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.
It is estimated that 50 million people in the US are affected by airborne allergens, including approximately 35 million affected by upper respiratory allergies (allergic rhinitis, hay fever and pollinosis) [
The immunological basis of allergy-related disease is universally recognized. At the level of adaptive immunity, the recognition of specific allergens by antibodies and T cells plays major roles both as effectors and regulators of allergic diseases. Several bioinformatics resources, cataloging and describing allergen protein sequences, are available to the scientific community such as the
The immune epitope database (IEDB) was created, to provide the scientific community with a repository of freely accessible immune epitope data (
Recently, curation of allergy-related references was completed, and as a result, close to 10,000 records, capturing 4,800 different epitopes, and the biological assays associated with their recognition have become available within the IEDB. By analogy with what was done in the case of epitopes associated with influenza, tuberculosis, malaria, and other diseases [
This analysis includes data for antibody and T-cell epitopes associated with allergic disease in human and nonhuman (animal models) hosts. To identify within the IEDB the subset of data which is allergy related, we followed the process described in more detail by Davies et al. [
The allergy-related epitopes represent both peptidic as well as non-peptidic structures from a wide range of sources, including pollens, dust mites, molds, dander and foods, nonprotein moieties of plants (carbohydrates), as well as drugs, haptens, metals, and chemical substances from occupational exposures. The curated data was obtained using a variety of different assays, such as ELISA, Western blot, proliferation assays, surface plasmon resonance (SPR), radio immunoassay (RIA), and X-ray crystallography, and describes epitope-related reactivity such as histamine release, hypersensitivity (PCA), delayed-type hypersensitivity (DTH), and immunotherapy assays.
All of the data described herein were captured directly from the peer-reviewed literature (PubMed) by Ph.D. level scientists or through direct submission to the IEDB by research groups. Antibody and T-cell epitope definitions (length and mass restrictions) as well as IEDB inclusion criteria can be found at
The entirety of the allergy-related data identified as described above was first inventoried to identify the total number of structures (positive and negative epitopes), their chemical nature (peptidic or non-peptidic), the total number of antibody/B-cell versus T-cell epitopes, as well as the effector cell phenotype or antibody isotype, and finally the total number of peer-reviewed references from which the data were derived. The second step involved investigating the distribution of epitopes among hosts: those epitopes defined in humans versus those identified using nonhuman animal models of allergy. In each case, the inventory of epitopes per host species included a breakdown according to reactivity: B cell (linear or conformational) or T cell (CD4, CD8 or unspecified).
Following the initial inventory, the data were categorized according to the following established allergy categories: food, airborne (respiratory), contact, drug, and allergies to biting insects. This categorization was based on the
The individual compounds representing drugs/pharmaceuticals were parsed into 21 subcategories on the basis of its chemical type (e.g., beta-lactam antibiotic) or by the way the compound is used to treat a particular condition (e.g., muscle relaxant). Contact allergen data were also further parsed into subcategories based on their species of origin (plants), chemical type (metals, model haptens), or mode of exposure (chemical agents from occupational exposure).
The allergy-related data extracted from the IEDB (
An overview of all allergy-related data captured by our analysis is provided in Tables
Overview of allergy epitope data included in the IEDB.
Category | Total number |
---|---|
References | 678 |
Epitopes (positive structures) | 4,800 |
Negative structures | 4,137 |
Antibody/B cell | 3,194 |
Linear natural peptides | 2,730 |
Linear analogs/no natural source | 163 |
Discontinuous determinants | 65 |
T cell | 1,646 |
CD4+/Class II | 1,530 |
CD8+/Class I | 17 |
Unspecified | 99 |
Unique allergens (peptidic/nonpeptidic) | 550 |
Source species | 88 |
Food allergy epitopes | 2,322 (53%) |
Airborne allergy epitopes | 1,750 (40%) |
Stinging insects epitopes | 127 (3%) |
Drug allergy epitopes | 106 (~2%) |
Contact allergy epitopes | 82 (~2%) |
Antibody isotype associated with epitope reactivity.
