Asp f 2
Summary
Asp f 2, a cell wall-associated extracellular protein, is a major allergen of and marker of genuine sensitization to 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 2 binds fibrinogen, plasminogen, and extracellular matrix proteins, contributing to fungal defense and host colonization.
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 2 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 (reviewed in [2, 3]). Despite wide variations, Asp f 2 sensitization presents with higher prevalence and higher levels in ABPA as compared to control populations. For example, Asp f 2 sensitization in ABPA was found at 68% and 75% in two Japanese cohorts [4, 5] and at 97.5% - 100% in Indian, British and French patients [6-8]. In asthmatic patients with A. fumigatus sensitization, detectable IgE to Asp f 2 was reported in 16-23% of Japanese patients [4, 5], in 31% of German and Polish patients [9] and in 61% of Indian patients [6]. In CF patients without ABPA but with A. fumigatus-sensitization, detectable Asp f 2 IgE was found in 33% (British) [7], 82% (France)[8] or all (United States) [10]. Detectable Asp f 2 IgE is usually absent in subjects (healthy, asthmatic, or CF) lacking detectable skin or blood A. fumigatus sensitization [5, 6, 10]. Asp f 2 sensitization was infrequent in patients with COPD [11]
Clinical Relevance
Detailed information regarding A. fumigatus is available in the whole allergen section. The demonstration of Asp f 2 IgE confirms genuine sensitization to A. fumigatus [14].
Clinical relevance of Asp f 2 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, 15]. The levels, rather than the prevalence, of Asp f 2 sensitization have been proposed as a diagnostic criterion for ABPA [2, 8, 16]. Median levels of IgE to Asp f 2 in ABPA patients may vary from 1.6 kUA/L to 10.1 kUA/L among different cohorts [5, 7, 8, 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 2 was 0.796 to 0.923 in different populations [8, 16]. A meta-analysis showed a pooled sensitivity of 71% and pooled specificity of 84% for Asp f 2 as a diagnostic tool for ABPA in asthmatic patients, and 75% both for the diagnosis of ABPA in CF patients [2]. 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 2 IgE in asthmatic or CF patients are statistically associated to an increased risk of ABPA, as explained above. Higher levels of Asp f 2 IgE have been associated with inadequate control of asthma symptoms in ABPA patients [16]. In contrast to Asp f 1, Asp f 2 sensitization was neither higher, nor associated with bronchiectasis and poor prognosis in patients with COPD [11].
Cross-reactive molecules
Asp f 2 shares a sequence identity of 80% or higher with only four homologues from other Aspergillus species [18].
Diagnostics
Disease Severity
High levels of Asp f 2 IgE are associated with ABPA [2] and inadequate asthma control [11]
Cross-Reactivity
Asp f 2 is a marker of genuine sensitization to A. fumigatus, without clinically relevant IgE cross-reactivity between Asp f 2 and other fungal described to date.
Exposure
Asp f 2 sensitization occurs through inhalation upon exposure to A. fumigatus [14].
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.
- 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.
- Muthu, V., et al., Role of recombinant Aspergillus fumigatus antigens in diagnosing Aspergillus sensitisation among asthmatics. Mycoses, 2020. 63(9): p. 928-936.
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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.
- Banerjee, B., et al., Purification of a major allergen, Asp f 2 binding to IgE in allergic bronchopulmonary aspergillosis, from culture filtrate of Aspergillus fumigatus. J Allergy Clin Immunol, 1997. 99(6 Pt 1): p. 821-7.
- Banerjee, B., et al., Immunological characterization of Asp f 2, a major allergen from Aspergillus fumigatus associated with allergic bronchopulmonary aspergillosis. Infect Immun, 1998. 66(11): p. 5175-82.
- Matricardi, P.M., et al., EAACI Molecular Allergology User's Guide. Pediatr Allergy Immunol, 2016. 27 Suppl 23: p. 1-250.
- 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., 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.
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- 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.
- AllFam. AllFam AF211 Asp f 2. November 9 2021]; Available from: http://www.meduniwien.ac.at/allfam/details.php?family=AF211.
- Dasari, P., et al., Aspf2 From Aspergillus fumigatus Recruits Human Immune Regulators for Immune Evasion and Cell Damage. Front Immunol, 2018. 9: p. 1635.
- Wilson, D. and G.S. Deepe, Jr., The intersection of host and fungus through the zinc lens. Curr Opin Microbiol, 2019. 52: p. 35-40.
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