The Spectrum of Fungal Allergy

Abstract

Fungi can be found throughout the world. They may live as saprophytes, parasites or symbionts of animals and plants in indoor as well as outdoor environment. For decades, fungi belonging to the ascomycota as well as to the basidiomycota have been known to cause a broad panel of human disorders. In contrast to pollen, fungal spores and/or mycelial cells may not only cause type I allergy, the most prevalent disease caused by molds, but also a large number of other illnesses, including allergic bronchopulmonary mycoses, allergic sinusitis, hypersensitivity pneumonitis and atopic dermatitis; and, again in contrast to pollen-derived allergies, fungal allergies are frequently linked with allergic asthma. Sensitization to molds has been reported in up to 80% of asthmatic patients. Although research on fungal allergies dates back to the 19th century, major improvements in the diagnosis and therapy of mold allergy have been hampered by the fact that fungal extracts are highly variable in their protein composition due to strain variabilities, batch-to-batch variations, and by the fact that extracts may be prepared from spores and/or mycelial cells. Nonetheless, about 150 individual fungal allergens from approximately 80 mold genera have been identified in the last 20 years. First clinical studies with recombinant mold allergens have demonstrated their potency in clinical diagnosis. This review aims to give an overview of the biology of molds and diseases caused by molds in humans, as well as a detailed summary of the latest results on recombinant fungal allergens.

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Review
Int Arch Allergy Immunol 2008;145:58–86
DOI: 10.1159/000107578
The Spectrum of Fungal Allergy
Birgit Simon-Nobbe Ursula Denk Verena Pöll Raphaela Rid
Michael Breitenbach
Department of Cell Biology, University of Salzburg, Salzburg , Austria
dates back to the 19th century, major improvements in the
diagnosis and therapy of mold allergy have been hampered
by the fact that fungal extracts are highly variable in their
protein composition due to strain variabilities, batch-to-
batch variations, and by the fact that extracts may be pre-
pared from spores and/or mycelial cells. Nonetheless, about
150 individual fungal allergens from approximately 80 mold
genera have been identified in the last 20 years. First clinical
studies with recombinant mold allergens have demonstrat-
ed their potency in clinical diagnosis. This review aims to
give an overview of the biology of molds and diseases caused
by molds in humans, as well as a detailed summary of the
latest results on recombinant fungal allergens.
Copyright © 2007 S. Karger AG, Basel
Introduction
Fungi are eukaryotic, non-chlorophyllous and hetero-
trophic organisms that depend on external nutrients and
therefore live as saprophytes, parasites or symbionts of
animals and plants under nearly all environmental con-
ditions. The phenotype of molds ranges from a unicellu-
lar to a dimorphic or filamentous appearance. Out of over
100,000 fungal species reported, a few hundred occur as
opportunists and about 100 are known to elicit mycoses
in man and animals [1]
. More than 80 mold genera have
Key Words
Allergy ⴢ Cross-reactivity ⴢ Epitope ⴢ Fungi ⴢ IgE ⴢ Mold ⴢ
Recombinant allergen
Abstract
Fungi can be found throughout the world. They may live as
saprophytes, parasites or symbionts of animals and plants in
indoor as well as outdoor environment. For decades, fungi
belonging to the ascomycota as well as to the basidiomy-
cota have been known to cause a broad panel of human dis-
orders. In contrast to pollen, fungal spores and/or mycelial
cells may not only cause type I allergy, the most prevalent
disease caused by molds, but also a large number of other
illnesses, including allergic bronchopulmonary mycoses, al-
lergic sinusitis, hypersensitivity pneumonitis and atopic der-
matitis; and, again in contrast to pollen-derived allergies,
fungal allergies are frequently linked with allergic asthma.
Sensitization to molds has been reported in up to 80% of
asthmatic patients. Although research on fungal allergies
Published online: August 20, 2007
Correspondence to: Dr. Birgit Simon-Nobbe
Department of Cell Biology, Division Genetics
University of Salzburg, Hellbrunnerstrasse 34
AT–5020 Salzburg (Austria)
Tel. +43 662 8044 5791, Fax +43 662 8044 144, E-Mail birgit.simon@sbg.ac.at
© 2007 S. Karger AG, Basel
1018–2438/07/1451–0058$23.50/0
Accessible online at:
www.karger.com/iaa
ABPA = Allergic bronchopulmonary aspergillosis; ABPM = allergic
bronchopulmonary mycosis; AD = atopic dermatitis; GST = glutathi-
one-S-transferase; HSP = heat shock protein; MnSOD = manganese-
dependent superoxide dismutase; RAST = radioallergosorbent test;
SPT = skin prick test.

Fungal Allergy
Int Arch Allergy Immunol 2008;145:58–86
59
been shown to induce type I allergies in susceptible per-
sons, whereas allergenic proteins have been identified in
23 fungal genera.
For decades, fungal spores and mycelial cells have
been known to be a major health risk. In contrast to air-
borne pollen, fungal spores are not primarily associated
with IgE-mediated type I allergies but also with a broad
panel of other diseases, e.g. life-threatening primary and
secondary infections in immunocompromised patients.
Additionally, molds have been described to cause allergic
bronchopulmonary mycosis (ABPM) and hypersensitiv-
ity pneumonitis, fungal sinusitis and toxic pneumonia,
and a large number of mycotoxins have been listed [2, 3] .
The broad panel of diseases results from the inhalation
and ingestion of fungal spores and vegetative cells (hy-
phae) or the contact with fungal cells. In contrast to oth-
er allergenic sources, fungi are very common in the envi-
ronment, and exposure to airborne spores is almost con-
stant throughout the year. A major difference to other
sources, e.g. house dust mite or pollen, is that fungi may
colonize the human body, and they may damage airways
by the production of toxins, proteases, enzymes [4] and
volatile organic compounds [5] . Thus, molds have a far
greater impact on the patients’ immune system than pol-
len or other allergenic sources.
Biology of Molds
Fungi are eukaryotic, filamentous and mostly spore-
bearing organisms representing a separate entity within
living organisms. In general, a sexual generation is fol-
lowed by an asexual generation during a life cycle. Each
of these generations may propagate independently, ex-
hibiting different morphologies (pleomorphism). The
broad majority of allergy-causing molds belong to the di-
visions of ascomycota or basidiomycota. Ascomycota
produce their ascospores in the course of sexual repro-
duction in the ascus, whereas basidiomycota produce
their meiospores or basidiospores, respectively, in the ba-
sidium. About 30,000 species of ascomycota and 25,000
species of basidiomycota have been described. The size of
fungal spores ranges from 2–3 ␮ m (Cladosporium , Asper-
gillus and Penicillium) up to 160 ␮ m (Helminthosporium) .
The average size lies between 2 and 10 ␮ m, but spores of
500 ␮ m (Alternaria longissima) [6] have also been
found.
Although optimal growth conditions vary among
molds, their optimal growth temperature ranges from 18
to 32
° C. For growth, they require oxygen, water and a
carbohydrate source. Molds occur in outdoor and indoor
environments, and they grow on virtually any substrate,
including glass and plastic surfaces.
The outdoor spore concentration ranges from 230 to
10
6
spores/m
3
[7, 8] . Atmospheric fungal spore concentra-
tion exceeds mean pollen concentration 100–1,000 times
[9] . Spore concentration in the air varies substantially de-
pending on climatic factors such as temperature, wind
and moisture. The majority of the fungal species grow in
the outdoor environment. Examples are Alternaria , Cla-
dosporium , Epicoccum and Ganoderma .
Indoor fungi are a mixture of those growing indoors
and those that have entered from outdoors [10] . Their in-
cidence is influenced by humidity, ventilation, the con-
tent of biologically degradable material, and the presence
of pets, plants and carpets [11] . In general, indoor spore
concentration is less than half of the outdoor count (un-
less there is indoor mold growth) varying from 100 to
1,000 spores/m
3
[10, 12] . In a Danish study on 23 mold-
infected buildings, the most frequent mold genera en-
countered were Penicillium (68%) and Aspergillus (56%),
followed by Chaetomium , Ulocladium , Stachybotrys and
Cladosporium (ranging from 22 to 15%) [13] .
Fungal Type II, III and IV Allergies
The immunological mechanisms underlying mold al-
lergies are hypersensitivity reactions of types I, II, III and
IV. The spectrum of allergic symptoms caused by these
hypersensitivity reactions is very broad, including rhini-
tis, asthma, atopic dermatitis (AD) and ABPM. Since this
review has its main focus on IgE-mediated type I aller-
gies, only a short overview about allergic diseases of
types II, III and IV is given.
Clinical Manifestations of Fungal Type II, III and IV
Allergies
Allergic Bronchopulmonary Mycoses
Most frequently, ABPM is caused by Aspergillus fu-
migatus , which may grow in the bronchial lumen, leading
to a persistent bronchial inflammation inducing bron-
chiectasis in asthmatic patients. Seven to 22% of asth-
matic patients suffer from allergic bronchopulmonary
aspergillosis (ABPA) [14] . Besides A. fumigatus, ABPM is
induced by Candida albicans , Curvularia , Geotrichum
and Helminthosporium [ 1 4 ] . Allergic reactions involved
include types I, III and IV.