Antibody isotypes | Number of reactive epitopes | ||
---|---|---|---|
Overall | Human | Nonhuman | |
Allergy-specific IgE | 2,205 | 2,135 | 70 |
IgG, unspecified | 495 | 192 | 303 |
IgG1 | 132 | 0 | 132 |
IgG4 | 72 | 72 | 0 |
IgM | 50 | 32 | 18 |
IgG2b | 10 | 0 | 10 |
IgA | 5 | 0 | 5 |
IgG3 | 5 | 2 | 3 |
IgG2a | 2 | 0 | 2 |
IgG2c | 1 | 0 | 1 |
A relatively smaller number of T-cell epitopes have been identified (1,646 epitopes) (Table
The host distribution of epitopes can be found in Table
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 |
---|---|---|---|---|---|---|---|
Human | 1,483 | 1,406 | 9 | 2,590 | 2,541 | 49 | 4,073 |
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 |
Human | 50 | 42 | 1 | 72 | — | — | 122 |
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 |
These include both peptidic and non-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 animal species (Table
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 (
Category | All T cell | CD4/class II | CD8/class I | All B cell | Linear B cell | Non-linear B cell | Total epitopes |
---|---|---|---|---|---|---|---|
Common food allergen sources | |||||||
Cow’s milk ( | 90 | 90 | 0 | 661 | 659 | 2 | 751 |
Peanut ( | 26 | 26 | 0 | 337 | 337 | 0 | 363 |
Egg ( | 75 | 59 | 1 | 150 | 149 | 1 | 225 |
Common wheat ( | 0 | 0 | 0 | 128 | 127 | 1 | 128 |
Soybean ( | 1 | 1 | 0 | 71 | 71 | 0 | 72 |
Hazelnut ( | 27 | 27 | 0 | 27 | 27 | 0 | 54 |
Brown shrimp ( | 0 | 0 | 0 | 53 | 53 | 0 | 53 |
Cashew ( | 0 | 0 | 0 | 27 | 27 | 0 | 27 |
Common walnut ( | 0 | 0 | 0 | 27 | 27 | 0 | 27 |
Sesame seed ( | 0 | 0 | 0 | 11 | 11 | 0 | 11 |
Baltic cod ( | 0 | 0 | 0 | 10 | 10 | 0 | 10 |
Brazil nut ( | 0 | 0 | 0 | 7 | 7 | 0 | 7 |
Other plant species | |||||||
Peach ( | 43 | 43 | 0 | 15 | 15 | 0 | 58 |
Banana ( | 1 | 1 | 0 | 51 | 51 | 0 | 52 |
Buckwheat ( | 0 | 0 | 0 | 39 | 39 | 0 | 39 |
Apple ( | 1 | 1 | 0 | 27 | 24 | 3 | 28 |
Celery ( | 14 | 0 | 0 | 0 | 0 | 0 | 14 |
Muskmelon ( | 0 | 0 | 0 | 12 | 12 | 0 | 12 |
Oriental mustard ( | 0 | 0 | 0 | 9 | 9 | 0 | 9 |
Rice ( | 0 | 0 | 0 | 5 | 5 | 0 | 5 |
American plum ( | 0 | 0 | 0 | 4 | 4 | 0 | 4 |
European plum ( | 0 | 0 | 0 | 4 | 4 | 0 | 4 |
Chinese date ( | 0 | 0 | 0 | 4 | 4 | 0 | 4 |
Sweet cherry ( | 1 | 0 | 0 | 3 | 0 | 3 | 4 |
Common oat ( | 4 | 4 | 0 | 0 | 0 | 0 | 4 |
Tomato ( | 0 | 0 | 0 | 2 | 2 | 0 | 2 |
Yellow mustard ( | 0 | 0 | 0 | 2 | 1 | 1 | 2 |
Chinese cucumber ( | 0 | 0 | 0 | 1 | 1 | 0 | 1 |
Goat grass ( | 1 | 1 | 0 | 0 | 0 | 0 | 1 |
Naked oats ( | 1 | 1 | 0 | 0 | 0 | 0 | 1 |
Mango ( | 0 | 0 | 0 | 1 | 1 | 0 | 1 |
Other animal species | |||||||
Beef ( | 2 | 2 | 0 | 10 | 10 | 0 | 12 |
Human breast milk ( | 0 | 0 | 0 | 6 | 6 | 0 | 6 |
Cow gelatin ( | 0 | 0 | 0 | 3 | 3 | 0 | 3 |
Horned turban snail ( | 0 | 0 | 0 | 2 | 2 | 0 | 2 |
Red abalone ( | 0 | 0 | 0 | 1 | 0 | 1 | 1 |
Fish nematode ( | 0 | 0 | 0 | 1 | 1 | 0 | 1 |
According to the CDC [
Epitopes defined for aeroallergens represent the second largest group within the IEDB, accounting for 40% of the records, including peptidic and non-peptidic determinants derived from plants, animals, fungal allergens, and some industrial chemical agents. Here, the data was parsed into the categories of most common airborne sources, other plant, fungal, and animal species (Table
