Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Towards Defining Molecular Determinants Recognized by Adaptive Immunity in Allergic Disease: An Inventory of the Available Data

Towards Defining Molecular Determinants Recognized by Adaptive Immunity in Allergic Disease: An... Hindawi Publishing Corporation Journal of Allergy Volume 2010, Article ID 628026, 12 pages doi:10.1155/2010/628026 Research Article Towards Defining Molecular Determinants Recognized by Adaptive Immunity in Allergic Disease: An Inventory of the Available Data 1 1 1 1 1 1 Kerrie Vaughan, Jason Greenbaum, Yohan Kim, Randi Vita, Jo Chung, Bjoern Peters, 2 3 1 1 David Broide, Richard Goodman, Howard Grey, and Alessandro Sette The Immune Epitope Database (IEDB), La Jolla Institute for Allergy & Immunology (LIAI), La Jolla, CA 92037, USA School of Medicine, Allergy and Immunology, University of California, San Diego, La Jolla, CA 92093, USA Food Allergy Research and Resource Program, University of Nebraska-Lincoln, Lincoln, NE 68583, USA Correspondence should be addressed to Kerrie Vaughan, kvaughan@liai.org Received 6 December 2010; Accepted 20 December 2010 Academic Editor: Fabienne Rance´ Copyright © 2010 Kerrie Vaughan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Adaptive immune responses associated with allergic reactions recognize antigens from a broad spectrum of plants and animals. Herein a meta-analysis was performed on allergy-related data from the immune epitope database (IEDB) to provide a current inventory and highlight knowledge gaps and areas for future work. The analysis identified over 4,500 allergy-related epitopes derived from 270 different allergens. Overall, the distribution of the data followed expectations based on the nature of allergic responses. Namely, the majority of epitopes were defined for B cells/antibodies and IgE-mediated reactivity, and relatively fewer T-cell epitopes, mostly CD4 /class II. Interestingly, the majority of food allergen epitopes were B-cells epitopes whereas a fairly even number of B- and T-cell epitopes were defined for airborne allergens. In addition, epitopes from nonhumans hosts were mostly T-cell epitopes. Overall, coverage of known allergens is sparse with data available for only ∼17% of all allergens listed by the IUIS database. Thus, further research would be required to provide a more balanced representation across different allergen categories. Furthermore, inclusion of nonpeptidic epitopes in the IEDB also allows for inventory and analysis of immunological data associated with drug and contact allergen epitopes. Finally, our analysis also underscores that only a handful of epitopes have thus far been investigated for their immunotherapeutic potential. 1. Introduction significant incidence and are thus important component of allergic diseases in humans. These figures underscore the It is estimated that 50 million people in the US are affected growing societal impact of allergy-related disease both in by airborne allergens, including approximately 35 million terms of human suffering as well as annual cost burden. The immunological basis of allergy-related disease is affected by upper respiratory allergies (allergic rhinitis, hay fever and pollinosis) [1], and 16 million affected by asthma universally recognized. At the level of adaptive immunity, [2, 3]. The cost of allergies in the US (treatment and loss the recognition of specific allergens by antibodies and T cells plays major roles both as effectors and regulators of of work) is estimated to be more than $18 billion per year [4]. Food allergies, representing the second largest category allergic diseases. Several bioinformatics resources, cataloging after respiratory allergies, are thought to affect 6–8% of and describing allergen protein sequences, are available to the children and nearly 4% of adults. In the US, there are scientific community such as the Allergome,which provides ∼30,000 episodes of food-induced anaphylaxis, associated information on allergenic molecules causing IgE-mediated with 100–200 deaths per year [5, 6]. Finally, skin contact disease, and Allergen.org, which is the official site for the allergies and allergies to insect venoms also occur with systematic allergen nomenclature approved by the World 2 Journal of Allergy Health Organization and International Union of Immuno- assays, surface plasmon resonance (SPR), radio immunoas- logical Societies (WHO/IUIS) Allergen Nomenclature Sub- say (RIA), and X-ray crystallography, and describes epitope- related reactivity such as histamine release, hypersensitivity committee]. However, until recently, a resource describing (PCA), delayed-type hypersensitivity (DTH), and immun- the actual epitopes (defined as the molecular structures otherapy assays. coming in contact with antibodies or T-cell receptors), and All of the data described herein were captured directly the immunological events associate with epitope recognition, from the peer-reviewed literature (PubMed) by Ph.D. level was not available. scientists or through direct submission to the IEDB by The immune epitope database (IEDB) was created, to research groups. Antibody and T-cell epitope definitions provide the scientific community with a repository of freely (length and mass restrictions) as well as IEDB inclusion cri- accessible immune epitope data (http://www.immuneepi- teria can be found at http://tools.immuneepitope.org/wiki/ tope.org/). It contains data curated from published litera- index.php/Main Page. For the purpose of this report, the ture, -submitted by the NIAID’s high-throughput epitope total number of epitopes reported in each case represents the discovery projects, and imported from other databases. The total number of unique molecular structures experimentally database contains antibody and T-cell data for human, shown to react with a B- cell or T-cell receptor (no nonhuman primate, and rodent hosts, as well as a number predictions included). The IEDB captures these structures of other animal species, and targets epitopes associated as they are defined in the literature and thus includes with infectious diseases, autoimmunity, transplantation, and data describing structures categorized as minimal/optimal allergy. Data related to both peptidic and non-peptidic epitopes (11–15 resides), larger less well-defined regions epitopes are curated within the IEDB. (20–50 residues), and key residues identified as being Recently, curation of allergy-related references was com- involved in binding (1-2 residues). pleted, and as a result, close to 10,000 records, capturing 4,800 different epitopes, and the biological assays associated 2.2. Analysis Approach. The entirety of the allergy-related with their recognition have become available within the data identified as described above was first inventoried to IEDB. By analogy with what was done in the case of identify the total number of structures (positive and negative epitopes associated with influenza, tuberculosis, malaria, epitopes), their chemical nature (peptidic or non-peptidic), the total number of antibody/B-cell versus T-cell epitopes, and other diseases [7–9], herein we report the results of an in-depth analysis of all published immune epitope data as well as the effector cell phenotype or antibody isotype, and finally the total number of peer-reviewed references related to Allergy. This analysis provides an inventory of from which the data were derived. The second step involved epitope structures and associated data in order to enhance investigating the distribution of epitopes among hosts: those basic research and facilitate the development of therapeutics, epitopes defined in humans versus those identified using as well as diagnostics. The analysis also identified certain nonhuman animal models of allergy. In each case, the knowledge gaps and points to potential areas for future inventory of epitopes per host species included a breakdown study. according to reactivity: B cell (linear or conformational) or T cell (CD4, CD8 or unspecified). 2. Methods Following the initial inventory, the data were categorized according to the following established allergy categories: 2.1. Data Inclusion Criteria. This analysis includes data food, airborne (respiratory), contact, drug, and allergies to for antibody and T-cell epitopes associated with allergic biting insects. This categorization was based on the allergen disease in human and nonhuman (animal models) hosts. To and genus species of the organism from which the epitope identify within the IEDB the subset of data which is allergy was derived. These main categories were then further parsed related, we followed the process described in more detail into subcategories on the basis of taxonomic origins (plant, by Davies et al. [10]. More specifically, we define herein animal or fungus) and included a subcategory for the most allergy-related data on the basis of the source from which commonly encountered species in that main category. the epitope is derived (known allergen), and also on the The individual compounds representing drugs/pharma- basis of the type of response and/or clinical presentation. ceuticals were parsed into 21 subcategories on the basis of Accordingly, we included IgE-mediated, type I (immediate) its chemical type (e.g., beta-lactam antibiotic) or by the way hypersensitivity, atopic, “allergen-sensitization,” exposure- the compound is used to treat a particular condition (e.g., based asthma, allergic rhinitis, pollinosis, contact dermatitis, muscle relaxant). Contact allergen data were also further atopic dermatitis, documented anaphylaxis, and all data parsed into subcategories based on their species of origin from allergy-related animal models. (plants), chemical type (metals, model haptens), or mode of The allergy-related epitopes represent both peptidic as exposure (chemical agents from occupational exposure). well as non-peptidic structures from a wide range of sources, including pollens, dust mites, molds, dander and foods, non- 2.3. Computational Methods. The allergy-related data extra- proteinmoietiesofplants(carbohydrates),aswellasdrugs, cted from the IEDB (http://www.immuneepitope.org/)was haptens, metals, and chemical substances from occupational stored in a MySQL database. The use of MySQL allows for exposures. The curated data was obtained using a variety of the tailoring of database schema to the specific analysis and different assays, such as ELISA, Western blot, proliferation to keep the data synchronized with updates of the IEDB data Journal of Allergy 3 Table 1: Overview of allergy epitope data included in the IEDB. epitopes (both peptidic and non-peptidic) were defined for antibody responses, including both linear (∼3,000) and Category Total number conformational (or discontinuous) determinants (peptidic References 678 only) (Table 1). A total of 2,205 IgE epitopes were reported Epitopes (positive structures) 4,800 for all allergens, and less numerous other reactivities related Negative structures 4,137 to total IgG followed distantly by IgG1 IgG4, IgM, IgA, IgG2b, IgG3, IgG2a, and IgG2c (Table 2). As