Molecular Immunology 100 (2018) 3–13

Contents lists available at ScienceDirect

Molecular Immunology
journal homepage: www.elsevier.com/locate/molimm

WHO/IUIS Allergen Nomenclature: Providing a common language T

a b c d e
Anna Pomés , Janet M. Davies , Gabriele Gadermaier , Christiane Hilger , Thomas Holzhauser ,
Jonas Lidholmf, Andreas L. Lopatag, Geoffrey A. Muellerh, Andreas Nandyi, Christian Radauerj,
Sanny K. Chank, Uta Jappel, Jörg Kleine-Tebbem, Wayne R. Thomasn, Martin D. Chapmana,
⁎
Marianne van Hageo, Ronald van Reep, Stefan Viethsq, Monika Raulfr, Richard E. Goodmans, , on
behalf of the WHO IUIS Allergen Nomenclature Sub-Committee
a
Indoor Biotechnologies, Basic Research, Charlottesville, VA, USA
b
School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
c
University of Salzburg, Dept. of Molecular Biology, Salzburg, Austria
d
Luxembourg Institute of Health, Dept. of Infection and Immunity, Luxembourg, Luxembourg
e
Paul-Ehrlich-Institute, Division of Allergology, Langen, Germany
f
Thermo Fisher Scientific, Uppsala, Sweden
g
James Cook University, Molecular Allergy Research Laboratory, Townsville, Queensland, Australia
h
National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
i
ALLERGOPHARMA GmbH & Co. KG, Reinbek, Germany
j
Medical University of Vienna, Dept. of Pathophysiology and Allergy Research, Vienna, Austria
k
National Jewish Health, Dept. of Pediatrics, Div. of Allergy, Denver, CO, USA
l
Division of Clinical and Molecular Allergology, ARCN, DZL, Research Center Borstel, Borstel, Germany
m
Allergy & Asthma Center Westend, Outpatient Clinic & Clinical Research Center, Berlin, Germany
n
Telethon Kids Institute, University of Western Australia, WA, Australia
o
Karolinska Institute, Department of Medicine Solna, Immunology and Allergy Unit, Karolinska University Hospital, Stockholm, Sweden
p
Academic Medical Center, Deptartments of Experimental Immunology and Otorhinolaryngology, Amsterdam, The Netherlands
q
Paul-Ehrlich-Institute, Langen, Germany
r
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany
s
Food Allergy Research and Resource Program, University of Nebraska-Lincoln, Lincoln, NE, USA

A R T I C LE I N FO A B S T R A C T

Keywords: A systematic nomenclature for allergens originated in the early 1980s, when few protein allergens had been
Allergen database described. A group of scientists led by Dr. David G. Marsh developed a nomenclature based on the Linnaean
WHO/IUIS Allergen Nomenclature taxonomy, and further established the World Health Organization/International Union of Immunological
IgE Societies (WHO/IUIS) Allergen Nomenclature Sub-Committee in 1986. Its stated aim was to standardize the
Taxonomic name
names given to the antigens (allergens) that caused IgE-mediated allergies in humans. The Sub-Committee first
Isoallergen
published a revised list of allergen names in 1986, which continued to grow with rare publications until 1994.
Between 1994 and 2007 the database was a text table online, then converted to a more readily updated website.
The allergen list became the Allergen Nomenclature database (www.allergen.org), which currently includes
approximately 880 proteins from a wide variety of sources. The Sub-Committee includes experts on clinical and
molecular allergology. They review submissions of allergen candidates, using evidence-based criteria developed
by the Sub-Committee. The review process assesses the biochemical analysis and the proof of allergenicity
submitted, and aims to assign allergen names prior to publication. The Sub-Committee maintains and revises the
database, and addresses continuous challenges as new “omics” technologies provide increasing data about po-
tential new allergens. Most journals publishing information on new allergens require an official allergen name,
which involves submission of confidential data to the WHO/IUIS Allergen Nomenclature Sub-Committee, suf-
ficient to demonstrate binding of IgE from allergic subjects to the purified protein.

⁎
Corresponding author.
E-mail address: [email protected] (R.E. Goodman).

https://doi.org/10.1016/j.molimm.2018.03.003
Received 24 February 2018; Accepted 6 March 2018
Available online 04 April 2018
0161-5890/ © 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).
A. Pomés et al. Molecular Immunology 100 (2018) 3–13

Fig. 1. Historical perspective: A) Key discoveries in the allergy field. B) Developments in allergen nomenclature. Important milestones in development of clinical allergy and in
nomenclature are described.

