key: cord-0019878-drgxgqpc
authors: Chruszcz, Maksymilian; Chew, Fook Tim; Hoffmann‐Sommergruber, Karin; Hurlburt, Barry K.; Mueller, Geoffrey A.; Pomés, Anna; Rouvinen, Juha; Villalba, Mayte; Wöhrl, Birgitta M.; Breiteneder, Heimo
title: Allergens and their associated small molecule ligands—their dual role in sensitization
date: 2021-05-02
journal: Allergy
DOI: 10.1111/all.14861
sha: 4baade4aba7726453d02faa04a3bf0c96b0e0af2
doc_id: 19878
cord_uid: drgxgqpc

Many allergens feature hydrophobic cavities that allow the binding of primarily hydrophobic small‐molecule ligands. Ligand‐binding specificities can be strict or promiscuous. Serum albumins from mammals and birds can assume multiple conformations that facilitate the binding of a broad spectrum of compounds. Pollen and plant food allergens of the family 10 of pathogenesis‐related proteins bind a variety of small molecules such as glycosylated flavonoid derivatives, flavonoids, cytokinins, and steroids in vitro. However, their natural ligand binding was reported to be highly specific. Insect and mammalian lipocalins transport odorants, pheromones, catecholamines, and fatty acids with a similar level of specificity, while the food allergen β‐lactoglobulin from cow's milk is notably more promiscuous. Non‐specific lipid transfer proteins from pollen and plant foods bind a wide variety of lipids, from phospholipids to fatty acids, as well as sterols and prostaglandin B2, aided by the high plasticity and flexibility displayed by their lipid‐binding cavities. Ligands increase the stability of allergens to thermal and/or proteolytic degradation. They can also act as immunomodulatory agents that favor a Th2 polarization. In summary, ligand‐binding allergens expose the immune system to a variety of biologically active compounds whose impact on the sensitization process has not been well studied thus far.

The EAACI and WAO nomenclature task force has defined an allergen as an antigen that causes an allergic disease. 1, 2 The task force did not further characterize allergens as being either harmless or noxious environmental substances. Such a bias was intentionally avoided based on the fact that allergens can fall into either of these categories, or they may belong to two additional ones defined below. The vast majority of allergens induce the synthesis of specific IgE (sIgE) which depends on the Th2 polarization of naïve T helper cells during a type 2 immune response. While type 1 immune responses that target replicating microbial pathogens have been studied in great detail, elucidation of the mechanisms leading to type 2 immune responses to multicellular parasites, venoms, and allergens is lagging behind.

However, this area of research is starting to gain momentum. 3 The ability of an allergen to initiate the very first steps that will eventually result in a type 2 immune response can be based on its "rather harmless" interaction with innate immune receptors present on epithelial cells, as has been shown for invertebrate tropomyosins. 4 The interaction of an allergen with a host organism can also result in damage to innate receptors or other constituent parts of its cells. Such has been shown for airborne allergenic proteases from the mold Alternaria alternata or from house dust mite, which cause damage to the respiratory epithelium resulting in a type 2 immune response. 5 On the far end of the spectrum, allergenic toxins such as phospholipases A2 present in venoms of stinging and hematophagous insects or predatory animals can cause necrotic cell death that leads to the induction of a strong type 2 response. 6 There is another category of allergens that requires either components from the matrix 7 or bound ligands 8 to act as adjuvants and whose presence is essential for the induction of a type 2 immune response. 9 Certain lipids from the Brazil nut matrix are necessary for inducing signaling pathways that ultimately result in the synthesis of sIgE against the major Brazil nut allergen Ber e 1, a seed storage 2S albumin. 10 The major birch pollen allergen Bet v 1 by itself neither stimulated dendritic cells in vitro nor induced Th2 polarization in vivo; it required components from the pollen matrix present in a birch pollen extract to manifest a Th2 polarization. 11 Pru p 3, a nonspecific lipid transfer protein (nsLTP) and major allergen of peach, harbors a derivative of camptothecin bound to phytosphingosine as a ligand. 12 The phytosphingosine part of the ligand was responsible for the activation of antigen-presenting cells. 13 Moreover, mice exposed to Pru p 3 plus ligand developed more Pru p 3-sIgE than when exposed to Pru p 3 alone.

In addition to their immunological adjuvanticity, ligands can also increase the stability of allergens against proteolytic degradation.