Simon-Nobbe/Denk/Pöll/Rid/
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Int Arch Allergy Immunol 2008;145:58–86
60
Allergic Sinusitis
Molds (e.g. Aspergillus , Curvularia , Alternaria and Bi-
polaris ) may cause allergic sinusitis and fungal ball pro-
duction in the patients’ sinuses [15] . In case of allergic
sinusitis, multiple sinuses are affected, whereas tissue in-
vasion does not occur. In the patients’ mucus, fungal hy-
phae are detectable. Additionally, patients may show a
cutaneous hypersensitivity to specific allergens along
with specific IgE and IgG antibodies and an elevated total
IgE level [14] . Immunologically, allergic sinusitis is a type
I-, III- and IV-mediated allergic reaction.
Hypersensitivity Pneumonitis
Hypersensitivity pneumonitis (also known as extrin-
sic allergic alveolitis) is based on type III/IV allergic reac-
tions to repeated inhalation of allergens and may lead to
a chronic disease with irreversible lung damage. It is
characterized by the presence of precipitating antibodies
and an antigen-induced lymphocyte stimulation. The
following molds have been associated with hypersensitiv-
ity pneumonitis: Aspergillus and Penicillium species, and
the basidiomycetes Lentinus edodes , Merulius lacrymans
and P. ostreatus [16, 17] .
Molds not only cause various allergic reactions but
they may also produce mycotoxins which affect the im-
mune system.
M y c o t o x i n s
Mycotoxins – non-volatile, secondary metabolites of
low molecular weight produced by fungi – impair the im-
mune system and have neurotoxic, mutagenic, carcino-
genic and teratogenic effects. Diseases caused by myco-
toxins are called mycotoxicoses. The severity of toxic ef-
fects depends on the type of mycotoxin, the duration and
dose of exposure and the age, health and nutritional sta-
tus of the individual affected. Mycotoxins may occur in
spores, mycelia, and the matrix in which fungi grow.
They are a health risk for farm workers, for persons liv-
ing in houses with excessive mold growth and for persons
exposed to moldy material at the workplace. So far, ap-
proximately 300 mycotoxins have been identified. Chron-
ic exposure to mycotoxins causes immunosuppression of
varying extent. Prominent examples for mycotoxins are
aflatoxin (Aspergillus flavus and A. parasiticus) , ergot al-
kaloids (Claviceps spp., A. fumigatus and Penicillium
chermesinum) , ochratoxins (A. ochraceus , A. alliaceus , A.
terreus , P. niger and P. viridicatum) and trichothecenes
(Fusarium sporotrichioides , Microdochium nivale and
Stachybotrys atra) [18, 19] .
Fungal Type I Allergy
Type I allergy is induced by a large number of fungal
genera. The majority of them are members of the asco-
mycota or the basidiomycota. The most important aller-
gy-causing fungal genera belonging to the ascomycota
are Alternaria , Aspergillus , Bipolaris , Candida , Cladospo-
rium, Epicoccum and Phoma, whereas Calvatia , Copri-
nus , Ganoderma , Pleurotus and Psilocybe are the most
prominent genera of the basidiomycota ( table 1 ). In ta-
ble 1 , all allergy-causing fungal genera belonging to
the ascomycota, the basidiomycota and the zygomycota
along with their prevalence reported in the literature are
listed.
The incidence of mold allergy ranges from 6 [20] to
24% [21] in the general population, up to 44% among
atopics [22] and 80% among asthmatics [23] . The inci-
dence of mold allergy within asthmatic children is 45%
whereas it is 70% in asthmatic adults [24] .
A high proportion of mold-allergic patients is polysen-
sitized with specific IgE reactivity to various mold, pollen
and even food allergens [10, 25] .
Clinical Manifestations of Fungal Type I Allergy
Allergic Rhinitis
Allergic rhinitis is characterized by sneezing, rhinor-
rhea, pruritus and nasal obstructions. It is induced by a
large number of fungal species, with Alternaria , Aspergil-
lus , Bipolaris , Cladosporium , Curvularia and Penicillium
being the most prominent.
A l l e r g i c A s t h m a
Comparing the size of pollen grains and fungal spores,
it is obvious that fungal spores are smaller in general.
Therefore, they may reach the alveolar surface of the lung
inducing chronic inflammation of the lung tissue [26,
27] .
In many studies, an apparent link between asthma and
fungal sensitization was described [28] . In children, fun-
gal allergy was shown to be associated with increased
bronchial reactivity [29–31] , whereas in adults severe
asthma, intensive care unit admission and even death
was observed [32, 33] . In an US study performed in asth-
matic patients, up to 80% of the subjects showed sensiti-
zation to molds [23] . In a study on 981 4-year-old children
from the Isle of Wight (UK), asthma was the most com-
mon disease in children sensitized to molds [20] . Reed
[34] stated that fungi have been considered an important

Fungal Allergy
Int Arch Allergy Immunol 2008;145:58–86
61
cause of asthma for more than 60 years. In a Canadian
study dealing with ‘thunderstorm asthma’, high spore
(but not pollen) counts in the course of thunderstorms
were strongly correlated with asthma exacerbations [35] .
Additionally, a strong association between fungal sensi-
tivity, exposure to fungal spores and life-threatening
asthmatic episodes was described [28, 36] . Taken togeth-
er, the molds Alternaria , Aspergillus , Cladosporium, Hel-
minthosporium, Epicoccum, Aureobasidium and Penicil-
lium have frequently been implicated in allergic asthma
[27, 37–39] .
A t o p i c D e r m a t i t i s
AD is a chronic inflammatory disease of the skin that
is associated with high levels of total and allergen-spe-
cific IgE [40] .
In recent years, Malassezia furfur has been implicated
in the pathogenesis of AD whereas 40–65% of AD pa-
tients either have a positive skin test, atopy patch test or
radioallergosorbent test (RAST) with M. furfur extract
[41] . Sensitization to Malassezia allergens may be favored
by impaired epidermal barriers, increased T-cell reactiv-
ity and distinctive features of antigen-presenting cells
[42, 43] . Manganese-dependent superoxide dismutase
(MnSOD) may be involved as an autoallergen in the
pathogenesis of AD; 36% of patients with a positive Ma-
lassezia sympodialis skin test (n = 69) react with fungal
and human MnSOD [44] .
Saccharomyces cerevisiae is another yeast species
showing a significant correlation between a positive skin
prick test (SPT) and AD [45] .
F u n g a l A l l e r g e n s
Allergens from the Ascomycota
Alternaria alternata
Among molds associated with allergic disorders, A. al-
ternata is one of the most frequently encountered species,
predominantly occurring in the outdoor environment.
The incidence of A. alternata sensitization within atopics
varies between 3.6 and 39.4% ( table 1 ) depending on the
climatic zone and the population tested.
Mari et al. [46] showed that in a cohort of 4,962 pa-
tients with respiratory symptoms, 65% were SPT positive
to at least one allergenic source, and 19% of these allergics
reacted to at least one fungal extract, whereas the inci-
dence of sensitization to A. alternata was 66%. Interest-
ingly, within the group of patients being sensitized to a
single fungal species, Alternaria , Candida and Tricho-
phyton were the most common.
In several studies, a strong association between an A.
alternata sensitization and asthma severity was demon-
strated [26, 27, 29, 31, 37, 38, 47] . In a cross-sectional study
by Zureik et al. [26] , asthma severity was not associated
with sensitization to pollen and cats. According to a study
by Halonen et al. [29] , Alternaria sensitization at the age
of 6 and 11 years, respectively, resulted in a statistically
significantly increased risk to develop asthma in child-
hood. In a large scale study performed in the United
States, 38.3% of 1,286 asthmatic children had positive
skin test responses to Alternaria s p e c i e s [ 4 7 ] .
Before 1990, little was known about the relevant aller-
gens of A. alternata . Meanwhile 13 allergens of A. alter-
nata have been identified ( table 2 ). Most of these aller-
gens are intracellular housekeeping proteins. Nine of
these allergens, e.g. NADP-dependent mannitol dehy-
Prevalence, %
total population atopics
ASCOMYCOTA
Pezizomycota
Acremonium (Cephalosporium) 16
a
[267]
Alternaria 3.6–5.5 [20, 180] 66.1
b
[46]
12.6 [46] 39.4 [22]
14.6
c
[179]
13.5
c
[183]
3–14.6 [181,
182]
Aspergillus 2.4 [46] 27.6 [22]
21.3
c
[179]
15 [182]
5
c
[183]
Aureobasidium 20.5
d
[22]
Bipolaris
(Drechslera, Helminthosporium)
36.8 [22]
18.8
c
[179]
Botrytis 28.2
d
[22]
Chaetomium 7.4 [268]
Chrysosporium
Cladosporium 2.5 [46] 3–18.2 [181,
182]
2.9 [20] 15.9
c
[179]
7.4
c
[183]
Claviceps
Curvularia 18.4 [22]
28 [184]
Cylindrocarpon
Table 1. Molds inducing type I allergy

Simon-Nobbe/Denk/Pöll/Rid/
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Int Arch Allergy Immunol 2008;145:58–86
62
Prevalence, %
total population atopics
Boletus 5.4 [123]
Calvatia 7.8 [122]
Cantharellus
Chlorophyllum
Coprinus 5.4 [122]
6.2 [123]
Dacrymyces
Ganoderma 9.3 [122]
Geastrum 6.4 [122]
Hypholoma
Inonotus
Lentinus
Lycoperdon
Merulius
Pisolithus 5.4 [122]
Podaxis
Polyporus
Pleurotus 10.6 [122]
8.3 [123]
Psilocybe
13.7 [122]
Schizophyllum
Scleroderma 5.6 [122]
Sporotrichum
Stereum
Trichosporon
Urediniomycetes
Hemileia
14.7
h
[262]
Puccinia
Rhodotorula
28
c
[63]
Sporobolomyces
Ustilaginomycetes
Malassezia (Pityrosporum) 19.8 [186]
50.4
b
[130]
66
b
[41]
Tilletia
Tilletiopsis
Ustilago 14 [266]
ZYGOMYCOTA
Zygomycetes
Absidia
Mucor 20.5
d
[22]
Rhizopus 2.7
c
[183]
Table 1 (continued)
Prevalence, %
total population atopics
Daldinia
Didymella
Embellisia
Epicoccum 25.6
d
[22]
Epidermophyton
Eurotium
Fusarium 3.4
c
[183]
24.5
e
[185]
Gliocladium
Leptosphaeria
Microsphaera
Monilia
Neurospora
Nigrospora
Nimbya (Macrospora)
Paecilomyces 33
b
[265]
Penicillium 1.5 [46] 22
f
[101]
13.9
c
[179]
13.1 [22]
7.3 [182]
Scopulariopsis
Stemphylium (Pleospora) 30.7
d
[22]
Trichoderma 23
d
[22]
Trichophyton 1.9 [46] 10.2
b
[46]
46.7
g
[264]
Ulocladium
Xylaria
Saccharomycotina
Candida 8.5 [46] 44.3
d
[46]
28.9 [22]
23.1
c
[179]
Saccharomyces 1.4 [46] 7.4
b
[46]
Mitosporic ascomycota
Phoma 30.7
d
[22]
Stachybotrys 9.4 [263]
Thermomyces (Humicola)
Trichothecium
Wallemia
BASIDIOMYCOTA
Hymenomycetes
Agaricus (Amanita)
Armillaria
Boletinellus
The taxonomy is compiled according to the NCBI Taxonomy
Browser (http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/) and
the NEWT Taxonomy Browser of the European Bioinformatics In-
stitute (http://www.ebi.ac.uk/newt/display). Synonymous genus
names are given in parentheses. Allergy prevalence data of the fun-
gal genera listed are given based on published data, whereas the
numbers refer either to the percentage of prevalence within the to-
tal population or within atopics. The detailed specification of the
atopic test populations is as follows:
a
allergic asthmatics,
b
mold-
allergic patients,
c
asthmatic,
d
atopic patients with strong suspi-
cion of having mold allergy,
e
atopic individuals with symptoms of
mold allergy,
f
asthmatic children,
g
patients with allergic asthma
and tinea (fungal infection of the skin), and
h
atopic individuals
residing in coffee-growing regions. If no superscript is given, then
the test population is atopic with no further specification. No data
are available for those fungi where no prevalence data are given.

