPID STRUCTURES — Several food allergens are able to associate with cell membranes and other lipid structures [142]. Such interactions may increase allergen uptake in the gastrointestinal tract. These associations may also delay or inhibit proteolytic degradation of allergens because the sections of protein embedded in the lipid structure are no longer accessible to proteases. In addition, the interaction of food allergens with the membranes of intestinal epithelial cells may regulate epithelial gene expression to promote allergic sensitization [143].

2S albumins — 2S albumins function primarily as seed storage proteins. However, other functions have been ascribed to them, including antifungal activity. This antifungal activity results from an interaction with and permeabilization of fungal cellular membranes [144,145]. This ability to affect membrane permeability also may play a role in gastrointestinal processing.

The allergenic 2S albumin from mustard interacts with phospholipid vesicles, causing both vesicle aggregation, mixing of lipids between vesicles, and vesicle leakage [146]. The extracellular leaflet of intestinal brush border membranes contains greater amounts of acidic phospholipid bilayers compared with other plasma membranes [147]. Interactions with these lipid bilayers may affect the uptake and processing of 2S albumin allergens in the gastrointestinal tract, increasing their allergenic potential [146].

Sunflower albumin-8 (SFA-8), an allergenic 2S albumin of sunflower seeds, is known for its emulsification properties [148,149]. The 2S albumin allergens from sesame seeds (Ses i 1) and Brazil nuts (Ber e 1) can penetrate intestinal epithelial layers intact and sensitize the mucosal immune system or elicit an allergic response [150]. Immunofluorescence microscopy revealed significant binding to the apical Caco-2 membrane and internalization of Ara h 2, the allergenic peanut 2S albumin [151]. The ability of Ara h 2 to bind to epithelial cell membranes facilitates and increases its transport across the intestinal epithelium.

Cupins — Sin a 2 and Ara h 1, major allergenic seed storage proteins of the cupin superfamily, are present in yellow mustard seeds and peanuts, respectively. Sin a 2 and Ara h 1 bind to phosphatidylglycerol (PG) vesicles derived from their respective allergen source, and this interaction confers resistance to gastrointestinal digestion, reduces their uptake by dendritic cells, and enhances their stability to microsomal degradation [152].

Alpha-lactalbumin — Albumins are the main proteins of plasma. They bind water, cations, fatty acids, hormones, bilirubin, and drugs. Their main function is to regulate the colloidal osmotic pressure of blood. Bovine alpha-lactalbumin, although present in milk in low quantities, is an important cow's milk allergen [153]. Interactions between alpha-lactalbumin and phosphatidylcholine, a surfactant that is abundant in milk and is actively secreted by the stomach, slow the breakdown of the allergen during in vitro digestion [154]. Alpha-lactalbumin adsorption and incorporation into lipid membranes are accompanied by protein conformational changes and lead to alterations in membrane structure and morphology [155].

Nonspecific lipid transfer proteins — Nonspecific lipid transfer proteins (nsLTPs) are also able to interact with lipid structures. This ability is implicit in their function to transfer lipids between donor and acceptor vesicles [156]. An nsLTP from wheat inserts into lipid monolayers, which is a simplified model of biologic membranes [157]. Wheat nsLTP can bind two single chain lipids, suggesting that this protein may even form bridges between lipid structures [158]. Although the nsLTP from sunflower seeds is unable to stabilize an emulsion due to the rapid coalescence of oil droplets, it was shown to absorb at air-oil interfaces [148]. The physiologic importance of these molecular properties might be the ability to interact with epithelial cell membranes to induce proallergenic cytokine production and to enable the allergen to cross the intestinal monolayer followed by the uptake by mucosal dendritic cells. Pru p 3, the peach nsLTP1, was able to cross an epithelial cell monolayer without disturbing the integrity of the tight junctions, indicating an active transcellular transport of the allergen following its contact with cell membranes [159]. Pru p 3 induced the epithelial cell-derived production of the T helper cell type 2 (Th2) promoting cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL) 25, and IL-33.

Thaumatin-like proteins — Many thaumatin-like proteins (TLPs) have been reported to inhibit the growth of fungal hyphae, including the apple allergen Mal d 2 [80] and the allergenic TLP from banana [82]. The precise mechanism of this biologic activity is not clear, but it may result from permeabilization of fungal membranes [160,161]. TLPs may also interact directly with the lipid bilayer of the fungal plasma membrane. This lipid bilayer is composed of sphingolipids, phospholipids, and sterols that occur in membranes of all living organisms. The membrane permeabilizing activity of linusitin, an antifungal TLP from flax seeds, depends upon membrane composition and is amplified by increased content of negatively charged phospholipids and the presence of sterols [162].