The birch pollen-derived E1-phytoprostane, recently identified as another Bet v 1 ligand, was shown to enhance the resistance of Bet v 1 to the proteolytic processing by endolysosomal extracts, which was proposed to directly influence its allergenicity. 14 Likewise, the binding of fatty acids by the cockroach allergen Bla g 1 was found to significantly enhance the allergen's thermostability while inhibiting cleavage by cathepsin S, an endosomal protease essential for antigen processing and presentation. 15 These topics are discussed in more details below.

This review summarizes our current knowledge on allergenic proteins that bind small molecule ligands. It also gives an overview on which types of ligands may bind to allergens and what their role in inducing a type 2 response is or might be. Thus, the intention is to indicate new avenues of scientific inquiry into the sensitizing capacities of allergens that are neither damaging nor toxic to host cells by themselves (Box 1).

Serum albumins (SAs) are members of a highly conserved protein family that includes numerous allergens. [31] [32] [33] SAs are clinically relevant allergens that originate from animals, where they are major blood components. SAs are also present in milk, muscle, and epithelia. It was demonstrated that ~30% of individuals allergic to animal dander show IgE reactivity toward SAs. 34 A mature SA molecule is composed of approximately 585 amino acid residues that fold into three distinctive domains of similar size and whose structure is stabilized by several disulfide bridges (Figure 1, Equ c 3) . 35 The molecular architecture of SAs allows these molecules to adopt multiple conformations that facilitate simultaneous binding of various ligands (Figure 1 ), 36 making SAs highly capable smallmolecule carrier proteins. 37, 38 SAs bind many endogenous and exogenous compounds. 39 In addition, SAs play a very important role in the transport of metal cations. [40] [41] [42] Structural studies revealed the presence of many ligand-binding sites. Currently, nine fatty acidbinding sites have been identified, as well as several sites that are responsible for binding drugs and various metabolites or hormones. 43

• Availability of experimental molecular structures for a range of allergens with hydrophobic cavities 16, 17 • Establishment of biophysical and biochemical methods to study ligand-protein interaction and its impact on local structural changes [18] [19] [20] [21] [22] [23] • Identification of group 2 house dust mite (HDM) allergens as ligand-binding proteins 16, 17 • Discovery of the natural ligand of Bet v 1 [24] [25] [26] • Discovery of the natural ligand of Pru p 3 12

• Elucidation of the role of the phytosphingosin part of the Pru p 3 ligand in the sensitization process 27

• Discovery of Bla g 1 ligands 15, 28 • Discovery of the natural ligand of Cor a 1 29

• Allergens from the PR-10 family bind a broader spectrum of ligands in vitro than in vivo 25, 26, 30 • Ligand enhances proteolytic resistance of Bet v 1 and inhibits endolysosomal cathepsin S protease activity 14 The most relevant allergenic SAs originate from mammals and birds. 32 The allergenic mammalian SAs have very high sequence identities and similarities, cat and dog SAs being the most similar to the human homologue (approximately 83% identities). Even avian SAs display quite high sequence identities (>45%) and similarities (>60%) to human SA (HSA). Therefore, it is not surprising that SAs, due to their high sequence identities, show significant levels of cross-reactivity. 33, 41, 44 To date, there are eight SAs whose structures have been determined: bovine (BSA, Bos d 6), canine (CSA, Can f 3), equine (ESA, Equ c 3), feline (FSA, Fel d 2), HSA, goat (GSA), ovine (OSA),and rabbit (RSA). 35, 41, [45] [46] [47] [48] While the ligand-binding properties of human serum albumin are best studied, there is also a significant body of literature on interactions of small-molecule compounds with BSA and ESA. 39, 43, 49 Structural studies clearly show that SAs bind a broad spectrum of compounds that are biologically active, some of which may affect the human immune system. For example, SAs bind steroid hormones, saturated and unsaturated fatty acids, thyroxine, vitamin D, and flavonoid metabolites, as well as many exogenous compounds like drugs (Table 1) . [37] [38] [39] 43, [49] [50] [51] It was also shown that small-molecule compounds like carbohydrates may bind SAs through the amino groups of lysine residues that are located on the surface of these proteins. 49, 52 It was shown that derivatives of carbohydrates, such as the food additive D-mannitol, can form stable covalent derivatives with SAs, leading to the haptenization of these proteins. 52 In fact, Dmannitol is a member of a large group of small molecule compounds that form covalent bonds with proteins like SAs. The interaction of the small molecule compounds with SA does not always require an aqueous solution, but the proteins may be modified by compounds present in air. One such example is the modification of HSA by vapors of hexamethylene diisocyanate leading to immunogenic protein derivatives. 53 In summary, SAs are able to simultaneously bind many diverse compounds and it can be assumed that some small molecule compounds are always bound to these proteins. Therefore, the human immune system is exposed to SAs that are tightly associated with small molecules that may have immunomodulatory properties.