can be seen, Antibody/B cell 3,194 the majority of antibody determinants were defined in Linear natural peptides 2,730 humans. In animal models of disease, not only relatively Linear analogs/no natural source 163 fewer epitopes were defined, but only about 10% of them Discontinuous determinants 65 are epitopes recognized by IgE. This highlights a crucial T cell 1,646 knowledge gap and suggests that more research could be CD4 /Class II 1,530 directed at the definition of the epitopes recognized by IgE CD8 /Class I 17 in animal models of allergy. Unspecified 99 A relatively smaller number of T-cell epitopes have Unique allergens (peptidic/nonpeptidic) 550 been identified (1,646 epitopes) (Table 1). Of the T-cell epitopes defined in both peptidic and non-peptidic allergens, Source species 88 CD4 /Class II epitopes were most numerous, and far fewer Food allergy epitopes 2,322 (53%) CD8 /Class I epitopes were reported. Given their potential Airborne allergy epitopes 1,750 (40%) role in contact dermatitis and other delayed-type hypersen- Stinging insects epitopes 127 (3%) sitivity reactions, it is likely that more effort could be devoted Drug allergy epitopes 106 (∼2%) to the definition of class I epitopes. Supplementary Figure 1 Contact allergy epitopes 82 (∼2%) (see Figure s1 in supplementary material available on line at doi: 10.1155/2007/628026) provides a response summary for all epitope data. Table 2: Antibody isotype associated with epitope reactivity. The host distribution of epitopes can be found in Table 3. Not surprisingly, the vast majority of epitopes were defined Number of reactive epitopes Antibody isotypes in humans. However, epitopes were also described for mon- Overall Human Nonhuman keys, pigs, dogs, rabbits, guinea pigs, rats, and mice. Of the Allergy-specific IgE 2,205 2,135 70 nonhuman species, epitopes defined in mice represented the Other antibody reactivity second largest group. Within epitopes defined in mice, more IgG, unspecified 495 192 303 than 30 different strains were represented (data not shown). IgG1 132 0 132 BALB/c predominated, followed distantly by C57BL/6 and IgG4 72 72 0 C3H/He. Data from human HLA transgenic strains (HLA-A, DR4, DQ6, DQ8, and DR3-DQ2) were also reported. Table 1 IgM 50 32 18 also describes a breakdown of epitope numbers categorized IgG2b 10 0 10 as related to food allergies, airborne or respiratory allergies, IgA 5 0 5 allergies to stinging insects, drug allergies, and contact IgG3 5 2 3 allergies. Food allergens represent by far the largest group IgG2a 2 0 2 of data in the IEDB. There are currently 2,322 (53%) B- IgG2c 1 0 1 and T-cell epitopes identified from this group. After food allergens, epitopes defined for aeroallergens represent the second largest group, accounting for 40% of the records. To production database. Data were periodically checked against date, the database contains 125 antibody and T-cell epitopes the IEDB webpage using simple or advanced query interfaces related to the venom of stinging insects, which make up for consistency and accuracy. Results from each query 3% of the epitope total. Drug allergies account for ∼2% were exported as Excel files and further analyzed in that of epitopes. Contact allergies manifested through the skin format. Tables and figures were generated from Excel. Data account for ∼2% of allergy epitopes. The following sections exclusions included structures for which only MHC binding describe each epitope category in more detail. data were available, as well as those instances in which the epitope was simultaneously used as both immunogen and 3.2. Food Allergies. These include both peptidic and non- assay antigen. peptidic determinants derived from both plants and animals. The data have been parsed into three broad categories; most common food allergen sources, other plant, and other 3. Results animal species (Table 4). Peanut (Arachis hypogaea)allergens 3.1. Data Overview. An overview of all allergy-related data which comprise nearly 40% of the total plant allergen captured by our analysis is provided in Tables 1 and 2. epitopes. Epitopes described for food allergens derived from Consistent with the importance of immunoglobulin-related animals fall into six taxonomic categories. These include responses as effectors of allergy responses, the majority of mammals (human and cow milk, beef, beef gelatin), bony 4 Journal of Allergy Table 3: Host distribution for peptidic and non-peptidic epitopes. Allergic host All T cell CD4, class II CD8, class I All B cell Linear B cell Nonlinear Overall Peptidic epitopes Human 1,483 1,406 9 2,590 2,541 49 4,073 Animal models Japanese macaque 0 0 0 2 2 0 2 Pig 0 0 0 5 5 0 5 Dog 23 23 0 0 0 0 23 Rabbit 0 0 0 337 337 0 337 Rat 1 1 0 6 6 0 7 Mouse 304 271 6 388 357 31 692 Nonpeptidic epitopes Human 50 42 1 72 — — 122 Animal models Rabbit 0 0 0 36 — — 36 Guinea pig 8 0 0 12 — — 20 Rat 2 1 0 2 — — 4 Mouse 26 5 2 50 — — 76 fish (cod), bird (chicken eggs), mollusks (abalone and snails), broad taxonomic categories: insects (cockroach and midge), crustaceans (shrimp and prawns), and nematodes (fish meat arachnids (house dust mite, Storage mite, and Fodder mite), parasite). By far, the largest number of epitopes has been and mammals (cat, dog, horse, cow, rat, and mouse). Among identified for allergens related to cow’s milk allergy, followed the insects, epitopes derived from the midge are the most by epitopes defined from eggs, representing 70% and 20% of numerous, and within the Arachnid class, European house the total, respectively. Non-peptidic food epitopes reported dust mites are the most heavily studied. to date are comprised of carbohydrates derived from peanuts, Three non-peptidic determinants were described (see sugar beets, celery, and sea squirt (see also supplemental supplemental Table 6). These included α-L-Fuc-(1->3)-[α- Table 6). D-Man-(1->3)-[α-D-Man-(1->6)]-[β-D-Xyl-(1->2)]-β-D- According to the CDC [11], allergens derived from Man-(1->4)-β-D-GlcNAc-(1->4)]-D-GlcNAc from cedar milk, eggs, peanuts, tree nuts, fish, shellfish, soy, and wheat pollen, D-glucopyranuronic acid from the fungus Trichospo- account for 90% of all food allergies. The epitope data in ron cutaneum, and mono-β-arabinofuranose from mugwort general reflect this distribution. However, fewer epitopes pollen. In addition, a number of non-peptidic chemicals were identified from fish (only 10 epitopes for one species) were identified, including compounds causing respiratory and shellfish other than shrimp. Conversely, there was a symptoms following occupational exposure; toluene 2,4-di- surprising number of epitopes described from fruit allergens, isocyanate (TDI), toluene meta-diisocyanate, 4-tolyl isocy- namely peaches, apples, and bananas. This observation may anate, diphenylmethane-4,4-diisocyanate, hexameth-ylene reflect the involvement of these species in the oral allergy diisocyanate, phenyl isocyanate, phthalic anhydride, and syndrome (OAS) or pollen-food allergy and cross-reactions trimellityl group (data not shown). between foods (fruits, nuts) and inhaled allergens [12–15]. Here again, the epitope data reflects the overall trends related to airborne allergy. Grass, tree, and weed pollen 3.3. Airborne Allergies. Epitopes defined for aeroallergens epitopes represent the majority of the data (∼60%), followed represent the second largest group within the IEDB, account- by pet dander and house dust mite allergens. These findings ing for 40% of the records, including peptidic and non- are consistent with the overall prevalence of hay fever and/or peptidic determinants derived from plants, animals, fungal allergic rhinitis in the general population, affecting some 18 allergens, and some industrial chemical agents. Here, the million people annually [16]. Perhaps somewhat unexpected, data was parsed into the categories of most common was the fairly low number of epitopes defined for cat airborne sources, other plant, fungal, and animal species allergens. Interestingly, the majority of food allergen epitopes (Table 5). Epitopes identified from pellitory pollen, as well as were B-cells epitopes (86%) whereas a fairly even number of those from birch and Japanese cedar pollen, are numerous. B (43%) and T-cell (57%) epitopes were defined for airborne Epitopes reported for grass pollens come primarily from allergens (data not shown). Timothy grass, ryegrass species, and Kentucky blue grass. In the taxonomic grouping representing fungi, which 3.4. Allergies to Stinging Insects. To date, the IEDB contains includes yeasts and molds, epitopes identified in antigens 125 antibody and T-cell epitopes related to the venom of from Aspergillus species dominate (70%). Finally, epitopes stinging insects (Table 6). These include honeybee (Apis derived from aeroallergens from animals fall into three mellifera), bald-faced hornets (Dolichovespula maculate), Journal of Allergy 5 Table 4: Epitope data related to food allergy. Genus species have been modified to match IUIS usage. Synonyms for querying the IEDB: tomato (Solanum lycopersicum) and brown shrimp is (Farfantepenaeus aztecus). Non- CD4/class CD8/class Linear B Total Category All T cell All B cell linear B II I cell epitopes cell Common food allergen sources Cow’s milk (Bos domesticus) 90 90 0 661 659 2 751 Peanut (Arachis hypogaea) 26 26 0 337 337 0 363 Egg (Gallus domesticus) 75 59 1 150 149 1 225 Common wheat (Triticum aestivum) 0 0 0 128 127 1 128 Soybean (Glycine max) 1 1 0 71 71 0 72 Hazelnut (Corylus avellana) 27 27 0 27 27 0 54 Brown shrimp (Penaeus aztecus) 0 0 0 53 53 0 53 Cashew (Anacardium occidentale) 0 0 0 27 27 0 27 Common walnut (Juglans regia) 0 0 0 27 27 0 27 Sesame seed (Sesamum indicum) 0 0 0 11 11 0 11 Baltic cod (Gadus callarias) 0 0 0 10 10 0 10 Brazil nut (Bertholletia excelsa) 0 0 0 7707 Other plant species Peach (Prunus persica) 43 43 0 15 15 0 58 Banana (Musa acuminata) 1 1 0 51 51 0 52 Buckwheat (Fagopyrum esculentum) 0 0 0 39 39 0 39 Apple (Malus x domestica) 1 1 0 27 24 3 28 Celery (Apium graveolens)14 0 0 0 0 0 14 Muskmelon (Cucumis melon) 0 0 0 12 12 0 12 Oriental mustard (Brassica juncea) 0 0 0 9909 Rice (Oryza sativa japonica) 0 0 0 5505 American plum (Prunus armeniaca) 0 0 0 4404 European plum (Prunus domestica) 0 0 0 4404 Chinese date (Ziziphus mauritiana) 0 0 0 4404 Sweet cherry (Prunus avium) 1 0 0 3034 Common oat (Avena sativa) 4 4 0 0004 Tomato (Lycopersicum esculentum) 0 0 0 2202 Yellow mustard (Sinapis alba) 0 0 0 2112 Chinese cucumber (Trichosanthes kirilowii) 0 0 0 1101 Goat grass (Aegilops markgrafii) 1 1 0 0001 Naked oats (Avena nuda) 1 1 0 0001 Mango (Mangifera indica) 0 0 0 1101 Other animal species Beef (Bos domesticus) 2 2 0 10 10 0 12 Human breast milk (H. sapiens) 0 0 0 6606 Cow gelatin (Bos domesticus) 0 0 0 3303 Horned turban snail (Turbo cornutus) 0 0 0 2202 Red abalone (Haliotis rufescens) 0 0 0 1011 Fish nematode (Anisakis simplex) 0 0 0 1101 black-bellied hornets (Vespa basalis), common wasps Surprisingly, only 2 B-cell epitopes for ant venom, (Vespula vulgaris), and ants (Myrmecia pilosula). Of these, 1 B-cell epitope for Black-faced hornets, and no antibody