Fungal Allergy
Int Arch Allergy Immunol 2008;145:58–86
63
Species Allergen Prevalence
%
Biochemical name RA MW
kDa
GenBank
Accession No.
Ref.
ASCOMYCOTA
Alternaria alternata Alt a 1 93
a
(n = 43) [171]
47
b
(n = 19) [171]
98 (n = 42) [54]
+ 28 U82633 [164]
Alt a 2 0 (n = 42) [54]
61 (n = 26) [59]
+ 25 U62442 [59]
Alt a 3 HSP70 70 U87807,
U87808
[56]
Alt a 4 protein disulfide isomerase 57 X84217 [48]
Alt a 5 acid ribosomal protein P2 + 11 X78222,
U87806
[48]
Alt a 6 21.7 (n = 42) [52]
15 (n = 42) [54]
enolase + 45 U82437 [52]
Alt a 7 flavodoxin (YCP4 homologue) + 22 X78225 [48]
Alt a 8 41 (n = 22) [50] mannitol dehydrogenase + 29 AY191815 [50]
Alt a 10 aldehyde dehydrogenase + 53 X78227,
P42041
[48]
Alt a 12 acid ribosomal protein P1 + 11 X84216 [48]
Alt a 13 82 (n = 17) [187] GST + 26 AY514673 [187]
Alt a 70 kDa 70 [188]
Alt a NTF2 nuclear transport factor 2 + 13.7 AJ493280 [189]
Alternaria argyranthemi Alt arg 1 Alt a 1 related AY563280 [190]
Alternaria brassicicola Alt b 1 Alt a 1 related AF499002 [191]
Alternaria blumeae Alt bl 1 Alt a 1 related AY563291 [190]
Alternaria brassicae Alt br 1 Alt a 1 related AY563309 [190]
Alternaria capsici Alt c 1 Alt a 1 related AY563298 [190]
Alternaria carotiincultae Alt ca 1 Alt a 1 related AY563287 [190]
Alternaria cetera Alt ce 1 Alt a 1 related AY563278 [190]
Alternaria cheiranthi Alt ch 1 Alt a 1 related AY563290 [190]
Alternaria cinerariae Alt ci 1 Alt a 1 related AY563308 [190]
Alternaria conjuncta Alt co 1 Alt a 1 related AY563281 [190]
Alternaria crassa Alt cr 1 Alt a 1 related AY563293 [190]
Alternaria cucumerina Alt cu 1 Alt a 1 related AY563300 [190]
Alternaria dauci Alt d 1 Alt a 1 related AY563292 [190]
Alternaria dumosa Alt du 1 Alt a 1 related AY563305 [190]
Alternaria eryngii Alt e 1 Alt a 1 related AY563313 [190]
Alternaria ethzedia Alt et 1 Alt a 1 related AY563284 [190]
Alternaria euphorbiicola Alt eu 1 Alt a 1 related AY563314 [190]
Alternaria japonica Alt j 1 Alt a 1 related AY563312 [190]
Alternaria limoniasperae Alt l 1 Alt a 1 related AY563306 [190]
Alternaria longipes Alt lo 1 Alt a 1 related AY563304 [190]
Alternaria macrospora Alt m 1 Alt a 1 related AY563294 [190]
Alternaria metachromatica Alt me 1 Alt a 1 related AY563285 [190]
Alternaria mimicula Alt mi 1 Alt a 1 related AY563310 [190]
Alternaria mouchaccae Alt mo 1 Alt a 1 related AY563279 [190]
Alternaria oregonensis Alt o 1 Alt a 1 related AY563279 [190]
Alternaria petroselini Alt p 1 Alt a 1 related AY563288 [190]
Alternaria photistica Alt ph 1 Alt a 1 related AY563282 [190]
Alternaria porri Alt po 1 Alt a 1 related AY563296 [190]
Alternaria pseudorostrata Alt ps 1 Alt a 1 related AY563295 [190]
Alternaria radicina Alt r 1 Alt a 1 related AY563286 [190]
Alternaria solani Alt s 1 Alt a 1 related AY563299 [190]
Alternaria smyrnii Alt sm 1 Alt a 1 related AY563289 [190]
Alternaria sonchi Alt so 1 Alt a 1 related AY563307 [190]
Alternaria tagetica Alt t 1 Alt a 1 related AY563297 [190]
Alternaria tenuissima Alt te 1 Alt a 1 related AY563302 [190]
Table 2. List of fungal allergens

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Int Arch Allergy Immunol 2008;145:58–86
64
Species Allergen Prevalence
%
Biochemical name RA MW
kDa
GenBank
Accession No.
Ref.
Aspergillus flavus Asp fl 13 64
a
(n = 14) [192] alkaline serine protease + 34 AF137272 [192,
193]
Asp fl 18 vacuolar serine protease [194]
Aspergillus fumigatus Asp f 1 100
e
(n = 20) [195]
75
g
(n = 24) [90]
60
f
(n = 20) [195]
46
c
(n = 20) [73]
ribonuclease + 18 M83781,
S39330
[71,
196]
Asp f 2 87
g
(n = 24) [90] fibrinogen binding protein + 37 U56938 [72]
Asp f 3 100
c
(n = 11) [85]
100
d
(n = 20) [195]
90
f
(n = 20) [195]
62.5
d
(n = 8) [85]
32
d
(n = 16) [90]
peroxisomal membrane protein + 19 U20722 [84,
85]
Asp f 4 80
e
(n = 20) [195]
77
g
(n = 24) [90]
0
f
(n = 20) [195]
+ 30 AJ001732 [70]
Asp f 5 74
c
(n = 35) [73]
92.6
c
(n = 54) [73]
metalloprotease + 40 Z30424 [197]
Asp f 6 70
e
(n = 20) [195]
63
g
(n = 24) [90]
56
d
(n = 54) [73]
0
c
(n = 35) [73]
0
f
(n = 20) [195]
MnSOD + 26.5 U53561 [88]
Asp f 7 46
d
(n = 54) [73]
29
c
(n = 35) [73]
+ 12 AJ223315 [73]
Asp f 8 acid ribosomal protein P2 + 11 AJ224333 [91]
Asp f 9 89
d
(n = 54) [73]
31
c
(n = 35) [73]
+ 34 AJ223327 [73]
Asp f 10 28
d
(n = 54) [73]
3
c
(n = 35) [73]
aspartic protease + 34 X85092 [198]
Asp f 11 90 (n = 30) [199] peptidyl-prolyl isomerase + 24 AJ006689 [200,
201]
Asp f 12 HSP90 + 90 U92465 [92]
Asp f 13 alkaline serine protease + 34 Z11580 [202]
(Asp f 15) serine protease 16 AJ002026 [203]
(Asp f 16) 70
g
(n = 26) [204] + 43 AF062651 [204]
Asp f 17 + 27 AJ224865 [205]
Asp f 18 vacuolar serine protease + 34 Y13338 [93]
Asp f 22 enolase 46 AF284645 [96]
Asp f 23 26.7
g
(n = 30) [206] L3 ribosomal protein + 44 AF464911 [206]
Asp f 27 cyclophilin + 18 [150]
Asp f 28 thioredoxin + 12 [152]
Asp f 29 thioredoxin 12
Asp f 34 PhiA cell wall protein 19.3 AM496018
(Asp f 56 kDa) 75.5
g
(n = 12) [207] protease + 56 [207]
Asp f GST GST 26 [187]
Aspergillus nidulans Aspe ni 2 + 29 Z50175 [208]
Aspergillus niger Asp n 14 4
h
(n = 171) [209]
␤-xylosidase
+ 105 AF108944 [209]
Asp n 18 vacuolar serine protease + 34 M96758 [210]
Asp n 25 36.8
i
(n = 38) [211] 3-phytase B (phosphatase) + 84 P34754 [211,
212]
Asp n glucoamylase 8
h
(n = 171) [209]
19
j
(n = 24) [213]
glucoamylase + [214]
Asp n hemicellulase 43
j
(n = 24) [213] hemicellulase + [215]
Aspergillus oryzae Asp o 13 alkaline serine protease + 34 X17561 [210,
216]
Table 2 (continued)

Fungal Allergy
Int Arch Allergy Immunol 2008;145:58–86
65
Species Allergen Prevalence
%
Biochemical name RA MW
kDa
GenBank
Accession No.
Ref.
Asp o 21 67
j
(n = 24) [213]
23
h
(n = 171) [209]
0.9
k
(n = 679) [217]
1
n
(n = 529) [218]
6.2
n
(n = 259) [219]
TAKA-amylase A + 53 D00434,
M33218
[220]
Asp o lactase
Asp o lipase
31.4
n
(n = 207) [221]
28.7
o
(n = 94) [222]
+
+
[223]
[224]
Beauveria bassiana Bb-Eno 1 enolase 47.4 DQ767719 [225]
Bb-f2 28.6 DQ767720 [225]
Bb-Ald aldehyde dehydrogenase 53.9 DQ767721 [225]
Bb-Hex N-acetylhexosaminidase 72 DQ767722 [225]
Candida albicans Cand a 1 alcohol dehydrogenase + 40 X81694 [226]
Cand a 3 56.25
l
(n = 16) [227] peroxisomal membrane protein + 29 AY136739 [227]
Cand a CAAP 36.7
p
(n = 49) [111] acid protease [111]
Cand a CyP >50
b
(n = 21) [228] cyclophilin (rotamase) + 18 [148]
Cand a enolase 37 (n = 54) [229] enolase + L04943 [230,
231]
Cand a HSP90 HSP90 90 [232]
Candida boidinii Cand b 2 100
m
(n = 89) [84] peroxisomal membrane protein + 20 J04984, J04985 [84,
129]
Cand b FD formate dehydrogenase 40.2 AJ011046 [233]
Cladosporium herbarum
Cla h 1 13 [234]
Cla h 2 23 [234]
Cla h 5 acid ribosomal protein P2 + 11 X78223 [48,
235]
Cla h 6 22 [61] enolase + 46 X78226 [48]
Cla h 7 flavodoxin (YCP4 homolog) + 22 X78224 [48]
Cla h 8 57.1 (n = 21) [49] mannitol dehydrogenase + 28.3 AY191816 [49]
Cla h 9 19.2 (n = 26) [143] vacuolar serine protease + 55 AY787775
Cla h 10 aldehyde dehydrogenase + 53 X78228 [48]
Cla h 12 acid ribosomal protein P1 + 11 X85180 [236]
Cla h 8 CSP cold shock protein 8 [237]
Cla h GST GST [147]
Cla h HCh1 type I hydrophobin 10.5 AJ496190 [238]
Cla h HSP70 HSP70 70 X81860 [53]
Cla h NTF2 nuclear transport factor 2 14 AJ493279 [189]
Cladosporium cladosporoides Cla c 9 vacuolar serine protease 36 EF407520
Curvularia lunata Cur l 1 80 (n = 15) [239] serine protease AY034826 [239]
Cur l 2 100
q
(n = 15) [240] enolase + 48 AY034826 [240]
Cur l 3 cytochrome C 12 AY034827
Cur 1 ADH alcohol dehydrogenase 37 A1YDT6
Cur l GST GST [147]
Cur l oryzin 14.2 AY291575
Cur l SOD SOD 21.4 AY291574
Cul l Trx thioredoxin 12.3 AY291577
Cur l ZPS1 17.3 AY291573
Embellisia allii Emb a 1 Alt a 1 related AY563322 [190]
Embellisia indefessa Emb i 1 Alt a 1 related AY563323 [190]
Embellisia novae-zelandiae Emb nz 1 Alt a 1 related AY563324 [190]
Embellisia telluster Emb t 1 Alt a 1 related AY563325 [190]
Epicoccum purpurascens Epi p 1 serine protease 30 P83340 [241]
(Epicoccum nigrum)
Epi p GST GST 26 [147]
Fusarium culmorum Fus c 1 35 (n = 26) [242] acid ribosomal protein P2 + 11 AY077706 [242]
Fus c 2 50 (n = 26) [242] thioredoxin-like protein + 13 AY077707 [242]
Fus c 3 15 (n = 26) [242] + 49 [242]
Fusarium solani Fus s 1 65 P81010 [243]
Fus s 45 kDa enolase 45 [244]
Table 2 (continued)