1. Introduction During the past decades, advances in protein biochemistry and mo-
lecular biology have accelerated the discovery and characterization of
Early reports of adverse health problems that are thought to re- allergens, being generated by recombinant DNA technology for a variety
present allergies and asthma date back more than 3000 years from of applications, including basic and clinical research, allergen product
Egypt, Rome and China, but these are not well documented. Likely standardization, allergy diagnostics and development of novel ther-
cases of allergy to various inhalation sources or insect bites or stings are apeutic approaches. Investigation of individual patient sensitization
often dismissed as the nature and cause of the reactions were unknown. profiles has recently become possible via application of their sera to solid
Allergic diseases are complex and broad in terms of organs affected and phased purified allergens in single assays or on microarrays with over
severity, ranging from highly prevalent allergic rhinitis to life-threa- 100 purified allergens, to accurately identify IgE-binding proteins and
tening anaphylaxis (Cohen and Zelaya-Quesada, 2002). Progress in the sources that likely cause their symptoms. Clear IgE binding to 2S albu-
allergy field started in 1869 when Dr. Charles H. Blackley demonstrated mins of peanut or soybean or to oleosins in peanut are likely to indicate
that pollen was the apparent cause of his hay fever (Taylor and Walker, higher risks of severe reactions (Beyer et al., 2015; Ebisawa et al., 2013;
1973), and continued throughout the 1900s with the establishment of Schwager et al., 2017). Measuring specific IgE patterns can also help
immunotherapy using whole allergen extracts as a routine practice by guide clinicians to treat patients with allergen immunotherapy (Sastre
the 1970′s (summarized in Fig. 1). A need to develop a systematic et al., 2012). Clinicians seeing patients allergic to bee and wasp venom
nomenclature for allergens became apparent in the early 1980s, when may also improve diagnostic and therapeutic success for patients with
only few allergens had been identified and allergen names were in- so-called double-sensitizations using valuable molecular markers to
consistently used in publications. This article focuses on allergen no- prove primary sensitizations to the culprit venom (Seyfarth et al., 2017).
menclature in the context of Immunoglobulin E (IgE)-mediated aller- In the future, individual immunotherapeutic reagents and prescriptions
gies, directed against apparently harmless substances, mostly proteins may be available for improved therapy. These developments further
and glycoproteins from diverse biological origins. Allergen sources in- underpin the need for a consistent and unambiguous nomenclature of
clude pollen, mites, animal epithelia and saliva, fungi, insect venoms allergens. In parallel, the Allergen Nomenclature Sub-Committee has
and a variety of plant and animal foods. adapted to these changes by updating the criteria for defining a new
Allergen extracts contain many other proteins and components in allergen and the information requested in the submission form. This
addition to allergenic proteins. The first identified allergenic protein, article provides an update on these criteria and challenges facing the
antigen E (AgE), was isolated from pollen of short ragweed (Ambrosia existing system. Publishing the criteria ensures consistency and trans-
artemisiifolia) by King and Norman in 1962 (Marsh et al., 1981). Other parency of the process. Researchers are strongly encouraged to address
ragweed allergens identified at an early stage included Ra3 and Ra5 them, with support of appropriate data reported confidentially to the
(Marsh et al., 1981). Around the same time, proteins from ryegrass WHO/IUIS Sub-Committee, to demonstrate evidence of allergenicity in
pollen (Rye I and Rye II, later called Lol p I and Lol p II) were identified as order to receive an official allergen name prior to publication.
prominent allergens by Johnson and Marsh as reviewed in Freidhoff
et al. (1986). In the course of this and subsequent discovery work ori- 2. The beginning of the systematic Allergen Nomenclature: three
ginally aiming for a better understanding of HLA-associations with al- men in a boat 1980
lergic immune responses, the potential of using specific allergenic mo-
lecules for more precise diagnosis and possibly for immunotherapy was The idea for the current allergen nomenclature system originated from
gradually emerging (Yunginger and Gleich, 1972; Baer et al., 1980). a discussion among Drs. David Marsh (USA), Henning Løwenstein

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A. Pomés et al. Molecular Immunology 100 (2018) 3–13

(Denmark) and Thomas Platts-Mills (UK) during a boat ride on Lake 4. Current allergen nomenclature conventions
Constance (Bodensee), Konstanz, Germany, during the 13th Symposium of
the Collegium Internationale Allergologicum in July 1980 (Marsh et al., As defined in the 1994 revision, allergen names consist of the first
1986; Chapman, 2004). The revised nomenclature system was first de- three letters from the genus, one letter from the species epithet, fol-
scribed in the Bulletin of the World Health Organization by the committee lowed by an Arabic numeral. Occasionally, a letter is added to the genus
of clinicians who joined the International Union of Immunological Society (Sola for tomato, Solanum lycopersicum, as Sol was used for multiple ant
(IUIS) Sub-Committee for Allergen Nomenclature, with David Marsh as species, Solenopsis sp.) or to the species (Hel as 1 for a snail Helix aspersa
Chair (Marsh et al., 1986). Many of the Sub-Committee scientists listed in as Hel a was used for sunflower, Helianthus annuus) abbreviation to
the 1986 publication have been active in the evolution of rules and de- differentiate otherwise identical names of allergens from different
cisions on proposed allergen nomenclature. Other members have chaired species. Sometimes, the taxonomic name of the species is changed (e.g.
the Sub-Committee over time (Wayne Thomas, Heimo Breiteneder and Betula verrucosa became Betula pendula), but the Sub-Committee might
now Richard E. Goodman), with Jørgen N. Larsen pioneering the devel- decide to keep the same original allergen name if it has been widely
opment of a web site, which was refined by John Wise at the University of used in the literature (e.g. Bet v 1 for the major birch pollen allergen).
Nebraska. In 2017, there are 22 active members and five members at large Allergens from the same source are classified in biochemical groups
(listed on the website). The website http://allergen.org/originally showed (designated by Arabic numeral that contains two digits), usually ac-
allergens and information as a simple table, while a searchable database cording to the order in which they were identified (e.g. Der p 1 or Bet v
was established in 2007 and entries are since then added as they are 1). When possible, allergens from different species, related up to the
agreed upon by the Sub-Committee. taxonomic level of family or order, that belong to the same biochemical
Allergen names are assigned by the WHO/IUIS Allergen protein family will be assigned the same number across species.
Nomenclature Sub-Committee through a defined submission process as However, due to the historical naming convention, some allergens of
described in Section 5. This process ensures that an appropriate, ap- the same biochemical protein family have been assigned different
proved and non-redundant name is assigned to the allergen for any numbers (e.g. pectate lyases Amb a 1 and Art v 6, PR-10 proteins Bet v 1
further publication. The benefit of this nomenclature system is that and Ara h 8, or the profilins Amb a 8, Bet v 2, Phl p 12 and Art v 4).
allergens are named in a properly documented, consistent and un- Within each group, allergens can be isoallergens or variants (isoforms)
ambiguous manner, creating and maintaining clarity amongst the sci- depending on their amino acid sequence identity. Isoallergens are
entific, clinical and regulatory communities. homologous allergens that share the following common biochemical
properties: similar molecular size, similar or identical biological func-
3. Evolution of allergen names tion, if known, and an amino acid sequence identity of at least 67% (as
a guideline not always followed if justified). Each isoallergen may have
During the early 1980′s, the Sub-Committee established guidelines multiple forms of highly identical sequences (> 90% identity, typically
for naming allergens based on the taxonomic name of the source or- differing in only few amino acids), which are designated as variants (or
ganism. Original allergen names comprised the first three letters of the isoforms). Isoallergens and their variants defined in this way are dis-
genus and the first letter of the species epithet (both in italics) followed tinguished by numerical suffixes following a dot after the allergen
by a Roman numeral to indicate the allergen in the chronological order number. The first two numerals 01–99 refer to a particular isoallergen
of isolation from the same source (Marsh et al., 1986). The publication (e.g. Amb a 1.01 and Amb a 1.02), and the two subsequent numerals
described the requirements for data that should be provided as pre- 01–99 define each variant of a particular isoallergen (e.g. Amb a 1.0101
requisite for naming allergens including and Amb a 1.0102). Generally, allergen names should always be spelled
out in full and partial abbreviation of allergen names (e.g. Ara h 1/2 or
- molecular weight (estimated mass by SDS-PAGE or gel-filtration), Ara h 1 and 2) is discouraged.
- isoelectric point,
- amino acid composition or sequence, and 5. Review process by the Allergen Nomenclature Sub-Committee
- immunochemical characterization, i.e. allergen recognition by pa-
tient IgE and/or animal antisera. The review process of a candidate allergen is shown in Fig. 2. The
scientist submitting a protein as a candidate allergen should complete
Epidemiology of allergens was called for in early publications of the the submission form (www.allergen.org) and forward it to the Sub-
Sub-Committee in terms of frequency of positive IgE binding from 20 to Committee Chair by email. The scientist may suggest an allergen name
30 human subjects. Over time, as biochemical, immunochemical and (including isoallergen and variant number) based on current WHO/IUIS
biophysical methods have improved, the expectations for description of nomenclature.
allergens have grown and several nomenclature conventions have been Each submission is assigned for review to two or three members of
changed including a requirement of fewer subjects. the Sub-Committee, selected by the Chair of the Sub-Committee ac-
In 1994, the nomenclature was revised, so that allergen names cording to their area of expertise. Any possible conflict of interest with a
would not be in italics (reserved for genes), and the Roman numbers potential reviewer can be indicated by the scientist submitting the form
were replaced by Arabic ones (e.g. Amb a 1, Der p 1) (King et al., 1994). on the first page. The submission is held confidential within the Sub-
The 1994 update included a statement that sequence information would Committee until a final decision is made. In case of uncertainty re-
be required for new allergens (described in Radauer et al., 2014). The garding particular criteria, descriptions or methods used, additional
focus was on the amino acid (AA) sequence of the protein which is the information may be requested. Final decisions are made by the Sub-
relevant target for IgE. However, criteria for acceptance of sequences to Committee, based on the current criteria for allergen nomenclature, and
the database have been adjusted over time as methods of protein de- communicated to the investigators who should then use the assigned
termination have improved. A few new allergens were identified in a name in their publication and in sequence databases. The process
1995 WHO/IUIS update (King et al., 1995). normally requires two weeks from submission to review, but may re-
In the 1990s, many allergens were being cloned and expressed as quire longer depending on a need for additional data.
recombinant proteins and that led to the identification of multiple,
highly homologous sequences. Then the WHO/IUIS Allergen 6. Essential criteria for acceptance of a protein as an allergen in
Nomenclature Sub-Committee recognized the need to name homo- the database
logous allergens in the same organism as either isoallergens or variants
(isoforms), as described below. Acceptance of a protein as an allergen in the database essentially

