rAsp f 1

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Code: m218
Latin name: Aspergillus fumigatus
Source material: An E. coli strain carrying a cloned cDNA encoding Aspergillus fumigatus allergen Asp f 1.
Common names: Ribotoxin
Aspergillus fumigatus allergen components

Available ImmunoCAP®:

Summary

Recombinant components from Aspergillus fumigatus (A. fumigatus) are available for allergen-specific IgE antibody testing.

Available fungal extracts used either for serological detection of IgE antibodies or for skin testing, although very effective, may not be as effective as a single recombinant or a mix of recombinant allergens. This is mainly because of the lack of recognised standardisation procedures, resulting in large batch-to-batch variation of the allergen content in the extracts used (1). A. fumigatus is able to produce more than 40 IgE-binding proteins, and this makes standardisation of extracts a difficult task, the growth phases of the fungus complicating it further. Molecular cloning production and characterisation of A. fumigatus allergens has contributed to improving the precision of the diagnosis of sensitisation to A. fumigatus (2).

Recombinant allergens, which are biotechnology produced molecules originally identified from allergen extracts, have IgE antibody binding usually comparable to that of natural allergens and generally show good reactivity in in vitro and in vivo diagnostic tests (3). To date, many different recombinant allergens have been cloned, sequenced, and expressed.

Recombinant allergens have a wide variety of uses, from the diagnosis and management of allergic patients to the development of immunotherapy to the standardisation of allergenic test products as tools in molecular allergology.

Inhalation of the conidia and the mycelium of A. fumigatus is responsible for many allergic respiratory diseases, the most notable of which – due to its severity – is allergic bronchopulmonary aspergillosis (ABPA). The complexity of the antigenic structure of A. fumigatus and the varying host immune responses determine the severity, on a wide spectrum, of the clinical conditions seen, which include allergic asthma, extrinsic allergic alveolitis (hypersensitivity pneumonitis), Farmer’s Lung, invasive aspergillosis, and aspergilloma. It is reported that 15 to 20% of allergic asthmatics suffer from Aspergillus-induced allergies.

The allergenic proteins are derived from 2 function categories: secreted and cytoplasmic proteins. Secreted allergens are recognised by serum IgE antibodies of A. fumigatus-sensitised individuals with or without ABPA, whereas nonsecreted allergens are exclusively recognised by serum IgE antibodies of ABPA patients (4). The use of recombinant allergens therefore may be of great value in assessing individuals affected by this mould.

ABPA is an immunologically complex disorder. Various allergens and antigens of A. fumigatus induce IgE-mediated but also other hypersensitivity reactions in ABPA patients. Elevated levels of total IgE, allergen-specific IgE and IgG antibodies in sera are important immunodiagnostic criteria for ABPA (5). High levels of IgE and IgG antibodies in these patients are of diagnostic value (6). However, the large differences reported in the incidence of ABPA in asthmatics sensitised to A. fumigatus, ranging from 7% to 22%, and from 0.1% to 12% in patients with cystic fibrosis, may partially be explained by the lack of reliable A. fumigatus extracts (7).

Through molecular characterisation, several allergenic components have been identified: complex carbohydrate moieties, heat-shock proteins, and enzymes such as elastase, protease, catalase, dismutase, and cytotoxic ribonuclease. Some have a multifunctional nature, which may play an important role in the pathogenesis of the disease (6).

Studies have evaluated different combinations of recombinant allergens for diagnostic use in Aspergillus allergy.

In one study of serum IgE antibodies to the recombinant A. fumigatus allergens rAsp f 1, 3, 4 and 6 in 74 patients suffering from cystic fibrosis (CF) with and without ABPA, 40 were found to be sensitised to A. fumigatus, of which 23 had ABPA. Of the 23 ABPA patients, 11 expressed the full clinical ABPA picture, and 12 had positive serology indicating ABPA but did not show sufficient clinical signs of the disease. The 23 ABPA patients had 16-18 times higher serum levels of allergen-specific IgE to rAsp f 4 and/or rAsp f 6. The combination of increased total serum IgE (>1000 IU/l) and increased IgE antibodies to rAsp f 4 and/or rAsp f 6 was associated with symptomatic ABPA with 100% specificity and 64% sensitivity, and with a high positive predictive value (100%) and a high negative predictive value (94%) (2).