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66
Species Allergen Prevalence
%
Biochemical name RA MW
kDa
GenBank
Accession No.
Ref.
Nimbya caricis Nim c 1 Alt a 1 related AY563321 [190]
Penicillium brevicompactum Pen b 13 alkaline serine protease 33 [245]
Pen b 26 acid ribosomal protein P1 + 11 AY786077 [109]
Penicillium chrysogenum
(Penicillium notatum) Pen ch 13 33
a
(n = 212) [246] alkaline serine protease + 34 AF193420 [94,
105]
Pen ch 18 76.9
r
(n = 13) [106]
100
r
(n = 8) [107]
vacuolar serine protease + 32 AF263454 [94,
106]
Pen ch 20 N-acetyl glucosaminidase + 68 S77837 [247]
Pen ch 31 calreticulin 61.6 AY850367
Pen ch 33 16
Penicillium citrinum Pen c 1 alkaline serine protease + 33 AF084546 [248]
Pen c 3 46.4
a
(n = 28) [108] peroxisomal membrane protein + 18 AF144753 [108]
Pen c 13 alkaline serine protease 33 AF084546 [248]
Pen c 18 vacuolar serine protease + 37.3 AF245168 [102]
Pen c 19 41 (n = 34) [103] HSP70 + 70 U64207 [103]
Pen c 22 30.4
s
(n = 23) [96] enolase + 46 AF254643 [96]
Pen c 24 7.6
a
(n = 92) [110]
elongation factor 1␤
+ 25 AY363911 [110]
Pen c 30 catalase 80.7 Q2V6Q5
Pen c 32 pectate lyases EF159713
Penicillium oxalicum Pen o 18 vacuolar serine protease + 34 AF243425 [94,
104]
Pleospora herbarum
Ple h 1 Alt a 1 related AY563277 [190]
Stemphylium botryosum Ste b 1 Alt a 1 related AY563274 [190]
Saccharomyces cerevisiae Sac c CyP cyclophilin (rotamase) [148]
Sac c enolase 95 (n = 20) [249]
20
t
(n = 20) [229]
enolase 46.8 J01322 [96,
250]
Sac c MnSOD MnSOD 25.7 X02156 [148]
Stachybotrys chartarum Sta c cellulase cellulase/glycosyl hydrolase [145]
Sta c hemolysin 38 (n = 21) [251] hemolysin [251]
Sta c stachyrase-A 80.9 (n = 21) [251] [251]
Stemphylium callistephi Ste c 1 Alt a 1 related AY563276 [190]
Stemphylium vesicarium Ste v 1 Alt a 1 related AY563275 [190]
Thermomyces lanuginosus The l lipase lipase AF054513 [252]
Trichophyton mentagrophytes Tri me 2 vacuolar serine protease AJ430837,
AJ430838,
AJ430839,
AJ430840
Tri me 4 alkaline serine protease AJ430836
Trichophyton rubrum Tri r 2 vacuolar serine protease AF082515 [253]
Tri r 4 alkaline serine protease AF082514 [253]
Trichophyton schoenleinii Tri sc 2 vacuolar serine protease AJ430841
Tri sc 4 alkaline serine protease AJ430626
Trichophyton tonsurans Tri t 1 30 [254]
Tri t 4 alkaline serine protease 83 P80514 [253]
Ulocladium alternariae
Ulo a 1 Alt a 1 related AY563316 [190]
Ulocladium atrum Ulo at 1 Alt a 1 related AY563318 [190]
Ulocladium botrytis Ulo b 1 Alt a 1 related AY563317 [190]
Ulocladium chartarum Ulo c 1 Alt a 1 related AY563319 [190]
Ulocladium cucurbitae Ulo cu 1 Alt a 1 related AY563315 [190]
BASIDIOMYCOTA
Coprinus comatus Cop c 1 25
u
(n = 92) [121] transcription factor/leucine
zipper motif
+ 11 AJ132235 [121]
Cop c 2 thioredoxin + 11.7 AJ242791
Cop c 3 AJ242792
Cop c 4
Cop c 5 + 15.6 AJ242793
Table 2 (continued)

Fungal Allergy
Int Arch Allergy Immunol 2008;145:58–86
67
Species Allergen Prevalence
%
Biochemical name RA MW
kDa
GenBank
Accession No.
Ref.
Cop c 6
Cop c 7 AJ242794
Malassezia furfur Mal f 1 43–61
v
(n = 95) [255]
17.5
v
(n = 40) [256]
cell wall protein + 35.9 [257]
Mala f 2 71.9
v
(n = 64) [130] peroxisomal membrane protein + 21 AB011804 [130]
Mala f 3 70.3
v
(n = 64) [130] peroxisomal membrane protein + 20 AB011805 [130]
Mala f 4 83.3
v
(n = 36) [132] mitochondrial malate
dehydrogenase
+ 35 AF084828 [132]
Mal f 5 48 (n = 25) [131]
35
v
(n = 40) [256]
putative peroxisomal membrane
protein
+ 18.2 AJ011955 [131]
Mala f 6 92 (n = 48) [199]
>50
b
(n = 21) [228]
48 (n = 25) [131]
40
v
(n = 40) [256]
putative cyclophilin + 17.2 AJ011956 [131]
Mal f 7 48 (n = 25) [131]
40–60
v
(n = 25) [258]
+ 16.2 AJ011957 [131]
Mal f 8 24 (n = 25) [131]
10–18
v
(n = 25) [258]
+ 19.2 AJ011958 [131]
Mal f 9 24–36
v
(n = 25) [258]
20 (n = 25) [131]
+ 14.0 AJ011959 [131]
Malassezia sympodialis Mala s 1 18.9
y
(n = 127) [259]
46
x
(n = 97) [260]
peroxisomal membrane protein + X96486 [257]
Mala s 5 29.1
y
(n = 127) [259]
19
x
(n = 97) [260]
putative peroxisomal membrane
protein
+ 18.2 AJ011955 [131]
Mala s 6 25.2
y
(n = 127) [259]
21
x
(n = 97) [260]
cyclophilin (rotamase) + 17 AJ011956 [131]
Mala s 7 3
x
(n = 97) [260] + AJ011957 [258]
Mala s 8 8
x
(n = 97) [260] + 19 AJ011958 [258]
Mala s 9 37.6
y
(n = 125) [259]
24
x
(n = 97) [260]
+ 37 AJ011959 [258]
Mala s 10 69
w
(n = 28) [133] HSP88 + 70 AJ428052 [97,
133]
Mala s 11 75
w
(n = 28) [133]
42
b
(n = 67) [44]
MnSOD + 23 AJ548421 [133]
Mala s 12 62
x
(n = 21) [261] glucose-methanol-choline
oxidoreductase
+ 67 AJ871960
Mala s 13 thioredoxin + 12
Psilocybe cubensis Psi c 1
Psi c 2 cyclophilin (rotamase) + 16 [136]
Rhodotorula mucilaginosa Rho m 1 21.4 (n = 14) [137] enolase + 47 AF382946 [137]
Rho m 2 vacuolar serine protease + 31 AY547285 [63]
Table 2 (continued)
Allergens listed in the ‘official list of allergens’ of the International
Union of Immunological Societies Allergen Nomenclature Subcommittee
(http://www.allergen.org/) are shown in black, whereas allergens high-
lighted in grey are taken from other sources like the Allergome data-
base (http://www.allergome.org/). Prevalence data are given based on pub-
lished data, the specification of the respective test populations is as fol-
lows:
a
asthmatics,
b
patients with atopic dermatitis,
c
A. fumigatus-sensi-
tized asth
matics with ABPA,
d
A. fumigatus-sensitized asthmatics with-
out ABPA,
e
cystic fibrosis patients having ABPA,
f
A. fumigatus-sensitized
cystic fibrosis patients,
g
ABPA patients,
h
bakers with workplace-related
symptoms,
i
subjects occupationally exposed to powdered A. niger phytase
having work-related respiratory symptoms,
j
subjects with baker’s asthma,
k
employees in flour milling and packing operations,
l
C. albicans CAP test-
positive asthmatics,
m
A. fumigatus-sensitized asthmatics with no C. albi-
cans infection,
n
workers formulating and packaging lactase,
o
pharmaceu-
tical workers exposed to lactase,
p
asthmatic patients with positive imme-
diate skin response to crude C. albicans antigen,
q
C. lunata IgE-reac-
tive patients suffering from allergic bronchial asthma and/or rhinitis,
r
P. chrysogenum IgE-reactive asthmatics,
s
Penicillium IgE-reactive asth-
matics,
t
C. albicans-sensitized patients reactive with the C. albicans
enolase,
u
basidiomycete-sensitized individuals,
v
M. furfur IgE-reactive
atopic dermatitis patients,
w
M. sympodialis IgE-reactive patients with
atopic eczema/dermatitis syndrome,
x
M. sympodialis IgE-reactive atopic
eczema patients,
y
patients with atopic eczema.
If no superscript is given then the test population is allergic against the
respective mold. Some Aspergillus allergens are given in parentheses since
some inconsistencies have been identified when the coding sequences were
compared with their genomic counterparts [97]. RA = Recombinant aller-
gen, stating whether a given allergen has been cloned as a recombinant al-
lergen. In the last column, the first publication of the respective fungal
allergen is shown.