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A. Pomés et al. Molecular Immunology 100 (2018) 3–13

Fig. 2. Summary of workflow for the submission and evaluation of candidate allergens to the WHO/IUIS Allergen Nomenclature Sub-Committee. In many cases questions are
forwarded to submitters in order to assure an appropriate science-based review. The goal is to provide a decision within two weeks, but sometimes decisions are delayed. Submitters
should contact the Chair if they have questions.

relies on the demonstration of its presence in the source that causes The amino acid sequence of the protein should be deposited in a
allergies, characterization of the protein by standard methods of bio- general protein database (UniProt or GenBank Protein) and the acces-
chemistry and molecular biology (Section 6.1), and, most importantly, sion number specified in the application form. The experimentally de-
the proof of specific recognition by relevant human serum IgE (Section termined protein sequence, as well as the determined DNA sequence,
6.2). The main criteria for acceptance of a candidate allergen, sum- should be entered in the submission form. If the amino acid sequence is
marized in the decision chart of Fig. 3, are: incomplete (due to gaps for example), each amino acid gap should be
entered as “xxx”. In cases where only a partial sequence was de-
• Description of the allergenic source, including taxonomic name. termined by N-terminal or LC–MS/MS sequencing, which is identical to
• Information on the purification and characterization of the candi- a published protein sequence from the same species, the accession
date allergenic protein including amino acid sequence. number of the published sequence should be added with a clear note in
• Description of the allergic human serum donors used to test IgE the submission form. If the sequence has not been published before, the
binding to the candidate protein. authors have the option to request that a non-public sequence remains
• Demonstration of specific IgE binding with five sera of relevant confidential until publication.
patients. To enable evaluation of potentially confounding data, scientists
submitting a name are encouraged to provide additional information
Over time, the WHO/IUIS Sub-Committee has refined the criteria such as glycosylation state and purity of the protein isolated from the
for inclusion of proteins in the allergen database, as methods of testing natural source or recombinant allergen. For glycosylated proteins, al-
by investigators and knowledge of allergen structures have improved though not required, possible involvement of the glycan in IgE binding
(Chapman et al., 2007, Breiteneder and Chapman, 2014). The database could be assessed following deglycosylation or by performing an in-
currently includes 880 allergens, about 100 of which have had their hibition assay using a high glycan source such as phytohemagglutinin
three-dimensional structure determined (Pomés et al., 2015). Demon- (PHA) from Phaseolus vulgaris. Alternatively, IgE reactivity with a non-
strated biochemical function and tertiary structure are not necessary to glycosylated recombinant allergen protein provides evidence that car-
obtain a name from the Sub-Committee, but may help in the overall bohydrate binding is not essential for allergen recognition if the re-
understanding of allergenicity and potential cross-reactivity. combinant protein has been demonstrated to fold like the native al-
lergen. If the protein identity has been verified by monoclonal
6.1. Analysis of candidate allergens by biochemistry and molecular biology antibodies, the identity of the hybridoma and the assay method used
should be described to allow the Sub-Committee to evaluate the quality
The WHO/IUIS allergen database includes only proteins and gly- and relevance of the data presented. If the cDNA sequence was de-
coprotein allergens. Ideally, the full amino acid and nucleotide se- termined by polymerase chain reaction (PCR) the sequence and position
quence of the allergen should be provided on the submission form. If of primers should be described. If the sequence has already been pub-
the full sequence is not available (i.e. for purified native allergens that lished, the reference should be provided. If the sequence and descrip-
have not been cloned), a partial amino acid sequence must be de- tion was already presented at a scientific conference, the abstract and
termined (i.e. by mass spectrometry). poster or relevant presentation slides should be provided.
The apparent MW of the protein should be estimated based on mi- Finally, IgE-mediated allergies are also induced by small molecules
gration compared to standards in SDS-PAGE, by size exclusion chro- if bound to carrier proteins (e.g. human serum albumin). These are low-
matography, by mass spectrometry, or by calculation based on the MW organic compounds such as various drugs (e.g. antibiotics, muscle
amino acid sequence. Mass spectrometry determines the absolute mo- relaxants, opioids) and various organic compounds that can act as IgE-
lecular mass and is more definitive than SDS-PAGE, but its use is not a binding haptens and cause clinical reactions (Deak et al., 2016). There
mandatory requirement. are also certain carbohydrate structures, such as specific plant- or

