Asp f 3
Summary
Asp f 3, located in peroxisomes, belongs to the highly conserved family of peroxiredoxins, involved in redox homeostasis and response to oxidative stress. Asp f 3 is a major allergen of the ubiquitous environmental mold Aspergillus fumigatus (A. fumigatus), an agent of 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 3 displays cross-reactivity with homologues from other fungal species and genera
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 3 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 3 sensitization presents with higher prevalence and higher levels in ABPA as compared to control populations. Asp f 3 was first described in European patients with stable asthma and sensitized to A. fumigatus, with a prevalence of 72% [2]. A similar figure of 73% was reported in 2020 in A. fumigatus-sensitized asthmatic patients from India [3]. Conversely, 31% or fewer among two cohorts of A. fumigatus-sensitized Japanese asthmatic patients displayed Asp f 3 sensitization [4, 5]. The prevalence of Asp f 3 sensitization was higher in ABPA patients investigated in parallel with asthmatic ones: 57% - 67% in Japanese patients and 89% in Indian patients [3-5]. Among German and Polish self-reported asthmatic patients with A. fumigatus sensitization, 46% displayed IgE to Asp f 3 [6]. In Chinese patients from Guangzhou, Asp f 3 sensitization was found in 45% of A. fumigatus-sensitized asthmatic patients and in 70% of ABPA patients [7]. Considering CF patients with A. fumigatus-sensitization, without ABPA but, detectable Asp f 3 sensitization was found in 58% (British) [8] and 45% (France) [9]. Detectable Asp f 3 IgE is usually absent in subjects (healthy, asthmatic, or CF) lacking detectable skin or blood A. fumigatus sensitization [3, 5, 10]. Asp f 3 sensitization was found in 6.7% of patients with COPD, statistically not different from 2% in controls [11].
Clinical Relevance
Detailed information regarding A. fumigatus is available in the whole allergen section.
Clinical relevance of Asp f 3 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 [13, 14]. Given the cross-reactivity of Asp f 3 with other fungal allergens, it is not a marker of genuine sensitization to A. fumigatus, but it may improve the sensitivity of ABPA detection [10]. Detection of IgE to either Asp f 1 and Asp f 3 had a diagnostic sensitivity for ABPA at 96% in asthmatic patients and at 93% in CF patients, with a specificity of 50-55% [15, 16]. However, most studies reported that the levels, rather than the prevalence, of Asp f 3 sensitization were potentially useful for the diagnosis of ABPA [9, 15, 16]. Median levels of IgE to Asp f 3 in ABPA patients vary from 0.74 kUA/L to 10.7 kUA/L among different cohorts [5, 7-9, 16], supporting the observation that statistically determined cut-off levels in a given population perform better than fixed cut-offs [16]. Using population-based cut-offs, the reported area under the receiver operating curve of Asp f 3 was 0.728 to 0.968 in different populations [9, 16]. Diagnostic performance of Asp f 2 is improved when used in conjunction with other A. fumigatus molecular allergens [16, 17].
Disease severity and prediction
Increasing levels of Asp f 3 IgE in asthmatic or CF patients are statistically associated to an increased risk of ABPA, as explained above. Asp f 3 sensitization is associated with bronchiectasis in patients with AFAD or COPD, but not with poorer lung function [11, 18]. In ABPA patients displaying high-attenuation bronchial mucus, a pathognomonic radiological sign of ABPA, levels of Asp f 3 IgE were significantly lower [16].
Cross-reactive molecules
Cross-reactivity between Asp f 3 and other peroxiredoxins allowed for its characterization and has now been established for a range of homologues, comprising human proteins [2, 12].
Diagnostics
Disease Severity
High levels of Asp f 3 IgE are associated with ABPA [15] and bronchiectasis [11, 18]
Cross-Reactivity
Asp f 3 is considered as a cross-reactive fungal allergen [16].
Exposure
Asp f 3 sensitization occurs through inhalation upon exposure to A. fumigatus [25].
References
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- 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.
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- Kurup, V.P., et al., Specific antibodies to recombinant allergens of Aspergillus fumigatus in cystic fibrosis patients with ABPA. Clin Mol Allergy, 2006. 4: p. 11.
- 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.
- Hillmann, F., et al., The Crystal Structure of Peroxiredoxin Asp f3 Provides Mechanistic Insight into Oxidative Stress Resistance and Virulence of Aspergillus fumigatus. Sci Rep, 2016. 6: p. 33396.
- 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.
- Lukaszewicz, R., et al., Medical algorithm: Aspergillus fumigatus components in the diagnosis of Allergic Bronchopulmonary Aspergillosis. Allergy, 2021.
- Woolnough, K., et al., rAsp f3 and rAsp f4 are associated with bronchiectasis in allergic fungal airways disease. Ann Allergy Asthma Immunol, 2018. 120(3): p. 325-326.
- Brantl, V., et al., Peroxiredoxin Asp f3 Is Essential for Aspergillus fumigatus To Overcome Iron Limitation during Infection. mBio, 2021. 12(4): p. e0097621.
- Diaz-Arevalo, D., J.I. Ito, and M. Kalkum, Protective Effector Cells of the Recombinant Asp f3 Anti-Aspergillosis Vaccine. Front Microbiol, 2012. 3: p. 299.
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- 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=.
- UniProt, B. UniProtKB - O43099 (PRX5_ASPFU) Asp f 3. 2021 November 18 2021]; Available from: https://www.uniprot.org/blast/uniprot/B20211118F248CABF64506F29A91F8037F07B67D101FF9B9.
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