I hope you're doing well and enjoying fall. I also hope that you'll find the following
article about fungal allergens by Dr. Harriet Burge both interesting and useful.
With best wishes,
By Dr. Harriet Burge, EMLab P&K Chief Aerobiologist and Director of Scientific Advisory Board
Introduction: Allergic Disease
Nature of Allergens
For the purpose of this discussion, allergen will be defined as an antigen capable of stimulating
an inappropriate IgE response in a susceptible person. A few definitions are necessary here.
First, an ANTIGEN is a molecule that can be bound at the antigen-binding site of an antibody.
A single antigen may have several distinct binding sites called EPITOPES. Antigens are complex
molecules, usually proteins or polysaccharides.
IgE (Immunoglobulin E) is a molecule produced by the human immune system possibly to guard
against parasite infections. At least a third of the human population has the genetic propensity
to produce IgE against non-parasitic antigens. These people are called ATOPIC.
Nature of the Allergic Response
In an atopic person, the first encounter with an allergen stimulates B cells (through a series
of interactions with other cells) to produce IgE antibodies that are specifically designed to
recognize the allergen. Because the allergen may have several different binding sites (epitopes),
the B cells may produce several different kinds of IgE antibodies, each specific to one of the
epitopes. These antibodies circulate in the blood stream, and eventually bind to two types of
white blood cells: MAST cells and BASOPHILS. Both of these cell types are filled with granules
containing histamine and other inflammatory agents. Mast cells are attached to tissues (including
mucous membranes), and basophils circulate in the blood. At this point, the exposed person has
become sensitized to the allergen, but does not have symptoms. It probably takes a series of
exposures to the same antigen before this process leads to the next step: symptom production.
Once sensitization has been accomplished, the next encounter with the same allergen may cause
symptoms. Symptoms result when the allergen molecule encounters an appropriately sensitized
mast cell or basophil. When the allergen binds to the antibodies on the surface of these cells,
the inflammatory agents they contain are released into the surrounding tissue and cause dilation
of local blood vessels (leading to redness), mucous secretion (runny nose), nerve stimulation
(itchiness) and smooth muscle contraction (difficulty breathing). The overall type of reaction
the individual experiences depends on how the allergen enters the body, the nature of the
individual's sensitivity, and the nature of the allergen. If the chemical mediators travel
throughout the body, then anaphylaxis occurs. Asthma is the result of exposure to the lower
airways. Allergic rhinitis occurs primarily from allergens borne on relatively large particles
that impact in the eyes and upper airways. Eczema (atopic dermatitis) is localized to the skin.
Other factors may play a role in sensitization. For example, ADJUVANTS (immunostimulants) may
stimulate a stronger response than the allergen alone. For example, the fungus Alternaria
has adjuvant-like properties that stimulate sensitization in the lower airways (Kobayashi
et al., 2009). Holt et al. (2009) postulate that early failure of the innate mucosal immune
system predisposes some infants and young children to respiratory infections and the development
of allergies. This predisposition is probably genetically controlled.
Fungal allergens are generally proteins, and are often enzymes released from the fungal spore
during germination, although some may also be proteins located on the surface of spores. For
surface allergens, the spore may not need to be living to cause sensitization. However,
internally produced allergens must be released from the cell before they can be effective.
Fungi with hydrophilic cell walls (e.g., Fusarium, Acremonium, Stachybotrys,
and many others) may release internal allergens as soon as they contact a water source (e.g.,
the respiratory mucosa). Whether or not these spores need to be living has not been studied,
although it is likely that long dead spores would not have retained the intact allergens.
Hydrophobic fungal spores have an outer surface composed of rodlets called hydrophobins. A
pathway must develop through these hydrophobins before internal allergens can be released.
This pathway occurs during spore germination. Thus, for allergens to be released from hydrophobic
spores, the spore must be alive (Aimanianda et al., 2010; Dague et al., 2008).
Probably all fungi can produce some allergen. However, apparently some very common ones are less
likely than others to lead to sensitization and symptoms. Using human IgE immunostaining and
confocal microscopy, Green et al. (2009) found that among the identifiable spores in their air
samples, Cladosporium, Alternaria, Bipolaris, Curvularia, Pithomyces
and Stachybotrys contained allergens reacting to the IgE, but Epicoccum, Fusarium,
and Spegazzinia did not. It would be interesting to know whether or not any of these spores
were actually able to germinate under the conditions used. If not, then this study is biased toward
those spore types with surface allergen, and those that can release allergens without germination.
Using a mouse model, Chung et al. (2010) found that allergens derived from Stachybotrys chartarum
were less potent than those from house dust mites. More than twice as much Stachybotrys
allergen had to be administered to match the response to house dust mite allergen. Again, it is
not possible to know whether the Stachybotrys spores were germinated to produce the allergen.
House dust mite allergens are readily released from their fecal packages.
Recognizing that fungal enzymes are allergenic, Horner (2010) used human sera and commercially
available fungal enzymes in a RAST (radioallergosorbent) test to evaluate specific IgE presence.
They found that invertase (from bakers yeast), cellulase (from Trichoderma viride), and
glucosidase (from brewer's yeast) reacted with the patient IgE. This doesn't necessarily mean that
the patients were sensitized to these specific fungi. It may be that these enzymes, which are
produced by many fungi, are sufficiently homologous that their source is irrelevant. This may
explain much of the cross-reactivity found among different fungal allergens. In fact, Soeria-Atmadja
et al. (2010) used cluster analysis to determine that fungal specific IgE clustered according to
relationships within the fungal kingdom. He found the following groupings:
Exposure to Fungal Allergens
Most exposure to fungal allergens probably occurs from inhalation of spores in outdoor air. All
of the fungi found indoors are also part of the outdoor ecology, making separation of indoor
and outdoor exposures difficult. Given that some spores must be alive to release allergens, it
is possible that spores produced in an indoor environment would be "fresher" and more
likely to be alive than those outdoors. If this were true, then indoor exposures to some fungi
may be more important than outdoor exposure.