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A. Pomés et al. Molecular Immunology 100 (2018) 3–13

Fig. 3. Essential criteria for allergen acceptance.

The primary questions of the submission form are
designed to allow the reviewers to understand what
was done, how complete the characterization of the
allergen candidate was, indicating the protein se-
quence and physical characteristics, the selection of
serum donors, tests for IgE binding as well as biolo-
gical tests (SPT or BAT). The scientists submitting the
form should provide enough information to demon-
strate that their protein is most likely to be an al-
lergen.

insect-derived asparagine-linked glycans, commonly called cross-re- patients is not required, but adds value in demonstrating mast cell
active carbohydrate determinants (CCD) that can bind IgE, but rarely or degranulation. Such tests should only be performed following informed
never elicit allergic reactions (Van der Veen et al., 1997; Foetisch et al., consent of subjects, ethical review panel approval and appropriately
2003; Mari et al., 2008). The carbohydrate structure galactose alpha- controlled, sterile antigens.
1,3 galactose (alpha-gal), present on many non-primate mammalian Proof of allergy to the allergen source is also preferred. In general,
proteins, has recently been found to cause severe delayed IgE-mediated the route of exposure might contribute to identify symptoms. For ex-
reactions following consumption of red meat in those who have been ample, the natural route of pollen, animal dander, fungal spores and
sensitized by salivary proteins from tick bites (Commins et al., 2009; airborne occupational allergen exposure is inhalation. Thus, rhino-
Commins and Platts-Mills, 2013). Similar relationships between tick conjunctivitis or asthma is the expected clinical outcome. Food aller-
bites and meat allergy have been found in Europe (by the tick Ixodes gens should be linked to objective symptoms of oral allergy syndrome,
ricinus; Hamsten et al., 2013a; Hamsten et al., 2013b; Wilson et al., angioedema of the larynx, symptoms from the gastro-intestinal tract or
2017), as well as Asia (Chinuki et al., 2016). These glycoproteins are systemic symptoms such as urticaria, asthma or anaphylaxis after
unusual targets of IgE binding. Since the antibody recognition is di- consumption of the food. Insect bites or stings should generally include
rected to the glycan structure rather than the protein structure, they are urticaria plus angioedema as well as other possible systemic reactions.
not included in the WHO/IUIS database as allergens unless IgE binding However, exceptions will always occur. Skin symptoms after ingestion
has been demonstrated against the deglycosylated (unglycosylated) of allergens are quite common, and the same is true for respiratory
protein. symptoms. Patients with urticaria might not be the best candidates for
skin testing. For some allergens (e.g. from mites) it is difficult to relate
6.2. Proof of allergenicity of the newly identified proteins clinical symptoms to natural exposure. Also, some individuals with high
levels of allergen specific IgE or skin test reactivity are asymptomatic
Allergens are usually only accepted in the database if the purified upon natural exposure (Abraham et al., 2007). Therefore, in some cases
protein is demonstrated to specifically bind IgE antibodies from at least larger samples might be required to demonstrate the association with
five patients allergic to the respective allergen source. Specificity is clinically relevant allergy.
demonstrated by lack of IgE binding in atopic and non-atopic control Sensitization and/or elicitation of an allergic response to the source
donors. Exceptions to the patients’ number may be made in particularly (allergen extract) may be demonstrated in vitro by basophil activation
justified cases (such as in the field of occupational allergy or allergens or in vivo through inhalation, ingestion, intradermal injection, prick-to-
in novel foods or new products), where it might be difficult to find five prick tests or mucosal contact if performed under institutional review
specifically allergic patients to prove allergenicity. In these cases, ad- board guidance and following ethical approval.
ditional proof of allergenicity might then be requested, such as IgE Positive reactions should be based on criteria such as at least three
immunoblots, dot blots, ELISA, basophil activation tests or mediator mm wheal size for allergen extracts greater than the negative SPT
release assays (i.e. RBL) with the pure allergen. The IgE binding should control or greater than an established cut-off (e.g. three times the
be tested in a described and well controlled assay with the purified standard deviation of negative control subjects by in vitro IgE binding
(natural or recombinant) allergen. Data from in vivo provocation of for ELISA) for extracts or the purified protein.