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Int Arch Allergy Immunol 2008;145:58–86
68
drogenase, enolase, aldehyde dehydrogenase, flavodoxin
(YCP4 homolog), acid ribosomal protein P1 and P2, heat
shock protein (HSP) 70, nuclear transport factor 2 and
glutathione-S-transferase (GST), have not only been
identified in A. alternata but also in the closely related
mold Cladosporium herbarum [ 4 8 – 5 3 ] .
Most of the A. alternata allergens cloned so far are mi-
nor allergens except for Alt a 1, which is recognized by up
to 98% of A. alternata -sensitized patients [54] . Alt a 1 can
be found as a predominant component in mycelial and
culture filtrate extracts [55, 56] . A 20-mer peptide of Alt
a 1 located at the N-terminal end showed weak binding
of patients’ IgE antibodies and induced antibody synthe-
sis in Balb/c mice indicating that this peptide harbors a
linear B-cell and a T-cell epitope [57] .
Two clinical studies using recombinant allergens of A.
alternata have been performed. Unger et al. [58] tested
seven A. alternata -allergic patients with Alt a 1 and Alt a
6 (enolase), which is recognized by 15–22% of A. alter-
nata -allergic patients [52, 54] . In this study, all seven A.
alternata -allergic patients reacted to the two recombi-
nant allergens whereas commercially available fungal ex-
tracts partially failed to correctly diagnose the patients’
allergy. Asturias et al. [54] tested 42 A. alternata -allergic
patients with natural and recombinant Alt a 1 (rAlt a 1),
rAlt a 2 and rAlt a 6. Although the prevalence of Alt a 2
was previously determined to be 61% [59] , none of the 42
patients reacted with rAlt a 2, but 41 of the 42 patients
specifically reacted with rAlt a 6 (enolase) and rAlt a 1.
Thus, the combination of Alt a 1 and Alt a 6 (maybe sup-
plemented with one or two additional allergens) is a
promising, molecule-based approach for the diagnosis
and therapy of A. alternata allergy.
Alt a 1, the major allergen of A. alternata , was ana-
lyzed in respect to its B-cell epitopes. Kurup et al. [60]
synthesized overlapping decapeptides (12 amino acids)
spanning the entire Alt a 1 protein sequence and tested
these peptides for their IgE reactivity with patient sera.
They identified four linear IgE epitopes whereas two of
them (K41-P50 and Y54-K63) showed strong IgE reactiv-
ity in all 4 A. alternata- sensitized patients tested.
Cladosporium herbarum
Airborne spores of C. herbarum are prominent causes
of fungal allergy and can be found indoors as well as out-
doors.
In a study by Tariq et al. [20] , 2.9% of 981 4-year-old
children reacted to C. herbarum . In their study, C. her-
barum together with A. alternata were the third most
common causes of sensitization after house dust mite
and grass pollen. Mari et al. [46] tested 4,962 patients
having respiratory symptoms. The overall incidence of
C. herbarum sensitization was 13%, but within the
group of patients sensitized to more than two fungal
sources, the prevalence of C. herbarum sensitization
reached 84%. In other words, monosensitization to C.
herbarum is rather seldom within mold-allergic pa-
tients.
So far, 14 allergens have been identified from C. her-
barum , whereas seven of them have been cloned as
recombinant proteins ( table 2 ). Except for one, all of
these allergens are minor allergens with a prevalence of
about 20%. The only major allergen, Cla h 8, an NADP-
dependent mannitol dehydrogenase, is recognized by
57% of the C. herbarum -allergic patients and represents
a predominant component of the crude extract [49,
61, 62] .
For some of the allergens (e.g. enolase and serine pro-
teases), extensive cross-reactivity was demonstrated (see
also Cross-Reactivity and Auto-Reactivity), making these
proteins fungal pan-allergens [51, 52, 63] .
IgE epitopes of C. herbarum enolase have been tested by
a PCR-based approach. Ten different peptides spanning
the entire protein sequence were tested for their IgE reac-
tivity. Six peptides showed specific IgE reactivity in all pa-
tients tested (n = 10), whereas the smallest of them, with a
length of 69 amino acids, corresponded to the overlapping
region of the five other IgE-reactive peptides [52, 64] .
Aspergillus Species
The saprophytic genus Aspergillus includes 132 differ-
ent species. It is distributed ubiquitously in our natural
environment and represents a dominant indoor patho-
gen [65–67] . Aspergillus grows outdoors on decaying veg-
etation or indoors (e.g. in air conditioning systems) and
has the ability to release large quantities of small conid-
iospores of 2–3 ␮ m. In case of inhalation, they either
reach terminal airways or are deposited in large clusters
in the upper respiratory tract [14, 65, 68, 69] . Human dis-
orders caused by Aspergillus range from colonization of
the respiratory tract, hypersensitivity pneumonitis (ex-
trinsic allergic alveolitis), allergic rhinitis, sinusitis and
asthma, to life-threatening systemic invasive aspergillo-
sis and ABPA [66, 68] . Very often aspergillosis is favored
by a n i mpa ired immu ne stat us of t he pat ient eit her caused
by immunosuppressive treatment after transplantation
surgery, HIV infection, certain leukemias or hospitaliza-
tion under intensive care.
The biological characteristics of Aspergillus are its
small spore size, its thermo-tolerance allowing growth at

Fungal Allergy
Int Arch Allergy Immunol 2008;145:58–86
69
human body temperature, its resistance to oxidative kill-
ing and its ability to produce small metabolites and en-
zymes with proteolytic or even immunosuppressive ac-
tivity [70–72] .
Since A. fumigatus is implicated in about 80% of As-
pergillus -related infections, a large number of allergens
were cloned from cDNA and phage display libraries, and
characterized and purified as recombinant proteins [70,
73–75] . The spectrum of the more than 40 IgE-binding
components of A. fumigatus that account for the com-
plex, variable and heterogeneous pattern obtained in
Western blot experiments includes for example acid ribo-
somal proteins, enzymes such as proteases, toxins, HSPs
as well as several unique proteins exhibiting no signifi-
cant sequence homologies to structures already deposit-
ed in the databases [69, 76] . At molecular level, all these
molecules differ in their allergenicity and can be subdi-
vided into two separate categories, namely secreted and
cytoplasmic proteins.
Among the most important A. fumigatus allergens
identified through molecular approaches is Asp f 1, a
non-glycosylated 18-kDa major allergen originally de-
tected in the urine of patients suffering from invasive as-
pergillosis. It is related to ribotoxins, which are known to
inhibit protein translation by cleaving a conserved region
of the 28S acid ribosomal RNA [77] . Asp f 1, which was
considered to be a kind of virulence factor promoting col-
onization as well as infection of human tissue, seems to
be abundantly secreted after spore germination and dur-
ing early phases of fungal growth [71, 78] . Although it is
recognized by 85% of ABPA patients as well as A. fumiga-
tus SPT-positive asthmatics, its effectiveness in diagnosis
and therapy is still controversial because of its high toxic-
ity [68, 69, 79] . Asp f 1 is one of the A. fumigatus allergens
which have been analyzed regarding B- and T-cell epi-
topes. Kurup et al. [78] synthesized 13 linear decapep-
tides spanning the whole Asp f 1 molecule and tested
them for their IgE reactivity and their potency to stimu-
late peripheral blood mononuclear cells from ABPA pa-
tients. They revealed several peptides harboring B- and
T-cell epitopes, whereas the C-terminal region (aa 115–
149) was shown to be involved in humoral as well as in
cell-mediated immunoresponses in ABPA. Most of the
Asp f 1-specific T-cell clones reacted with the peptides aa
46–65 and aa 106–125 restricted by HLA-DR2 and HLA-
DR5 alleles [80] .
Banerjee et al. [81] performed two studies on the B-cell
epitopes of Asp f 2, identifying nine epitopes located in
hydrophilic regions [81] , with a putative major B-cell ep-
itope at the N-terminus [82] . T-cell clones were generated
from ABPA patients using synthetic peptides from Asp f
2, identifying aa 54–74 as a major T-cell epitope [83] .
The 19-kDa Asp f 3, which shares common IgE-bind-
ing epitopes with the peroxisomal membrane proteins A
and B from Candida boidinii , can be regarded as the sec-
ond major allergen of this fungus (94% IgE reactivity),
with clinical relevance being already demonstrated in
vivo by the provocation of mediator release [67, 73, 84,
85] . B-cell epitopes were analyzed using synthetic pep-
tides and constructing Asp f 3 mutants. Ramachandran
et al. [86] identified seven linear IgE-binding regions
spanning the entire protein sequence. They identified 12
amino acids at the N-terminus and 8 amino acids at the
C-terminus to be critical for IgE binding.
In case of Asp f 4, three cysteine deletion mutants were
generated by selectively deleting cysteine residues. These
mutants reacted differently with the IgE antibodies from
ABPA patients. The authors concluded that the N-termi-
nal IgE-epitope regions of the protein are crucial for the
maintenance of the proper three-dimensional structure
whereas the C-terminal cysteines play a significant sup-
porting role in IgE binding [87] .
Asp f 6, an MnSOD, represents a phylogenetically
highly conserved protein belonging to the metalloen-
zyme superfamily, which is required for the conversion of
superoxide radicals to hydrogen peroxide and oxygen
[88] . Since Asp f 2, Asp f 4, whose biological function still
is unresolved, and the MnSOD Asp f 6 are strictly intra-
cellular proteins and thus very unlikely to be available as
aeroallergens under normal conditions, sensitization
against these two marker molecules seems to be sufficient
to allow a precise diagnosis of ABPA [70, 89, 90] . ABPA is
the result of fungal proliferation in the respiratory tract,
exposing especially atopic asthmatics and patients suffer-
ing from cystic fibrosis to non-secreted A. fumigatus al-
lergens due to cellular defense mechanisms and fungal
damage [76] .
A. fumigatus acid ribosomal protein P2, Asp f 8, shows
a high degree of conservation among eukaryotic organ-
isms and is characterized by the presence of cross-reac-
tive epitopes shared with the homologous allergens from
C. herbarum and A. alternata [48, 91] .
Asp f 12, a HSP90 protein, may play a major role dur-
ing stress response and possesses considerable homology
to the HSP90 molecules from C. albicans , S. cerevisiae ,
Trypanosoma , housefly, mouse and homo sapiens. Asp f
12 is also thought to play a role in ABPA and other Asper-
gillus - i n d u c e d d i s e a s e s [ 9 2 ] .
Furthermore, alkaline as well as vacuolar serine pro-
teases have been identified to be major allergens in case

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70
of A. fumigatus (Asp f 13 and Asp f 18), A. flavus (Asp f l
13 and Asp fl 18) and A. oryzae (Asp o 13) sharing IgE
and IgG epitopes with each other as well as with fungal
serine proteases from Penicillium spp . (Pen b 13, Pen c 13,
Pen n 13, Pen n 18 and Pen o 18) [68, 93, 94] . In order to
analyze the B-cell epitopes from Asp f 13, the protein was
chemically and enzymatically cleaved and subsequently
the N-terminal sequences were determined. At the end,
3 of 13 linear epitopes located at the C-terminus were
proven to be immunodominant [95] .
Another important A. fumigatus allergen is enolase
(Asp f 22), a protein of 47 kDa, whose cross-reactivity
with Pen c 22 (Penicillium citrinum) , Alt a 6 (A. alternata)
and Cla h 6 (C. herbarum) has been proven by inhibition
immunoblotting [52, 96] .
Recently, Bowyer and Denning [97] compared previ-
ously published A. fumigatus allergen sequences with A.
fumigatus genomic sequences and revealed that Asp f 15
is identical to Asp f 13. Additionally, they observed par-
tial homology between Asp f 16 and Asp f 9, whereas the
Asp f 16 sequence, in contrast to the Asp f 9 sequence,
could not be localized on two different A. fumigatus ge-
nomic sequences. Assuming either sequencing errors or
the existence of an isoform, the authors concluded that
the Asp f 9 sequence is more reliable and that Asp f 16 also
should be termed Asp f 9. In case of the Asp f 56-kDa al-
lergen, the authors could not find any corresponding ge-
nomic sequence. Since these new results have not been
included into the WHO allergen list so far, the respective
allergens were kept in the list of fungal allergens ( table 2 )
but were parenthesized.
Additionally, A. oryzae ␣ -amylase (Asp o 21) and A.
niger ␤ -xylosidase (Asp n 14), which are used as baking
additives in the food industry as well as in the starch in-
dustry, show allergenic activity [65, 67] .
Recombinant Asp f 1, rAsp f 4, rAsp f 6 (MnSOD) and
rAsp f 8 (acid ribosomal protein P2), have been tested in
several clinical studies [84, 85, 88, 91] involving patients
suffering from asthma, ABPA and AD. In these studies,
the diagnostic specificity was better in case of recombi-
nant A. fumigatus allergens, and additionally no adverse
reactions have been reported.
P e n i c i l l i u m Species
More than 150 Penicillium species exist, some of which
have been described to be common indoor molds. Wei et
al. [98] analyzed 88 homes in the Taipei area in order to
isolate and identify the indoor Penicillium species. Their
results showed that P. citrinum is the most common Pen-
icillium species in this area. Muilenberg et al. [99] have
reported that P. citrinum , P. oxalicum and Penicillium
chrysogenum (former P. notatum ) are the five most fre-
quently encountered species of Penicillium in Topeka
(Kans., USA). Penicillium can cause atopic asthma in
sensitive persons after inhalation of their spores [100] . In
Taiwan, 22% of the asthmatic children showed a positive
reaction in intracutaneous skin tests for Penicillium spe-
cies [101] . Shen et al. [93] showed that IgE antibodies
against components of P. citrinum , P. notatum , P. oxali-
cum and P. brevicompactum could be detected in the sera
of 16–24% of asthmatic patients. In 100 patients, P. chrys-
ogenum had the highest positive intradermal skin test re-
activity (68%). Therefore,
P. chrysogenum is the most fre-
quent Penicillium species used for the clinical diagnosis
of fungal allergy.
Results from Shen et al. [93] showed that 80–93% of
asthmatics displayed IgE reactivity to the 32- to 34-kDa
serine proteases from P. citrinum , P. chrysogenum , P. ox-
alicum , P. brevicompactum , A. fumigatus , A. flavus , A.
oryzae and A. niger , suggesting a role as major allergens.
Alkaline and vacuolar serine proteases from Aspergillus
and Penicillium were termed group 13 and group 18 al-
lergens, respectively, by the World Health Organization-
International Union of Immunological Societies Aller-
gen Nomenclature Subcommittee [93] , whereby there
also exist homologous and partially cross-reactive alka-
line and serine proteases in other fungal species ( table 3 ;
see also Cross-Reactivity and Auto-Reactivity). Serine
proteases are expressed as large precursor molecules
which are posttranslationally cleaved forming the ma-
ture enzymes. Besides N-terminal cleavage of a pre-pro-
sequence, which has been described for all serine prote-
ases during maturation [94, 102–104] , Pen c 18 and Pen o
18 also undergo C-terminal processing [104] .
The alkaline serine protease Pen ch 13 was analyzed
for linear IgE epitopes. Eleven peptide fragments span-
ning the whole molecule were generated and tested for
their IgE reactivity in dot blot immunoassays. Determi-
nation of the IgE reactivity [105] revealed that peptide f-
2n (aa 31–61) showed the highest frequency (77.1%, n =
35). Three further peptides were IgE reactive with inci-
dences ranging from 31 to 51%. The B-cell epitope analy-
sis was refined by narrowing down peptide f-2n and site-
directed mutagenesis of Pen ch 13. Finally, one major lin-
ear B-cell epitope was identified to be located within aa
48–55.
In case of Pen ch 18, a dominant linear IgE epitope was
mapped within aa 73–95 of the N-terminally processed
allergen [106] . A similar result was observed by Yu et al.
[107] who located nine different IgE-binding epitopes

