i210 Pol d 5

Summary

Pol d 5, a member of the antigen 5 family, is a venom allergen of Polistes dominula (European paper wasp), a worldwide distributed species predominant in Southern Europe. Pol d 5 is a marker allergen for genuine sensitization to Vespid venoms, most adequate for P. dominula venom (PDV). Pol d 5 is usually considered a major PDV allergen. The prevalence of Pol d 5 sensitization in PDV allergic patients varies from 20 to 80%. In patients sensitized to both PDV and honeybee venom (HBV) extracts, demonstration of Pol d 5-specific IgE confirms genuine sensitization to Vespid venom, thus helping to differentiate true double positivity from cross-reactivity, and to identify adequate venom immunotherapy (VIT) in eligible patients.

Pol d 5 cross-reacts with venom antigen 5 proteins from other Vespids, notably Vespula vulgaris (common wasp or yellow jacket), hampering its use for identifying the primary Vespid sensitizer.

Epidemiology

Worldwide distribution

P. dominula is a social wasp species native to temperate regions of Southern Europe, the Middle East, Central and Eastern Asia that has spread in recent decades to Central and Northern Europe, North America, South Africa and Australia [1-3]. In Southern Europe, PDV allergy is frequent, either as monosensitization or in association with YJV allergy; its prevalence could be underestimated in other regions, where PDV is not included in Vespid allergy investigation [4]. Pol d 5 is a relevant diagnostic tool for Vespid venom allergy in areas with high prevalence of P. dominula [4]. The prevalence of Pol d 5 sensitization in Vespid allergic patients varies between 20% and 85% depending on the location and the clinical characteristics of the cohorts, the format and cut-off of the diagnostic assay employed for Pol d 5 sensitization, and the prevalence of concomitant sensitization to YJV [5-8].

Given the high prevalence of up to 40% of asymptomatic sensitization to Vespid venom extracts in the general population [5], asymptomatic Pol d 5 sensitization is expected to be a common finding, but data are lacking since Pol d 5, unlike Ves v 5, has not been investigated in cohorts of the general population, nor in selected groups of people with high exposure to Hymenoptera stings. In a study addressing pediatric sensitization in nine European birth cohorts, 8% of Swedish teenagers from the BAMSE cohort were sensitized to Pol d 5; this allergen was not assessed in all cohorts [9].

Environmental characteristics                       

Source and tissue

Pol d 5, a member of the venom antigen 5 family, is secreted into the venom sac of P. dominula, where it is found in high abundance [5, 10, 11].

Risk factors

Sensitization to Pol d 5 occurs through injection (P. dominula sting) [5, 12].

Clinical relevance

Specific molecules

Pol d 5 is a marker allergen of genuine sensitization to Vespid venoms, most adequate for PDV sensitization [5]. Pol d 5 does not cross-react with HBV allergens, therefore, Pol d 5 is a marker allergen allowing to discriminate between Vespid and HBV genuine sensitization [5, 11]. On the other hand, the mere demonstration of Pol d 5 sensitization is not a reliable marker for PDV sensitization in the context of sensitization to multiple Vespid venom extracts [5].

Cross-reactive molecules

A member of the venom antigen 5 family, Pol d 5 cross-reactivity is well established with homologues from other Vespid venoms, Ves v 5 being the most frequent in clinical practice [1, 5, 13]. As an example, Pol d 5-specific IgE were detected in 81-86% YJV-allergic patients from Germany, where PDV primary sensitization is deemed absent [8].

Disease severity

Neither the prevalence of Pol d 5 sensitization, nor the levels of Pol d 5-specific IgE are predictive of the severity of PDV-induced reactions [5].

Molecular aspects                  

Biochemistry

Pol d 5, also known as PDV antigen 5, is a  member of the CAP (CRISP, antigen 5 and PR1) superfamily of proteins with  a molecular weight of 23 kDa (227 aminoacids including the signal peptide), displaying multiple disulfide bonds and lacking N-glycosylation sites [8, 10, 12]. Although antigen 5 family members are considered the most potent allergens in Vespid venoms and comprise the most abundant proteins in Vespid venom, their biological function is currently unknown [5, 11].

Isoforms, epitopes, antibodies

As of August 18, 2023, a unique isoallergen, Pol d 5.0101, has been included in the World Health Organization (WHO) and International Union of Immunological Societies (IUIS) Allergen Nomenclature [12].

Cross-reactivity due to structural similarity

A sequence identity percentage of 50% or higher between Pol d 5 and many of its homologues from other Vespid venoms has been established [4, 5, 8, 11, 14]. Pol d 5 displays structure identity percentages of 80% or higher with Polistinae homologues and around 60% with YJV and hornet ones [11].

Diagnostic relevance              

Diagnosis of genuine sensitization to Polistes dominula (European paper wasp) venom

Pol d 5 is a marker allergen for genuine Vespid venom sensitization, most adequate in regions with a high prevalence of P. dominula exposure and allergy, such as the Mediterranean. Therefore, the demonstration of specific IgE to Pol d 5 confirms genuine sensitization to Vespid venom, helps identifying the primary sensitizer in patients with double IgE positivity to HBV and PDV extracts, and supports the initiation of PDV VIT in eligible patients [5].