epitopes derived from honeybees represent the largest determinants for wasp venom were defined. There are portion, followed by wasps and bald-faced hornets. also two non-peptidic determinants for antibody reactivity 6 Journal of Allergy Table 5: Epitope data related to Airborne/Respiratory Allergy. Genus species have been modified to match IUIS usage. Synonyms for querying the IEDB: Arizona cypress (Hesperocyparis arizonica). Non- CD4/class CD8/class Linear B Total Category All T cell All B cell linear B II I cell epitopes cell Common airborne allergen sources Birch tree (Betula verrucosa) 175 167 0 36 30 6 211 Japanese cedar (Cryptomeria japonica) 181 180 0 19 19 0 200 European house dust mite (D. pteronyssinus) 104 87 2 53 39 14 157 Mold (Aspergillus fumigatus) 16 16 0 115 111 4 131 Timothy grass (Phleum pratense) 72 71 1 49 48 1 121 Perennial ryegrass (Lolium perenne) 69 60 0 36 32 4 105 Midge (Chironomus thummi thummi) 30 30 0 60 60 0 90 Olivetree(Olea europaea)14 0 0 65 65 0 79 Cat (Felis catus) 48 46 0 18 18 0 66 Japanese cypress (Chamaecyparis obtusa)62 60 0 1 1 0 63 Spreading pellitory (Parietaria judaica) 1 1 0 61 60 1 62 Kentucky bluegrass (Poa pratensis)18 0 0 34 34 0 52 Cereal rye (Secale cereale) 0 0 0 51 51 0 51 Dog (Canis lupus familiaris)50 50 0 0 0 0 50 American house dust mite (D. farinae) 36 36 0 12 9 3 48 Mold (Penicillium chrysogenum) 0 0 0 45 44 1 45 Horse (Equus caballus)42 42 0 1 0 1 43 Bermuda grass (Cynodon dactylon)23 23 0 3 3 0 26 Annual ragweed (Ambrosia artemisiifolia) 12 12 0 13 13 0 25 Other plant species Common wormwood (Artemisia vulgaris)19 19 0 0 0 0 19 Sunflower (Helianthus annuus) 0 0 0 18 18 0 18 Common velvet grass (Holcus lanatus) 0 0 0 14 14 0 14 Ashe juniper tree (Juniperus ashei) 0 0 0 13 13 0 13 Great ragweed (Ambrosia trifida) 5 5 0 0005 Loblolly pine tree (Pinus taeda) 0 0 0 4404 Lichwort (Parietaria officinalis) 0 0 0 2202 Mouse ear cress (Arabidopsis thaliana) 2 2 0 0002 Queen Anne’s Lace (Daucus carota) 1 0 0 0001 Elegant zinnia (Zinnia violacea) 1 1 0 0001 Tobacco (Nicotiana tabacum) 0 0 0 1101 Tall fescue grass (Festuca arundinacea) 0 0 0 1101 Arizona cypress tree (Cupressus arizonica) 0 0 0 1101 Formosan juniper tree (Juniperus formosana) 0 0 0 1101 Other fungal species Alternaria alternata 00 0 5 5 0 5 Malassezia sympodialis 00 0 1 0 1 1 Candida albicans 00 0 1 1 0 1 Paracoccidioides brasiliensis 10 0 0 0 0 1 Aspergillus restrictus 00 0 1 1 0 1 Other animal species Rat (Rattus norvegicus)19 0 0 4 4 0 23 Storage mite (Blomia tropicalis) 0 0 0 18 16 2 18 Fodder mite (Lepidoglyphus destructor)10 10 0 5 5 0 15 German cockroach (Blattella germanica)9 9 0 5 3 2 14 Journal of Allergy 7 Table 5: Continued. Non- CD4/class CD8/class Linear B Total Category All T cell All B cell linear B II I cell epitopes cell Cow dander (Bos domesticus)8 8 0 2 0 2 10 Mayne’s house dust mite (Euroglyphus maynei)10 0 0 0 0 0 10 American cockroach (Periplaneta americana) 0 0 0 9819 Mouse (Mus musculus) 4 2 0 4408 Table 6: Epitope data related to stinging insects. CD4/class CD8/class Linear B Non-linear Total Allergen source All T cell All B cell II I cell Bcell epitopes Allergen source species Honey bee (Apis mellifera) 48 470 7 5 255 Jack jumper ant (Myrmecia pilosula) 0 002202 Black-bellied hornet (Vespa basalis) 0 001101 Common wasp (Vespula vulgaris) 36 360 0 0 036 Bald-faced hornet (Dolichovespula maculata) 20 17 0 11 11 0 31 Table 7: Summary of allergen coverage. This table provides a 3.6. Contact Allergies. Thus far, more than 80 contact comparison of the total number of allergens designated by the IUIS allergens have been captured by the IEDB, as summarized and housed within database Allergen.org that match the allergy- in Figure 2. Epitopes identified from latex-allergic indi- related species reported in the IEDB. viduals represent the largest number of contact allergen determinants, making up 59% of the total. A total of Allergy category Allergen.org IEDB Percent coverage reported 207 latex epitopes include both linear and nonlinear Food 86 39 45% antibody epitopes,aswellasT-cellepitopes,primarily of the Airborne or Respiratory 184 65 35% CD4 /class II phenotype. Stinging insects 14 6 43% Three additional categories of contact allergens include Contact 13 5 38% non-peptidic entities such as metals, industrial chemicals 297 115 39% encountered by way of occupational exposure, and model haptens. A total of seven different metals described as associated with allergic contact dermatitis include to honey bee venom. These include α-1,3-fucose and an beryllium (beryllium sulfate tetrahydrate, beryllium sulfate), N(4)-[α-L-fucosyl-(1->3)-N-acetyl-4-O-glycosyl-D-glucos- chromium (chromium trichloride), cobalt (cobalt dichlo- aminyl]-L-asparagine residue (see supplemental Table 6). ride), copper (copper sulfate, copper chloride), nickel (nickel chloride, nickel sulfate) palladium (palladium chloride), and 3.5. Drug Allergies. The IEDB currently contains curated zinc chloride. Of these, no single metal entity stands predom- data relating to immunological reactions to more than 90 inates, and as a group metals comprise only 7% of the contact different drugs associated with allergic disease. In most allergens. Beryllium, chromium, zinc chloride, and cobalt cases, the authors do not identify the exact reactive moiety are most often encountered in the industrial/manufacturing setting, whereas nickel, copper, and palladium allergies of these non-peptidic chemical entities because the assays are carried out using the intact drug. These drugs can are most frequently associated with jewelry. Furthermore, be further classified into 21 categories based primarily on the IEDB contains curated data relating to more than biological function and structure (Figure 1). These include 70 compounds utilized in the manufacture of cosmetics, beta-lactam antibiotics (the penicillins), barbiturate anes- dyes, and certain constituents of manufacturing. A very thetics, bactericidal/antimicrobial, muscle relaxants, anti- large number of curated assays relate to model haptens, hypertensive, antiparasitic drugs, neurotransmitters, sulfa- which include skin sensitizers such as trinitrophenyl (TNP), based antibiotics, local anesthetics, hormones, antifibrinolyt- dinitrophenyl (DNP), 1-fluoro-2,4-dinitrobenzene (DNFB), and dinitrochlorobenzene (DNCB). These compounds have ics, antiemetics, antihistamines, antipsychotics, antitussives, muscle stimulants, opiates, radiocontrast media, spermi- been used classically to define mechanisms of type IV contact cides, and a vasoactive agonist. Antibiotics as a whole hypersensitivity. Of these, DNCB appears to have received comprise nearly half (49%) of the reported drug allergens, the greatest focus. A detailed list of all contact allergens can with the vast majority of which are beta-lactam antibiotics. be found in supplemental Table 1. 8 Journal of Allergy 1% 1% 1% 1% 1% 1% 1% 2% 1% 2% 3% 2% 2% 2% 2% 3% 52% β-lactam 3% 6% 6% 10% β-lactam antibiotic (64) Barbiturate anesthetic (12) Bactericidal/antiseptic (7) Muscle relaxant (7) Anti-hypertensive (4) Anti-parasitic (4) Neurotransmitter (3) Sulfa-based antibiotic (3) Local anesthetic (2) Hormone (2) Anti-fibrinolytic (1) Antiemetic (1) Antihistamine (1) Anti-psychotic (2) Anti-tussive (1) Muscle stimulant (1) Opiate (1) Radiocontrast media (2) Figure 1: Drug allergens by functional category. Determinants identified under this category have been broadly classified into 21 groups according to their overall biological functional. The chart presents these data as percentages with the total number of unique assays in parentheses. 3.7. Epitope Distribution by Allergen. As a further evaluation, a few of the known allergens (e.g., 6/29 Der p and Der f we determined the relative epitope distribution by allergen allergens for house dust mite), whereas other species have for each source species (supplementary Tables 2–5). The total intermediate distribution (e.g., 4/6 Lol p allergens from rye number of epitopes described per allergen varies greatly, and grass) (Table 7). Furthermore, when we compared the total well-known allergens (e.g., Ara h 1, Bet v 1, or Phl p 1) tended number of allergens in the IUIS that match the allergy- to have greater numbers of defined epitopes compared to related species reported in the IEDB, we find that ∼40% of other allergens from the same organism (e.g., seed storage the IUIS-designated allergens are represented in the epitope protein SSP2, Bet v 2, Bet v 4, Phl p 2, or Phl p 11). Similarly, data (115 out of 297). However, for an additional 380 the total number of T-cell versus B-cell epitopes varied known IUIS allergens, no match could be found between greatly, with the vast majority of allergens heavily weighted the species in the IUIS and the species described in the toward one or the other phenotype and few having a relative papers in the scientific literature describing specific epitopes. balance of defined B and T epitopes (data not shown). Many of these include organisms from known genera, but Next, we analyzed the extent to which the allergens with as yet nonlisted species, as well as other nomenclature comprising the epitope-related data represent all known inconsistencies. These results suggest that more efforts can allergens, as listed by the Allergen.org resource, the official site be devoted to reconciling the origin of allergen-derived data. for the systematic allergen nomenclature (Linnean system) that is approved by the World Health Organization and Inter- 3.8. Epitopes Associated with Clinical Disease or Disease national Union of Immunological Societies (WHO/IUIS) Models. Isolated epitopes can be utilized to induce or Allergen Nomenclature Sub-committee. This site maintains modulate allergic reactions in animal models. The use a list of all currently known (described) allergens derived of synthetic epitopes to modulate allergic reactions has from plant, animal, and fungal species. We found that total also been proposed and tested in a limited number of number of allergens from which epitope data have been clinical trials [17, 18]. Indeed, the epitopes defined in the described varies from one allergen source to another. In some course study of human allergic conditions may enable the instances, epitope data is comprehensive, showing epitope investigation of their potential in the immunotherapeutic data for all allergens identified by the IUIS list for a given setting. species (e.g., 9/9 Phl p allergens for timothy grass). However To inventory which epitopes had been tested in these in other cases, allergen distribution is low, showing only settings, we queried for antibody and T-cell epitopes that Journal of Allergy 9 Table 8: Epitopes associated with modulation of allergic disease. Epitope name Epitope sequence Host Response Allergy model Bermuda grass Cyn d 1 (127–146) KAGELTLQFRRVKCKYPSGT Human T cell, DCP pollen Bermuda grass Cyn d 1 (19–38) LEAKATFYGSNPRGAAPDDH Human T cell, DCP pollen Bermuda grass Cyn d 1 (154–173) KGSNDHYLALLVKYAAGDGN Human T cell, DCP pollen Bermuda grass Cyn d 1 (136–155) RRVKCKYPSGTKITFHIEKG Human T cell, DCP