Epitope data related to Airborne/Respiratory Allergy. Genus species have been modified to match IUIS usage. Synonyms for querying the IEDB: Arizona cypress (
Category | All T cell | CD4/class II | CD8/class I | All B cell | Linear B cell | Non-linear B cell | Total epitopes |
---|---|---|---|---|---|---|---|
Common airborne allergen sources | |||||||
Birch tree ( | 175 | 167 | 0 | 36 | 30 | 6 | 211 |
Japanese cedar ( | 181 | 180 | 0 | 19 | 19 | 0 | 200 |
European house dust mite (D. pteronyssinus) | 104 | 87 | 2 | 53 | 39 | 14 | 157 |
Mold ( | 16 | 16 | 0 | 115 | 111 | 4 | 131 |
Timothy grass ( | 72 | 71 | 1 | 49 | 48 | 1 | 121 |
Perennial ryegrass ( | 69 | 60 | 0 | 36 | 32 | 4 | 105 |
Midge ( | 30 | 30 | 0 | 60 | 60 | 0 | 90 |
Olive tree ( | 14 | 0 | 0 | 65 | 65 | 0 | 79 |
Cat ( | 48 | 46 | 0 | 18 | 18 | 0 | 66 |
Japanese cypress ( | 62 | 60 | 0 | 1 | 1 | 0 | 63 |
Spreading pellitory ( | 1 | 1 | 0 | 61 | 60 | 1 | 62 |
Kentucky bluegrass ( | 18 | 0 | 0 | 34 | 34 | 0 | 52 |
Cereal rye ( | 0 | 0 | 0 | 51 | 51 | 0 | 51 |
Dog ( | 50 | 50 | 0 | 0 | 0 | 0 | 50 |
American house dust mite ( | 36 | 36 | 0 | 12 | 9 | 3 | 48 |
Mold (Penicillium chrysogenum) | 0 | 0 | 0 | 45 | 44 | 1 | 45 |
Horse ( | 42 | 42 | 0 | 1 | 0 | 1 | 43 |
Bermuda grass ( | 23 | 23 | 0 | 3 | 3 | 0 | 26 |
Annual ragweed ( | 12 | 12 | 0 | 13 | 13 | 0 | 25 |
Other plant species | |||||||
Common wormwood ( | 19 | 19 | 0 | 0 | 0 | 0 | 19 |
Sunflower ( | 0 | 0 | 0 | 18 | 18 | 0 | 18 |
Common velvet grass ( | 0 | 0 | 0 | 14 | 14 | 0 | 14 |
Ashe juniper tree ( | 0 | 0 | 0 | 13 | 13 | 0 | 13 |
Great ragweed ( | 5 | 5 | 0 | 0 | 0 | 0 | 5 |
Loblolly pine tree ( | 0 | 0 | 0 | 4 | 4 | 0 | 4 |
Lichwort ( | 0 | 0 | 0 | 2 | 2 | 0 | 2 |
Mouse ear cress ( | 2 | 2 | 0 | 0 | 0 | 0 | 2 |
Queen Anne’s Lace ( | 1 | 0 | 0 | 0 | 0 | 0 | 1 |
Elegant zinnia ( | 1 | 1 | 0 | 0 | 0 | 0 | 1 |
Tobacco ( | 0 | 0 | 0 | 1 | 1 | 0 | 1 |
Tall fescue grass ( | 0 | 0 | 0 | 1 | 1 | 0 | 1 |
Arizona cypress tree ( | 0 | 0 | 0 | 1 | 1 | 0 | 1 |
Formosan juniper tree ( | 0 | 0 | 0 | 1 | 1 | 0 | 1 |
Other fungal species | |||||||
| 0 | 0 | 0 | 5 | 5 | 0 | 5 |
| 0 | 0 | 0 | 1 | 0 | 1 | 1 |
| 0 | 0 | 0 | 1 | 1 | 0 | 1 |
| 1 | 0 | 0 | 0 | 0 | 0 | 1 |
| 0 | 0 | 0 | 1 | 1 | 0 | 1 |
Other animal species | |||||||
Rat ( | 19 | 0 | 0 | 4 | 4 | 0 | 23 |
Storage mite ( | 0 | 0 | 0 | 18 | 16 | 2 | 18 |
Fodder mite ( | 10 | 10 | 0 | 5 | 5 | 0 | 15 |
German cockroach ( | 9 | 9 | 0 | 5 | 3 | 2 | 14 |
Cow dander ( | 8 | 8 | 0 | 2 | 0 | 2 | 10 |
Mayne's house dust mite ( | 10 | 0 | 0 | 0 | 0 | 0 | 10 |
American cockroach ( | 0 | 0 | 0 | 9 | 8 | 1 | 9 |
Mouse ( | 4 | 2 | 0 | 4 | 4 | 0 | 8 |
In the taxonomic grouping representing fungi, which includes yeasts and molds, epitopes identified in antigens from
Three non-peptidic determinants were described (see supplemental Table 6). These included
Here again, the epitope data reflects the overall trends related to airborne allergy. Grass, tree, and weed pollen epitopes represent the majority of the data (~60%), followed by pet dander and house dust mite allergens. These findings are consistent with the overall prevalence of hay fever and/or allergic rhinitis in the general population, affecting some 18 million people annually [
To date, the IEDB contains 125 antibody and T-cell epitopes related to the venom of stinging insects (Table
Epitope Data Related to Stinging Insects.
