m229 Alt a 1

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.

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 17^th 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].

Source and tissue

Alt a 1 is found as a preformed protein in the cell wall and the cytoplasm of mature A. alternata spores, while it is absent from hyphae and earlier stages of spore formation [11, 12]. It is rapidly released upon hydration and slightly acidic pH [12].

Risk factors

The concentration of airborne Alt a 1 displays seasonal variations according to local climate, weather and pollution conditions, with maximum amounts during summer, coincident with peaks in asthma exacerbation [1, 13, 14]. Alt a 1 is mainly found in the 2.5-10 micrometer fraction of airborne particulate matter [15]. A. alternata spores contain variable amounts of Alt a 1, for example 2.3 to 34.7 x 10-3 picograms/spore in a study performed in Poland [14]. Airborne Alt a 1 sources are intact A. alternata spores and fungal fragments [13, 15]. 

Detection methods

Immunoassays detecting Alt a 1 in house dust samples help evaluating the indoor allergen burden. As an example, Alt a 1 was detected in 25.5% of bedroom dust samples from allergen-tested US homes participating in the NHANES (National Health and Nutrition Examination Survey) 2005-2006 [16].

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/m3 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]. 

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].

Biochemistry

Alt a 1 is a heat-stable, acidic, homodimeric protein with a molecular weight of 30 kDa [12, 25]. Reducing or acidic conditions disrupt the intermolecular disulfide bridge, releasing two monomers of 16.4 and 15.3 kDa [25, 26]. In the presence of its flavonoid ligand, dimeric Alt a 1 aggregates into tetramers [27].

Alt a 1 folds as a β-barrel with 11 antiparallel strands and defines a structural family exclusively found in fungi [25]. However, partial conformational similarity was recently uncovered between Alt a 1 and the human siderocalin, conferring shared recognition and internalization by the latter molecule receptor SLC22A17 in bronchial epithelial cells [27].

The function and biological role of Alt a 1 have yet to be clearly established. In human experimental models, Alt a 1 induced bronchial epithelial cells to secrete cytokines and chemokines involved in innate and adaptive immune responses: interleukin (IL)-8 (CXCL8, major neutrophil chemotactic factor), IL-33 (alarmin and type 2 signaling), IL-25 (type 2 signaling) [10]. Ligand-bearing Alt a 1 tetramer was recognized and bound by the siderocalin receptor SLC22A17 in bronchial epithelial cells [27]. Alt a 1 contributions to pathogenicity and plant-fungus interactions have also been reported, including the partial inhibition of PR-5 fruit proteins [21]. 

Isoforms, epitopes, antibodies

As of December 15th, 2021, Alt a 1 comprises two isoallergens officially published by the World Health Organization (WHO) and the International Union of Immunological Societies (IUIS) Allergen Nomenclature: Alt a 1.0101 and Alt a 1.0102 [26].

Cross-reactivity due to structural similarity

Alt a 1 displays structural similarity to few allergens from phylogenetically related members of the Pleosporaceae family and is therefore considered as a species (or family)-specific allergen, marker of primary sensitization to A. alternata [2, 28]. Ulo c 1, the first fully identified Alt a 1-like allergen, has a 89% protein sequence identity to Alt a 1 and is found in the mainly indoor mold Ulocladium chartarum [23].  

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].

Author: Joana Vitte

Reviewer: Dr. Christian  Fischer

Last reviewed:January 2022