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A. Pomés et al. Molecular Immunology 100 (2018) 3–13

7. Challenges to the Allergen Nomenclature Sub-Committee sequence identities. One is the ragweed allergen Amb a 2 that has a
high amino acid sequence identity to group 1, and was therefore
7.1. Revision of allergen names renamed as Amb a 1.0501. The other is a seed storage glycinin al-
lergen in peanut, Ara h 4 that is > 90% identical to Ara h 3.0101
Due to the risk of confusion and the fact that some names have and it was therefore renamed as Ara h 3.0201 in 2012.
already been published, the WHO/IUIS Sub-Committee generally takes
a conservative position regarding changing allergen names. However, 7.2. Difficulty in naming certain allergens
some allergen names have been revised or further specified as the ori-
ginal characterization was incomplete or associations were determined Some allergens are difficult to name for different reasons.
to be wrong based on new evidence.
7.2.1. Complexity
1. The seed storage proteins of soybean provide two examples. The Gly The major cat allergen Fel d 1 (Morgenstern et al., 1991), has a
m 5 protein is a complex of three beta-conglycinin subunits that crystal structure similar to that of secretoglobin (Kaiser et al., 2007).
were not characterized at the time the allergen name was assigned. This allergen is a tetrameric protein formed by two heterodimers of
One subunit is now known as beta-conglycinin alpha (67 kDa), the chain 1 and chain 2, which are encoded by separate genes. Unlike Gly m
second as beta-conglycinin alpha’ (71 kDa) and the third as beta- 5 and Gly m 6 mentioned above, two different proteins are under one
conglycinin beta (50 kDa) as described by Holzhauser et al. (2009). allergen name, Fel d 1.0101 (King et al., 1995). The allergen has a
The alpha- and alpha′- subunits are approximately 82% identical. unique structure and there is no evidence of IgE cross-reactivity with
The sequence of the beta-subunit is only 76% identical to the two secretoglobulins of other species (Hilger et al., 2014). A revision of this
alpha subunits. The three subunits fit together to form a trimeric name in the future is possible but unlikely, given the widely spread use
structure. However, different ratios of Gly m 5 subunits form mul- of Fel d 1 in the scientific community.
timeric associations in protein bodies of the soybean (Maruyama
et al., 2002). IgE from soybean allergic subjects may bind to one, 7.2.2. Low amino acid identity
two or three subunits of Gly m 5. The protein complex was originally Glutathione S-transferases (GST) from cockroach are structurally
named Gly m 5, but following analysis of intact complexes, various and functionally related and belong to different GST classes. GSTs at-
combinations of beta-conglycinins were identified to form the tach a glutathione molecule to highly different substrates leading to the
multimeric complexes (Holzhauser et al., 2009). Therefore, the in- high GST diversity regarding function and sequence. The question is
dividual subunits were finally named as isoallergens Gly m 5.01, Gly whether allergens with a similar biochemical function deserve the same
m 5.02 and Gly m 5.03 in 2009, with minor variants (e.g. Gly m group number, despite highly different sequences. It seems that iden-
5.0301 and Gly m 5.0302). tical group numbers within a species should generally alert scientists to
2. Similarly, glycinin (Gly m 6) was also named with an understanding the possibility of cross-reactivity. Nevertheless, cockroach GSTs from P.
that the whole protein has a complex hexameric structure, made of americana and B. germanica were assigned to the same group 5, despite
combinations of different subunits (Nielsen et al., 1989). With fur- their low amino acid identity (15.7% between Bla g 5 and Per a 5; way
ther gene and protein characterization, it was recognized that at under the suggested threshold of 67% to be in the same group as iso-
least five genes encode the subunits (Nielsen et al., 1989) and the allergens). More recently the Sub-Committee is trying to reserve the
allergen can be an arrangement of these five proteins which have same number for homologous proteins from different species.
individual IgE binding properties (Holzhauser et al., 2009), and
which were renamed as five isoallergens in 2009. 7.2.3. Hydrophobic nature of some allergen parts
3. Bovine milk casein was originally named Bos d 8, but full char- Oleosins are hydrophobic allergens with an unusual hydrobophic
acterization has demonstrated that it is composed of complexes core and few hydrophilic sections responsible for IgE antibody binding.
made up of four primary proteins (Willis et al., 1982). One is now Assignment of names to oleosins was difficult, because the molecular
called Bos d 9 (alpha S1 casein) as described by Nagao et al. (1984). structure was taken into consideration to dissect and compare only the
The other caseins are defined as Bos d 10 (alpha S2 casein), Bos d 11 hydrophilic portions of the protein. Other proteins challenging to
(beta casein) and Bos d 12 (kappa casein) with IgE binding defined analyze for the purpose of assigning an allergen name include vitello-
by Natale et al. (2004). These proteins have high sequence diversity genins of chicken (Walsh et al., 1988). Vitellogenins are encoded as
and they form complexes associated with calcium ions involved in a polyproteins and expressed in the liver as phospholipoproteins, then
micellar structure. IgE antibodies from cow’s milk allergic subjects transported via blood and taken up and processed in egg yolk. The
may bind to any combination of these subunits. Additional IgE process includes proteolysis into independent shorter proteins and one
binding from cow’s milk allergic individuals involves beta-lacto- has been listed now as an allergen by WHO/IUIS (Gal d 6) (De Silva
globulin, alpha-lactalbumin and for some, IgG or lactoferrin. et al., 2016). Similar cases were reported earlier for fish roe proteins
4. There are examples of homologous allergen domains or whole al- (Shimizu et al., 2009). The proteins are complex and assignment of IgE
lergens from grass pollen of related species (Lolium sp, Dactylon sp, binding has often been to the holoprotein.
and Phleum sp.) with proteins sharing considerable sequence identity
which are difficult to assign to either the same or a different group. 7.3. Assignment of names to isoallergens or variants (isoforms)
For example, Lol p 2 and Lol p 3 share approximately 60% identity.
Dag g 2 is 60% identical to Lol p 3, 65% identical to Dac g 3 and Isoallergens or variants (isoforms) are currently defined based on
65% identical to Phl p 2, which is within the differences in isoforms their amino acid sequence identity, but they might be originated in
accepted by the Sub-Committee. However, both grass pollen groups different ways (Table 1). In some cases, information on whether they
2 and 3 were kept separate as there is high conservation across are encoded by separate but related genes or the same gene with
species and a marked reduction in sequence identity between group polymorphisms could assist in the identification. For example, there are
2 and group 3 proteins among grass pollen. There is also some 7 gene loci that encode beta expansins in Johnson grass pollen, in-
homology to group 1 beta-expansin proteins of the group 2 and 3 cluding Sor h 1. The two allergens Sor h 1.0101 and Sor h 1.0201 are
grass pollens though the major group 1 beta-expansin grass pollen encoded by separate gene loci (Campbell et al., 2015). Similarly, the
allergens including Lol p 1 are much longer proteins and share little cockroach allergens Bla g 1.0101 and Bla g 1.0201 are listed as iso-
IgE cross-reactivity (Devanaboyina et al., 2014). allergens due to the high sequence similarity, but recent genomic evi-
5. Two examples exist of allergens that were renamed due to high dence suggests they are distinct gene products (Fig. 4). Investigators are