It has also been suggested that the measurement of IgE antibodies for A. fumigatus with purified recombinant allergens may differentiate ABPA from atopic cystic fibrosis (CF). In a study evaluating serum IgE reactivity to 7 recombinant purified allergens and to a crude extract of A. fumigatus in 15 ABPA patients, in 23 CF patients with skin reactivity to A. fumigatus, and in 19 CF patients with no skin reactivity to A. fumigatus, ABPA patients had significantly increased IgE reactivity to rAsp f 2, f 3, f 4, f 6, and f 16, compared with the 2 other groups of patients. In the ABPA patients studied before and after developing ABPA, IgE reactivity also increased to rAsp f 2, f 3, f 4, and f 6, and to the crude extract. In ABPA CF patients, IgE reactivity to rAsp f 1, f 2, f 3, and f 6 significantly increased during periods of ABPA flares, compared with periods of remission. IgE antibodies to rAsp f 3 and rAsp f 4 gave the best sensitivity and specificity and were more useful than IgE reactivity to a crude extract of Aspergillus. Furthermore, in ABPA patients studied during periods of remission, the IgE reactivity to Asp f 3 and f 4 remained significantly elevated compared with the other groups. The conclusion reached was that allergen-specific IgE reactivity to a panel of purified Aspergillus allergens, especially to Asp f 3 and f 4, differentiates ABPA patients from atopic Aspergillus skin-specific positive and non-ABPA CF patients. In particular, serial evaluation of IgE reactivity to individual purified Aspergillus antigens, especially Asp f 3, showed that increases in IgE reactivity may provide improved distinction between stages of flares and remission, compared with changes in IgE reactivity to a crude Aspergillus extract (8).

Recombinant Aspergillus allergens Asp f 1, f 2, f 3, f 4, and f 6 were studied for their specific binding to IgE antibodies in the sera of ABPA patients and A. fumigatus skin-specific IgE-positive asthmatics from the USA and Switzerland. Serum IgE to all the recombinant allergens was detected in sera from patients with ABPA, whereas only a few asthmatics had serum IgE antibodies detected to these allergens. Asp f 2, f 4, and f 6 were reported to be effective in the serodiagnosis of ABPA, with allergen-specific IgE being detected to these 3 recombinant allergens together in all the ABPA patients studied. IgE antibodies to Asp f 1 and f 3 were not specific (9).

Another study suggested that a smaller panel of recombinant Aspergillus allergens might allow reliable diagnosis of ABPA. Fifty patients with CF were evaluated using skin-specific IgE tests: 12 had ABPA, and 21 had allergy to A. fumigatus. All patients with ABPA reacted to at least 1 of the 2 allergens rAsp f 4 and rAsp f 6. IgE antibodies in skin prick test were negative or only marginally positive in the patients with allergy to A. fumigatus, and completely negative in the CF control patients. The authors concluded that rAsp f 4 and rAsp f 6 can be considered specific markers for ABPA, and that early diagnosis of the disease, allowing optimal management, might help to prevent irreversible lung damage and minimise possible steroid-mediated side-effects (10).

Similarly, in a study examining the differential IgE antibody responses to the allergens in A. fumigatus-sensitised CF patients with or without ABPA and in CF controls without sensitisation to A. fumigatus, rAsp f 1 and rAsp f 3 were recognised by sera from A. fumigatus-sensitised CF-patients with or without ABPA. rAsp f 6 and rAsp f 4 were recognised exclusively by IgE antibodies from sera of CF patients with ABPA. The study concluded that Asp f 4 and Asp f 6 were specific markers for ABPA and allowed a sensitive, fully specific diagnosis of the disease (11). Specific sensitisation found to nonsecreted Aspergillus proteins in ABPA suggests substantial differences in the pathways of exposure to and immunologic recognition of this mould and a specific disease (7), supporting the use of recombinant single allergens for diagnosis in these situations.

It has been reported that A. fumigatus is an important causative agent in allergic fungal sinusitis (AFS) in the southeastern United States, that most confirmed AFS patients have A. fumigatus-specific IgE, and that many have specific IgE antibodies to rAsps (12).
The recombinant allergens, Asp f 1, Asp f 3, Asp f 4 and Asp f 6 have also been tested in large-scale skin test studies in patients with asthma or cystic fibrosis and coexisting sensitisation to A. fumigatus, and have been demonstrated to be reliable diagnostic reagents (7,13-15). The dissection of the causes of IgE-mediated immune responses down to single A. fumigatus allergens will allow the clinician to discriminate between the various clinical manifestations attributed to the same mould with high specificity and sensitivity (4).


Allergens from Aspergillus fumigatus listed by IUIS*

Asp f 1 Asp f 2 Asp f 3
Asp f 4 Asp f 5 Asp f 6
Asp f 7 Asp f 8 Asp f 9
Asp f 10 Asp f 11 Asp f 12
Asp f 13 Asp f 15 Asp f 16
Asp f 17 Asp f 18 Asp f 22W
Asp f 23 Asp f 27 Asp f 28
Asp f 29 Asp f 34  
*International Union of Immunological Societies (www.allergen.org) Jan. 2008.


m218 rAsp f 1

Recombinant non-glycosylated protein produced in an E. coli strain carrying a cloned cDNA encoding Aspergillus fumigatus allergen Asp f 1

Common name: Ribotoxin
Biological function: Ribonuclease
Mw: 18 kDa

Allergen description

Asp f 1 (2,4,7-9,11-12,14-23) is a major allergen produced by the mycelia of Aspergillus fumigatus (A. fumigatus). It is not present in spores and can be used as a specific marker for the detection of germination of this fungus (24). Asp f 1 is a species-specific allergen, in contrast to other IgE-binding proteins of A. fumigatus that are highly cross-reactive with related proteins from phylogenetically distant species (25). Asp f 1 is a ribotoxin; ribotoxins are potent inhibitors of eukaryotic protein synthesis (4).

