Summary

Lep d 2 is a major group 2 allergen found in the intestine and fecal pellets of a storage mite (SM), Lepidoglyphus destructor. It is responsible for occupational allergies among grain-storage workers, farmers, agricultural workers, and bakers in rural settings as well as humid urban dwellings. The allergic reactions manifested are moderate-to-severe asthma, allergic rhinitis, conjunctivitis, and atopic dermatitis. High IgE-mediated cross-reactivity was found among the different storage mite species while a limited cross-reactivity was found between storage mite and house dust mite allergens. The allergen exhibits cross-reactivity with Gly d 2 and Tyr p 2 from the species Glycyphagus domesticus and Tyrophagus putrescentiae, respectively, reflecting a closeness in their amino acid sequences.

Epidemiology

Worldwide distribution

Lep d 2 from Lepidoglyphus destructor is one of the most significant group 2 allergens of storage mites (SM), (Gafvelin et al. 2001, Cuevas et al. 2022). Lep d 2 is associated with sensitization in allergic individuals due to occupational exposure or in rural and humid urban dwellings (20-30°C, >65% relative humidity) (Hilger et al. 2014, Cuevas et al. 2022,).

Specific IgE against Lep d 2 is consistently identified in a high percentage of individuals who exhibit sensitization. In a recent study conducted in Spain with 150 adult patients (mean age 31.8 years) categorized according to their underlying atopic phenotype (such as allergic rhinitis [AR], allergic asthma, and atopic dermatitis [AD]), both house dust mites (HDMs) and SMs were found to be the most common airborne source of sensitization. Among SM allergens, Lep d 2 was the most frequently reported with a sensitization frequency of 76% (114/150 patients) (Gonzalez-Perez et al. 2023).

Another Spanish study conducted on 133 patients (median age 26.0 years) diagnosed with moderate-to-severe non-occupational type 2 (T2) persistent asthma and who had a positive skin prick test (SPT) to any SM reported that Lep d 2 was the most found SM allergen showing positive specific IgE in 83.45% (111/133) of patients, followed by other group 2 allergens, Gly d 2 of Glycyphagus domesticus (69.17%) and Tyr p 2 of Tyrophagus putrescentiae (47.37%) (Gonzalez-Perez et al. 2022).

Environmental characteristics       

Source and tissue

The allergens of SM are usually present in the body of the mites and their excreta and sometimes in their eggs. Lep d 2 protein is specifically concentrated in the gut of SM (Cuevas et al. 2022).

Risk factors

Occupational exposure to SMs among farmers, grain-storage or agricultural workers, and bakers are common risk factors for development of SM allergy. Besides, individuals exposed to house dust with high concentrations of  L. destructor have an increased risk of developing an allergic response (Gafvelin et al. 2001, Sigsgaard et al. 2020).

In a study conducted in Polish farm buildings, mites in debris and litter were found to be a serious risk factor for developing allergic reactions among farm and agricultural workers. In 60 samples collected from different farm buildings, L. destructor species were among the most reported allergens (66% incidence) (Solarz et al. 2019).

Clinical relevance

Disease severity

L. destructor plays a pivotal role in exacerbating respiratory allergic reactions, leading to pronounced disease severity. Symptoms associated with L. destructor sensitization often manifest prominently and include moderate-to-severe asthma, AR, conjunctivitis, and AD (Solarz et al. 2019, Marques et al. 2022).

In a cross-sectional, multicenter study of 101 patients complaining of respiratory allergy symptoms, Lep d 2 was identified to be significantly more frequently associated with asthma than AR (43.5% vs. 13.5%). Moreover, it is also linked to the severity of the symptoms in patients with moderate-to-severe AR as compared to mild AR (33.3% vs. 12.1%) (Til-Perez et al. 2019).

Cross-reactive molecules

SMs are cross-reactive with each other; however, there exists very low cross-reactivity between SM and HDM. Studies have highlighted inhibitory interactions between extracts of different mite species, such as D. pteronyssinus and L. destructor, emphasizing the complex interplay and cross-inhibition phenomena among closely related mite extracts (Gafvelin et al. 2001, Cuevas et al. 2022).