pollen Bermuda grass Cyn d 1 (28–47) SNPRGAAPDDHGGACGYKDV Human T cell, DCP pollen Bermuda grass Cyn d 1 (82–101) VECSGEPVLVKITDKNYEHI Human T cell, DCP pollen Bermuda grass Cyn d 1 (227–246) VIPANWKPDTVYTSKLQFGA Human T cell, DCP pollen Bermuda grass Cyn d 1 (91–110) VKITDKNYEHIAAYHFDLSG Human T cell, DCP pollen Bermuda grass Cyn d 1 (73–92) CYEIKCKEPVECSGEPVLVK Human T cell, DCP pollen Fel d 1 IPC-2 KALPVVLENARILKNCVDAKMTEEDKE Human T cell, LSC, NSC Cat allergy Fel d 1 IPC-1 KRDVDLFLTGTPDEYVEQVAQYKALPV Human T cell, LSC, NSC Cat allergy peptide 4 (P93-110) TKCYKLEHPVTGCGERTE Human T cell, CLPR Honey bee sting peptide 1 (P81-98) YFVGKMYFNLIDTKCYKL Human T cell, CLPR Honey bee sting Bet v 1 SKEMGETLLRAVESYLLAHSD Mouse B cell, AWI Birch pollen Der p 1 111–139 FGISNYCQIYPPNANKIREALAQPQRYCR Mouse T cell, DTP European HDM Der p 1 113–127 ISNYCQIYPPNANKI Mouse T cell, DTP European HDM Der p I (101–154) QSCRRPNAQRFGISNYCQIYPPNVNKIREALAQTHSAIAVIIGIKDLDAFRHYD Mouse T cell, DTP European HDM Der p 1 110–131 RFGISNYCQIYPPNANKIREAL Mouse T cell, DTP European HDM Der p I 114–129 SNYCQIYPPNANKIR Mouse B cell, DTH European HDM Der p 2 87–129 DIKYTWNVPKIAPKSENVVVTVKVMGDDGVLACAIATHAKIRD Mouse B cell, BPR, AWI European HDM Der p I (98–140) AREQSCRRPNAQRFGISNYCQIYPPNVNKIREALAQTHSAIAV Mouse T cell, DTP European HDM Api m 4 7–19 KVLTTGLPALISW Mouse B cell, IgG1 Honey bee sting Dol m 5 176–195 IEDNWYTHYLVCNYGPGGND Mouse B cell, IgG1 Hornet sting Dol m 5 41–60 KNEILKRHNDFRQNVAKGLE Mouse T cell, DTP Hornet sting Dol m 5 141–160 NYKVGLQNSNFRKVGHYTQM Mouse T cell, DTP Hornet sting 10 Journal of Allergy Table 8: Continued. Epitope name Epitope sequence Host Response Allergy model Japanese cedar Cry j 2 247–258 AEVSYVHVNGAK Mouse B cell, CSI pollen Japanese cedar Cry j 2 P2 246–259 RAEVSYVHVNGAKF Mouse T cell, NS pollen Ole 1 109–130 TVNGTTRTVNPLGFFKKEALPK Mouse B cell, AWI Olive tree pollen Timothy grass Phl p 5 peptide YAATVATAPEVKYTVFETALKKAI Mouse B cell, AWI pollen Timothy grass Phl p 1 peptide LRSAGELELQFRRVKCKYPEG Mouse B cell, AWI pollen Betv1/Phlp1/Phl p MGETLLRAVESYAGELELQFRRVKCKYTVATAPEVKYTVFETALK Mouse B cell, AWI Tree/Grass pollen 5hybrid PI-1 IgECHε2 LYCFIYGHI Mouse T cell, PCA Mouse (109-117) nOVA 173–196 VLVNAIVFKGLWEKAFKDEDTQAM Rat B cell, PCA Chicken Egg OVA (257–264) SIINFEKL Mouse T cell, AWI Asthma OVA (323–339) ISQAVHAAHAEINEAGR Mouse T cell, AWI Asthma HDM: house dust mite. Mouse strains consisted of BALB/c and C57BL/6. Rats were Norway strain. AWI: airway inflammation (histology). NS: nasal symptoms (sneezing and rubbing). CSI: cytokine suppression of allergen-IgE production. BPR: bronchopulmonary resistance. DTH: delayed type hypersensitivity. LSC: lung score. NSC: nasal score. CLPR: cutaneous late-phase reaction. DTP: decrease allergen-specific T cell proliferation. DCP: decreased allergen-specific cytokine production. Journal of Allergy 11 related to the study of allergic reactions in humans, and fewer epitopes defined for mice and occasional epitopes defined for 24, 7% other hosts such as monkeys, pigs, dogs, rabbits, guinea pigs, and rats. The majority of peptidic epitopes were defined for foods (cow’s milk, wheat, peanuts) and plants (tree and grass 47, 13% pollens), while the majority of non-peptidic epitopes defined for drugs and biologicals (antibiotics). Interestingly, the vast majority of food allergen-related 207, 59% epitopes were described for B-cells, whereas a fairly even number of B- and T-cell epitopes were defined for airborne 73, 21% allergens. It is not clear why this is the case but may have to do with historical analysis of allergies to foods such as milk, peanuts, and eggs which represent a large portion of that data. The distribution of epitopes varies greatly between allergen and species. This observation suggests that definition of T-cell epitopes involved in food allergies is lacking and could be the focus of further experimental investigations. Latex Another unexpected finding of our analysis was that the Occupational Haptens epitopes defined in hosts other than humans were mostly T- Metals cell epitopes, and far fewer antibody epitopes were defined. While it is surprising that so little of the nonhuman antibody Figure 2: Categories of contact allergen epitopes. The chart pro- responses are allergy-specific IgE; this may point to an vides a broad overview of the contact allergen epitope distribution. important area for experimental investigation, to provide investigators with animal models faithfully reproducing human allergic reactions. were tested either in vivo for their ability to decrease The current analysis also revealed that coverage of known allergic reactivity in vivo (as measure by the reduction of human allergen by epitope definition studies is very sparse. symptoms) and for those that were shown to decrease in The overall completeness of the epitope-specific allergy data vitro markers of allergic disease. This is done by selecting with respect to known allergens on a species basis is about all B-cell or T-cell contexts designated in the IEDB as assay 40%. Furthermore, epitope data is available for only ∼17% of type equals “Reduction of Disease after Treatment” (B cell) all allergens listed by IUIS. For certain species, the majority or “Treatment” (T cell). Here, the assay type assigned by (if not all) of the known allergens have epitope-related the IEDB indicates the nature of the immune response, data (e.g., timothy grass allergens), while other species have and the details of the type of assay used (lung function, epitope data from only a small number of known allergens DTH, PCA, etc.) can be found within the curated data (e.g., apple). from the assay comments field. Table 8 shows the PubMed The recent completion of curation of non-peptidic identification, epitope name, epitope sequence, the host, the allergy-related epitopes in the IEDB allows a first time inven- type of response, and allergy model classification for peptidic tory and assessment of important drug and contact allergens. epitopes identified from the data as having a positive effect on The integration within the IEDB of representation and disease in vivo or on markers of disease as measured in vitro. search capabilities based on the chemical entity of biological interest (ChEBI) (http://www.ebi.ac.uk/chebi/) database will further enable the scientific community to quickly retrieve 4. Discussion and analyze the immunological data associated with these The analysis presented herein identified over 4,500 allergy- important classes of allergens. related epitopes derived from 270 different allergens. Pro- Finally, our analysis also inventoried which epitopes have been used to actively induce allergic disease in animal models tein allergens were categorized according to their source organism, which included plants, animals, insects, parasites, or to modulate disease. Only a handful of epitopes have and fungi. Non-peptidic allergens were categorized into been investigated for their immunotherapeutic potential. If the promising results from human clinical trials were to four groups including drugs and biologicals, industrial compounds, or those related to occupational exposure, be verified in later phase trails, we anticipate that the data metals, model haptens, and carbohydrates from plants. cataloged within the IEDB might provide a wealth of leads Overall, the distribution of the data follows expectations for therapeutic intervention regimens. based on the nature of adaptive responses involved in allergy. Namely, the vast majority of allergy epitopes were defined Acknowledgments for B cells/antibodies (and in these records, IgE-mediated reactivity figured prominently), and relatively fewer T-cell We gratefully acknowledge the helpful contribution of epitopes (mostly defined as CD4 /class II, with very few Alison Deckhut, Matthew Fenton, and Michael Minnicozzi being defined for CD8 /class I). Likewise, most of the records in reviewing this paper. The La Jolla Institute of Allergy 12 Journal of Allergy and Immunology is supported by the National Institutes of Health National Institute of Allergy and Infectious Diseases, Allergy Contract no. HHSN272200700048C, and HHSN26620040006C under the Immune Epitope Database and Analysis Program. References [1] Airborne Allergens: something in the air, http://www.niaid .nih.gov/topics/allergicDiseases/Documents/airborne allerg- ens.pdf. [2] Asthma, http://www.cdc.gov/nchs/fastats/asthma.htm. [3] Asthma, http://www.who.int/mediacentre/factsheets/fs307/en /index.html. [4] Allergic diseases, http://www.niaid.nih.gov/topics/allergicDi- seases/Pages/introductionGoals.aspx. [5] Food allergy, http://www.niaid.nih.gov/topics/foodallergy/un- derstanding/pages/quickfacts.aspx. [6] CDC Study Finds 3 Million U.S. Children have Food or Digestive Allergies, http://www.cdc.gov/media/pressrel/2008/ r081022.htm?s cid=mediarel r081022 x. [7] H. H. Bui, B. Peters, E. Assarsson, I. Mbawuike, and A. Sette, “Ab and T cell epitopes of influenza A virus, knowledge and opportunities,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 1, pp. 246–251, [8] M. J. Blythe, Q. Zhang, K. Vaughan et al., “An analysis of the epitope knowledge related to Mycobacteria,” Immunome Research, vol. 3, no. 1, article no. 10, 2007. [9] K. Vaughan, M. Blythe, J. Greenbaum et al., “Meta-analysis of immune epitope data for all Plasmodia: overview and applications for malarial immunobiology and vaccine-related issues,” Parasite Immunology, vol. 31, no. 2, pp. 78–97, 2009. [10] V. Davies, K. Vaughan, R. Damie, B. Peters, and A. Sette, “Classification of the universe of immune epitope literature: representation and knowledge gaps,” PLoS ONE,vol. 4, no.9, article no. e6948, 2009. [11] Food allergies, http://www.cdc.gov/healthyyouth/foodaller- gies/. [12] S. J. Maleki, A. W. Burks, and R. M. Helm, Food Allergy,ASM Press, Washington, DC, USA, 2006. [13] S. H. Sicherer and D. Y. M. Leung, “Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects,” Journal of Allergy and Clinical Immunology, vol. 119, no. 6, pp. 1462–1469, 2007. [14] S. H. Sicherer, A. Munoz-Furlong, and H. A. Sampson, “Prevalence of peanut and tree nut allergy in the United States determined by means of a random digit dial telephone survey: a 5-year follow-up study,” Journal of Allergy and Clinical Immunology, vol. 112, no. 6, pp. 1203–1207, 2003. [15] S. H. Sicherer, “Clinical implications of cross-reactive food allergens,” Journal of Allergy and Clinical Immunology, vol. 108, no. 6, pp. 881–890, 2001. [16] Allergies and hay fever, http://www.cdc.gov/nchs/fastats/aller- gies.htm. [17] M. Larche, ´ “Peptide immunotherapy for allergic diseases,” Allergy, vol. 62, no. 3, pp. 325–331, 2007. [18] M. Larche, ´ “Update on the current status of peptide immunotherapy,” Journal of Allergy and Clinical Immunology, vol. 119, no. 4, pp. 906–909, 2007. MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Allergy Hindawi Publishing Corporation

Towards Defining Molecular Determinants Recognized by Adaptive Immunity in Allergic Disease: An Inventory of the Available Data

Download PDF
13 pages

Loading next page...
