Table of Contents

m222 Asp f 6 Scientific Information Summary Epidemiology Environmental Characteristics Clinical Relevance Molecular Aspects Diagnostic Relevance Compiled By

Component

m222 Asp f 6

m222 Asp f 6 Scientific Information

Type:

Component

Name; WHO/IUIS:

Asp f 6

Biological function:

Mitochondrial superoxide dismutase

Allergen code:

m222

Molecular Weight:

26.5 kDa

Source Material:

Recombinant, CCD-free protein

Other Names :

Mn superoxide dismutase

Summary

Asp f 6 is a phylogenetically conserved mitochondrial manganese superoxide dismutase (MnSOD) from the ubiquitous environmental mold Aspergillus fumigatus (A. fumigatus), an agent of allergic fungal airway diseases (AFAD) which include severe asthma with fungal sensitization (SAFS) and allergic bronchopulmonary aspergillosis (ABPA). Asp f 6 sensitization occurs mainly in patients with ABPA, but not with other AFAD, and therefore may contribute to the diagnosis of ABPA. Cross-reactivity to Asp f 6 is frequent in atopic dermatitis (AD), as a result of sensitization to Mala s 11 from Malassezia sympodialis, and to human MnSOD.

Epidemiology

Worldwide distribution

A. fumigatus is a cosmopolitan, thermotolerant airborne fungus affecting human health through multiple pathways: allergy, infection, direct toxicity [1].

The prevalence of Asp f 6 sensitization is highly variable depending on the study population in terms of geography, underlying lung condition, i.e. asthma, cystic fibrosis (CF), or chronic obstructive pulmonary disease (COPD), stage of AFAD, method of assessment (skin prick test, blood tests) and cut-off values. Despite wide variations, Asp f 6 sensitization presents with higher prevalence and higher levels in ABPA as compared to asthmatic patients and healthy individuals. Early reports in European asthmatic patients sensitized to A. fumigatus found that Asp f 6 sensitization was specific of ABPA, with a prevalence of 55% [2, 3]. Later studies showed that Asp f 6 sensitization is also found, albeit with lower prevalence figures, outside ABPA. For example, 89% of ABPA and 44% of A. fumigatus-sensitized, non-ABPA Indian asthmatics displayed detectable Asp f 6 sensitization in a 2020 study [4]. Conversely, the prevalence of Asp f 6 sensitization was only 38-50% in ABPA patients among two cohorts of Japanese asthmatics, compared to 9-31% of A. fumigatus-sensitized asthmatics without ABPA [5, 6]. In Chinese asthmatic patients from Guangzhou, Asp f 6 sensitization was found in 70% of ABPA patients and in 15% of A. fumigatus-sensitized asthmatic patients without ABPA [7]. Considering CF patients with A. fumigatus-sensitization without ABPA, the prevalence of Asp f 6 sensitization varied from 0% in a Swiss study [8] to 20% in a French one [9], and 25 in a British one [10], increasing to 55% - 89% in ABPA patients from the same cohorts [8-10]. Lower figures were reported in a pediatric CF cohort from the US, with Asp f 6 sensitization present in 25% of ABPA patients and in none of 23 A. fumigatus-sensitized patients without ABPA [11]. Among German and Polish self-reported asthmatic patients with A. fumigatus sensitization, 15% displayed Asp f 6 sensitization, but 17% of non-asthmatic subjects exposed to mold also displayed Asp f 6 sensitization [12].

In patients suffering of AD, Asp f 6 sensitization can be detected with increasing prevalence from 0-5% in mild AD to 27-40% in severe AD [13, 14]. In a Japanese cohort, Asp f 6 sensitization was more frequent in AD patients with (62%) or without (56%) asthma, compared to asthmatic patients free of AD (9%) [5].

Asp f 6 sensitization was found in 6% A. fumigatus sensitized German patients with allergic rhinitis, usually associated to sensitization to other molecular components [15]. In COPD patients, the prevalence of Asp f 6 sensitization was 1%, not different from 0% in controls [16].

Asp f 6 sensitization is usually absent in subjects (healthy, asthmatic, or CF) lacking detectable skin or blood A. fumigatus sensitization [4, 6].

Environmental Characteristics

Source and tissue

Asp f 6 is a somatic protein located in the mitochondria of A. fumigatus [17, 18]. Predominantly produced during late germination steps, Asp f 6 is abundant in hyphae and mycelia, but is not secreted [18, 19].