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A. Pomés et al. Molecular Immunology 100 (2018) 3–13

Table 1
Possible origins of isoallergens, variants and other types of allergen heterogeneity.

Type of heterogeneity Origin Characteristics Known examples in the

Allergen Nomenclature
database

Dispersed amino acid sequence Allelic One isoallergen/variant per haplotype.a Der f 2; Bet v 1 variants
variability. Named as isoallergens Differential IgE antibody recognition of isoallergens are in part allelic
or variants, depending on level of may occur but is less likely for variants.
sequence divergence. Multigene family Multiple isoallergens/variants, encoded by different Bet v 1
genes per haplotype, may be present per organism.a
Differential IgE antibody recognition of isoallergens Ara h 2
may occur but is less likely for variants.
Size and/or charge distribution Posttranslational modifications such as addition Each individual proteins may contain multiple No examples
of carbohydrate, phosphate groups, hydroxy- postranslationally modified allergen forms.
proline, C-terminal proteolytic cleavage or other Differential IgE antibody recognition of glycoforms
moietiesb may occur.
Chemical composition Chemical modification of the allergenb Modification of the allergen during airborne transport No examples
(for aeroallergens), storage and processing (for food
allergens), or preparation of extracts, e.g. oxidization,
reactions with polyphenols, Maillard reaction during
roasting of foods.
Block differences: amino acid sequence Different protein cleavage Each individual contains multiple differentially Hev b 6.02 and Hev b 6.03
differences in segment/s of the cleaved forms.
protein. IgE antibody recognition may be affected depending
on epitope distribution.
Alternative mRNA splicing None yet identified for allergens. No examples
Modular differences: Different subunit Alternative subunit composition Each individual contains multiple allergen forms, Gly m 5, Gly m 6
(entire gene product) composition. depending on subunit combinations.
IgE antibody recognition may be affected depending
on epitope distribution.

a
Polyploidy (more than two haplotypes) will further increase the number of genes (each of which can harbor different allelic isoallergens/variants).
b
This kind of modification does not lead to different isoallergens or variants.

Fig. 4. Genetic and chemical structure of group 1 Blattela germanica

allergens. A) Bla g 1 isoallergens are encoded by different genes (in
italics), which are composed of fully and partially repeated genetic ele-
ments indicated by the boxes. Blue rectangles represent regions with
76–99% sequence identity to either the yellow or green rectangle. The
defined allergens at WHO/IUIS only partially cover the full open reading
frame. B) The structure of the second half of Bla g 1.0101 was de-
termined (4JRB, Mueller et al., 2013). The yellow and green coloring
corresponds to the portion of gene similarly colored in A. The long lin-
kers between structured elements suggest the full protein will resemble
beads on a string. (For interpretation of the references to colour in this
figure legend, the reader is referred to the web version of this article.)

not required to provide information on gene structure or location, but allergenic proteins are allergens themselves, binding IgE and if so,
as this information becomes available it might help to improve the whether patients show symptoms upon exposure. Antibody cross-re-
understanding of protein structures and potential name assignments. activity can occur with only few amino acids (1–3) in common between
New isoallergens will only be accepted in the database if IgE binding homologous proteins (Glesner et al., 2017), but it does not necessarily
has been demonstrated to the isoallergen. New variants will only be translate into clinical cross-reactivity. Serum IgE cross-reactivity has
accepted if there is justified evidence that the variant is expressed in the been observed between PR-10 related allergens from birch pollen (Bet v
organism and tissue causing allergies. The use of PCR based cloning 1), apple (Mal d 1) and other plant-derived foods. However, birch
techniques and genome analysis has increased the potential identifi- pollen is usually the primary sensitizer and elicitor of the allergic im-
cation of erroneous sequences. The committee would like investigators mune response, whereas cross-reactive IgE binding to Mal d 1 is often of
to sequence multiple clones from independent experiments and to lower avidity, or may involve a single IgE epitope and therefore may or
provide accurate information on the source and methods used to de- may not be clinically relevant for individual patients. Similarly, there
termine sequences. Ideally, the existence of the protein in the natural are patient-specific patterns of IgE cross-reactivity to fish parvalbumins
source should be verified by mass spectrometry or N-terminal sequen- coupled with clinical sensitivity to some fish, but not to other fish
cing with sufficient length to verify that the protein sequence matches species (Kuehn et al., 2014) or to chicken (fish-chicken syndrome)
the nucleic acid sequence. Additional information for inclusion into the (Kuehn et al., 2016). There are numerous examples of reactivity to
database are the characterization of the purified recombinant variant, homologous allergens from multiple allergen sources that can be ex-
confirmation of the source and identity of the organism, as well as IgE plained by IgE cross-reactivity. For example, there is cross-reactivity
reactivity with the recombinant protein. among lipocalins Can f 6 of dog dander, Fel d 4 of cat dander and Equ c
1 of horse dander (Nilsson et al., 2012). Each of these three allergens
can act as primary sensitizer, co-sensitizer or cross-reacting molecule,
7.4. Cross-reactivity might impair the identification of source-specific depending on the exposure profile of the patient. Cross-reactivity with
allergens Can f 6 was responsible for a clinically relevant positive specific IgE to
dog dander in a horse allergic patient (Jakob et al., 2013). Data on
Considerations include whether proteins that are homologs of