The IgE inhibition experiments found a high level of IgE-mediated cross-reactivity among the different SM species (Zhang et al. 2012). An extensive cross-reactivity was observed between the group 2 allergens Lep d 2 and Gly d 2, and Tyr p 2, but limited cross-reactivity was seen between Lep d 2 and Der p 2 (Dermatophagoides pteronyssinus), a major allergen of HDM (Gafvelin et al. 2001).

Molecular aspects    

Biochemistry

Lep d 2 is an MD-2-related lipid recognition (ML) domain-containing protein with a molecular weight of 16 kDa (WHO/IUIS 2023). Lep d 2 can be expressed as a recombinant protein with high IgE reactivity in vitro and in vivo (Fernandez-Caldas et al. 2014). 

Isoforms, epitopes, antibodies

Lep d 2 has two isoforms, Lep d 2.01 and Lep d 2.02, with differences in 13 AA and several nucleotides (Kaiser et al. 2003, Fernandez-Caldas et al. 2014). According to the WHO/IUIS allergen nomenclature, four isoallergens and variants of Lep d 2 exist, namely Lep d 2.0101, Lep d 2.0102, Lep d 2.0201 and Lep d 2.0202 (WHO/IUIS 2023).

Specific IgE against Lep d 2.01 is more commonly found than Lep d 2.02 IgE in sensitized individuals and thus may be associated with higher rates of sensitization (Eriksson et al. 2001). Isoform Lep d 2.01 has two variants containing similar AA sequences with differences in their DNA constitution (Kaiser et al. 2003).

A study results indicated that both cultured and wild L. destructor mites display same Lep d 2 polymorphism patterns. However, the diversity in the Lep d 2 sequence doesn't appear to have any effect on either IgE binding or the abilty to trigger the release of T cell cytokines (Kaiser et al. 2003).

Cross-reactivity due to structural similarity

IgE cross-reactivity is reported between Lep d 2 and group 2 allergens of other mites. A comparison of amino acid sequence shows that Lep d 2 is 79% identical to Gly d 2, 43% with Tyr p 2 and 37% with Der p 2 (Gafvelin et al. 2001).

Diagnostic relevance

Disease Severity

Lep d 2 can be considered as a potential biomarker for detecting mild asthma cases as significant differences were seen mainly in moderate asthma compared to the severe cases. It was reported that IgE response to Der p 2 can be seen in more than 90% of patients with moderate-to-severe T2 persistent asthma (n=133), and more than half of these patients were co-sensitized to Lep d 2 and other group 2 allergens, such as Gly d 2 and Tyr p 2. Fewer patients (16.52%) were found to be sensitized to Lep d 2 and Der p 2 due to a low sequence homology (Gonzalez-Perez et al. 2022).

Cross-Reactivity

The extracts of L. destructor and G. domesticus demonstrated a substantial level of cross-inhibition due to phylogenetic closeness of these mite species (Gafvelin et al. 2001).

Exposure

The main route of allergen exposure is through the airway via inhalation of allergens present in fecal pellets of the mite species (Sigsgaard et al. 2020).

Explained results

Allergen Information

Lep d 2, a 16-kDa protein, belongs to the group 2 allergen of L. destructor and is one of the most commonly found SM allergens (Sigsgaard et al. 2020, Gonzalez-Perez et al. 2023).

Clinical relevance

Typical allergic reactions to Lep d 2 include bronchial asthma, allergic rhinitis, conjunctivitis, and AD due to inhalation of contaminated fecal pellets (Solarz et al. 2019, Marques et al. 2022).

Cross-reactivity

A significant cross-reactivity between Lep d 2, Gly d 2, and Tyr p 2 has been reported due to close sequence similarity (Gafvelin et al. 2001). L. destructor and G. domesticus exhibit a substantial level of cross-reactivity in their extracts.

Author: Turacoz
Reviewed: Dr. Ulrica Olsson