 
/lp/hindawi-publishing-corporation/towards-defining-molecular-determinants-recognized-by-adaptive-DQqC40S8K5
Publisher
Hindawi Publishing Corporation
Copyright
Copyright © 2010 Kerrie Vaughan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN
1687-9783
DOI
10.1155/2010/628026
Publisher site
See Article on Publisher Site

Abstract

Hindawi Publishing Corporation Journal of Allergy Volume 2010, Article ID 628026, 12 pages doi:10.1155/2010/628026 Research Article Towards Defining Molecular Determinants Recognized by Adaptive Immunity in Allergic Disease: An Inventory of the Available Data 1 1 1 1 1 1 Kerrie Vaughan, Jason Greenbaum, Yohan Kim, Randi Vita, Jo Chung, Bjoern Peters, 2 3 1 1 David Broide, Richard Goodman, Howard Grey, and Alessandro Sette The Immune Epitope Database (IEDB), La Jolla Institute for Allergy & Immunology (LIAI), La Jolla, CA 92037, USA School of Medicine, Allergy and Immunology, University of California, San Diego, La Jolla, CA 92093, USA Food Allergy Research and Resource Program, University of Nebraska-Lincoln, Lincoln, NE 68583, USA Correspondence should be addressed to Kerrie Vaughan, kvaughan@liai.org Received 6 December 2010; Accepted 20 December 2010 Academic Editor: Fabienne Rance´ Copyright © 2010 Kerrie Vaughan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Adaptive immune responses associated with allergic reactions recognize antigens from a broad spectrum of plants and animals. Herein a meta-analysis was performed on allergy-related data from the immune epitope database (IEDB) to provide a current inventory and highlight knowledge gaps and areas for future work. The analysis identified over 4,500 allergy-related epitopes derived from 270 different allergens. Overall, the distribution of the data followed expectations based on the nature of allergic responses. Namely, the majority of epitopes were defined for B cells/antibodies and IgE-mediated reactivity, and relatively fewer T-cell epitopes, mostly CD4 /class II. Interestingly, the majority of food allergen epitopes were B-cells epitopes whereas a fairly even number of B- and T-cell epitopes were defined for airborne allergens. In addition, epitopes from nonhumans hosts were mostly T-cell epitopes. Overall, coverage of known allergens is sparse with data available for only ∼17% of all allergens listed by the IUIS database. Thus, further research would be required to provide a more balanced representation across different allergen categories. Furthermore, inclusion of nonpeptidic epitopes in the IEDB also allows for inventory and analysis of immunological data associated with drug and contact allergen epitopes. Finally, our analysis also underscores that only a handful of epitopes have thus far been investigated for their immunotherapeutic potential. 1. Introduction significant incidence and are thus important component of allergic diseases in humans. These figures underscore the It is estimated that 50 million people in the US are affected growing societal impact of allergy-related disease both in by airborne allergens, including approximately 35 million terms of human suffering as well as annual cost burden. The immunological basis of allergy-related disease is affected by upper respiratory allergies (allergic rhinitis, hay fever and pollinosis) [1], and 16 million affected by asthma universally recognized. At the level of adaptive immunity, [2, 3]. The cost of allergies in the US (treatment and loss the recognition of specific allergens by antibodies and T cells plays major roles both as effectors and regulators of of work) is estimated to be more than $18 billion per year [4]. Food allergies, representing the second largest category allergic diseases. Several bioinformatics resources, cataloging after respiratory allergies, are thought to affect 6–8% of and describing allergen protein sequences, are available to the children and nearly 4% of adults. In the US, there are scientific community such as the Allergome,which provides ∼30,000 episodes of food-induced anaphylaxis, associated information on allergenic molecules causing IgE-mediated with 100–200 deaths per year [5, 6]. Finally, skin contact disease, and Allergen.org, which is the official site for the allergies and allergies to insect venoms also occur with systematic allergen nomenclature approved by the World 2 Journal of Allergy Health Organization and International Union of Immuno- assays, surface plasmon resonance (SPR), radio immunoas- logical Societies (WHO/IUIS) Allergen Nomenclature Sub- say (RIA), and X-ray crystallography, and describes epitope- related reactivity such as histamine release, hypersensitivity committee]. However, until recently, a resource describing (PCA), delayed-type hypersensitivity (DTH), and immun- the actual epitopes (defined as the molecular structures otherapy assays. coming in contact with antibodies or T-cell receptors), and All of the data described herein were captured directly the immunological events associate with epitope recognition, from the peer-reviewed literature (PubMed) by Ph.D. level was not available. scientists or through direct submission to the IEDB by The immune epitope database (IEDB) was created, to research groups. Antibody and T-cell epitope definitions provide the scientific community with a repository of freely (length and mass restrictions) as well as IEDB inclusion cri- accessible immune epitope data (http://www.immuneepi- teria can be found at http://tools.immuneepitope.org/wiki/ tope.org/). It contains data curated from published litera- index.php/Main Page. For the purpose of this report, the ture, -submitted by the NIAID’s high-throughput epitope total number of epitopes reported in each case represents the discovery projects, and imported from other databases. The total number of unique molecular structures experimentally database contains antibody and T-cell data for human, shown to react with a B- cell or T-cell receptor (no nonhuman primate, and rodent hosts, as well as a number predictions included). The IEDB captures these structures of other animal species, and targets epitopes associated as they are defined in the literature and thus includes with infectious diseases, autoimmunity, transplantation, and data describing structures categorized as minimal/optimal allergy. Data related to both peptidic and non-peptidic epitopes (11–15 resides), larger less well-defined regions epitopes are curated within the IEDB. (20–50 residues), and key residues identified as being Recently, curation of allergy-related references was com- involved in binding (1-2 residues). pleted, and as a result, close to 10,000 records, capturing 4,800 different epitopes, and the biological assays associated 2.2. Analysis Approach. The entirety of the allergy-related with their recognition have become available within the data identified as described above was first inventoried to IEDB. By analogy with what was done in the case of identify the total number of structures (positive and negative epitopes associated with influenza, tuberculosis, malaria, epitopes), their chemical nature (peptidic or non-peptidic), the total number of antibody/B-cell versus T-cell epitopes, and other diseases [7–9], herein we report the results of an in-depth analysis of all published immune epitope data as well as the effector cell phenotype or antibody isotype, and finally the total number of peer-reviewed references related to Allergy. This analysis provides an inventory of from which the data were derived. The second step involved epitope structures and associated data in order to enhance investigating the distribution of epitopes among hosts: those basic research and facilitate the development of therapeutics, epitopes defined in humans versus those identified using as well as diagnostics. The analysis also identified certain nonhuman animal models of allergy. In each case, the knowledge gaps and points to potential areas for future inventory of epitopes per host species included a breakdown study. according to reactivity: B cell (linear or conformational) or T cell (CD4, CD8 or unspecified). 2. Methods Following the initial inventory, the data were categorized according to the following established allergy categories: 2.1. Data Inclusion Criteria. This analysis includes data food, airborne (respiratory), contact, drug, and allergies to for antibody and T-cell epitopes associated with allergic biting insects. This categorization was based on the allergen disease in human and nonhuman (animal models) hosts. To and genus species of the organism from which the epitope identify within the IEDB the subset of data which is allergy was derived. These main categories were then further parsed related, we followed the process described in more detail into subcategories on the basis of taxonomic origins (plant, by Davies et al. [10]. More specifically, we define herein animal or fungus) and included a subcategory for the most allergy-related data on the basis of the source from which commonly encountered species in that main category. the epitope is derived (known allergen), and also on the The individual compounds representing drugs/pharma- basis of the type of response and/or clinical presentation. ceuticals were parsed into 21 subcategories on the basis of Accordingly, we included IgE-mediated, type I (immediate) its chemical type (e.g., beta-lactam antibiotic) or by the way hypersensitivity, atopic, “allergen-sensitization,” exposure- the compound is used to treat a particular condition (e.g., based asthma, allergic rhinitis, pollinosis, contact dermatitis, muscle relaxant). Contact allergen data were also further atopic dermatitis, documented anaphylaxis, and all data parsed into subcategories based on their species of origin from allergy-related animal models. (plants), chemical type (metals, model haptens), or mode of The allergy-related epitopes represent both peptidic as exposure (chemical agents from occupational exposure). well as non-peptidic structures from a wide range of sources, including pollens, dust mites, molds, dander and foods, non- 2.3. Computational Methods. The allergy-related data extra- proteinmoietiesofplants(carbohydrates),aswellasdrugs, cted from the IEDB (http://www.immuneepitope.org/)was haptens, metals, and chemical substances from occupational stored in a MySQL database. The use of MySQL allows for exposures. The curated data was obtained using a variety of the tailoring of database schema to the specific analysis and different assays, such as ELISA, Western blot, proliferation to keep the data synchronized with updates of the IEDB data Journal of Allergy 3 Table 1: Overview of allergy epitope data included in the IEDB. epitopes (both peptidic and non-peptidic) were defined for antibody responses, including both linear (∼3,000) and Category Total number conformational (or discontinuous) determinants (peptidic References 678 only) (Table 1). A total of 2,205 IgE epitopes were reported Epitopes (positive structures) 4,800 for all allergens, and less numerous other reactivities related Negative structures 4,137 to total IgG followed distantly by IgG1 IgG4, IgM, IgA, IgG2b, IgG3, IgG2a, and IgG2c (Table 2). As can be seen, Antibody/B cell 3,194 the majority of antibody determinants were defined in Linear natural peptides 2,730 humans. In animal models of disease, not only relatively Linear analogs/no natural source 163 