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71
Cross-reactivity
within 1 fungal
phylum
between fungal
phyla
with non-fungal
species
Aldehyde dehydrogenase
Alternaria alternata Alt a 10 +
Beauveria bassiana
Bb-Ald +
Cladosporium herbarum Cla h 10 +
Harmonia axyridis Har a 2 +
Alt a 1 related
Alternaria argyranthemi
Alt arg 1 +
Alternaria brassicicola
Alt b 1 +
Alternaria blumeae Alt bl 1 +
Alternaria brassicae
Alt br 1 +
Alternaria capsici
Alt c 1 +
Alternaria carotiincultae
Alt ca 1 +
Alternaria cetera Alt ce 1 +
Alternaria cheiranthi
Alt ch 1 +
Alternaria cinerariae Alt ci 1 +
Alternaria conjuncta
Alt co 1 +
Alternaria crassa
Alt cr 1 +
Alternaria cucumerina
Alt cu 1 +
Alternaria dauci
Alt d 1 +
Alternaria dumosa Alt du 1 +
Alternaria eryngii
Alt e 1 +
Alternaria ethzedia
Alt et 1 +
Alternaria euphorbiicola Alt eu 1 +
Alternaria japonica
Alt j 1 +
Alternaria limoniasperae Alt l 1 +
Alternaria longipes
Alt lo 1 +
Alternaria macrospora Alt m 1 +
Alternaria metachromatica
Alt me 1 +
Alternaria mimicula Alt mi 1 +
Alternaria mouchaccae
Alt mo 1 +
Alternaria oregonensis Alt o 1 +
Alternaria petroselini
Alt p 1 +
Alternaria photistica
Alt ph 1 +
Alternaria porri Alt po 1 +
Alternaria pseudorostrata
Alt ps 1 +
Alternaria radicina Alt r 1 +
Alternaria solani
Alt s 1 +
Alternaria smyrnii Alt sm 1 +
Alternaria sonchi
Alt so 1 +
Alternaria tagetica Alt t 1 +
Alternaria tenuissima
Alt te 1 +
Embellisia allii Emb a 1 +
Embellisia indefessa Emb i 1 +
Embellisia novae-zelandiae
Emb nz 1 +
Embellisia telluster
Emb t 1 +
Nimbya caricis Nim c 1 +
Pleospora herbarum Ple h 1 +
Stemphylium botryosum Ste b 1 +
Stemphylium callistephi
Ste c 1 +
Stemphylium vesicarium
Ste v 1 +
Ulocladium alternariae
Ulo a 1 +
Ulocladium atrum
Ulo at 1 +
Ulocladium botrytis Ulo b 1 +
Ulocladium chartarum
Ulo c 1 +
Ulocladium cucurbitae Ulo cu 1 +
Table 3. Cross- and/or auto-reactive fungal allergens

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Cross-reactivity
within 1 fungal
phylum
between fungal
phyla
with non-fungal
species
Cyclophilin
Aspergillus fumigatus Asp f 11 +
Asp f 27 +
Betula verrucosa Bet v 7 +
Candida albicans
Cand a CyP +
Catharanthus roseus Cat r 1 +
Daucus carota
Dauc c cyclophilin +
Homo sapiens Hom s CyP A +
Hom s CyP B +
Hom s CyP C +
Malasezzia furfur
Mala f 5 +
Malasezzia sympodialis Mala s 6 +
Psilocybe cubensis Psi c 2 +
Saccharomyces cerevisiae
Sac c Cyp +
Enolase
Alternaria alternata Alt a 6 +
Aspergillus fumigatus Asp f 22 +
Beauveria bassiana
Bb-Eno1 +
Candida albicans
Cand a enolase +
Cladosporium herbarum Cla h 6 +
Curvularia lunata Cur l 2 +
Cynodon dactylon Cyn d 22 +
Hevea brasiliensis Hev b 9 +
Penicillium citrinum Pen c 22 +
Rhodotorula mucilaginosa Rho m 1 +
Saccharomyces cerevisiae
Sac c enolase +
Flavodoxin (YCP4 homolog)
Alternaria alternata Alt a 7 +
Cladosporium herbarum Cla h 7 +
Saccharomyces cerevisiae YCP4 +
GST
Alternaria alternata Alt a 13 +
Aspergillus fumigatus
Asp f GST +
Blattella germanica Bla g 5 +
Blomia tropicalis
Blo t 8 +
Cladosporium herbarum
Cla h GST +
Curvularia lunata Cur l GST +
Dermatophagoides farinae
Der f 8 +
Dermatophagoides pteronyssinus Der p 8 +
Epicoccum purpurascens
Epi p GST +
Sarcoptes scabiei
Sar s GST +
HSP70
Alternaria alternata Alt a 3 +
Blomia tropicalis
Blo t HSP70 +
Cladosporium herbarum
Cla h HSP70 +
Dermatophagoides farinae Der f HSP70 +
Penicillium citrinum Pen c 19 +
Toxoplasma gondii
Tox g HSP70 +
Mannitol dehydrogenase
Alternaria alternata Alt a 8 +
Cladosporium herbarum Cla h 8 +
Table 3 (continued)

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Int Arch Allergy Immunol 2008;145:58–86
73
Cross-reactivity
within 1 fungal
phylum
between fungal
phyla
with non-fungal
species
MnSOD
Aspergillus fumigatus Asp f 6 +
Curvularia lunata
Cur l SOD +
Drosophila melanogaster
Dro m MnSOD +
Hevea brasiliensis Hev b 10 +
Homo sapiens
Hom s MnSOD +
Malasezzia sympodialis Mala s 11 +
Olea europaea Ole e 5 +
Saccharomyces cerevisiae
Sac s MnSOD +
NTF2
Alternaria alternata
Alt a NTF2 +
Cladosporium herbarum Cla h NTF2 +
Peroxisomal membrane protein
Aspergillus fumigatus Asp f 3 +
Candida albicans Cand a 3 +
Candida boidinii Cand b 2 +
Malasezzia furfur Mala f 2 +
Mala f 3 +
Mal f 5 +
Malasezzia sympodialis Mala s 1 +
Penicillium citrinum Pen c 3 +
Acid ribosomal protein P1
Alternaria alternata Alt a 12 +
Cladosporium herbarum Cla h 12 +
Penicillium brevicompactum Pen b 26 +
Acid ribosomal protein P2
Alternaria alternata Alt a 5 +
Aspergillus fumigatus Asp f 8 +
Cladosporium herbarum Cla h 5 +
Fusarium culmorum Fus c 1 +
Homo sapiens
Homo s P2 +
Prunus dulcis Pru du 5 +
Serine protease
Apis mellifera Api m 7 +
Cucumis melo Cuc m 1 +
Curvularia lunata Cur l 1 +
Epicoccum purpurascens Epi p 1 +
Periplaneta americana Per a 10w +
Polistes dominulus Pol d 4 +
Polistes exclamans Pol e 4 +
Alkaline serine protease
Aspergillus flavus Asp fl 13 +
Aspergillus fumigatus Asp f 13 +
Aspergillus oryzae Asp o 13 +
Bacillus lentus
Bac l subtilisin +
Penicillium brevicompactum Pen b 13 +
Penicillium chrysogenum Pen ch 13 +
Penicillium citrinum Pen c 13 +
Trichophyton mentagrophytes Tri me 4 +
Trichophyton rubrum Tri r 4 +
Trichophyton schoenleinii Tri sc 4 +
Trichophyton tonsurans Tri t 4 +
Table 3 (continued)