On the other hand, the reported prevalence of Pol d 5 sensitization in PDV allergic patients may be as low as 20% and up to a maximum of 80%, while Pol d 1, the phospholipase 1, a major and marker allergen of PDV, is not widely available for routine investigations [5-7]. Therefore, genuine PDV or Vespid sensitization cannot be excluded in a patient without detectable Pol d 5-specific IgE.

Several studies have evaluated the relative amount of specific IgE to Pol d 5 versus Ves v 5 as a possible tool for identifying the primary Vespid sensitization [13, 15, 16]. The overall conclusion was that in selected cases, such as those with Pol d 5-specific IgE levels at least twice those of Ves v 5-specific IgE, primary PDV sensitization is probable [13, 15]. A significant proportion of cases was not solved with the use of molecular allergens, hence, IgE-inhibition using whole PDV and YJV extracts or Pol d 5 and Ves v 5 was the most performant in all cohorts [8, 13, 15, 16].

In a recent study on 128 Vespid-allergic patients, the best diagnostic accuracy for Polistes venom sensitization was obtained when receiver operator curves were built using combined IgE ratios of Pol d 5/Ves v 5, Pol d 1/Ves v 1 and whole Polistes spp/Vespula vulgaris venom extracts [6].

Cross-Reactivity

Pol d 5 cross-reactivity within the antigen 5 family hampers its use for the differential diagnosis of PDV versus YJV or other Vespid venom genuine sensitization [5, 11]. As an example, in 20 Spanish PDV-allergic patients with Pol d 5-specific IgE, 75% also exhibited sensitization to Ves v 5, 70% with Poly s 5 from Polybia scutellaris and 65% with Pol a 5 from Polistes annularis [8].

Disease severity

In Hymenoptera venom IgE testing, the quantitative result of specific IgE to a molecular allergen or whole venom extract is neither predictive of, nor correlated to the severity of the reaction [5]. 

Sensitivity of in vitro assays

The prevalence of sensitization to individual PDV allergens, including Pol d 5, in PDV-allergic patients varies depending on multiple factors such as geography, patient inclusion criteria, single or double positivity to PDV and other Hymenoptera venoms, the use of a recombinant versus a natural purified allergen, assay format, and positivity cut-off values [5, 6, 8, 17]. Thus, the diagnostic sensitivity of specific IgE to Pol d 5 ranges from 20 to 80% in PDV-allergic patients [5].  The choice of the cut-off value for reporting detectable Pol d 5-specific IgE, usually debated between 0.35 kUA/L and 0.10 kUA/L, leads to variations in the prevalence and therefore the analytical sensitivity of the test. The EAACI 2023 guidelines suggest that the 0.10 kUA/L cut-off might be clinically relevant even in patients without mast cell disorders [5].

Data on Pol d 5 sensitization in confirmed PDV allergic patients without detectable sensitization to PDV extract are lacking. A prevalence of 21% of Pol d 5-positive, Polistes spp negative patients was reported in a large cohort of French Hymenoptera-allergic patients using conventional (non-spiked) venom extract of American Polistes spp [17]. In this study, using the Pol d 5-spiked Polistes spp extract commercially available since 2012 led to only 4% of extract-negative, Pol d 5-sensitized patients [17].

Pol d 5 sensitization can be detected with commercially available singleplex and multiplex methods.

Diagnostic specificity

Detection of Pol d 5-specific IgE is a hallmark of genuine sensitization to Vespid venom. Quantitative comparison of Pol d 5-specific IgE with Ves v 5-specific IgE helps identifying genuine PDV sensitization in a proportion of patients [5, 13, 15, 16]. Importantly, PDV sensitization and hence Pol d 5 sensitization in the general population is not synonymous with PDV allergy due to the high prevalence of asymptomatic Vespid sensitization [5, 9].

AIT Prescription

Achieving accurate identification of the primary venom sensitizer is important for therapeutic guidance towards a safe and effective VIT in eligible patients [18]. Demonstrated sensitization to Pol d 5 confirms genuine sensitization to Vespid venom in patients with a convincing clinical history, thus supporting the choice of adequate VIT in eligible patients [5].

Explained results

Allergen Information

Pol d 5 is the molecular allergen of P. dominula (European paper wasp) venom representative of the antigen 5 family, CAP superfamily. It is a non-glycosylated protein of unknown biological function with a molecular weight of 23 kDa. P. dominula has spread in recent decades to Central Europe, North America, Australia and South Africa.

Clinical information

Pol d 5 is a marker allergen for Vespid venom genuine sensitization, most adequate for regions with high exposure to P. dominula. Thus, Pol d 5-specific IgE identifies genuine Vespid sensitization and discriminates it from HBV sensitization in patients who are double positive to Vespid and HBV extracts. In PDV-allergic patients, the prevalence of Pol d 5 sensitization is 20-80%. Asymptomatic Pol d 5 sensitization is frequent in the general population.

Cross-reactivity

Pol d 5 cross-reacts with other venom antigen 5 molecules, with notable clinical relevance for P. dominula and Vespula spp double sensitization.

Author: Dr. Joana Vitte

Reviewed: Dr. Michael Spangfort