Asp f 1
Summary
Asp f 1, the ribonuclease mitogillin, a member of the ribotoxin family, is a major allergen of and marker of genuine sensitization to the ubiquitous environmental mold Aspergillus fumigatus (A. fumigatus), associated to allergic fungal airway diseases (AFAD) affecting upper and lower airways, such as allergic fungal rhinosinusitis (AFRS), severe asthma with fungal sensitization (SAFS), and allergic bronchopulmonary aspergillosis (ABPA). Asp f 1, a secreted protein, exerts cytotoxic and proinflammatory effects.
Epidemiology
Worldwide distribution
A. fumigatus is a cosmopolitan, thermotolerant airborne fungus affecting human health through multiple pathways: sensitization and allergy, infection, direct toxicity [1].
The prevalence of Asp f 1 sensitization is highly variable depending on the study population in terms of geography, underlying lung condition (asthma, CF, or COPD), stage of AFAD, method of assessment (skin prick test, blood tests) and cut-off values (reviewed in [2, 3]). Despite wide variations, Asp f 1 sensitization presents with higher prevalence and higher levels in ABPA as compared to control populations. For example, Asp f 1 sensitization in ABPA was found at 60% and 67% in two Japanese cohorts [4, 5], at 83% in British patients [6] and at 100% in French patients [7]. In asthmatic patients with A. fumigatus sensitization, detectable IgE to Asp f 1 was reported in 18% of Japanese patients [4] and in 46% of German and Polish patients [8].
In an unselected population of 23,077 consecutive Italian subjects with a suspicion of airborne or food allergy, 0.43% displayed detectable IgE sensitization to Asp f 1, ranking 64 among 75 assayed allergenic molecules, and in 10% Asp f 1 presented as apparent monosensitization [9]
Clinical Relevance
Detailed information regarding A. fumigatus is available in the whole allergen section. The demonstration of Asp f 1 IgE confirms genuine sensitization to A. fumigatus [10].
Clinical relevance of Asp f 1 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 [3, 11]. The levels, rather than the prevalence, of Asp f 1 sensitization have been proposed as a diagnostic criterion for ABPA [2, 7, 12]. Median levels of IgE to Asp f 1 in ABPA patients may vary from 2.5 kUA/L to 17 kUA/L among different cohorts [5-7, 12], supporting the observation that statistically determined cut-off levels in a given population perform better than fixed cut-offs [12]. Using population-based cut-offs, the reported area under the receiver operating curve of Asp f 1 was close to 0.9 in different populations [7, 12]. A meta-analysis showed a pooled sensitivity of 80% and pooled specificity of 70.1% for Asp f 1 as a diagnostic tool for ABPA in asthmatic patients, and 78.9% and 81.9% respectively for the diagnosis of ABPA in CF patients [2]. Diagnostic performance of Asp f 1 is improved when used in conjunction with other A. fumigatus molecular allergens [12-14].
Disease severity and prediction
Increasing levels of Asp f 1 IgE in asthmatic or CF patients are statistically associated to an increased risk of ABPA, as explained above. Outside ABPA, it has long been known that sensitization to A. fumigatus is associated with lung function deterioration in adult and pediatric asthmatic patients [15, 16]. Using molecular allergen diagnostics in a COPD cohort, it was shown that Asp f 1 sensitization, rather than A. fumigatus sensitization, was associated with bronchiectasis, an irreversible complication leading to poorer lung function and mortality [17]. In this study, Asp f 1 sensitization was detectable in 12% of COPD patients and in 2% of controls (p = 0.02) and was associated with an odds ratio of 2.8 for having bronchiectasis.
Cross-reactive molecules
Asp f 1 is a member of the ribotoxin family and shares a sequence identity of 80% or with homologues from a small number of other Aspergillus species, mainly restrictocin from A. restrictus, and α-sarcin from A. giganteus [18-20].
Diagnostics
Disease Severity
Asp f 1 sensitization, a marker of genuine sensitization to A. fumigatus, is associated with ABPA [2]and lung function deterioration in COPD patients [17]
Cross-Reactivity
Asp f 1 displays clinically relevant cross-reactivity with a small number of related allergens from other Aspergillus species.
Exposure
Asp f 1 sensitization is believed to occur mainly through inhalation upon exposure to A. fumigatus [10]
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.
- 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.
- 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.
- 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.
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- 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.
- Vitte, J., et al., Multivariate Analysis As a Support for Diagnostic Flowcharts in Allergic Bronchopulmonary Aspergillosis: A Proof-of-Concept Study. Frontiers in Immunology, 2017. 8.
- Lukaszewicz, R., et al., Medical algorithm: Aspergillus fumigatus components in the diagnosis of Allergic Bronchopulmonary Aspergillosis. Allergy, 2021.
- Woolnough, K.F., et al., The relationship between biomarkers of fungal allergy and lung damage in asthma. Clin Exp Allergy, 2017. 47(1): p. 48-56.
- Welsh, K.G., et al., Fungal sensitization and positive fungal culture from sputum in children with asthma are associated with reduced lung function and acute asthma attacks respectively. Clin Exp Allergy, 2021. 51(6): p. 790-800.
- 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.
- Olombrada, M., et al., Fungal Ribotoxins: A Review of Potential Biotechnological Applications. Toxins (Basel), 2017. 9(2).
- Arruda, L.K., et al., Aspergillus fumigatus allergen I, a major IgE-binding protein, is a member of the mitogillin family of cytotoxins. J Exp Med, 1990. 172(5): p. 1529-32.
- UniProt, B. BLAST UniProtKB - P67875 (RNMG_ASPFU) Asp f 1. November 7 2021]; Available from: https://www.uniprot.org/blast/uniprot/B20211107A084FC58F6BBA219896F365D15F2EB4401C12BI.
- Patel, G. and P.A. Greenberger, Allergic bronchopulmonary aspergillosis. Allergy Asthma Proc, 2019. 40(6): p. 421-424.
- 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=.