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74
distributed throughout the whole protein. One peptide,
peptide C12 (V44-W62), was also located at the N-termi-
nal end and was recognized by 75% (n = 8) of the patients
tested.
Besides the highly cross-reactive serine proteases, sev-
eral other Penicillium allergens have been identified. In
case of P. citrinum , six allergens have been identified. One
of them is Pen c 3, a peroxisomal membrane protein.
Thirteen out of 28 (46.4%) sera of Penicillium -sensitized
asthmatic patients demonstrated IgE binding to Pen c 3.
Immunoblot inhibition experiments showed cross-reac-
tivity between Pen c 3 and Asp f 3, which share 82.6%
sequence identity [108] .
Another P. citrinum -allergen was described to be
HSP70. Members of the 70-kDa heat shock gene family
are highly conserved across a wide range of organisms.
They assist the proper folding of polypeptides, inhibit
protein aggregation and target misfolded proteins for
degradation. The new allergen was designated Pen c 19,
and 14 out of 34 (41%) allergic patients showed IgE bind-
ing to the recombinant and natural allergen [103] .
A 47-kDa IgE-reactive component was shown to be an
enolase (Pen c 22) being cross-reactive with enolases from
A. fumigatus and A. alternata . Seven out of 23 (30.4%)
sera of Penicillium -sensitized asthmatic patients reacted
with a 47-kDa P. citrinum protein from the extract and
the recombinant Pen c 22, respectively [96, 109] .
Pen c 24, elongation factor 1␤ (EF-1␤), shows a se-
quence identity of 53% with its yeast (S. cerevisiae) homo-
log [110] . The N-terminal (aa 1–118) half of the protein
was recognized by 2 out of 7 Pen c 24-reactive patient
sera, whereas 5 out of 7 sera reacted to the C-terminal half
(aa 119–228) [110] , indicating that on both halves B-cell
epitopes are present.
Cross-reactivity
within 1 fungal
phylum
between fungal
phyla
with non-fungal
species
Vacuolar serine protease
Aspergillus flavus Asp fl 18 +
Aspergillus fumigatus Asp f 18 +
Aspergillus niger
Asp n 18 +
Cladosporium herbarum Cla h 9 +
Cladosporium cladosporioides Cla c 9 +
Penicillium chrysogenum
Pen ch 18 +
Penicillium citrinum Pen c 18 +
Penicillium oxalicum Pen o 19 +
Rhodotorula mucilaginosa Rho m 2 +
Trichophyton mentagrophytes Tri me 2 +
Trichophyton rubrum Tri r 2 +
Trichophyton schoenleinii Tri sc 2 +
Thioredoxin
Aspergillus fumigatus Asp f 28 +
Asp f 29 +
Coprinus comatus Cop c 2 +
Curvularia lunata
Cur l Trx +
Fusarium culmorum Fus c 2 +
Hevea brasiliensis
Hev b Trx +
Homo sapiens Homo s Trx +
Malasezzia sympodialis Mala s 13 +
Triticum aestivum Tri a 25 +
Zea mays Zea m 25 +
Table 3 (continued)
For each cross- and/or auto-reactive allergen, a list of fungal
species is given where the respective allergen has been identified.
Additionally, the name of the allergen is listed along with the
information whether cross-reactivity occurs within one fungal
phylum, within several fungal phyla or even within non-fungal
species. Allergen names deposited in the official allergen list
are shown in black, all others in grey. NTF2 = Nuclear transport
factor 2.

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Int Arch Allergy Immunol 2008;145:58–86
75
An acid ribosomal protein, P1, was characterized to be
an allergen of P. brevicompactum by Sevinc et al. [109] . It
was designated Pen b 26, and only sera of individuals who
were sensitized to this mold reacted with the protein. It is
a polypeptide of 11 kDa, rich in acidic residues ( 1 20%)
and its isoelectric point is 3.87.
Candida albicans
Although six C. albicans allergens have been described
so far, it is still controversial whether the inhalation of
this mold is causative for its allergenicity [111, 112] .
Cand a enolase, for example, was isolated and ana-
lyzed for its B-cell epitopes by testing six proteolytic frag-
ments for their IgE reactivity [113] . Ito et al. [113] identi-
fied a C-terminal fragment (F-171-I-399), which reacted
to 90% IgE antibodies examined (n = 10). A similar result
was obtained by Eroles et al. [114] , who also demonstrat-
ed the high immunogenicity of the C-terminus.
Allergens from the Basidiomycota
Among fungi, the basidiomycota are a very large phy-
lum comprising approximately 20,000 species including
puffballs, bracket fungi, toad stools, jelly fungi, plant
rusts, smuts and mushrooms like the edible Boletus , Can-
tharellus and Coprinus . Of the large number of basidio-
mycete species, about 25 species have been shown to be
allergenic [115] . Basidiospores contribute most of all to
the airborne fungal spore load ranging from 5 to 30% [8,
65, 116] . They particularly occur outdoors, but can also
be found indoors, e.g. on wet decaying wood or as infil-
trates from outdoors. In temperate zones, seasonal peaks
of basidiospores are observed in spring and autumn [116] .
The diameter of basidiospores ranges from 3 to 15 ␮ m
enabling them to reach the lower respiratory tract [117] .
In contrast to ascomycota, basidiomycota do not have
vegetative spore production. Since not only the spores but
also the fruiting bodies of Ganoderma , Coprinus and
Pleurotus contain allergens, they may induce food allergy
in sensitized patients upon consumption of these mush-
rooms [118, 119] . Hence, basidiomycota as well as asco-
mycota are known to cause atopic asthma in susceptible
persons [120] . The incidence of basidiomycota-caused al-
lergy ranges from 3.5 [121] to 25.4% [122] .
In a study performed in Europe and the USA [122] , a
total of 701 adults were tested for their reactivity to eight
basidiomycete species. The majority (70%) of the indi-
viduals tested were classified to be atopic. Out of these 701
persons, 25.4% reacted to at least one basidiomycete ex-
tract, whereas Psilocybe cubensis elicited most of the pos-
itive skin reactions (13.7%) followed by Pleurotus ostrea-
tus (10.6%), Ganoderma meredithae (9.3%) and Coprinus
quadrifidus (5.4%). In a study by Helbling et al. [123] ,
9.8% of atopic subjects, who were not preselected with
regard to mold allergy, were sensitized to at least one ba-
sidiomycete species. Within 457 atopic patients, 8.3% re-
acted to Pleurotus pulmonalis , 6.2% to Coprinus comatus
and 5.4% to Boletus edulis . Moreover, they found that
only 4% of the basidiomycete-sensitive subjects were ex-
clusively skin test positive to basidiomycete extracts.
Up to now, the knowledge about basidiomycete aller-
gens lags behind the information about ascomycete aller-
gens. One of the reasons is the lack of source material
since cultivation of basidiomycetes is much more compli-
cated and in some cases even impossible.
Coprinus comatus
Among basidiomycota-sensitized patients, C. comatus
shows a sensitization rate of 58% [123] . In 1999, Cop c 1
was cloned. It harbors two leucine zipper motifs. Its bio-
logic function is unknown, and it represents a minor al-
lergen being recognized by 25% of C. comatus -sensitized
patients [121] . In sensitized individuals, Cop c 1 is skin
test reactive in the picomolar range, making it a clini-
cally relevant allergen [121] . Six further allergens with an
open reading frame between 68 and 342 amino acids
were isolated, whereas only in case of Cop c 2 (thioredox-
in) any homology to previously isolated proteins was ob-
served [124] .
M a l a s s e z i a f u r f u r
M. furfur , previously also known as Pityrosporum ova-
le or Pityrosporum orbiculare, is a member of the normal
cutaneous flora, preferentially colonizing the skin of the
head-neck-face region as single-cell yeast, normally being
non-pathogenic [125] . Nevertheless, this yeast can act as
a pathogen causing pityriasis versicolor and seborrheic
dermatitis [41, 126] .
IgE reactivity to M. furfur, as shown in skin tests and
radioallergosorbent tests, has frequently been observed
in patients with AD [127] . M. furfur contains several IgE-
reactive proteins ranging from 14 to 94 kDa [128] .
Mala f 2 and Mala f 3 are peroxisomal proteins form-
ing homodimers with an apparent molecular weight of 21
and 20 kDa, respectively, under reducing conditions in
SDS-PAGE. They have a sequence identity of 51% and ex-
hibit a high sequence similarity with Asp f 3 from A. fu-
migatus and two peroxisomal membrane proteins from
C. boidinii [84, 129] . In a study of Yasueda et al. [130] , 64

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76
of 127 AD patients reacted with M. furfur extract, and
71.9 and 70.3% were IgE reactive to Mala f 2 and Mala f
3, respectively, making these proteins major allergens.
Lindborg et al. [131] published the isolation of Mala f 5,
which again has a high sequence identity with Mala f 2
(57%) and Mala f 3 (58%) and is recognized by 48% of M.
furfur extract-reactive patients. Additionally, Mala f 6, a
putative cyclophilin, was isolated, having an incidence of
IgE reactivity of 48% [131] .
Further allergens identified are Mala f 4, a mitochon-
drial malate dehydrogenase, with 83.3% of patients hav-
ing elevated serum IgE levels to purified Mala f 4 [132] .
Malassezia sympodialis
M. sympodialis as well as M. furfur are associated with
AD. Several allergens were cloned, including MnSOD
(Mala s 11) and HSP88 (Mala s 10) with IgE reactivities of
75 and 69%, respectively [97, 133] . First, Mala s 10 was
published to be an HSP70 protein [133] , but Nierman et
al. [134] compared the published allergen sequences with
the genomic sequences obtained recently and concluded
that this allergen is actually an HSP88 protein.
Psilocybe cubensis
Skin test reactivity to P. cubensis spore extract is the
highest (13.7%) among basidiomycetes in Europe and the
USA [122] . More than ten allergens have been identified
by SDS-PAGE immunoblots. Psi c 2, the first recombi-
nant basidiomycete allergen (molecular weight: 16 kDa)
shows high homology to cyclophilins and is recognized
by 82%, representing a major allergen [135, 136] .
R h o d o t o r u l a m u c i l a g i n o s a
Rhodotorula mucilaginosa , also known as R. rubra , is
one of the most frequently encountered yeast species in
our environment. Chang et al. [137] published the isola-
tion of an enolase (Rho m 1) which shows high sequence
identity with other fungal IgE-reactive enolases. Rho m 1
is recognized by 21.4% of R. mucilaginosa -sensitized pa-
tients and cross-reacts with several fungal enolases. Rho
m 2, a vacuolar serine protease, is the second cloned al-
lergen, which also cross-reacts with other fungal vacuolar
serine proteases [63] .
Cross-Reactivity and Auto-Reactivity
Cross-reactivity can be seen when IgE antibodies orig-
inally directed against a given allergen also bind to a
structurally related allergen from another allergen source
[138] , thus it is the result of shared B-cell epitopes among
homologous proteins. A sequence identity of more than
50% between homologous allergens seems to be neces-
sary in order to exhibit cross-reactivity [139] . Cross-reac-
tivity may be analyzed by various techniques, e.g. immu-
noblots, RAST and ELISA inhibition. Cross-reactivity
between two allergens of different molds has to be distin-
guished from ‘co-sensitization’ of an allergic person to an
allergen originating from another allergenic source. Co-
sensitization and cross-reactivity may be differentiated
by inhibition experiments between two extracts originat-
ing from distinct fungal species, where the degree of
inhibition is determined. Cross-reactivity has been
described for about 20 fungal allergens. Partly, the cross-
reactivity observed may be ascribed to the close phylo-
genetic relationship of some fungal species. O’Neil et al.
[140] performed skin tests with selected ascomycota and
basidiomycota species demonstrating an association be-
tween P. ostreatus , A. alternata , Fusarium solani and
Epicoccum purpurascens , as well as between Calvatia cy-
athiformis , A. alternata and F. solani . C. quadrifidus was
associated with F. solani and P. cubensis with A. fumiga-
tus . Thus, cross-reactivity is widespread within the two
phyla and is one explanation for the clinical observation
that the majority of mold-allergic patients react with sev-
eral fungal species in vitro and/or in vivo [25] . Interest-
ingly, very often cross-reactive fungal allergens repre-
sent intracellular proteins, whereas some species-specif-
ic mold allergens tend to be secreted, as it was shown for
Asp f 1 [71] from A. fumigatus and Cop c 1 [121] from C.
comatus .
Cross-reactive allergens may be subdivided according
to the origin of their cross-reactive partners. In table 3 ,
all cross-reactive fungal allergens are listed, along with
the name of the allergen and whether or not the respec-
tive cross-reactive allergen can be found within one fun-
gal phylum, all fungal phyla or even non-fungal species.
In case of a few allergens, homologous human cross-reac-
tive proteins have also been identified, which may give
rise to auto-reactivity. The allergens showing only cross-
reactivity within one fungal phylum are Alt a 1, flavo-
doxin (YCP4-homolog), mannitol dehydrogenase, nucle-
ar transport factor 2 and the acid ribosomal protein P1.
Cross-reactivity between fungal phyla in general has been
obtained in case of peroxisomal proteins and vacuolar
serine proteases. More than half of the cross-reactive fun-
gal allergens (aldehyde dehydrogenase, alkaline serine
protease, serine protease, enolase, GST and HSP70) have
got homologous IgE-reactive proteins in non-fungal spe-
cies. In four of them (thioredoxin, cyclophilin, MnSOD

