m219 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]

Environmental Characteristics

Source and tissue

Asp f 2 is produced by A. fumigatus as a cell-wall associated and secreted protein, representing up to 40% of the fungal protein contents, most abundant in mycelia [12, 13]. 

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. 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].

Molecular Aspects

Biochemistry

Asp f 2 is a protein of 37 kDa, stabilized by four disulfide bonds, with potential glycosylation sites explaining variations in the apparent molecular weight [13]. Asp f 2 possesses confirmed allergenic activity [19].

Asp f 2 is currently classified as a fungal metallopeptidase-like protein of unknown function [20], but experimental data support its role in (1) fungal defense through evasion and subversion of host innate immune responses (2) disruption and penetration of host epithelial barriers and extracellular matrix (3) fungal growth through zinc capture  [13, 21, 22].

Isoforms, epitopes, antibodies

As of November 7th, 2021, Asp f 2 comprises only one isoallergen officially published by the World Health Organization (WHO) and the International Union of Immunological Societies (IUIS) Allergen Nomenclature: Asp f 2.0101 [23].

Cross-reactivity due to structural similarity

Asp f 2 shares a relatively low degree of sequence homology with few fungal orthologues such as the gene ASPND1 product from Aspergillus nidulans (60%), which has not been described as an allergenic fungus, and Pra 1 from Candida albicans (44%), suggesting low if any cross-reactivity at the IgE binding level [13, 22, 24].

Diagnostic Relevance

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].

Compiled By

Author: Joana Vitte

Reviewer: Dr. Christian  Fischer

Last reviewed:January 2022.