PR-10 proteins — The major birch pollen allergen, Bet v 1, is a member of the ubiquitous pathogenesis-related (PR) 10 family of proteins [163]. Bet v 1-related allergens are found in a wide range of plant foods and generally cause only mild oral symptoms. However, there are reports of severe and anaphylactic reactions caused by Bet v 1-related allergens, such as Gly m 4 from soybean [164,165]. The binding of Bet v 1 to membranes induces major structural rearrangements in the molecule [166]. This capability might provide a mechanism by which PR-10 proteins present in foods and, still intact in the digestive tract, cross the mucosal lining and become internalized, thereby facilitating an allergic reaction. Fra a 1, the Bet v 1 homolog from strawberries, was significantly enriched in the lipid bilayer surrounding extracellular micro- and nanovesicles [167]. (See "Pathogenesis of oral allergy syndrome (pollen-food allergy syndrome)".)

Parvalbumins — Lipid emulsion of turbot parvalbumin significantly enhanced its resistance to gastric digestion, facilitating the exposure of the intact allergen to the immune system [168]. Lipid-emulsified gastric digestion products of turbot parvalbumin significantly enhanced the release of active mediators and cytokines from histamine-releasing rat basophilic leukemia (RBL) cells [169].

LIGAND BINDING — Certain food allergens are able to bind nonallergenic organic compounds or ions as ligands, including glucocorticoids and a variety of lipid molecules. Ligand binding induces structural changes of allergens and increases the stability of an allergen to thermal and proteolytic degradation, thus enhancing its allergenic potential [9,170]. These allergen-associated small-molecule ligands can also act as immunomodulatory agents that favor T helper cell type 2 (Th2) polarization [171]. Several major food allergens bind lipid ligands in hydrophobic cavities or by hydrophobic interactions. Following the consumption of the respective foods, allergens and lipids are delivered to the immune system, possibly influencing the allergenic capacity of the allergen [17]. These allergens include members of the 2S albumins, nonspecific lipid transfer proteins (nsLTPs), and lipocalin families [19]. It is thought that the formation of additional hydrogen bonds between the ligand and the protein stabilizes the protein scaffold, increases its rigidity, and decreases its susceptibility to proteolysis. In addition, dietary lipids can act as adjuvants and might skew the immune response towards a Th2 phenotype [172].

Ionic ligands, such as metal ions, become part of the structure of a protein and are often deeply buried within the molecule. Ligand binding often results in reduced mobility of the polypeptide backbone. This leads to a decreased susceptibility to thermal and proteolytic denaturation since many proteases require a certain flexibility of the substrate protein. The loss of a metal ion often disrupts the protein folding and leads to an increase in protein mobility and, in some instances, to a transition to a partially folded form. Some proteins possess a cavity or a tunnel into which the ligand fits, and others bind ligands through surface interactions.

Nonspecific lipid transfer proteins — nsLTPs are able to bind lipid molecules in a tunnel that runs through the entire protein and is lined with hydrophobic residues. The size of the tunnel varies for different nsLTPs. The binding of a lipid ligand to nsLTPs has an impact on their allergenic properties and the allergic sensitization process [173].

Barley and wheat nsLTPs are able to bind a variety of fatty acids and phospholipids of differing lengths with high affinity [174,175]. Wheat nsLTP can bind a wide range of lipophilic molecules, including sphingolipids, prostaglandin, amphotericin B, and other hydrophobic drugs, due to the high plasticity of the hydrophobic cavity [176,177]. Barley nsLTP can accommodate two lipid molecules, lying side by side within the tunnel [174]. Disulfide bridges are essential for the existence of the cavity, whereas its plasticity depends upon both the hydrophobic residues lining the cavity and the C-terminal flexibility [178].

Structural features and ligand binding are both directly related to nsLTP stability. Grape nsLTP is unaltered after gastric digestion, and a C-terminally trimmed fragment is produced by duodenal digestion [179]. This fragment has the same in vitro and in vivo IgE reactivity as the intact protein. Inclusion of phosphatidylcholine protected the grape nsLTP, Vit v 1, to a limited extent against digestion. While the presence of lipid ligands was reported to increase the thermostability and resistance of the lentil nsLTP Len c 3 to digestion, the level of these effects was dependent upon the ligand's nature [180]. In contrast to the results obtained for the grape and lentil nsLTP1s, it was reported that the susceptibility of Tri a 14, the wheat nsLTP1, to proteolytic cleavage increased significantly upon lipid binding [181]. This was due to a conformational change following ligand binding and the ensuing exposure of an additional protease cleavage site. Jug r 3, an nsLTP1 from walnut, was found to bind oleic acid [182]. Binding of this lipid ligand significantly increased the IgE binding capacity of Jug r 3.