Allergen source | All T cell | CD4/class II | CD8/class I | All B cell | Linear B cell | Non-linear B cell | Total epitopes |
---|---|---|---|---|---|---|---|
Allergen source species | |||||||
Honey bee ( | 48 | 47 | 0 | 7 | 5 | 2 | 55 |
Jack jumper ant ( | 0 | 0 | 0 | 2 | 2 | 0 | 2 |
Black-bellied hornet ( | 0 | 0 | 0 | 1 | 1 | 0 | 1 |
Common wasp ( | 36 | 36 | 0 | 0 | 0 | 0 | 36 |
Bald-faced hornet ( | 20 | 17 | 0 | 11 | 11 | 0 | 31 |
The IEDB currently contains curated data relating to immunological reactions to more than 90 different drugs associated with allergic disease. In most cases, the authors do not identify the exact reactive moiety of these non-peptidic chemical entities because the assays are carried out using the intact drug. These drugs can be further classified into 21 categories based primarily on biological function and structure (Figure
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.
Thus far, more than 80 contact allergens have been captured by the IEDB, as summarized in Figure
Categories of contact allergen epitopes. The chart provides a broad overview of the contact allergen epitope distribution.
Three additional categories of contact allergens include
As a further evaluation, we determined the relative epitope distribution by allergen for each source species (supplementary Tables 2–5). The total number of epitopes described per allergen varies greatly, and well-known allergens (e.g., Ara h 1, Bet v 1, or Phl p 1) tended to have greater numbers of defined epitopes compared to other allergens from the same organism (e.g., seed storage protein SSP2, Bet v 2, Bet v 4, Phl p 2, or Phl p 11). Similarly, the total number of T-cell versus B-cell epitopes varied greatly, with the vast majority of allergens heavily weighted toward one or the other phenotype and few having a relative balance of defined B and T epitopes (data not shown).
Next, we analyzed the extent to which the allergens comprising the epitope-related data represent all known allergens, as listed by the
Summary of Allergen Coverage. This table provides a comparison of the total number of allergens designated by the IUIS and housed within database
Allergy category | Allergen.org | IEDB | Percent coverage |
---|---|---|---|
Food | 86 | 39 | 45% |
Airborne or Respiratory | 184 | 65 | 35% |
Stinging insects | 14 | 6 | 43% |
Contact | 13 | 5 | 38% |
297 | 115 | 39% |
Isolated epitopes can be utilized to induce or modulate allergic reactions in animal models. The use of synthetic epitopes to modulate allergic reactions has also been proposed and tested in a limited number of clinical trials [
To inventory which epitopes had been tested in these settings, we queried for antibody and T-cell epitopes that were tested either
Epitopes associated with modulation of allergic disease.