Fungal Allergy
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77
and ribosomal protein P2), cross-reactivity with the hu-
man homolog has been observed. Taken together, it is
obvious that within the last years the picture has changed
in a way that meanwhile more than half of the cross-reac-
tive fungal allergens show cross-reactivity to non-fungal
species, raising the importance of fungal allergens in gen-
eral.
Cross-Reactivity within One Fungal Phylum
Recently, several fungal species were tested for Alt a 1
homologues using a rabbit-anti-rAlt a 1 serum [141] . The
authors could show that cross-reactive proteins were de-
tectable in Stemphylium botryosum , Ulocladium botrytis ,
Curvularia lunata and Alternaria tenuissima , but not in
C. herbarum , P. chrysogenum and A. fumigatus .
Cross-Reactivity within All Fungal Phyla
Vacuolar Serine Protease. Vacuolar serine proteases
have been isolated from Aspergillus , Cladosporium , Peni-
cillium , Rhodotorula and Trichophyton . Lin et al. [142]
generated monoclonal antibodies against culture medi-
um and/or crude extract from P. citrinum and A. fumiga-
tus . They obtained five monoclonal antibodies directed
against serine proteases. Two of them (FUM20 and
PCM39) were shown to be cross-reactive with the vacu-
olar serine proteases from P. notatum , P. oxalicum and A.
fumigatus. From our work [143] we know that these mAbs
are also cross-reactive with Cla h 9, the vacuolar serine
protease from C. herbarum . Chou et al. [63] demonstrat-
ed cross-reactivity for the native and recombinant vacu-
olar serine proteases from R. mucilaginosa and P. chrys-
ogenum .
Peroxisomal Membrane Protein. In a cross-inhibition
study, Asp f 3 shared common IgE epitopes with Cand b
2, previously called peroxisomal membrane proteins A
and B (PMPA and PMPB) [84] .
Cross-Reactivity between Fungal and Non-Fungal
Species
Enolase. Enolase represents an allergen in many fun-
gal species, e.g. C. herbarum, A. alternata, C. albicans, S.
cerevisiae, A. fumigatus, F. solani, C. lunata, R. mucilagi-
nosa, Beauveria bassiana and P. citrinum . Preliminary
data also indicate that E. purpurascens [144] and Stachy-
botrys chartarum [145] have got IgE-reactive enolases.
Cynodon dactylon and Hevea brasiliensis are the non-
fungal species where enolase has been described to be an
allergen. The enolases of C. herbarum, A. alternata, A.
fumigatus and C. albicans were shown to be cross-reac-
tive by inhibition experiments [52] . Wagner et al. [146]
demonstrated cross-reactivity between A. alternata, C.
herbarum and Hevea brasiliensis by pre-incubating a se-
rum pool with rHev b 9 and testing this depleted serum
with rCla h 6 and rAlt a 6, where there was no IgE-bind-
ing detectable.
Glutathione-S-Transferase.
The crude extracts of A. al-
ternata , A. fumigatus , C. herbarum , C. lunata and E. pur-
purascens were proven to have GST-enzymatic activity.
Additionally, in all extracts a 26-kDa protein reacted
with anti-GST antibodies. Using these anti-GST anti-
bodies in ELISA inhibition experiments revealed inhibi-
tion in case of C. herbarum , A. alternata , C. lunata , A.
fumigatus and E. purpurascens [ 1 4 7 ] .
A u t o - R e a c t i v i t y
There is evidence that fungal sensitization also con-
tributes to auto-reactivity against self-antigens due to
shared epitopes between fungal and human proteins. The
underlying mechanism seems to be molecular mimicry
perpetuating severe chronic allergic diseases.
Cross-reactivity between fungal and human proteins
has been demonstrated for MnSOD [148, 149] , cyclophilin
[150] , acid ribosomal protein P2 [151] and thioredoxin
[152] . Based on our own research on C. herbarum and A.
alternata allergens, we could show that intracellular fun-
gal proteins are presented to the immune system. Intra-
cellular human proteins are normally not presented to
the immune system. However, in case of chronic inflam-
mation, tissue may be damaged and as a consequence
these proteins may be accessible for the immune system.
Thus human proteins like MnSOD or acid ribosomal
protein 2 may sustain allergic symptoms. In a recent
study on the pathogenesis of AD, 36% of the patients ex-
hibiting M. sympodialis colonization of the skin had spe-
cific IgE antibodies against human MnSOD [44] . These
patients were skin test positive to M. sympodialis extract,
to human recombinant MnSOD and to structurally re-
lated MnSODs. In an atopy patch test with patients suf-
fering from severe atopic eczema, the application of hu-
man recombinant MnSOD on healthy skin elicited an
eczematous reaction [44] . The release of intracellular self-
antigens as a consequence of inflammation processes
causing tissue damage is also proposed to be involved in
the pathogenesis of ABPA [88] .
Asp f 8, the acid ribosomal protein P2 from A. fumiga-
tus , cross-reacts with its human homologue P2. In skin
tests, a humoral autoimmune response to the human P2
protein was seen in ABPA patients and patients with se-
vere AD [91] .

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Int Arch Allergy Immunol 2008;145:58–86
78
Diagnosis of Fungal Allergy
For decades, the diagnosis of mold allergy has based
on the patient’s history, and on in vivo (e.g. SPT, intrader-
mal test or inhalation challenge) and in vitro tests (e.g.
RAST, ELISA and Western blot). However, the accuracy
and reliability of in vivo and in vitro assays is very high-
ly dependent on the quality of the fungal extracts used.
Unfortunately, the correlation of the results obtained
with skin tests and serological tests is very poor. A direct
comparison between in vitro and in vivo results is ham-
pered by the fact that extracts immobilized on testing
devices, e.g. ImmunoCAPs, are not available as SPT solu-
tion and vice versa.
The quality of crude extracts for diagnosis and thera-
py is very unsatisfactory in case of fungal extracts. Cur-
rently, the quality of mold extracts varies dramatically
between commercial suppliers in Europe and the USA
since no standardized extracts are available [46, 58, 153] .
The reasons for the insufficient quality are manifold. On
the one hand, crude extracts from ascomycota as well as
basidiomycota were shown to vary considerably in their
protein composition [154, 155] . These problems are
caused by strain variabilities [156] and batch-to-batch
variations [10, 74] . Additionally, mold extracts may be
produced from mycelial cells and/or spores, which may
vary in their protein pattern [157, 158] . On the other hand,
growth conditions, protein extraction methods and stor-
age conditions are critical with respect to the quantity
and even existence of individual allergens [61, 65, 157] .
Finally, degradation of the extracted proteins may occur,
too [159] . In case of A. alternata [160] , different allergens
had different optimal extraction times, whereas the com-
position of the extraction buffer did not significantly af-
fect the quantity of allergens extracted (with the excep-
tion that a low pH which resulted in a low protein yield).
The diagnosis of mold allergy is also hampered by the fact
that patients might not be aware of the mostly perennial
fungal exposure, thus molds may not be taken into ac-
count for medical history. Moreover, the panel of allergy-
causing molds exceeds by far the number of extracts that
reasonably can be used in routine assessments [161] .
To some extent, the problems with fungal extracts may
be overcome by the use of recombinant allergens. The
major advantages of recombinant proteins over crude
fungal extracts are threefold. Firstly, the protein prepara-
tions are reproducible and can be standardized for bio-
chemical and immunological tests, e.g. mass spectrom-
etry, circular dichroism, inhibition ELISAs, determina-
tion of T-cell reactivity and histamine release assays, and
thus will give a batch-to-batch consistency. Secondly, the
production of large quantities of pure proteins is possible.
Thirdly, using recombinant allergens, it is possible to dif-
ferentiate among co-exposure, co-sensitization and cross-
reactivity. This differentiation is important since prima-
ry sensitizing molds have to be known for a successful
immunotherapy. Although recombinant allergens have
got major advantages, they also have some properties
which have to be taken into account for their expression.
A few allergens undergo secondary modifications such as
glycosylation, phosphorylation, and N- and/or C-termi-
nal processing. Although these modifications may not
directly be involved in IgE binding, they nevertheless
may have a large impact on the three-dimensional struc-
ture and thus on the formation of IgE epitopes of a given
protein. Therefore, the choice of the expression system
is very important. Routinely, bacterial systems such as
Escherichia coli are employed, but since proteins may not
be folded properly and eukaryotic posttranslational mod-
ifications are not accomplished, alternative eukaryotic
systems like Pichia pastoris , S. cerevisiae, Yarrowia lipo-
lytica , Baculovirus and tobacco plant may be used [162,
163] . The P. pastoris system, for example, has been used
for the expression of Alt a 1, the major allergen of A. al-
ternata [ 1 6 4 ] .
In the last years, several diagnostic studies have prov-
en the concept of a component-resolved allergy diagnosis
instead of using crude extracts [165–169] .
In order to use a high throughput test, an allergogram
may be generated using a microarray format enabling a
large number of allergens to be tested in duplicate or trip-
licate with a small amount of patient sera, in order to re-
ceive a profile of the patient’s IgE reactivity pattern
[170] .
Since the total number of relevant IgE-reactive aller-
gens in molds is mostly higher than in pollens or food-
stuff, a panel of recombinant allergens may be necessary
in order to cover the patients’ allergen profile. Major al-
lergens of all fungal phyla like Alt a 1 [48, 171] , Cla h 8
[49] , Asp f 1 [78] , Pen n 18 [106] , Mala f 6 [131] , Mala s 11
[133] and Psi c 2 [136] have been described. These major
allergens combined with minor allergens are promising
candidate molecules for molecular-based, patient-tai-
lored immunotherapy.
In the last years, the first diagnostic studies have com-
pared recombinant fungal allergens and crude mold ex-
tracts with respect to their negative and positive predict-
ability of mold sensitization. In case of A. alternata two
clinical studies were performed [54, 58] in which two al-
lergens (Alt a 6 and Alt a 1) were promising candidate

Fungal Allergy
Int Arch Allergy Immunol 2008;145:58–86
79
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Using a defined panel of allergenic molecules instead
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Conclusions
Taken together, a large number of fungal allergens
have been isolated and characterized in the last years.
Some of them have already been tested in clinical trials,
demonstrating their benefit in the diagnosis of mold al-
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90] . It has been shown that the specificity of recombinant
allergens in serology and skin tests is clearly superior to
the specificity obtained with commercial extracts [165] .
Nevertheless, there is still a long way to go until im-
munotherapy of mold allergy will be safe and success-
ful.
Acknowledgement
This work was supported by project S8812-MED given to B.
Simon-Nobbe and M. Breitenbach by the Austrian Science Fund
(FWF).

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