One may speculate that the small molecule binding properties of SAs are responsible for these proteins to potentially become allergens despite the fact that mammalian SAs are very similar to HSA. 33 

Class 10 pathogenesis-related proteins (PR-10s) are part of a plant's immune defense against pathogens or abiotic stress. 54,55 PR-10s include a wide variety of clinically relevant pollen and food allergens that possess a conserved three-dimensional structure. 29, 56, 57 Typically they contain a hydrophobic cavity which can accommodate different ligands (Table 1) . 56 PR-10s are formed by a sevenstranded antiparallel β-sheet and a long C-terminal α-helix enclosed by two shorter helices arranged in a V-shape ( Figure 2A ). 58 and Ara h 8.02. Although they share only 55% amino acid sequence identity, both were shown to bind the same small molecule ligands (apigenin, genistein, quercetin, daidzein, progesterone, arachidic acid, palmitic acid, and resveratrol; Table 1 ). 65 has the same overall fold as Bet v 1. 68, 69 The crystal structure of Act d 11 purified from its natural source revealed the presence of an unknown ligand that is likely to contain an indole or a similar ring structure. While the identity of the ligand is still unknown, Act d 11

should be considered a "dressed allergen" that carries small molecule compounds capable of interacting with the human immune system. 63 IgE-binding assays and mediator release assays with Bet v 1 variants showed no increased binding affinities in the presence of ligand. 14,26 Furthermore, no increased activation of dendritic cells could be observed. 14 However, pollen-derived ligands like phytoprostane E1 enhanced the thermostability of Bet v 1 and increased its proteolytic resistance against the endolysosomal proteases cathepsin S and legumain. 14 Preliminary data with Api g 1.0101 from celery indicated that the protease stability of Api g 1.0101 against trypsin was higher in the presence of the flavonoid aglycon apigenin. 70 It has been shown that increased thermostability affects immunogenicity and allergenicity. 71 

c It is not clear whether the ligand in the Rat n 1 structure (PDB code: 2AG2) was properly identified. Table 1 ).

The major function of lipocalins is to transport poorly water-soluble ligands. 75, 76 Over 20 lipocalin allergens have been characterized, the majority of which are respiratory allergens except for the food allergen Bos d 5. 73 Bos d 5 or β-lactoglobulin occurs at the high concentration of 0.1 mM in bovine milk. 77, 78 The ligand-binding specificity of Bos d 5

is not very high as many different ligands, primarily fatty acids, have been reported for this allergen. The binding affinity for short chain fatty acids is weak (K D s are in mM range) but affinity is higher for and prostaglandin B2 (PGB 2 ), among others (Table 1 ; Figure 4 ). 98, 99 Accordingly, the lack of ligand specificity of nsLTPs resides in the high plasticity and flexibility of their lipid-binding cavity, which is able to accommodate anything from one or two fatty acids to singleor double-chain lipids. 100 A considerable number of allergenic nsLTPs from pollen and plant foods have been identified. Pru p 3 from peach, the first identified allergenic LTP1, is regarded as a major allergen that affects more than 50% of peach allergic patients, inducing symptoms that range from mild to severe. 101 Pru p 3 displayed preferential binding to unsaturated short chain fatty acids such as oleic acid 27,102,103 and phytosphingosine. 13 A structural model was developed for Jug r 3, the LTP1 from walnut, by using an NMR interaction study and datadriven docking calculations to assess the effect of ligand binding of oleate. 104 Applying the WaterLOGSY NMR method, binding of oleic acid versus stearic acid was compared and the preferred binding of oleic acid was confirmed. Furthermore, the OLE-binding sites were identified including the C-terminal region of helix alpha 2, most of helix alpha 3,2 the loop between helices alpha 3 and alpha 4 and the C-terminal loop. Regarding the ligand its hydrophobic tail is inside the cavity, while the carboxylate part is surface exposed. Overall, the internal cavity from Jug r 3 seems to be flexible depending on the ligand binding. In that context, the C-terminal loop undergoes a conformational change upon lipid binding resulting to a more sur- proteins that form a single immunoglobulin-fold domain consisting of two three-stranded antiparallel β-sheets ( Figure 5A ). 17, [115] [116] [117] The X-ray crystal (but not the NMR) structure of Der p 2 revealed a large internal hydrophobic cavity, defined by the two β-sheets, that was able to bind lipidic ligands. 17, 116 Similarly for Der f 2, the separation and angle between the two sheets in the first NMR and crystal structures ("closed") 118,119 were narrower than those described in a more recent X-ray crystal structure ("open"). 120 Der f 2 was shown to bind LPS (lipopolysaccharide) with nanomolar affinity. 16 a physiological setting. Second, the mimicry study utilized a Der p 2 Y91A mutant that was claimed to abolish LPS binding. 125 This is unlikely to be highly effective as this residue is not highly conserved in mites. 16 Biochemical studies establishing the affinity of Der p 2 binding to TLR4 and the affinity of Der p 2 Y91A binding to LPS would be useful to understand the physiological relevance of the proposed mimicry.