fewer epitopes were defined, but only about 10% of them Discontinuous determinants 65 are epitopes recognized by IgE. This highlights a crucial T cell 1,646 knowledge gap and suggests that more research could be CD4 /Class II 1,530 directed at the definition of the epitopes recognized by IgE CD8 /Class I 17 in animal models of allergy. Unspecified 99 A relatively smaller number of T-cell epitopes have Unique allergens (peptidic/nonpeptidic) 550 been identified (1,646 epitopes) (Table 1). Of the T-cell epitopes defined in both peptidic and non-peptidic allergens, Source species 88 CD4 /Class II epitopes were most numerous, and far fewer Food allergy epitopes 2,322 (53%) CD8 /Class I epitopes were reported. Given their potential Airborne allergy epitopes 1,750 (40%) role in contact dermatitis and other delayed-type hypersen- Stinging insects epitopes 127 (3%) sitivity reactions, it is likely that more effort could be devoted Drug allergy epitopes 106 (∼2%) to the definition of class I epitopes. Supplementary Figure 1 Contact allergy epitopes 82 (∼2%) (see Figure s1 in supplementary material available on line at doi: 10.1155/2007/628026) provides a response summary for all epitope data. Table 2: Antibody isotype associated with epitope reactivity. The host distribution of epitopes can be found in Table 3. Not surprisingly, the vast majority of epitopes were defined Number of reactive epitopes Antibody isotypes in humans. However, epitopes were also described for mon- Overall Human Nonhuman keys, pigs, dogs, rabbits, guinea pigs, rats, and mice. Of the Allergy-specific IgE 2,205 2,135 70 nonhuman species, epitopes defined in mice represented the Other antibody reactivity second largest group. Within epitopes defined in mice, more IgG, unspecified 495 192 303 than 30 different strains were represented (data not shown). IgG1 132 0 132 BALB/c predominated, followed distantly by C57BL/6 and IgG4 72 72 0 C3H/He. Data from human HLA transgenic strains (HLA-A, DR4, DQ6, DQ8, and DR3-DQ2) were also reported. Table 1 IgM 50 32 18 also describes a breakdown of epitope numbers categorized IgG2b 10 0 10 as related to food allergies, airborne or respiratory allergies, IgA 5 0 5 allergies to stinging insects, drug allergies, and contact IgG3 5 2 3 allergies. Food allergens represent by far the largest group IgG2a 2 0 2 of data in the IEDB. There are currently 2,322 (53%) B- IgG2c 1 0 1 and T-cell epitopes identified from this group. After food allergens, epitopes defined for aeroallergens represent the second largest group, accounting for 40% of the records. To production database. Data were periodically checked against date, the database contains 125 antibody and T-cell epitopes the IEDB webpage using simple or advanced query interfaces related to the venom of stinging insects, which make up for consistency and accuracy. Results from each query 3% of the epitope total. Drug allergies account for ∼2% were exported as Excel files and further analyzed in that of epitopes. Contact allergies manifested through the skin format. Tables and figures were generated from Excel. Data account for ∼2% of allergy epitopes. The following sections exclusions included structures for which only MHC binding describe each epitope category in more detail. data were available, as well as those instances in which the epitope was simultaneously used as both immunogen and 3.2. Food Allergies. These include both peptidic and non- assay antigen. peptidic determinants derived from both plants and animals. The data have been parsed into three broad categories; most common food allergen sources, other plant, and other 3. Results animal species (Table 4). Peanut (Arachis hypogaea)allergens 3.1. Data Overview. An overview of all allergy-related data which comprise nearly 40% of the total plant allergen captured by our analysis is provided in Tables 1 and 2. epitopes. Epitopes described for food allergens derived from Consistent with the importance of immunoglobulin-related animals fall into six taxonomic categories. These include responses as effectors of allergy responses, the majority of mammals (human and cow milk, beef, beef gelatin), bony 4 Journal of Allergy Table 3: Host distribution for peptidic and non-peptidic epitopes. Allergic host All T cell CD4, class II CD8, class I All B cell Linear B cell Nonlinear Overall Peptidic epitopes Human 1,483 1,406 9 2,590 2,541 49 4,073 Animal models Japanese macaque 0 0 0 2 2 0 2 Pig 0 0 0 5 5 0 5 Dog 23 23 0 0 0 0 23 Rabbit 0 0 0 337 337 0 337 Rat 1 1 0 6 6 0 7 Mouse 304 271 6 388 357 31 692 Nonpeptidic epitopes Human 50 42 1 72 — — 122 Animal models Rabbit 0 0 0 36 — — 36 Guinea pig 8 0 0 12 — — 20 Rat 2 1 0 2 — — 4 Mouse 26 5 2 50 — — 76 fish (cod), bird (chicken eggs), mollusks (abalone and snails), broad taxonomic categories: insects (cockroach and midge), crustaceans (shrimp and prawns), and nematodes (fish meat arachnids (house dust mite, Storage mite, and Fodder mite), parasite). By far, the largest number of epitopes has been and mammals (cat, dog, horse, cow, rat, and mouse). Among identified for allergens related to cow’s milk allergy, followed the insects, epitopes derived from the midge are the most by epitopes defined from eggs, representing 70% and 20% of numerous, and within the Arachnid class, European house the total, respectively. Non-peptidic food epitopes reported dust mites are the most heavily studied. to date are comprised of carbohydrates derived from peanuts, Three non-peptidic determinants were described (see sugar beets, celery, and sea squirt (see also supplemental supplemental Table 6). These included α-L-Fuc-(1->3)-[α- Table 6). D-Man-(1->3)-[α-D-Man-(1->6)]-[β-D-Xyl-(1->2)]-β-D- According to the CDC [11], allergens derived from Man-(1->4)-β-D-GlcNAc-(1->4)]-D-GlcNAc from cedar milk, eggs, peanuts, tree nuts, fish, shellfish, soy, and wheat pollen, D-glucopyranuronic acid from the fungus Trichospo- account for 90% of all food allergies. The epitope data in ron cutaneum, and mono-β-arabinofuranose from mugwort general reflect this distribution. However, fewer epitopes pollen. In addition, a number of non-peptidic chemicals were identified from fish (only 10 epitopes for one species) were identified, including compounds causing respiratory and shellfish other than shrimp. Conversely, there was a symptoms following occupational exposure; toluene 2,4-di- surprising number of epitopes described from fruit allergens, isocyanate (TDI), toluene meta-diisocyanate, 4-tolyl isocy- namely peaches, apples, and bananas. This observation may anate, diphenylmethane-4,4-diisocyanate, hexameth-ylene reflect the involvement of these species in the oral allergy diisocyanate, phenyl isocyanate, phthalic anhydride, and syndrome (OAS) or pollen-food allergy and cross-reactions trimellityl group (data not shown). between foods (fruits, nuts) and inhaled allergens [12–15]. Here again, the epitope data reflects the overall trends related to airborne allergy. Grass, tree, and weed pollen 3.3. Airborne Allergies. Epitopes defined for aeroallergens epitopes represent the majority of the data (∼60%), followed represent the second largest group within the IEDB, account- by pet dander and house dust mite allergens. These findings ing for 40% of the records, including peptidic and non- are consistent with the overall prevalence of hay fever and/or peptidic determinants derived from plants, animals, fungal allergic rhinitis in the general population, affecting some 18 allergens, and some industrial chemical agents. Here, the million people annually [16]. Perhaps somewhat unexpected, data was parsed into the categories of most common was the fairly low number of epitopes defined for cat airborne sources, other plant, fungal, and animal species allergens. Interestingly, the majority of food allergen epitopes (Table 5). Epitopes identified from pellitory pollen, as well as were B-cells epitopes (86%) whereas a fairly even number of those from birch and Japanese cedar pollen, are numerous. B (43%) and T-cell (57%) epitopes were defined for airborne Epitopes reported for grass pollens come primarily from allergens (data not shown). Timothy grass, ryegrass species, and Kentucky blue grass. In the taxonomic grouping representing fungi, which 3.4. Allergies to Stinging Insects. To date, the IEDB contains includes yeasts and molds, epitopes identified in antigens 125 antibody and T-cell epitopes related to the venom of from Aspergillus species dominate (70%). Finally, epitopes stinging insects (Table 6). These include honeybee (Apis derived from aeroallergens from animals fall into three mellifera), bald-faced hornets (Dolichovespula maculate), Journal of Allergy 5 Table 4: Epitope data related to food allergy. Genus species have been modified to match IUIS usage. Synonyms for querying the IEDB: tomato (Solanum lycopersicum) and brown shrimp is (Farfantepenaeus aztecus). Non- CD4/class CD8/class Linear B Total Category All T cell All B cell linear B II I cell epitopes cell Common food allergen sources Cow’s milk (Bos domesticus) 90 90 0 661 659 2 751 Peanut (Arachis hypogaea) 26 26 0 337 337 0 363 Egg (Gallus domesticus) 75 59 1 150 149 1 225 Common wheat (Triticum aestivum) 0 0 0 128 127 1 128 Soybean (Glycine max) 1 1 0 71 71 0 72 Hazelnut (Corylus avellana) 27 27 0 27 27 0 54 Brown shrimp (Penaeus aztecus) 0 0 0 53 53 0 53 Cashew (Anacardium occidentale) 0 0 0 27 27 0 27 Common walnut (Juglans regia) 0 0 0 27 27 0 27 Sesame seed (Sesamum indicum) 0 0 0 11 11 0 11 Baltic cod (Gadus callarias) 0 0 0 10 10 0 10 Brazil nut (Bertholletia excelsa) 0 0 0 7707 Other plant species Peach (Prunus persica) 43 43 0 15 15 0 58 Banana (Musa acuminata) 1 1 0 51 51 0 52 Buckwheat (Fagopyrum esculentum) 0 0 0 39 39 0 39 Apple (Malus x domestica) 1 1 0 27 24 3 28 Celery (Apium graveolens)14 0 0 0 0 0 14 Muskmelon (Cucumis melon) 0 0 0 12 12 0 12 Oriental mustard (Brassica juncea) 0 0 0 9909 Rice (Oryza sativa japonica) 0 0 0 5505 American plum (Prunus armeniaca) 0 0 0 4404 European plum (Prunus domestica) 0 0 0 4404 Chinese date (Ziziphus mauritiana) 0 0 0 4404 Sweet cherry (Prunus avium) 1 0 0 3034 Common oat (Avena sativa) 4 4 0 0004 Tomato (Lycopersicum esculentum) 0 0 0 2202 Yellow mustard (Sinapis alba) 0 0 0 2112 Chinese cucumber (Trichosanthes kirilowii) 0 0 0 1101 Goat grass (Aegilops markgrafii) 1 1 0 0001 Naked oats (Avena nuda) 1 1 0 0001 Mango (Mangifera indica) 0 0 0 1101 Other animal species Beef (Bos domesticus) 2 2 0 10 10 0 12 Human breast milk (H. sapiens) 0 0 0 6606 Cow gelatin (Bos domesticus) 0 0 0 3303 Horned turban snail (Turbo cornutus) 0 0 0 2202 Red abalone (Haliotis rufescens) 0 0 0 1011 Fish nematode (Anisakis simplex) 0 0 0 1101 black-bellied hornets (Vespa basalis), common wasps Surprisingly, only 2 B-cell epitopes for ant venom, (Vespula vulgaris), and ants (Myrmecia pilosula). Of these, 1 B-cell epitope for Black-faced hornets, and no antibody epitopes derived from honeybees represent the largest determinants for wasp venom were defined. There are portion, followed by wasps and bald-faced hornets. also two non-peptidic determinants for antibody reactivity 6 Journal of Allergy Table 5: Epitope data related to Airborne/Respiratory Allergy. Genus species have been modified to match IUIS usage. Synonyms for querying the IEDB: Arizona cypress (Hesperocyparis arizonica). Non- CD4/class CD8/class Linear B Total Category All