The natural ligand of the peach allergen Pru p 3 was identified as a derivative of camptothecin bound to phytosphingosine [183]. It was suggested that the ligand's physiologic role was to inhibit a second pollination and to deter herbivores. The ligand was shown to induce the maturation of monocyte-derived dendritic cells and, when in complex with Pru p 3, to induce higher sIgE levels than Pru p 3 without the ligand [184]. It was further revealed that the ligand was presented to invariant natural killer T (iNKT) cells by CD1d, which may result in a Th2–mediated inflammation. The immunologic activity resides in the phytosphingosine part of the ligand, which can be metabolized by human cells to phytosphingosine-phosphate and promote the migration immune cells [185].

2S albumins — The 2S albumin from Brazil nut, Ber e 1, has a potential lipid-binding cavity the same size as is seen in some nsLTPs. Ber e 1 by itself was not sufficient to cause IgE or immunoglobulin G (IgG) production in mice [186]. IgE and IgG1 responses were induced only when Ber e 1 was coadministered with lipids isolated from Brazil nut. Neutral and common phospholipids bound to Ber e 1 were required to trigger allergic Th2 responses in mice and to activate human T cell lines derived from allergic patients to produce interleukin (IL) 4 [187].

Parvalbumins — Parvalbumins constitute a class of calcium-binding proteins characterized by the presence of several helix-loop-helix motifs (two helixes, E and F, joined by a loop), termed an EF-hand because the shape of the protein structure is similar to a part of the human hand. The EF-hand motif consists of a 12-residue loop flanked on both sides by 12 residue alpha-helical domains. Parvalbumins possess three such EF-hand motifs [188], two of which are capable of binding calcium [189]. A mutated carp parvalbumin, mCyp c 1, was created by destroying the calcium binding sites, thereby rendering the molecule hypoallergenic [190].

Parvalbumins can be subdivided into two distinct evolutionary lineages, alpha- and beta-parvalbumins, although their overall folds are very similar. Beta-parvalbumins are present in the white muscle of many fish species in relative high amounts and are generally allergenic. Loss of parvalbumin-bound calcium triggers large conformational changes and an associated loss of conformation-dependent IgE epitopes [191-193]. Targeting the 3D conformation of parvalbumin by adding specific molecules to the fish diets to induce the calcium free apo-form has led to a reduction of 50 percent of the IgE reactivity of gilthead seabream [194]. Parvalbumins show a remarkable resistance to heat, denaturing chemicals, and proteases [195,196]. Sufficient IgE-reactive epitopes remain after cooking to trigger allergic reactions in susceptible individuals [197]. When the calcium binding sites of the carp parvalbumin Cyp c 1 were mutated, the resulting protein became more susceptible to gastric and pancreatic digestion, indicating the role of the calcium ligand in stabilizing the parvalbumin conformation [198]. (See "Seafood allergies: Fish and shellfish".)

Beta-lactoglobulin — The lipocalins are a diverse family of proteins comprising extracellular ligand-binding proteins with high specificity for small hydrophobic molecules [199]. Beta-lactoglobulin, Bos d 5, the major whey protein in milk of ruminants and many other mammals, is a cow's milk allergen that belongs to the lipocalin superfamily. It binds a diverse range of molecules, including retinol and its analogs, beta-carotene, saturated and unsaturated fatty acids, and aliphatic hydrocarbons [200].

The relative resistance of Bos d 5 to acid hydrolysis and protease degradation allows some of the protein to remain intact after digestion [201]. Bovine alpha-lactalbumin (Bos d 4) and Bos d 5 are the most common food allergens in cow's milk, and they can bind C18 unsaturated fatty acids (UFAs). C18 UFAs were reported to efficiently promote the gradual unfolding of the structures of bovine alpha-lactalbumin and Bos d 5 [202]. Heat treatment induces conformational changes in beta-lactoglobulin and increases its susceptibility to enzymatic digestion [127]. In addition, heat-induced denaturation of beta-lactoglobulin is associated with weaker binding of IgE from individuals with cow's milk allergy [203]. (See "Milk allergy: Clinical features and diagnosis" and "Milk allergy: Management".)