Risk factors

Sensitization and allergy to A. fumigatus occur mainly in subjects with pre-existent lung conditions, usually asthma or CF, with COPD increasingly recognized as another predisposing condition [1].

Clinical Relevance

Detailed information regarding A. fumigatus is available in the whole allergen section.

Clinical relevance of Asp f 6 IgE in ABPA

The diagnosis of ABPA is often complicated by symptoms due to underlying conditions and a complex pathophysiology combining IgE and IgG responses, sputum and systemic eosinophilia, and much debated fungal colonization [20, 21]. While Asp f 1 and Asp f 2 are major allergens and markers of genuine sensitization to A. fumigatus, Asp f 6 sensitization is a marker of a more complex sensitization pattern, associated with ABPA [20]. In a meta-analysis, detection of IgE to Asp f 6 offered a 42.6% (95%CI 8-75.7) pooled diagnostic sensitivity for ABPA in asthmatic patients and 51.3% (95%CI 20-75.7) in CF patients, with a pooled specificity of 94.9% (95%CI 70.1-99.9) in asthma and 97.5% (95%CI 87.3-99.9) in CF [22].

Along with the prevalence of Asp f 6 sensitization, Asp f 6 IgE levels are higher in asthmatic or CF patients with ABPA than in counterparts who are A. fumigatus-sensitized but free of ABPA [2, 9, 23, 24]. Median levels of IgE to Asp f 6 in ABPA patients are similar among cohorts from various locations, usually comprised between 2 and 3 kUA/L [7, 9, 10, 23, 24]. Using population-based cut-offs, the reported area under the receiver operating curve of Asp f 6 was 0.830 to 0.896 in different populations [9, 23].

Diagnostic performance of Asp f 6 is improved when used in conjunction with other A. fumigatus molecular allergens [23-25]. As an example, a meta-analysis revealed that the presence of either Asp f 4 or Asp f 6 sensitization improved the sensitivity for detecting ABPA in asthmatics up to 89.3% (95%CI 78.8-95.5) and in CF to 57% (95%CI 17.6-88.3), while pooled specificity reached 99% in asthmatic patients, and 93.9% in CF patients [22].

Clinical relevance of Asp f 6 IgE in AD

Asp f 6 sensitization detected in AD patients is considered as a marker of extended cross-reactivity among human and fungal MnSOD, with Mala s 11, a MnSOD from Malassezia sympodialis, a more probable primary sensitizer than A. fumigatus. In AD patients, Asp f 6 sensitization may occur in the absence of detectable sensitization to A. fumigatus extract and major allergens, supporting the hypothesis of a cross-reaction rather than a genuine sensitization [26, 27].

Disease severity and prediction

Asp f 6 sensitization and increasing levels of Asp f 6 IgE in asthmatic or CF patients are statistically associated to an increased risk of ABPA, as explained above [24, 28].

In AD patients, Asp f 6 sensitization is associated with disease severity [13, 14, 26] and autoreactivity to human MnSOD and Malassezia sympodialis Mala s 11, homologues of Asp f 6 [17, 26, 29].

Cross-reactive molecules

Asp f 6 cross-reacts with other eukaryotic MnSOD through sequential and conformational epitopes. Clinically, the most relevant cross-reactivity involves both IgE and T cells and is found with MnSOD from other Aspergillus species, with Mala s 11 from Malassezia sympodialis, and with human MnSOD, forming the basis of auto-antigenicity and autoreactivity seen in AD [29-32]. MnSOD may be considered as a panallergen due to cross-reactivity among members of this family [32].

Molecular Aspects

Biochemistry

Asp f 6 is a protein of 26.5 kDa. Similar to other MnSOD, Asp f 6 forms homotetramers with proven allergenicity involving both sequential and conformational epitopes [27, 33]. As a non-secreted protein, Asp f 6 exerts its detoxifying function intracellularly, protecting the fungus from superoxide anion molecules produced during the respiratory activity of mitochondria [19]. A. fumigatus mutants deficient for Asp f 6 exhibit delayed germination at high temperature and increased susceptibility to oxidative stress, but their virulence in immunocompromised model animals is not affected [18].

Isoforms, epitopes, antibodies

As of November 7th, 2021, Asp f 6 comprises only one isoallergen officially published by the World Health Organization (WHO) and the International Union of Immunological Societies (IUIS) Allergen Nomenclature: Asp f 6.0101 [34].