T cell All B cell linear B II I cell epitopes cell Common airborne allergen sources Birch tree (Betula verrucosa) 175 167 0 36 30 6 211 Japanese cedar (Cryptomeria japonica) 181 180 0 19 19 0 200 European house dust mite (D. pteronyssinus) 104 87 2 53 39 14 157 Mold (Aspergillus fumigatus) 16 16 0 115 111 4 131 Timothy grass (Phleum pratense) 72 71 1 49 48 1 121 Perennial ryegrass (Lolium perenne) 69 60 0 36 32 4 105 Midge (Chironomus thummi thummi) 30 30 0 60 60 0 90 Olivetree(Olea europaea)14 0 0 65 65 0 79 Cat (Felis catus) 48 46 0 18 18 0 66 Japanese cypress (Chamaecyparis obtusa)62 60 0 1 1 0 63 Spreading pellitory (Parietaria judaica) 1 1 0 61 60 1 62 Kentucky bluegrass (Poa pratensis)18 0 0 34 34 0 52 Cereal rye (Secale cereale) 0 0 0 51 51 0 51 Dog (Canis lupus familiaris)50 50 0 0 0 0 50 American house dust mite (D. farinae) 36 36 0 12 9 3 48 Mold (Penicillium chrysogenum) 0 0 0 45 44 1 45 Horse (Equus caballus)42 42 0 1 0 1 43 Bermuda grass (Cynodon dactylon)23 23 0 3 3 0 26 Annual ragweed (Ambrosia artemisiifolia) 12 12 0 13 13 0 25 Other plant species Common wormwood (Artemisia vulgaris)19 19 0 0 0 0 19 Sunflower (Helianthus annuus) 0 0 0 18 18 0 18 Common velvet grass (Holcus lanatus) 0 0 0 14 14 0 14 Ashe juniper tree (Juniperus ashei) 0 0 0 13 13 0 13 Great ragweed (Ambrosia trifida) 5 5 0 0005 Loblolly pine tree (Pinus taeda) 0 0 0 4404 Lichwort (Parietaria officinalis) 0 0 0 2202 Mouse ear cress (Arabidopsis thaliana) 2 2 0 0002 Queen Anne’s Lace (Daucus carota) 1 0 0 0001 Elegant zinnia (Zinnia violacea) 1 1 0 0001 Tobacco (Nicotiana tabacum) 0 0 0 1101 Tall fescue grass (Festuca arundinacea) 0 0 0 1101 Arizona cypress tree (Cupressus arizonica) 0 0 0 1101 Formosan juniper tree (Juniperus formosana) 0 0 0 1101 Other fungal species Alternaria alternata 00 0 5 5 0 5 Malassezia sympodialis 00 0 1 0 1 1 Candida albicans 00 0 1 1 0 1 Paracoccidioides brasiliensis 10 0 0 0 0 1 Aspergillus restrictus 00 0 1 1 0 1 Other animal species Rat (Rattus norvegicus)19 0 0 4 4 0 23 Storage mite (Blomia tropicalis) 0 0 0 18 16 2 18 Fodder mite (Lepidoglyphus destructor)10 10 0 5 5 0 15 German cockroach (Blattella germanica)9 9 0 5 3 2 14 Journal of Allergy 7 Table 5: Continued. Non- CD4/class CD8/class Linear B Total Category All T cell All B cell linear B II I cell epitopes cell Cow dander (Bos domesticus)8 8 0 2 0 2 10 Mayne’s house dust mite (Euroglyphus maynei)10 0 0 0 0 0 10 American cockroach (Periplaneta americana) 0 0 0 9819 Mouse (Mus musculus) 4 2 0 4408 Table 6: Epitope data related to stinging insects. CD4/class CD8/class Linear B Non-linear Total Allergen source All T cell All B cell II I cell Bcell epitopes Allergen source species Honey bee (Apis mellifera) 48 470 7 5 255 Jack jumper ant (Myrmecia pilosula) 0 002202 Black-bellied hornet (Vespa basalis) 0 001101 Common wasp (Vespula vulgaris) 36 360 0 0 036 Bald-faced hornet (Dolichovespula maculata) 20 17 0 11 11 0 31 Table 7: Summary of allergen coverage. This table provides a 3.6. Contact Allergies. Thus far, more than 80 contact comparison of the total number of allergens designated by the IUIS allergens have been captured by the IEDB, as summarized and housed within database Allergen.org that match the allergy- in Figure 2. Epitopes identified from latex-allergic indi- related species reported in the IEDB. viduals represent the largest number of contact allergen determinants, making up 59% of the total. A total of Allergy category Allergen.org IEDB Percent coverage reported 207 latex epitopes include both linear and nonlinear Food 86 39 45% antibody epitopes,aswellasT-cellepitopes,primarily of the Airborne or Respiratory 184 65 35% CD4 /class II phenotype. Stinging insects 14 6 43% Three additional categories of contact allergens include Contact 13 5 38% non-peptidic entities such as metals, industrial chemicals 297 115 39% encountered by way of occupational exposure, and model haptens. A total of seven different metals described as associated with allergic contact dermatitis include to honey bee venom. These include α-1,3-fucose and an beryllium (beryllium sulfate tetrahydrate, beryllium sulfate), N(4)-[α-L-fucosyl-(1->3)-N-acetyl-4-O-glycosyl-D-glucos- chromium (chromium trichloride), cobalt (cobalt dichlo- aminyl]-L-asparagine residue (see supplemental Table 6). ride), copper (copper sulfate, copper chloride), nickel (nickel chloride, nickel sulfate) palladium (palladium chloride), and 3.5. Drug Allergies. The IEDB currently contains curated zinc chloride. Of these, no single metal entity stands predom- data relating to immunological reactions to more than 90 inates, and as a group metals comprise only 7% of the contact different drugs associated with allergic disease. In most allergens. Beryllium, chromium, zinc chloride, and cobalt cases, the authors do not identify the exact reactive moiety are most often encountered in the industrial/manufacturing setting, whereas nickel, copper, and palladium allergies of these non-peptidic chemical entities because the assays are carried out using the intact drug. These drugs can are most frequently associated with jewelry. Furthermore, be further classified into 21 categories based primarily on the IEDB contains curated data relating to more than biological function and structure (Figure 1). These include 70 compounds utilized in the manufacture of cosmetics, beta-lactam antibiotics (the penicillins), barbiturate anes- dyes, and certain constituents of manufacturing. A very thetics, bactericidal/antimicrobial, muscle relaxants, anti- large number of curated assays relate to model haptens, hypertensive, antiparasitic drugs, neurotransmitters, sulfa- which include skin sensitizers such as trinitrophenyl (TNP), based antibiotics, local anesthetics, hormones, antifibrinolyt- dinitrophenyl (DNP), 1-fluoro-2,4-dinitrobenzene (DNFB), and dinitrochlorobenzene (DNCB). These compounds have ics, antiemetics, antihistamines, antipsychotics, antitussives, muscle stimulants, opiates, radiocontrast media, spermi- been used classically to define mechanisms of type IV contact cides, and a vasoactive agonist. Antibiotics as a whole hypersensitivity. Of these, DNCB appears to have received comprise nearly half (49%) of the reported drug allergens, the greatest focus. A detailed list of all contact allergens can with the vast majority of which are beta-lactam antibiotics. be found in supplemental Table 1. 8 Journal of Allergy 1% 1% 1% 1% 1% 1% 1% 2% 1% 2% 3% 2% 2% 2% 2% 3% 52% β-lactam 3% 6% 6% 10% β-lactam antibiotic (64) Barbiturate anesthetic (12) Bactericidal/antiseptic (7) Muscle relaxant (7) Anti-hypertensive (4) Anti-parasitic (4) Neurotransmitter (3) Sulfa-based antibiotic (3) Local anesthetic (2) Hormone (2) Anti-fibrinolytic (1) Antiemetic (1) Antihistamine (1) Anti-psychotic (2) Anti-tussive (1) Muscle stimulant (1) Opiate (1) Radiocontrast media (2) Figure 1: Drug allergens by functional category. Determinants identified under this category have been broadly classified into 21 groups according to their overall biological functional. The chart presents these data as percentages with the total number of unique assays in parentheses. 3.7. Epitope Distribution by Allergen. As a further evaluation, a few of the known allergens (e.g., 6/29 Der p and Der f we determined the relative epitope distribution by allergen allergens for house dust mite), whereas other species have for each source species (supplementary Tables 2–5). The total intermediate distribution (e.g., 4/6 Lol p allergens from rye number of epitopes described per allergen varies greatly, and grass) (Table 7). Furthermore, when we compared the total well-known allergens (e.g., Ara h 1, Bet v 1, or Phl p 1) tended number of allergens in the IUIS that match the allergy- to have greater numbers of defined epitopes compared to related species reported in the IEDB, we find that ∼40% of other allergens from the same organism (e.g., seed storage the IUIS-designated allergens are represented in the epitope protein SSP2, Bet v 2, Bet v 4, Phl p 2, or Phl p 11). Similarly, data (115 out of 297). However, for an additional 380 the total number of T-cell versus B-cell epitopes varied known IUIS allergens, no match could be found between greatly, with the vast majority of allergens heavily weighted the species in the IUIS and the species described in the toward one or the other phenotype and few having a relative papers in the scientific literature describing specific epitopes. balance of defined B and T epitopes (data not shown). Many of these include organisms from known genera, but Next, we analyzed the extent to which the allergens with as yet nonlisted species, as well as other nomenclature comprising the epitope-related data represent all known inconsistencies. These results suggest that more efforts can allergens, as listed by the Allergen.org resource, the official site be devoted to reconciling the origin of allergen-derived data. for the systematic allergen nomenclature (Linnean system) that is approved by the World Health Organization and Inter- 3.8. Epitopes Associated with Clinical Disease or Disease national Union of Immunological Societies (WHO/IUIS) Models. Isolated epitopes can be utilized to induce or Allergen Nomenclature Sub-committee. This site maintains modulate allergic reactions in animal models. The use a list of all currently known (described) allergens derived of synthetic epitopes to modulate allergic reactions has from plant, animal, and fungal species. We found that total also been proposed and tested in a limited number of number of allergens from which epitope data have been clinical trials [17, 18]. Indeed, the epitopes defined in the described varies from one allergen source to another. In some course study of human allergic conditions may enable the instances, epitope data is comprehensive, showing epitope investigation of their potential in the immunotherapeutic data for all allergens identified by the IUIS list for a given setting. species (e.g., 9/9 Phl p allergens for timothy grass). However To inventory which epitopes had been tested in these in other cases, allergen distribution is low, showing only settings, we queried for antibody and T-cell epitopes that Journal of Allergy 9 Table 8: Epitopes associated with modulation of allergic disease. Epitope name Epitope sequence Host Response Allergy model Bermuda grass Cyn d 1 (127–146) KAGELTLQFRRVKCKYPSGT Human T cell, DCP pollen Bermuda grass Cyn d 1 (19–38) LEAKATFYGSNPRGAAPDDH Human T cell, DCP pollen Bermuda grass Cyn d 1 (154–173) KGSNDHYLALLVKYAAGDGN Human T cell, DCP pollen Bermuda grass Cyn d 1 (136–155) RRVKCKYPSGTKITFHIEKG Human T cell, DCP pollen Bermuda grass Cyn d 1 (28–47) SNPRGAAPDDHGGACGYKDV Human T cell, DCP pollen Bermuda grass Cyn d 1 (82–101) VECSGEPVLVKITDKNYEHI Human T cell, DCP pollen Bermuda grass Cyn d 1 (227–246) VIPANWKPDTVYTSKLQFGA Human T cell, DCP pollen Bermuda grass Cyn d 1 (91–110) VKITDKNYEHIAAYHFDLSG Human T cell, DCP pollen Bermuda grass Cyn d 1 (73–92) CYEIKCKEPVECSGEPVLVK Human T cell, DCP pollen Fel d 1 IPC-2 KALPVVLENARILKNCVDAKMTEEDKE Human T cell, LSC, NSC Cat allergy Fel d 1 IPC-1 KRDVDLFLTGTPDEYVEQVAQYKALPV Human T cell, LSC, NSC Cat allergy peptide 4 (P93-110) TKCYKLEHPVTGCGERTE Human T cell, CLPR Honey bee sting peptide 1 (P81-98) YFVGKMYFNLIDTKCYKL Human T cell, CLPR Honey bee sting Bet v 1 SKEMGETLLRAVESYLLAHSD Mouse B cell, AWI Birch