Early studies have shown that 85% of A. fumigatus-allergic patients with allergic bonchopulmonary aspergillosis (ABPA) have IgE antibodies to Asp f 1, and that there is an absence of homologous proteins in other fungi (26-27). Significant levels of Asp f 1-specific antibodies are present in a majority of ABPA patients in the early stages of the disease (26).

rAsp f 1 has been shown to have similar characteristics to native Asp f 1, and can therefore be used as a standardised antigen/allergen for serologic and clinical diagnosis of A. fumigatus-associated diseases (17).

A study evaluated the diagnostic value of rAsp f 1 in 55 patients with cystic fribrosis (CF); based on clinical presentation and laboratory data, 10 of these CF patients had ABPA, 27 had Aspergillus allergy, and 18 were not allergic to A. fumigatus (CF control group). Serologic assays showed a 10-fold increase in rAsp f 1-specific IgE antibodies, a 5-fold increase in rAsp f 1 -specific IgG1, and a 4-fold increase in rAsp f 1-specific IgG4 antibodies in ABPA patients, compared with the Aspergillus allergy and CF control groups. The study concluded that rAsp f  1-specific serology is a highly sensitive and specific test that can be used to identify ABPA reliably in CF patients (21).

In an early study of sera from 147 CF patients, IgE antibodies to A. fumigatus and 5 common inhalant allergens were measured. Thirty (20%) of the patients had allergen-specific IgE antibodies to A. fumigatus, and 22 (15%) of these patients had developed total IgE levels higher than 400 kU/L, suggesting a diagnosis of ABPA. Eighty-four percent of the CF sera contained IgG antibodies to Asp f 1, compared with 6% of control patients and 20% of sera from allergic children with asthma (n = 25), only one of whom had IgE antibodies to A. fumigatus (28).

 

m219 rAsp f 2

Recombinant non-glycosylated protein produced in an E. coli strain carrying a cloned cDNA encoding Aspergillus fumigatus allergen Asp f 2

Biological function: Fibrinogen binding protein
Mw: 37 kDa

Allergen description

Asp f 2 (8-9,12,29-31) is a major allergen from the fungus Aspergillus fumigatus (A. fumigatus), and >90% of A. fumigatus-sensitised individuals have IgE antibodies to Asp f 2 (32).

In a study of 25 patients with allergic bronchopulmonary aspergillosis (ABPA), 96% had IgE antibodies directed against rAsp f 2, as did none of the subjects with allergic asthma, nor any of the normal control subjects (33).

 

m220 rAsp f 3

Recombinant non-glycosylated protein produced in an E. coli strain carrying a cloned cDNA encoding Aspergillus fumigatus allergen Asp f 3

Common names: Peroxisomal protein, PMP
Biological function: Peroxisomal protein
Mw: 19 kDa

Allergen description

rAsp f 3 (2,4,8-9,11-12,19,34), a peroxi-somal protein, was evaluated using skin and serum tests on 11 patients with allergic bronchopulmonary aspergillosis (ABPA) and 8 patients with allergic asthma with sensitisation to Aspergillus fumigatus (A. fumigatus). All 11 patients with ABPA and 5 of 8 (84%) A. fumigatus-sensitised asthmatics without ABPA exhibited an IgE-mediated skin test. Serum rAsp f 3 IgE antibodies were found in all rAsp f 3 skin positive subjects and none without skin positive tests to rAsp f 3. rAsp f 3-specific IgE APBA patients had significantly higher serum levels of IgG, IgG1, IgG4 and IgE, compared with A. fumigatus-sensitised asthmatics and healthy controls. The authors concluded that serological tests with recombinant allergens are of great use in diagnosing sensitisation to A. fumigatus (35).

rAsp f 3 has been demonstrated to have a 36% identity and a 58% similarity to 2 peroxisomal membrane proteins of Candida boidinii. Serum IgE antibodies to rAsp f 3 were found in 72% of 89 individuals sensitised to A. fumigatus, indicating that this protein represents a major allergen of this mould (34).  Cross-reactivity is likely between Pen c 3 (Penicillium citrinum) and Asp f 3, given an 82.6% identity between these proteins (36). A study of the allergens of Malassezia furfur reported significant homology between Mal f 3 and Asp f 3 (37).