Pathogenesis-related (PR) 10 proteins — The glycosylated flavonoid quercetin-3-O-sophoroside was identified as a physiologic ligand of the major birch pollen allergen Bet v 1 [204]. This finding offers a first insight into what types of natural ligands Bet v 1-related allergens from fruits, vegetables, and seeds might bind. Structures that show PR-10-like food allergens and their ligands were published for the mung bean allergen Vig r 6 in complex with the plant hormone zeatin [205] and for the peanut allergen Ara h 8 in complex with the flavonoid epicatechin [206]. Quercetin-3-O-(2"-O-beta-D-glucopyranosyl)-beta-D-galactopyranoside was identified by mass spectroscopy and nuclear magnetic resonance spectroscopy as the natural ligand of the hazelnut allergen Cor a 1.0401 [207]. (See "Pathogenesis of oral allergy syndrome (pollen-food allergy syndrome)".)

EFFECTS OF PROCESSING — Many of the foods consumed today have been processed. Conventional thermal methods include pasteurization, sterilization, drying, and roasting. Thermal processing promotes chemical and physical changes of food proteins and affects protein conformation, immunogenicity, and allergenicity, resulting in protein aggregation and glycation.

Formation of aggregates — Protein aggregation is the self-association of protein monomers either in their native states or in their non-native states in various degrees of unfolding. Non-native protein aggregation requires some degree of unfolding of the native conformation (eg, induced by elevated temperatures), which allows aggregation-prone regions to form stable interprotein contacts [208]. The basic immune reactions to non-native protein aggregation are being studied in detail for protein drug products [209].

The 7S and 11S globulin seed storage proteins of the cupin superfamily have a tendency to assemble into large structures [1]. They exist in an equilibrium of trimers and hexamers that are held together by noncovalent interactions [210]. Both 7S and 11S globulins are stable to heating. The cupin barrel is thought to remain intact during heat exposure. Unfolding of other regions through heating results in a loss of quaternary structure along with concomitant formation of large aggregates. These aggregates form flocculent precipitates when they become sufficiently large. At very high protein concentrations of 5 to 10 percent, similar to that found in processed foods, the aggregates form heat-set gel networks [211-213]. Heating most likely results in the formation of partially folded molten globule structures that rapidly go on to form large aggregated structures, becoming kinetically trapped in unfolded states in the process. Gly m 5/beta-conglycinin, an allergenic 7S globulin of soybeans, forms thermally induced aggregates [212].

Proteins, under altered environmental conditions, undergo misfolding and assemble into highly ordered beta-sheet structured fibrillar aggregates called amyloid fibrils. Amyloid formation is a sequence-dependent process. Amyloids are formed from locally or totally unfolded proteins and enhance a protein's stability. The amyloid state of Gad m 1, an allergenic parvalbumin of cod, was reported to be essential for its ability to bind IgE [214]. In addition, the formation of amyloid fibrils under simulated gastrointestinal conditions accounted for the observed resistance of Gad m 1 to proteases [215]. Amyloid formation greatly increased the affinity of Gad m 1 for IgE binding. Heated Cra g 1, an allergenic tropomyosin from oyster, produced higher IgE reactivity than the raw form as a result of its denaturation and formation of polymers [216]. Amyloid formation was also described for Bos d 5 (beta-lactoglobulin) [217], Bos d 10 (kappa-casein) [218], and Bos d 12 (alpha-s2-casein) [219]. Curly fibrils are less ordered than straight amyloid fibrils. The exemplary curly fibril-forming protein ovalbumin (Gal d 2) from hen's egg contains multiple aggregation prone regions (APRs) that facilitate curly fibril formation of the intact full-length protein [220]. Food-relevant heating conditions have the potential to induce protein fibrillation. Boiling wheat gluten proteins for at least 15 minutes converted 0.1 to 0.5 percent into beta-rich amyloid-like fibrils, suggesting their presence in heat-treated wheat gluten-containing food products [221].

Glycation during roasting — Glycation describes the nonenzymatic bonding of sugar molecules, typically reducing monosaccharides, to proteins or lipid molecules. Glycation contributes to the color, smell, and taste of many foods and food products. The process, also called the Maillard reaction, involves sugars reacting with free amino groups on proteins to form Amadori compounds. These compounds may then rearrange to produce a range of adducts known as advanced glycation end products (AGEs). AGEs are common nonenzymatic chemical modifications of food proteins. AGEs form during thermal processing, particularly during the application of dry heating procedures such as roasting. They also slowly form over days and months as a consequence of the aging process of foods. The Maillard reaction can alter the susceptibility of proteins to gastrointestinal digestion and modify the immunogenicity and allergenicity of food proteins [222,223]. Maillard reaction products have been linked to the increasing prevalence of diet- and inflammation-related noncommunicable diseases including food allergy [222,224]. Dendritic cells recognize AGE-modified proteins various receptors including the receptor for advanced glycation end products (RAGE), scavenger receptors (SRs), galectin-3, and CD36 [225]. Dendritic cells stimulated with AGE-modified proteins activated more IL-4-producing T cells than interferon (IFN) gamma-producing T cells [226]. However, the Maillard reaction can also reduce the IgE reactivity of allergens [227].

