Alt a 1
Summary
Alt a 1 is a major allergen of and marker of genuine sensitization to the airborne mold Alternaria alternata (A. alternata), mainly involved in the development, persistence, and severity of asthma.
Epidemiology
Worldwide distribution
A. alternata, a cosmopolitan airborne fungus, is involved in asthma (development and exacerbation), atopic dermatitis (AD), and in rare cases of allergic bronchopulmonary mycosis (ABPM). As a mesophilic fungus, A. alternata seldom causes bronchial colonization and invasive infections in humans [1, 2].
Alt a 1 is a major allergen of A. alternata, with 80%-95% of asthmatic or allergic rhinitis (AR) subjects sensitized to A. alternata extracts also displaying IgE sensitization to Alt a 1 [3-5]. Depending on the definition of asthma (doctor-diagnosed or self-reported questionnaire) and the cut-off level of A. alternata sensitization, IgE to Alt a 1 may be detectable in a lower proportion of patients, e.g. 59% of A. alternata-sensitized asthmatic patients from Germany and Poland [3].
The prevalence of Alt a 1 sensitization is lower in A. alternata-sensitized patients with different diseases, e.g. 47% in AD and 60% in cystic fibrosis (CF) patients [5]. Fungal cross-reactivity outside Alt a 1 is likely to explain this discrepancy, with Malassezia spp allergens predominantly involved in AD patients, and Aspergillus fumigatus in CF patients [5].
In line with reports for other fungal allergens, the prevalence of Alt a 1 sensitization varies as a function of geography and climate. Regional variation from 2.2% to 25.4% was reported in a Spanish study [6]. In Japanese asthmatics, the prevalence of Alt a 1 IgE was 2.2% [7]. Conversely, in Italy, the prevalence of Alt a 1 sensitization was 9.56% among subjects with a suspicion of airborne or food allergy [8]. The latter study, addressing 23,077 consecutive patients from Italy, ranked Alt a 1 as the 17th most frequent allergen among 75 assayed molecules, and reported greater prevalence of Alt a 1 sensitization in males (11.70%) as compared to females (7.83%) [8].
Alt a 1 sensitization is usually absent in subjects (healthy, asthmatic, or CF) lacking detectable A. alternata sensitization [3]. Apparent monosensitization to Alt a 1 among airborne allergens is infrequent [8], however, 70% of patients with A. alternata-related allergic rhinoconjunctivitis assayed for IgE binding to eight A. alternata individual allergens only recognized Alt a 1 [9].
The prevalence of Alt a 1 sensitization was stable in a longitudinal Japanese study on asthmatic patients followed during at least 10 years [7], but an increase between 2015 and 2021 was underlined in a Spanish study [6].
Testing for Alt a 1 IgE may be used as a substitute for A. alternata extract when assessing genuine versus cross-sensitization to this fungus, due to its sensitivity and specificity [3-5, 10].
Clinical Relevance
Clinical relevance of Alt a 1 IgE in asthma, allergic rhinitis and allergic rhinoconjunctivitis
A predictive model built using a Spanish cohort of asthma and AR patients monosensitized to A. alternata established airborne Alt a 1 concentrations as predictors of asthma and AR symptoms, with an Alt a 1 concentration threshold of 20.7 pg/ predictive of asthma and AR symptoms [13].
The detection of Alt a 1 sensitization was associated to AR in 92% of cases and to asthma in 64% of cases [6].
The prevalence and the levels of Alt a 1 IgE decreased after 2 years in patients with A. alternata-related allergic rhinoconjunctivitis receiving AIT with Alt a 1 [9, 17].
Clinical relevance of Alt a 1 IgE in atopic dermatitis
Alt a 1 sensitization is frequent in AD patients: up to 47% in those sensitized to A. alternata extract [5], and 26% in those without prior screening for extract sensitization [18]. Alt a 1 was the most prevalent fungal sensitization in 100 AD teenage and adult patients from the Czech Republic, among a panel of common airborne fungal extracts and molecules, but was not related to the severity of AD [18].
Clinical relevance of Alt a 1 in food-induced reactions
Fruit contamination by A. alternata results in Alt a 1 being released in the pulp and potentially inducing allergic reactions upon ingestion of contaminated fruit [19, 20]. Importantly, such food-induced reactions may occur in subjects without a history of food allergy [21].
From a mechanistic viewpoint, Alt a 1 interacts with fruit thaumatin-like proteins (Pathogenesis-Related Proteins group 5), such as Act d 2 from kiwifruit and thus interferes with plant defense mechanisms [19].
Disease severity and prediction
Sensitization to A. alternata, and hence to Alt a 1, is a risk factor for asthma development, asthma persistence, severe asthma, and asthma exacerbations [2, 13, 21]. Conversely, currently available data do not support a role for Alt a 1 sensitization as a predictor of AD severity [18]. Due to its ability to initiate sensitization, Alt a 1 is viewed as a trigger of allergy development [6, 21].