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A. Pomés et al. Molecular Immunology 100 (2018) 3–13

sequence and structural similarity combined with serum IgE binding genomic and transcriptomic data, detection of the proteins in the al-
must be carefully evaluated as demonstrated by the studies of IgE lergenic source material is essential. Predictive models of allergenicity
binding and allergy of Ole e 1 (olive pollen allergen), Fra e 1 (ash pollen based on sequence identity are not reliable due to the wide variations in
allergen) and Pla a 1 (English plantain pollen allergen). The overall the percentage of amino acid sequence identity that is associated with
structures are similar as could be predicted to some extent by sequence, cross-reactivity, and the lack of knowledge regarding the actual epi-
yet there is a clear gradation of IgE binding among patients, with un- topes for these proteins. Other factors are important for allergenicity,
ique clinical responses (Stemeseder et al., 2017). Thus, sequence or such as abundance and structural stability for food allergens or solu-
structural information alone is judged insufficient to name a protein as bility for aeroallergens. Thus the WHO/IUIS Sub-Committee strives to
an allergen. stimulate appropriate characterization of allergenic proteins and de-
monstration of IgE binding from appropriate human volunteers, to
7.5. Is the Sub-Committee naming too many allergens? demonstrate that a given protein is likely to cause allergy.

The WHO/IUIS Allergen Nomenclature database lists 17 allergens in 7.7. Assignment of names before publication
peanut Arachis hypogaea, 31 in house dust mite Dermatophagoides far-
inae, 20 in Dermatophagoides pteronyssinus and 23 in Aspergillus fumi- The goal of the WHO/IUIS Allergen Nomenclature Sub-Committee is
gatus. Some of those are likely minor allergens or only hypothetical to assign names to allergens before publication. The purpose is to as-
proteins from cDNA (such as Tri a 42 and Tri a 43 in wheat). Some sociate a name with the original publication. However, the danger of
simply have a low IgE binding capacity for some subjects that is only this process is that the data used to characterize the allergen have not
detected when presented at high concentration by in vitro assays, and been evaluated through peer-reviewed publication. In the last four
might not contribute to the IgE binding to the source because the al- years, the Sub-Committee has been asking for more comprehensive
lergen might not be well represented in the allergenic material or al- information prior to accepting a candidate as an allergen, and the
lergenic extracts (Casset et al., 2012). Others, like Der p 23, turned out submission form has been modified accordingly to reflect that and it
to be significant allergens (Weghofer et al., 2013). In contrast, some will likely continue evolving. One goal of this publication is to en-
allergens such as Der f 22, which shows a low identity (∼40%) to Der f courage investigators to meet the need for more relevant information
2 and no publications demonstrating evidence of IgE binding or re- prior to submission.
activity in the literature for nearly 10 years, probably should not have Journals cannot rely on reviewers to make sure that correct allergen
been accepted by the Sub-Committee. Der f 22 will be re-reviewed and nomenclature is used in publications unless it is emphasized by the
might be removed from the database unless new evidence is uncovered editorial office and forms part of the “Instructions to Authors”. Allergen
by the Sub-Committee in the future. The Sub-Committee is considering names are sometimes published that do not comply with the official
removing other allergens from the database. Some allergens (such as WHO/IUIS nomenclature, causing inconsistencies in the literature.
the tomato allergens Sola l 2), bind IgE only through carbohydrates, Currently, journals (especially journals that are not only allergy fo-
and this IgE is not clinically relevant. In other cases, IgE binding to high cused) still sometimes do not publish names accepted by the Sub-
concentrations of purified proteins that are naturally low in abundance Committee. To help improve the correct assignment and use of allergen
can mislead the assessment of a protein as an allergen. In these situa- names, the WHO/IUIS Allergen Nomenclature Sub-Committee has
tions, the use of non-glycosylated recombinant proteins at concentra- contacted in 2017 the editorial offices of the main journals that publish
tions mimicking natural protein abundance would assist in assessing allergen studies, to request the implementation of a policy requiring the
IgE binding to the desired protein. use of the official allergen nomenclature in their publications. There has
been a positive response from the journals and most of them have al-
7.6. Integration of big data from ‘omics’ research ready implemented such a change of the instructions to authors.
Some allergens not recognized and listed by the WHO/IUIS have
The application of massively parallel DNA and transcriptome se- been published in journals indexed in PubMed. Even more commonly,
quencing, proteomics, bioinformatics, mass-spectrometry and protein genomics, transcriptomics and proteomics projects are assigning pro-
chemistry processes coupled with sensitive high or multi-allergen array teins in sequence databases (e.g. GenBank) with “allergen-like” names
immunoassays is markedly increasing the capacity for data generation or even listing proteins or genes with a WHO/IUIS-like name, however,
and discovery. Through studies of whole allergen source tran- without having provided evidence-based data on protein allergenicity.
scriptomics and genomics, it is evident that multiple gene copies exist in Authors are encouraged to submit such allergens to the Sub-Committee
a given source for a single protein family that contains allergenic as for its consideration and having an official name assigned.
well as non-allergenic members. Thus not all putative allergen gene
sequences actually encode allergens. This may be for a variety of rea- 8. Other allergen sequence and structure databases
sons including that some gene loci are pseudogenes. Not all “genes” are
transcribed, translated and processed in the relevant tissue at the time Several publicly available allergen databases exist with different
when or location where sensitized individuals are exposed. Examples of purposes, strengths and weaknesses (reviewed by Radauer, 2017). The
this include the greater number (six of seven) genes encoding Johnson WHO/IUIS allergen nomenclature database provides a systematic and
grass pollen beta-expansin proteins that can be confirmed within the official allergen nomenclature for many allergens. Allergome (www.
pollen proteome, whilst only two of these gene loci encode IgE reactive allergome.org) comprises a large amount of partially filtered informa-
proteins isoforms. Similar findings have been observed and/or pro- tion and references of allergens, public references for the proteins and
posed for the multiple beta-expansin gene loci of rice (Devis et al., links to many reference sources. AllergenOnline (www.allergenonline.
2017) and Sorghum bicolor (Paterson et al., 2009) and profilins of rice org) is a peer-reviewed risk assessment tool for food safety and includes
(Devis et al., 2017). Other examples are the polcalcin protein family allergens from all sources (Goodman et al., 2016). AllergenOnline is
with the allergen Phl p 7, parvalbumins of fish (e.g. Gad m 1) and the updated annually with reviews of individual proteins and data of IgE
PR-10 family, which includes Bet v 1 from birch pollen (Erler et al., binding and clinical responses after publication of data on the allergens
2011). and allergenicity. The COMPARE database (comparedatabase.org)
Currently, there is good knowledge of many protein families that hosted by the Health and Environmental Sciences Institute was derived
contain allergens (Radauer et al., 2008). Yet many proteins within the from the AllergenOnline.org database (> 99% of entries in COMPARE)
families are not known to cause allergy. Although there are numerous and shows the same “year adopted” for entries as in the AllergenOnline
publications that attempt to predict allergens using bioinformatics with database. It does not yet have a sequence search system, but is intended