Epitope name | Epitope sequence | Host | Response | Allergy model |
---|---|---|---|---|
Cyn d 1 (127–146) | KAGELTLQFRRVKCKYPSGT | Human | T cell, DCP | Bermuda grass pollen |
Cyn d 1 (19–38) | LEAKATFYGSNPRGAAPDDH | Human | T cell, DCP | Bermuda grass pollen |
Cyn d 1 (154–173) | KGSNDHYLALLVKYAAGDGN | Human | T cell, DCP | Bermuda grass pollen |
Cyn d 1 (136–155) | RRVKCKYPSGTKITFHIEKG | Human | T cell, DCP | Bermuda grass pollen |
Cyn d 1 (28–47) | SNPRGAAPDDHGGACGYKDV | Human | T cell, DCP | Bermuda grass pollen |
Cyn d 1 (82–101) | VECSGEPVLVKITDKNYEHI | Human | T cell, DCP | Bermuda grass pollen |
Cyn d 1 (227–246) | VIPANWKPDTVYTSKLQFGA | Human | T cell, DCP | Bermuda grass pollen |
Cyn d 1 (91–110) | VKITDKNYEHIAAYHFDLSG | Human | T cell, DCP | Bermuda grass pollen |
Cyn d 1 (73–92) | CYEIKCKEPVECSGEPVLVK | Human | T cell, DCP | Bermuda grass 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 |
Cry j 2 247–258 | AEVSYVHVNGAK | Mouse | B cell, CSI | Japanese cedar pollen |
Cry j 2 P2 246–259 | RAEVSYVHVNGAKF | Mouse | T cell, NS | Japanese cedar pollen |
Ole 1 109–130 | TVNGTTRTVNPLGFFKKEALPK | Mouse | B cell, AWI | Olive tree pollen |
Phl p 5 peptide | YAATVATAPEVKYTVFETALKKAI | Mouse | B cell, AWI | Timothy grass pollen |
Phl p 1 peptide | LRSAGELELQFRRVKCKYPEG | Mouse | B cell, AWI | Timothy grass pollen |
Bet v 1/Phl p 1/Phl p 5 hybrid | MGETLLRAVESYAGELELQFRRVKCKYTVATAPEVKYTVFETALK | Mouse | B cell, AWI | Tree/Grass pollen |
PI-1 IgECH | LYCFIYGHI | Mouse | T cell, PCA | Mouse |
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.
The analysis presented herein identified over 4,500 allergy-related epitopes derived from 270 different allergens. Protein allergens were categorized according to their source organism, which included plants, animals, insects, parasites, and fungi. Non-peptidic allergens were categorized into four groups including drugs and biologicals, industrial compounds, or those related to occupational exposure, metals, model haptens, and carbohydrates from plants.
Overall, the distribution of the data follows expectations based on the nature of adaptive responses involved in allergy. Namely, the vast majority of allergy epitopes were defined for B cells/antibodies (and in these records, IgE-mediated reactivity figured prominently), and relatively fewer T-cell epitopes (mostly defined as CD4+/class II, with very few being defined for CD8+/class I). Likewise, most of the records related to the study of allergic reactions in humans, and fewer epitopes defined for mice and occasional epitopes defined for 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 pollens), while the majority of non-peptidic epitopes defined for drugs and biologicals (antibiotics).
Interestingly, the vast majority of food allergen-related epitopes were described for B-cells, whereas a fairly even number of B- and T-cell epitopes were defined for airborne 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.
Another unexpected finding of our analysis was that the epitopes defined in hosts other than humans were mostly T-cell epitopes, and far fewer antibody epitopes were defined. While it is surprising that so little of the nonhuman antibody responses are allergy-specific IgE; this may point to an important area for experimental investigation, to provide investigators with animal models faithfully reproducing human allergic reactions.
The current analysis also revealed that coverage of known human allergen by epitope definition studies is very sparse. The overall completeness of the epitope-specific allergy data with respect to known allergens on a species basis is about 40%. Furthermore, epitope data is available for only ~17% of all allergens listed by IUIS. For certain species, the majority (if not all) of the known allergens have epitope-related data (e.g., timothy grass allergens), while other species have epitope data from only a small number of known allergens (e.g., apple).
The recent completion of curation of non-peptidic allergy-related epitopes in the IEDB allows a first time inventory and assessment of important drug and contact allergens. The integration within the IEDB of representation and search capabilities based on the chemical entity of biological interest (ChEBI) (
Finally, our analysis also inventoried which epitopes have been used to actively induce allergic disease in animal models or to modulate disease. Only a handful of epitopes have been investigated for their immunotherapeutic potential. If the promising results from human clinical trials were to be verified in later phase trails, we anticipate that the data cataloged within the IEDB might provide a wealth of leads for therapeutic intervention regimens.
We gratefully acknowledge the helpful contribution of Alison Deckhut, Matthew Fenton, and Michael Minnicozzi in reviewing this paper. The La Jolla Institute 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.