In summary, these studies indicate that various hydrophobic ligands of mite group 2 allergens can be accommodated in the binding pocket via conformational changes, 16 The natural ligand for Der p 7 has not yet been identified, but the structural relation to a protein in the TLR pathway and the ability to bind bacterially derived lipid ligands are suggestive of a mechanism that would lead toward allergic sensitization to these proteins. This remains to be formally demonstrated for Der p 7.

Der p 13 ( Figure 5C ), which belongs to the fatty acid-binding protein (FABP) family, was shown to selectively bind fatty acids and induce airway epithelial cell activation in vitro through TLR2- 138 From an allergy standpoint, this is curious because Der p 13 is typically considered a minor allergen due to low prevalence of sIgE in mite-allergic patients. However, it is highly expressed at levels on par with the major allergen Der p 2, so it is likely an abundant mite protein. 139 The interpretation of these results appears to be that the binding and adjuvant properties of Der p 13 seem to be more consequential than the ability to stimulate IgE to itself.

Bla g 1 (Figure 5D ), also a lipid-binding protein, is not a major allergen for cockroach allergic patients, [140] [141] [142] as is the case for house dust mite (eg, Der p 1, Der p 2, and Der p 23) and birch pollen (eg, Bet v 1). 143 Bla g 1 is highly expressed in female cockroaches exclusively by midgut cells with a production that is modulated in relation to food intake. [144] [145] [146] A role of Bla g 1 in digestion and nutrient absorption has been suggested. 147 Bla g 1-encoding DNA has an interesting genetic structure. 148 Multiple tandem repeats of the gene are found in five different open reading frames, each with some homology to the currently described allergen. 149 It is currently not known whether all of these homologous proteins are allergens.

The protein structure of Bla g 1 corresponding to a tandem repeat is spherical with twelve α-helices that enclose a large cavity capable of enclosing up to four diacyl-phospholipids. 15, 28 Recombinant Bla g 1 contained a variety of phospholipids whose nature depended on the expression system ( Figure 5D ), whereas natural Bla g 1 bound a mixture of the fatty acids palmitate, oleate, and stearate. When loaded with these natural fatty acids, Bla g 1 was both more proteolytically resistant and thermally stable than when loaded with lipids with shorter or longer fatty acid chains. 150 The stabilizing effect of the ligands anticorrelated with the generation of known T-cell epitopes using an in vitro assay. 15 The implication is that the stabilizing property of the lipids could modulate the generation of T-cell epitopes and subsequent allergenicity. As precedent, isoforms of Bet v 1 that display enhanced stability are able to avoid premature processing in the endosome, yielding a stronger Th2 response than less allergenic variants. 71 This is a distinctly different role for the lipids in stabilizing Bla g 1, as opposed to the immunomodulatory properties of LPS, for example. It is possible that Bla g 1 ligands could also have immunomodulatory properties which have not been fully explored.

Lastly, Bla g 1 has a very high affinity for phosphatidylcholine (PC) that exceeds the affinity for the natural fatty acids. 15 

The fact that several types of allergens bind hydrophobic ligands has prompted the hypothesis that these ligands play a crucial role in inducing anallergic response. 8, 153 The binding of lipids to food allergens effects their degradation in the GI tract and their passage through epithelial barriers impacting on the sensitization process. 136 Len c 3, an nsLTP from lentils, otherwise sensitive to heating and digestion, increased its stability when binding lysopalmitoyl phosphatidylglycerol, a ligand-the authors argue-the allergen picks up during the cooking process. 154 The studies of the complex mixtures of molecules to which the human body and its immune system are exposed to are just starting. Therefore, we are convinced that not only allergenic proteins but also the small molecular compounds accompanying them play important and still not well-understood roles in allergic sensitization and diseases (Box 2).

The 

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How to cite this article: Chruszcz M, Chew FT, Hoffmann

Allergens and their associated small molecule ligands-their dual role in sensitization