pollen Der p 1 111–139 FGISNYCQIYPPNANKIREALAQPQRYCR Mouse T cell, DTP European HDM Der p 1 113–127 ISNYCQIYPPNANKI Mouse T cell, DTP European HDM Der p I (101–154) QSCRRPNAQRFGISNYCQIYPPNVNKIREALAQTHSAIAVIIGIKDLDAFRHYD Mouse T cell, DTP European HDM Der p 1 110–131 RFGISNYCQIYPPNANKIREAL Mouse T cell, DTP European HDM Der p I 114–129 SNYCQIYPPNANKIR Mouse B cell, DTH European HDM Der p 2 87–129 DIKYTWNVPKIAPKSENVVVTVKVMGDDGVLACAIATHAKIRD Mouse B cell, BPR, AWI European HDM Der p I (98–140) AREQSCRRPNAQRFGISNYCQIYPPNVNKIREALAQTHSAIAV Mouse T cell, DTP European HDM Api m 4 7–19 KVLTTGLPALISW Mouse B cell, IgG1 Honey bee sting Dol m 5 176–195 IEDNWYTHYLVCNYGPGGND Mouse B cell, IgG1 Hornet sting Dol m 5 41–60 KNEILKRHNDFRQNVAKGLE Mouse T cell, DTP Hornet sting Dol m 5 141–160 NYKVGLQNSNFRKVGHYTQM Mouse T cell, DTP Hornet sting 10 Journal of Allergy Table 8: Continued. Epitope name Epitope sequence Host Response Allergy model Japanese cedar Cry j 2 247–258 AEVSYVHVNGAK Mouse B cell, CSI pollen Japanese cedar Cry j 2 P2 246–259 RAEVSYVHVNGAKF Mouse T cell, NS pollen Ole 1 109–130 TVNGTTRTVNPLGFFKKEALPK Mouse B cell, AWI Olive tree pollen Timothy grass Phl p 5 peptide YAATVATAPEVKYTVFETALKKAI Mouse B cell, AWI pollen Timothy grass Phl p 1 peptide LRSAGELELQFRRVKCKYPEG Mouse B cell, AWI pollen Betv1/Phlp1/Phl p MGETLLRAVESYAGELELQFRRVKCKYTVATAPEVKYTVFETALK Mouse B cell, AWI Tree/Grass pollen 5hybrid PI-1 IgECHε2 LYCFIYGHI Mouse T cell, PCA Mouse (109-117) nOVA 173–196 VLVNAIVFKGLWEKAFKDEDTQAM Rat B cell, PCA Chicken Egg OVA (257–264) SIINFEKL Mouse T cell, AWI Asthma OVA (323–339) ISQAVHAAHAEINEAGR Mouse T cell, AWI Asthma HDM: house dust mite. Mouse strains consisted of BALB/c and C57BL/6. Rats were Norway strain. AWI: airway inflammation (histology). NS: nasal symptoms (sneezing and rubbing). CSI: cytokine suppression of allergen-IgE production. BPR: bronchopulmonary resistance. DTH: delayed type hypersensitivity. LSC: lung score. NSC: nasal score. CLPR: cutaneous late-phase reaction. DTP: decrease allergen-specific T cell proliferation. DCP: decreased allergen-specific cytokine production. Journal of Allergy 11 related to the study of allergic reactions in humans, and fewer epitopes defined for mice and occasional epitopes defined for 24, 7% other hosts such as monkeys, pigs, dogs, rabbits, guinea pigs, and rats. The majority of peptidic epitopes were defined for foods (cow’s milk, wheat, peanuts) and plants (tree and grass 47, 13% pollens), while the majority of non-peptidic epitopes defined for drugs and biologicals (antibiotics). Interestingly, the vast majority of food allergen-related 207, 59% epitopes were described for B-cells, whereas a fairly even number of B- and T-cell epitopes were defined for airborne 73, 21% allergens. It is not clear why this is the case but may have to do with historical analysis of allergies to foods such as milk, peanuts, and eggs which represent a large portion of that data. The distribution of epitopes varies greatly between allergen and species. This observation suggests that definition of T-cell epitopes involved in food allergies is lacking and could be the focus of further experimental investigations. Latex Another unexpected finding of our analysis was that the Occupational Haptens epitopes defined in hosts other than humans were mostly T- Metals cell epitopes, and far fewer antibody epitopes were defined. While it is surprising that so little of the nonhuman antibody Figure 2: Categories of contact allergen epitopes. The chart pro- responses are allergy-specific IgE; this may point to an vides a broad overview of the contact allergen epitope distribution. important area for experimental investigation, to provide investigators with animal models faithfully reproducing human allergic reactions. were tested either in vivo for their ability to decrease The current analysis also revealed that coverage of known allergic reactivity in vivo (as measure by the reduction of human allergen by epitope definition studies is very sparse. symptoms) and for those that were shown to decrease in The overall completeness of the epitope-specific allergy data vitro markers of allergic disease. This is done by selecting with respect to known allergens on a species basis is about all B-cell or T-cell contexts designated in the IEDB as assay 40%. Furthermore, epitope data is available for only ∼17% of type equals “Reduction of Disease after Treatment” (B cell) all allergens listed by IUIS. For certain species, the majority or “Treatment” (T cell). Here, the assay type assigned by (if not all) of the known allergens have epitope-related the IEDB indicates the nature of the immune response, data (e.g., timothy grass allergens), while other species have and the details of the type of assay used (lung function, epitope data from only a small number of known allergens DTH, PCA, etc.) can be found within the curated data (e.g., apple). from the assay comments field. Table 8 shows the PubMed The recent completion of curation of non-peptidic identification, epitope name, epitope sequence, the host, the allergy-related epitopes in the IEDB allows a first time inven- type of response, and allergy model classification for peptidic tory and assessment of important drug and contact allergens. epitopes identified from the data as having a positive effect on The integration within the IEDB of representation and disease in vivo or on markers of disease as measured in vitro. search capabilities based on the chemical entity of biological interest (ChEBI) (http://www.ebi.ac.uk/chebi/) database will further enable the scientific community to quickly retrieve 4. Discussion and analyze the immunological data associated with these The analysis presented herein identified over 4,500 allergy- important classes of allergens. related epitopes derived from 270 different allergens. Pro- Finally, our analysis also inventoried which epitopes have been used to actively induce allergic disease in animal models tein allergens were categorized according to their source organism, which included plants, animals, insects, parasites, or to modulate disease. Only a handful of epitopes have and fungi. Non-peptidic allergens were categorized into been investigated for their immunotherapeutic potential. If the promising results from human clinical trials were to four groups including drugs and biologicals, industrial compounds, or those related to occupational exposure, be verified in later phase trails, we anticipate that the data metals, model haptens, and carbohydrates from plants. cataloged within the IEDB might provide a wealth of leads Overall, the distribution of the data follows expectations for therapeutic intervention regimens. based on the nature of adaptive responses involved in allergy. Namely, the vast majority of allergy epitopes were defined Acknowledgments for B cells/antibodies (and in these records, IgE-mediated reactivity figured prominently), and relatively fewer T-cell We gratefully acknowledge the helpful contribution of epitopes (mostly defined as CD4 /class II, with very few Alison Deckhut, Matthew Fenton, and Michael Minnicozzi being defined for CD8 /class I). Likewise, most of the records in reviewing this paper. The La Jolla Institute of Allergy 12 Journal of Allergy and Immunology is supported by the National Institutes of Health National Institute of Allergy and Infectious Diseases, Allergy Contract no. HHSN272200700048C, and HHSN26620040006C under the Immune Epitope Database and Analysis Program. References [1] Airborne Allergens: something in the air, http://www.niaid .nih.gov/topics/allergicDiseases/Documents/airborne allerg- ens.pdf. [2] Asthma, http://www.cdc.gov/nchs/fastats/asthma.htm. [3] Asthma, http://www.who.int/mediacentre/factsheets/fs307/en /index.html. [4] Allergic diseases, http://www.niaid.nih.gov/topics/allergicDi- seases/Pages/introductionGoals.aspx. [5] Food allergy, http://www.niaid.nih.gov/topics/foodallergy/un- derstanding/pages/quickfacts.aspx. [6] CDC Study Finds 3 Million U.S. Children have Food or Digestive Allergies, http://www.cdc.gov/media/pressrel/2008/ r081022.htm?s cid=mediarel r081022 x. [7] H. H. Bui, B. Peters, E. Assarsson, I. Mbawuike, and A. Sette, “Ab and T cell epitopes of influenza A virus, knowledge and opportunities,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 1, pp. 246–251, [8] M. J. Blythe, Q. Zhang, K. Vaughan et al., “An analysis of the epitope knowledge related to Mycobacteria,” Immunome Research, vol. 3, no. 1, article no. 10, 2007. [9] K. Vaughan, M. Blythe, J. Greenbaum et al., “Meta-analysis of immune epitope data for all Plasmodia: overview and applications for malarial immunobiology and vaccine-related issues,” Parasite Immunology, vol. 31, no. 2, pp. 78–97, 2009. [10] V. Davies, K. Vaughan, R. Damie, B. Peters, and A. Sette, “Classification of the universe of immune epitope literature: representation and knowledge gaps,” PLoS ONE,vol. 4, no.9, article no. e6948, 2009. [11] Food allergies, http://www.cdc.gov/healthyyouth/foodaller- gies/. [12] S. J. Maleki, A. W. Burks, and R. M. Helm, Food Allergy,ASM Press, Washington, DC, USA, 2006. [13] S. H. Sicherer and D. Y. M. Leung, “Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects,” Journal of Allergy and Clinical Immunology, vol. 119, no. 6, pp. 1462–1469, 2007. [14] S. H. Sicherer, A. Munoz-Furlong, and H. A. Sampson, “Prevalence of peanut and tree nut allergy in the United States determined by means of a random digit dial telephone survey: a 5-year follow-up study,” Journal of Allergy and Clinical Immunology, vol. 112, no. 6, pp. 1203–1207, 2003. [15] S. H. Sicherer, “Clinical implications of cross-reactive food allergens,” Journal of Allergy and Clinical Immunology, vol. 108, no. 6, pp. 881–890, 2001. [16] Allergies and hay fever, http://www.cdc.gov/nchs/fastats/aller- gies.htm. [17] M. Larche, ´ “Peptide immunotherapy for allergic diseases,” Allergy, vol. 62, no. 3, pp. 325–331, 2007. [18] M. Larche, ´ “Update on the current status of peptide immunotherapy,” Journal of Allergy and Clinical Immunology, vol. 119, no. 4, pp. 906–909, 2007. MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Journal

Journal of Allergy – Hindawi Publishing Corporation

Published: Feb 13, 2011

References

  • Ab and T cell epitopes of influenza A virus, knowledge and opportunities,
    H. H. Bui, B. Peters, E. Assarsson, I. Mbawuike, and A. Sette
  • An analysis of the epitope knowledge related to Mycobacteria,
    M. J. Blythe, Q. Zhang, K. Vaughan et al.
  • Meta-analysis of immune epitope data for all Plasmodia: overview and applications for malarial immunobiology and vaccine-related issues,
    K. Vaughan, M. Blythe, J. Greenbaum et al.
  • Classification of the universe of immune epitope literature: representation and knowledge gaps,
    V. Davies, K. Vaughan, R. Damie, B. Peters, and A. Sette
  • Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects,
    S. H. Sicherer and D. Y. M. Leung
  • Prevalence of peanut and tree nut allergy in the United States determined by means of a random digit dial telephone survey: a 5-year follow-up study,
    S. H. Sicherer, A. Muñoz-Furlong, and H. A. Sampson
  • Clinical implications of cross-reactive food allergens,
    S. H. Sicherer
  • Peptide immunotherapy for allergic diseases,
    M. Larché
  • Update on the current status of peptide immunotherapy,
    M. Larché