Heating in either wet (eg, boiling) or dry processes (eg, frying) can denature and/or modify proteins. Glycation may underlie the different effects such processes have on the allergenicity of foods. As an example, glycation reactions may be responsible for the apparent increase in allergenic activity of peanuts following processes such as curing and roasting [228,229]. Peanuts and tree nuts are often subjected to thermal processing at low water levels and high heat (eg, roasting), unlike soybean and lentils, which are usually boiled. Proteins become more thermostable in low-water systems because protein denaturation requires the presence of water [230]. The major peanut allergen Ara h 1 only unfolds after roasting peanuts to 140ºC for 15 minutes [231]. Thermal treatment of Ara h 2, the 2S albumin from peanuts, in the presence of reactive carbohydrates induces a strong increase of its IgE-binding activity [232].

One potential mechanism of action for the enhanced T cell immunogenicity of AGEs was suggested in an in vitro murine study [233]. Ovalbumin (OVA) specific CD4+ T cell activation was enhanced when myeloid dendritic cells (mDCs) were cocultured with OVA with AGEs compared with native OVA or OVA thermally processed without glucose. mDC uptake of OVA with AGEs was mediated by scavenger receptor class A type I and II that target the major histocompatibility complex (MHC) class II pathway.

Native Ara h 1 is glycosylated at two amino acid residues and undergoes spontaneous modifications through the Maillard reaction, which leads to the formation of AGEs, especially when roasted [234]. AGE modifications of the peanut cupin allergens Ara h 1 and Ara h 3 were found in both raw and roasted peanuts [235]. RAGE selectively interacted with AGE-modified Ara h 1 and Ara h 3 [235]. AGE-modified Ara h 1 was demonstrated to influence the proliferation of Caco-2 cells [236]. Carboxymethyl-lysine (CML) is a modification of lysyl residues in proteins following a Maillard reaction and has also been identified in Ara h 1 [235]. It was shown that CML can act to stabilize Ara h 1 antigenic peptides against digestion by intestinal trypsin and thus preserve IgE epitopes [237]. The immune reactivity of the hazelnut allergens Cor a 9, Cor a 11, and Cor a 14 remained stable after roasting at 140°C, while roasting at 170°C caused a reduction in IgE binding that led to an almost complete disappearance of allergenicity [37].

A study of beta-lactoglobulin (Bos d 5), one of the major cow's milk allergens, revealed that glycation reduced its transcytosis by a Caco-2 cell monolayer [238]. The uptake of glycated Bos d 5 by bone marrow-derived murine dendritic cells via scavenger receptor-mediated endocytosis was increased compared with native Bos d 5. However, glycated Bos d 5 showed a lower CD4+ T cell stimulatory capacity than native Bos d 5, although the response was still clearly T helper cell type 2 (Th2) biased.

SUMMARY

Overview – Many of the food allergen-containing protein families, and, consequently, their individual members, possess characteristic molecular features that enhance stability, thus promoting allergenicity. Structural and biochemical features of complete food allergens appear to contribute to provoking T helper cell type 2 (Th2) biased immune responses in predisposed persons by interacting with innate immune receptors. (See 'Introduction' above and 'Overview' above.)

Stability – The conformational stability of an allergenic food protein is important to its allergenicity. Several structural features are related to stability, including the presence of disulfide bonds, glycosylation, and structurally disordered protein regions. Highly repetitive linear epitopes are to some degree unaffected by heat denaturation and partial proteolysis and may also augment allergenicity. (See 'Protein stability' above.)

Interactions with lipid structures – Interactions with cell membranes and other lipid structures may increase allergen uptake in the gastrointestinal tract and may also delay or inhibit proteolytic degradation of allergens. (See 'Interaction with membranes and other lipid structures' above.)

Ligand binding – Certain food allergens are able to bind nonallergenic organic compounds or ions as ligands. Ligand binding often results in a decreased susceptibility to thermal and proteolytic denaturation. (See 'Ligand binding' above.)

Aggregation – Aggregation that occurs naturally or is induced by food processing most likely affects sensitization by enhancing immunogenicity. (See 'Formation of aggregates' above.)

Glycation – Glycation reactions may be responsible for the apparent increase in allergenic activity of certain foods following processes such as roasting. (See 'Glycation during roasting' above.)

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Topic 2387 Version 14.0

References

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