m220 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].

Environmental Characteristics

Source and tissue

Asp f 3 is one of the most abundant proteins of A. fumigatus. It colocalizes with the membrane of the intracellular organelles called peroxisomes, where it acts as a detoxifier of hydrogen peroxide and organic hydroperoxides [12]. 

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 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]. 

Molecular Aspects

Biochemistry

Asp f 3 is a protein of 19 kDa, which can form dimers through two disulfide bonds [12]. Asp f 3 engages in cellular redox homeostasis and in the cellular response to oxidative stress. Asp f 3 performs additional roles in the fungal cell, such as preserving cell growth under conditions of iron starvation [19]. Through its ability to detoxify reactive oxygen species and to prevent growth arrest under iron limitation, both conditions associated with host antifungal responses, Asp f 3 is a virulence factor of A. fumigatus and a vaccine candidate [12, 19-21]. Asp f 3 possesses confirmed allergenic activity [22].

Isoforms, epitopes, antibodies

As of November 7th, 2021, Asp f 3 comprises only one isoallergen officially published by the World Health Organization (WHO) and the International Union of Immunological Societies (IUIS) Allergen Nomenclature: Asp f 3.0101 [23].

Cross-reactivity due to structural similarity

Asp f 3 shares a sequence identity of 80% or higher with various homologues from the peroxiredoxin family, including proteins from the genera Aspergillus, Candida, and Penicillium [2, 12, 24]. 

Diagnostic Relevance

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].

Compiled By

Author: Joana Vitte

Reviewer: Dr. Christian  Fischer

Last reviewed:January 2022.