I won't reiterate the abundance of data on sources for indoor exposure. Obviously, growth on
damp or wet materials is the primary source. I did find one study that documented the danger of
evaporative coolers with respect to fungal exposure. Prasad et al. (2009) report that 42% of
people with evaporative coolers had positive skin tests to at least one fungus, while only 19%
those without these appliances had such reactions. Six-year old children had the highest
prevalence of positive skin tests.
Nearly all the information we have about exposure/symptom relationships for the fungi come from
epidemiological studies. There are many of these. Data from three recent ones are presented here.
6-12 year asthmatic children (n=225)
Culturable air sampling
Peak expiratory flow variability
Only Penicillium concentrations strongly associated with outcome
Bundy et al., 2009
Children with and without positive skin tests to specific fungi
Culturable air sampling indoors and out
Symptom days; unscheduled doctor visits for asthma
Positive fungal skin test (any) predicted symptom days; indoor total fungal and Penicillium exposure predicted number of symptom days
Pongracic et al., 2010
Children 3 years old with and without visible house mold
Observation of visible mold; glucans measurement
High risk for asthma
Visible mold, high risk for asthma; glucans measures predicted low risk for asthma
Iossifova et al., 2009
Absenteeism associated with visible mold and poor building conditions
Simons et al., 2010
Much of the data from these recent studies reinforces the results of earlier studies. The most
interesting of these studies with respect to the nature of fungal allergens are those that seek
to clarify the extreme complexity of the fungi and their allergens. There remains an urgent need
to develop fungal skin testing materials that more broadly identify the fungal allergic patient.
This requires the recognition that fungal allergens are not readily released from intact spores,
and the patterns of cross-reactivity between different fungi.
1. Aimanianda V, Bayry J, Bozza S, Kniemeyer O, Perruccio K, Elluru SR, Clavaud C, Paris S,
Brakhage AA, Kaveri SV, Romani L, Latgé JP. 2009. Surface hydrophobin prevents immune recognitions
of airborne fungal spores. Nature 460(7259) 1117-U79.
2. Bundy KW,Gent JF, Beckett W, Bracken MB, Belanger K, Triche E, Leaderer BP. 2009. Household
airborne Penicillium associated with peak expiratory flow variability in asthmatic children.
Annals of Allergy Asthma & Immunology 103(1):26-30.
3. Chung YJ, Copland LB, Doerfler DL, Ward MDW. 2010. The relative allergencity of Stachybotrys
chartarum compared to house dust mite extracts in a mouse model. Inhalation Toxicology 22(6):460-468.
4. Dague E, Delcorte A, Latge JP, Dufrene YF. 2008. Combined use of atomic force microscopy, X-ray
photoelectron spectroscopy, and secondary ion mass spectrometry for cell surface analysis. Langmuir
5. Green BJ, Tovey ER, Beezhold DH, Perzanowski MS, Acosta LM, Divjan AI, Chew GL. 2009.
Surveillance of fungal allergic sensitization using the fluorescent halogen immunoassay. Journal De
Mycologie Medicale 19(4):253-261.
6. Holt PG, Strickland DH, Bosco A, Jahnsen FL. 2009. Pathogenic mechanisms of allergic
inflammation: Atopic asthma as a paradigm. Advances in Immunolgy 104:51-113.
7. Horner AA. 2010. Regulation of aeroallergen immunity by the innate immune system: laboratory
evidence for a new paradigm. Journal of Innate Immunity 2(2): 107-113.
8. Iossifova YY, Reponen T, Ryan PH, Levin L, Bernstein DI, Lockey JE, Hershey GKK, Villareal M,
LeMasters G. 2009. Mold exposure during infancy as a predictor of potential asthma development.
Ann Allergy Asthma & Immunology 102(2):131-137.
9. Kobayashi T, Iijima K, Radhakrishnan S. 2009. Asthma-related environmental fungus, Alternaria,
activates dendritic cell nd produces potent Th2 adjuvant activity. The Journal of Immunology 182: 2502-2510.
10. Pongracic JA, O'Connor GT, Muilenberg ML, Vaughn B, Gold D, Kattan M, Morgan WJ, Gruchalla RS,
Smartt E, Mitchell HE. 2010. Differential effects of outdoor versus indoor fungal spores on asthma
morbidity in inner city children. J Allergy Clinical Immunology 125(3):593-599.
11. Prasad C, Hogan MB, Peele K, Wilson NW. 2009. Effect of evaporative coolers on skin test
reactivity to dust mites and molds in a desert environment. Allergy and Asthma Proceedings 30(6):624-627.
12. Simons E, Hwang SA, Fitzgerald EF, Kielb C, Lin S. 2010. The impact of school building
conditions on student absenteeism in upstate New York. American J Public Health 100(9): 1679-1686.
13. Soeria-Atmadja D, Onell A, Borga A. 2010. IgE sensitization to fungi mirrors fungal
phylogenetic systematics. J Allergy Clin Immunology 125(6):1379-1386.
14. Warman K, Silver EJ, Wood PR. 2009. Modifiable risk factors for asthma morbidity in Bronx
versus other inner-city children. J Asthma 46(10):995-1000.