 

m221 rAsp f 4

Recombinant non-glycosylated protein produced in an E. coli strain carrying a cloned cDNA encoding Aspergillus fumigatus allergen Asp f 4

Biological function: Unknown
Mw: 30 kDa

Allergen description

The biological function of the allergen Asp f 4 (2,4,8-13,19) has not been determined yet. As a clear distinction between allergic sensitisation to Aspergillus fumigatus (A. fumigatus) and allergic bronchopulmonary aspergillosis (ABPA) is essential for therapy, to prevent deterioration of pulmonary function in subjects with ABPA, research constantly evaluates the significance of individual allergens as predictive indicators. One study demonstrated that rAsp f 4 and rAsp f 6 were able to provoke immediate skin reactions exclusively in patients with ABPA; i.e., these allergens are highly specific for ABPA. The reactions were elicited by a few nanograms of the allergens and therefore allowed a sensitive and highly specific diagnosis of ABPA (13). The rAsp f 4- and rAsp f 6-based serological diagnosis of ABPA has a specificity of 100% and reaches a sensitivity of 90% in asthmatic patients sensitised to A. fumigatus (38), whereas the serological discrimination between A. fumigatus sensitisation and ABPA in patients suffering from cystic fibrosis reached 100% (11). Specific sensitisation to nonsecreted Aspergillus proteins in ABPA suggests substantial differences in the pathways of exposure to and the immunologic recognition of this mould and a specific disease (7), supporting the use of recombinant single allergens for diagnosis in these situations.

 

m222 rAsp f 6

Recombinant non-glycosylated protein produced in an E. coli strain carrying a cloned cDNA encoding Aspergillus fumigatus allergen Asp f 6

Common names: Mn-SOD, SOD
Biological function: Mn superoxide dismutase
Mw: 26 kDa

Allergen description

Asp f 6 (2,4,8-13,18-19,39-41) is an allergen belonging to the manganese superoxide dismutase (MnSOD) protein family.

As a clear distinction between allergic sensitisation to A. fumigatus and allergic bronchopulmonary aspergillosis (ABPA) is essential for therapy, to prevent deterioration of pulmonary function in subjects with ABPA, research constantly evaluates the significance of individual allergens as predictive indicators. One study demonstrated that rAsp f 4 and rAsp f 6 were able to provoke immediate skin reactions exclusively in patients with ABPA; i.e., these allergens are highly specific for ABPA. The reactions were elicited by a few nanograms of the allergens and therefore allowed a sensitive and highly specific diagnosis of ABPA (13). The rAsp f 4- and rAsp f 6-based serological diagnosis of ABPA has a specificity of 100% and reaches a sensitivity of 90% in asthmatic patients sensitised to A. fumigatus (38), whereas the serological discrimination between A. fumigatus sensitisation and ABPA in patients suffering from cystic fibrosis reached 100% (11). Specific sensitisation to nonsecreted Aspergillus proteins in ABPA suggests substantial differences in the pathways of exposure to and the immunologic recognition of this mould and a specific disease (7), supporting the use of recombinant single allergens for diagnosis in these situations.

MnSODs from other organisms, including humans, are recognised by IgE antibodies from individuals sensitised to A. fumigatus MnSOD (40). The MnSOD from A. fumigatus has been reported to have homology with Drosophila melanogaster, Saccharomyces cerevisiae, and human MnSOD; cross-reactivity was shown between the MnSOD at B and T cell level; moreover, the different MnSODs can induce proliferative responses in peripheral blood mononuclear cells of sensitised individuals (39). Cross-reaction with human MnSOD suggests that human proteins can act as autoallergens in vivo (7). A cloned allergen from the yeast Malassezia sympodialis has also been reported to have a sequence similarity with MnSODs (42). A cloned Hevea brasiliensis (Latex) MnSOD protein, Hev b 10, was shown to have IgE binding in Latex- as well as A. fumigatus-allergic patients (43).

Based on the cross-reactivity of rAsp f 6 and MSODs’ potential to act as panallergens, rAsp f 6 is useful for assessing other cross-reactive allergens to which an individual may be sensitive.

 

Compiled by Dr Harris Steinman, harris@zingsolutions.com

References

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  42. Andersson A, Rasool O, Schmidt M, Kodzius R, Fluckiger S, Zargari A, Crameri R, Scheynius A Cloning, expression and characterization of two new IgE-binding proteins from the yeast Malassezia sympodialis with sequence similarities to heat shock proteins and manganese superoxide dismutase.
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  43. Wagner S, Sowka S, Mayer C, Crameri R, Focke M, Kurup VP et al. Identification of a Hevea brasiliensis Latex Manganese Superoxide Dismutase (Hev b 10) as a Cross-Reactive Allergen. Int Arch Allergy Immunol 2001;125(2):120-7

As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.