Cross-reactivity due to structural similarity

Asp f 6 exhibits sequence identity of 50% or higher with other MnSOD [27, 30, 31]. However, due to its homotetrameric structure, cross-reactivity is only partly explained by sequence identity [27, 29, 32].

Diagnostic Relevance

Disease Severity

Asp f 6 sensitization, especially at high levels, is a specific marker of ABPA in A. fumigatus-sensitized asthmatic and CF patients [17, 22], and an indicator of AD severity and autoreactivity [13, 14, 17, 26].

Cross-Reactivity

Asp f 6 exhibits clinically relevant cross-reactivity with fungal MnSOD, mainly Mala s 11 from Malassezia sympodialis, and with human MnSOD, and is therefore considered a marker of autoreactivity in AD [17, 29].

Exposure

Asp f 6 sensitization occurs through inhalation upon exposure to A. fumigatus [17].

Compiled By

Author:Joana Vitte

Reviewer: Dr. Christian Fischer

Last reviewed: March 2022

References

Wardlaw, A.J., et al., New Perspectives in the Diagnosis and Management of Allergic Fungal Airway Disease. J Asthma Allergy, 2021. 14: p. 557-573.
Hemmann, S., et al., Skin test reactivity to 2 recombinant Aspergillus fumigatus allergens in A fumigatus-sensitized asthmatic subjects allows diagnostic separation of allergic bronchopulmonary aspergillosis from fungal sensitization. J Allergy Clin Immunol, 1999. 104(3 Pt 1): p. 601-7.
Crameri, R., et al., Disease-specific recombinant allergens for the diagnosis of allergic bronchopulmonary aspergillosis. Int Immunol, 1998. 10(8): p. 1211-6.
Muthu, V., et al., Role of recombinant Aspergillus fumigatus antigens in diagnosing Aspergillus sensitisation among asthmatics. Mycoses, 2020. 63(9): p. 928-936.
Tanimoto, H., et al., Molecular-based allergy diagnosis of allergic bronchopulmonary aspergillosis in Aspergillus fumigatus-sensitized Japanese patients. Clin Exp Allergy, 2015. 45(12): p. 1790-800.
Kuwabara, K., et al., Serological analysis of sensitization in allergic bronchopulmonary aspergillosis: a study on allergen components and interspecies relationships. J Asthma, 2020. 57(6): p. 610-617.
Luo, W., et al., Molecular allergen sensitization of Aspergillus fumigatus between allergic bronchopulmonary aspergillosis and A fumigatus-sensitized asthma in Guangzhou, Southern China. J Clin Lab Anal, 2020. 34(10): p. e23448.
Hemmann, S., et al., Differential IgE recognition of recombinant Aspergillus fumigatus allergens by cystic fibrosis patients with allergic bronchopulmonary aspergillosis or Aspergillus allergy. Eur J Immunol, 1998. 28(4): p. 1155-60.
Vitte, J., et al., Aspergillus fumigatus components distinguish IgE but not IgG4 profiles between fungal sensitization and allergic broncho-pulmonary aspergillosis. Allergy, 2016. 71(11): p. 1640-1643.
Alghamdi, N.S., et al., Serum IgE and IgG reactivity to Aspergillus recombinant antigens in patients with cystic fibrosis. J Med Microbiol, 2019. 68(6): p. 924-929.
Knutsen, A.P., et al., IgE antibody to Aspergillus fumigatus recombinant allergens in cystic fibrosis patients with allergic bronchopulmonary aspergillosis. Allergy, 2004. 59(2): p. 198-203.
Kespohl, S. and M. Raulf, Mold Sensitization in Asthmatic and Non-asthmatic Subjects Diagnosed with Extract-Based Versus Component-Based Allergens. Adv Exp Med Biol, 2019. 1153: p. 79-89.
Scala, E., et al., beta-1,3-glucanase rOle e 9 and MnSOD rAsp f 6 IgE reactivity are the signature of atopic dermatitis in the Mediterranean area. Clin Exp Allergy, 2020. 50(4): p. 487-498.
Celakovska, J., et al., Atopic Dermatitis and Sensitisation to Molecular Components of Alternaria, Cladosporium, Penicillium, Aspergillus, and Malassezia-Results of Allergy Explorer ALEX 2. J Fungi (Basel), 2021. 7(3).