Cross-reactive molecules
The existence of Alt a 1 homologues in phylogenetically related fungi from the Pleosporaceae family (not to be mistaken for the larger Pleosporales order), such as Alternaria tenuis, Stemphylium botryosum, Ulocladium chartarum, and Curvularia lunata, has been reported since 2006 [22]. Ulo c 1 has been recently described [23]. Alt a 1 homologues have not been described outside the Pleosporaceae family, including at the genomic level [24].
Diagnostics
Disease Severity
Alt a 1 sensitization is a risk factor for asthma persistence, asthma exacerbations, and trigger of atopic sensitization to other allergens.
Cross-Reactivity
Alt a 1 cross-reactivity is limited to homologues from closely related species belonging to the Pleosporaceae family, such as Ulo c 1 from the indoor mold Ulocladium chartarum [23].
AIT Prescription
AIT with Alt a 1 decreased the symptoms, medication needs and prevalence and levels of IgE to Alt a 1 in patients with allergic rhinoconjunctivitis to A. alternata [17].
Exposure
Alt a 1 sensitization occurs through inhalation of spores or fungal fragments of A. alternata [15].
Prevention And Therapy
Experimental trials
Because Alt a 1 is a major allergen with limited cross-reactivity and can be produced as a recombinant molecule, it is a suitable candidate for AIT [21]. In a multicentric, randomized, double blind, placebo-controlled study conducted in Spain, subcutaneous AIT with Alt a 1 resulted in significant improvement based on a combined score of medication and symptoms [17].
References
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- De Vouge, M.W., et al., Isolation and expression of a cDNA clone encoding an Alternaria alternata Alt a 1 subunit. Int Arch Allergy Immunol, 1996. 111(4): p. 385-95.
- Vailes, L.D., et al., IgE and IgG antibody responses to recombinant Alt a 1 as a marker of sensitization to Alternaria in asthma and atopic dermatitis. Clin Exp Allergy, 2001. 31(12): p. 1891-5.
- Lopez Couso, V.P., et al., Fungi Sensitization in Spain: Importance of the Alternaria alternata Species and Its Major Allergen Alt a 1 in the Allergenicity. J Fungi (Basel), 2021. 7(8).
- Watai, K., et al., De novo sensitization to Aspergillus fumigatus in adult asthma over a 10-year observation period. Allergy, 2018. 73(12): p. 2385-2388.
- Scala, E., et al., Cross-sectional survey on immunoglobulin E reactivity in 23,077 subjects using an allergenic molecule-based microarray detection system. Clin Exp Allergy, 2010. 40(6): p. 911-21.
- Rodriguez, D., et al., Changes in the Sensitization Pattern to Alternaria alternata Allergens in Patients Treated with Alt a 1 Immunotherapy. J Fungi (Basel), 2021. 7(11).
- Hayes, T., et al., Innate Immunity Induced by the Major Allergen Alt a 1 From the Fungus Alternaria Is Dependent Upon Toll-Like Receptors 2/4 in Human Lung Epithelial Cells. Front Immunol, 2018. 9: p. 1507.
- Twaroch, T.E., et al., Predominant localization of the major Alternaria allergen Alt a 1 in the cell wall of airborne spores. J Allergy Clin Immunol, 2012. 129(4): p. 1148-9.
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- Gomez-Casado, C., et al., Alt a 1 from Alternaria interacts with PR5 thaumatin-like proteins. FEBS Lett, 2014. 588(9): p. 1501-8.
- Gabriel, M.F., et al., The major Alternaria alternata allergen, Alt a 1: A reliable and specific marker of fungal contamination in citrus fruits. Int J Food Microbiol, 2017. 257: p. 26-30.
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- Chruszcz, M., et al., Alternaria alternata allergen Alt a 1: a unique beta-barrel protein dimer found exclusively in fungi. J Allergy Clin Immunol, 2012. 130(1): p. 241-7 e9.
- IUIS/WHO. IUIS/WHO Allergen Nomenclature: Alternaria alternata. [cited 2021 22 December 2021]; Available from: http://allergen.org/search.php?allergenname=&allergensource=Alternaria+alternata&TaxSource=&TaxOrder=&foodallerg=all&bioname=.
- Garrido-Arandia, M., et al., Interaction of Alt a 1 with SLC22A17 in the airway mucosa. Allergy, 2019. 74(11): p. 2167-2180.
- Gutierrez-Rodriguez, A., et al., Identification of allergens homologous to Alt a 1 from Stemphylium botryosum and Ulocladium botrytis. Med Mycol, 2011. 49(8): p. 892-6