10
A. Pomés et al. Molecular Immunology 100 (2018) 3–13

to eventually be a risk assessment tool similar to AllergenOnline. The 10. Conclusions

Structural Database of Allergenic Proteins database (SDAP, fermi.utm-
b.edu) is linked to a structural database source and is intended as a risk The WHO/IUIS Allergen Nomenclature Sub-Committee serves as an
assessment tool. The Immune Epitope Database (IEDB, www.iedb.org) expert professional group that reviews supporting evidence of aller-
provides information on T-cell and B-cell epitopes as well as MHC genicity of proteins, assigns names and manages an official list of re-
binding proteins of many proteins including pathogens, viruses, bac- cognized allergens. The Sub-Committee also clarifies the understanding
teria and some allergens. The AllFam database (www.meduniwien.ac. of qualities of allergen molecules and focuses current thinking about the
at/allfam) focuses on protein families of allergens based on information criteria for allergenicity of proteins from molecular, biochemical, in
from publications, from WHO/IUIS, AllergenOnline and Pfam data- vitro immunoassay-based methods as well as clinical perspectives.
bases. Users of these databases should understand the information and Investigators are encouraged to follow the criteria set by the Sub-
intent of each of these databases and their limitations. Committee to provide evidence-based data on allergenicity prior to
submitting an allergen. Ultimately, whether a protein is an allergen for
9. Future directions and new initiatives a particular patient depends on the level of sensitisation, exposure and
clinical allergy status. As the introduction of allergen components has
A The Sub-Committee has had recognition and some financial support had major impact on analytical sensitivity, specificity and allergy di-
from the International Union of Immunological Societies (IUIS) for a agnosis (Matricardi et al., 2016), allergen nomenclature will remain
number of years. In 2016 the Sub-Committee gained additional and become increasingly important in the context of the application of
support from the European Academy of Allergy and Clinical the wide array of “omics” technologies in allergy research. In the future,
Immunology (EAACI) that recognized it as one of its committees. In the WHO/IUIS Allergen Nomenclature Sub-Committee will continue to
2017, support was gained from the American Academy of Allergy, provide expertise and criteria to evaluate evidence of the specificity of
Asthma and Immunology (AAAAI). The time and effort needed to IgE binding for candidate allergens. These criteria will most likely
maintain the database and for members to provide careful review of evolve as additional data are generated from new technologies. Re-
submissions is considerable. All members act on a voluntary basis, cently, there has been an explosion of “Big Data”, from various “omics”
without financial compensation. techniques that will impact on the submissions to the database. The
B Allergen database hosting. From 2007 through 2017 the WHO/IUIS continued activities of the WHO/IUIS Allergen Nomenclature Sub-
database was hosted without charge in the Department of Food Committee are an important component of the review process to assign
Science & Technology, on a Food Allergy Research and Resource names to allergens before peer-reviewed publication. These activities
Program server at the University of Nebraska-Lincoln (USA). The help scientists and reviewers to focus on relevant data supporting
Who/IUIS database was transferred to the EAACI computer server in characterization of allergens and IgE binding, and stimulate more rig-
November 2017 and the cost of maintaining the database will be orous review of clinical implications applied to allergens. The assign-
shared by the IUIS, EAACI and AAAAI. The WHO/IUIS Allergen ment of reliable names to allergens is useful for pharmaceutical com-
Nomenclature Sub-Committee is now an official committee in the panies making diagnostic and therapeutic materials for patients, helps
EAACI organization. provide information as the medical field of allergology continues to
C The Sub-Committee is reviewing and improving available informa- move from using crude extracts to the use of individual allergens.
tion and tools on the database to help researchers compare their However, database users should remember that a WHO/IUIS name
newly identified candidate allergens in the context of the database. designation relies on data provided by the scientist submitting the
The Sub-Committee welcomes suggestions that may be submitted to candidate allergens, before peer-review publication. The Sub-Com-
the Chairman or Sub-Committee members. mittee contributes to improve continued interactions of scientists and
D As advances are made in technology of gene sequencing, tran- clinicians in the effort to improve diagnoses, therapy and risk avoidance
scriptomics and proteomics, more questionable allergen candidates for those who have specific allergies.
are being submitted to the WHO/IUIS Sub-Committee and other
sequence databases. The Sub-Committee encourages that scientists Acknowledgements
revise and remove “unproven” allergens from protein databases
(GenBank Protein, and UniProt). However, it is important to note The authors thank the IUIS, EAACI and AAAAI organizations for
that as a committee on nomenclature, the mission is to provide a travel grants and administrative costs to the Sub-Committee.
framework for consistent allergen identification and not to pass
judgement on whether an allergen is a major, mid-tier, or minor References
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