Volgger, V., et al., Value of Component Resolved Diagnostics to Aspergillus fumigatus in Patients with Upper Airway Complaints. Int Arch Allergy Immunol, 2021. 182(2): p. 120-130.
Everaerts, S., et al., Sensitization to Aspergillus fumigatus as a risk factor for bronchiectasis in COPD. Int J Chron Obstruct Pulmon Dis, 2017. 12: p. 2629-2638.
Matricardi, P.M., et al., EAACI Molecular Allergology User's Guide. Pediatr Allergy Immunol, 2016. 27 Suppl 23: p. 1-250.
Lambou, K., et al., Functional analysis of the superoxide dismutase family in Aspergillus fumigatus. Mol Microbiol, 2010. 75(4): p. 910-23.
Schwienbacher, M., et al., Asp f6, an Aspergillus allergen specifically recognized by IgE from patients with allergic bronchopulmonary aspergillosis, is differentially expressed during germination. Allergy, 2005. 60(11): p. 1430-5.
Carsin, A., et al., Aspergillus fumigatus in cystic fibrosis: An update on immune interactions and molecular diagnostics in allergic bronchopulmonary aspergillosis. Allergy, 2017. 72(11): p. 1632-1642.
Asano, K., et al., New clinical diagnostic criteria for allergic bronchopulmonary aspergillosis/mycosis and its validation. J Allergy Clin Immunol, 2021. 147(4): p. 1261-1268 e5.
Muthu, V., et al., Utility of recombinant Aspergillus fumigatus antigens in the diagnosis of allergic bronchopulmonary aspergillosis: A systematic review and diagnostic test accuracy meta-analysis. Clin Exp Allergy, 2018. 48(9): p. 1107-1136.
Muthu, V., et al., Diagnostic Cutoffs and Clinical Utility of Recombinant Aspergillus fumigatus Antigens in the Diagnosis of Allergic Bronchopulmonary Aspergillosis. J Allergy Clin Immunol Pract, 2020. 8(2): p. 579-587.
Fricker-Hidalgo, H., et al., Recombinant allergens combined with biological markers in the diagnosis of allergic bronchopulmonary aspergillosis in cystic fibrosis patients. Clin Vaccine Immunol, 2010. 17(9): p. 1330-6.
Lukaszewicz, R., et al., Medical algorithm: Aspergillus fumigatus components in the diagnosis of Allergic Bronchopulmonary Aspergillosis. Allergy, 2021.
Schmid-Grendelmeier, P., et al., IgE-mediated and T cell-mediated autoimmunity against manganese superoxide dismutase in atopic dermatitis. J Allergy Clin Immunol, 2005. 115(5): p. 1068-75.
Fluckiger, S., et al., Comparison of the crystal structures of the human manganese superoxide dismutase and the homologous Aspergillus fumigatus allergen at 2-A resolution. J Immunol, 2002. 168(3): p. 1267-72.
Casaulta, C., et al., Time course of antibody response to recombinant Aspergillus fumigatus antigens in cystic fibrosis with and without ABPA. Pediatr Allergy Immunol, 2005. 16(3): p. 217-25.
Crameri, R., Immunoglobulin E-binding autoantigens: biochemical characterization and clinical relevance. Clin Exp Allergy, 2012. 42(3): p. 343-51.
BLAST, U. BLAST from UniProtKB - Q92450 (SODM_ASPFU) for Asp f 6. 2021 2021 December 5]; Available from: https://www.uniprot.org/blast/uniprot/B20211206A084FC58F6BBA219896F365D15F2EB44022AD70.
Bowyer, P., M. Fraczek, and D.W. Denning, Comparative genomics of fungal allergens and epitopes shows widespread distribution of closely related allergen and epitope orthologues. BMC Genomics, 2006. 7: p. 251.
Marti, P., et al., Allergen motifs and the prediction of allergenicity. Immunol Lett, 2007. 109(1): p. 47-55.
Caraballo, L., et al., The allergenic activity and clinical impact of individual IgE-antibody binding molecules from indoor allergen sources. World Allergy Organ J, 2020. 13(5): p. 100118.
IUIS/WHO. IUIS/WHO Aspergillus fumigatus. November 7 2021]; Available from: http://allergen.org/search.php?allergenname=&allergensource=Aspergillus+fumigatus&TaxSource=&TaxOrder=&foodallerg=all&bioname=.