k218 Hev b 5

Summary

Hev b 5, a structural protein of unknown function from natural rubber latex (NRL), is a major allergen in people allergic to NRL as a result of occupational exposure, repeated mucosal contact with NRL, or affected by a latex-food syndrome (LFS). Hev b 5 is a non-glycosylated protein from H. brasiliensis laticifers, found in the C-serum phase of latex after collection, treatment with ammonia and ultracentrifugation. 

Epidemiology

Worldwide distribution

NRL is extracted from rubber trees. Hevea brasiliensis, native to the Amazon rainforest, is more productive than other species of rubber trees and has therefore been imported to other continents [1]. South-East Asia is currently the largest producer of NRL worldwide [2].

Hev b 5 is a major allergen in all categories of latex-allergic patients, i.e., occupational allergy, a history of multiple surgeries with or without spina bifida (SB), and LFS [3-5]. The prevalence of Hev b 5 sensitization varies from 59% to 74% in healthcare workers (HCW) with latex allergy and from 46% to 55% in patients with SB or multiple surgery interventions [3, 5].

In an unselected population of 23,077 consecutive Italian subjects with a suspicion of airborne or food allergy, the prevalence of IgE sensitization to Hev b 5 was 0.69% (women: 0.89% vs men 0.44%, p<0.001), ranking 60 among 75 assayed allergenic molecules, in some cases presenting as apparent monosensitization [6]. Hev b 5 sensitization may be demonstrated in latex-sensitized, symptom-free patients, usually with lower figures of prevalence and quantitative IgE levels [5, 7, 8]. 

Environmental Characteristics

Source and tissue

Hev b 5 is present in the cytoplasm of laticifer cells and hence in the latex sap collected from the trunk [3, 9]. After collection of the latex sap, ammonia treatment and ultracentrifugation, Hev b 5 is found mainly as a soluble allergen of the C-serum phase [3]. Apparent Hev b 5 abundance in NRL extracts depends on the method of preparation; overall, Hev b 5 amounts in NRL extracts as compared to other latex molecular allergens are low [10], and supplementation of diagnostic latex extracts with recombinant Hev b 5 provides increased diagnostic sensitivity [3, 7, 11].

Clinical Relevance

Detailed information regarding latex allergy is available in the whole allergen section. In brief, NRL is associated with occupational latex allergy (extended to latex allergy occurring in multiple surgery and SB patients) and latex allergy in the context of pollen and/or plant food allergy [3]. The following sections apply to adult and pediatric subjects alike [12].

Clinical relevance in latex allergy occurring in spina bifida and other patients undergoing multiple surgeries

The prevalence of this type of latex allergy has diminished since the 1990s, due to appropriate prevention and diagnosis, including the assessment of Hev b 5 sensitization in the diagnostic algorithm [3, 9, 13].

As explained above, Hev b 5 sensitization may be found in  both latex-allergic and in asymptomatic SB patients [5]. Unfrequent asymptomatic sensitization to Hev b 5 has also been reported in grass-sensitized patients without latex allergy [7]. Therefore, a panel of major allergens comprising Hev b 5 alongside Hev b 6, Hev b 1, and Hev b 3 is advised as markers of genuine latex allergy, in order to identify clinically relevant NRL sensitization [3, 9, 13].

Clinical relevance in occupational latex allergy 

This type of latex allergy occurs in people who are occupationally exposed to NRL, such as HCW, and has also experienced a sharp decrease since the 1990s [3, 9]. Hev b 5 is a major allergen in this context too, with Hev b 5 sensitization demonstrated in up to 74% of HCW [5, 8]. Hev b 5 sensitization is found at early stages of occupational latex allergy, as demonstrated in HCW students with an exposure time of 5 years or less [11]. Indeed, Hev b 5 may become aerosolized from gloves, or act through direct contact [3, 5]. Hev b 5 assessment as part of the latex sensitization pattern contributes to stratification and prevention strategies [3, 4].

Clinical relevance in latex-food syndromes (LFS)

LFS comprises reactions to foods which occur in 21-58% of latex-allergic or latex-sensitized patients and have been attributed to cross-reactivity from latex allergens [9]. Such foods include the originally identified exotic fruit (banana, avocado) but have extended to a large array of other plant foods, such as chestnut, manioc, Rosaceae fruit [9, 14, 15]. Hev b 5 and Hev b 6 are the two major latex allergens widely recognized as contributors to LFS [3, 9]. Hev b 5 sensitization is a frequent finding in patients with LFS who are sensitized to NRL extracts [5, 7, 9], and has been reported in patients experiencing both latex glove anaphylaxis and allergy to fruit [5, 16].

At the molecular level, the first clinically relevant plant food homolog of Hev b 5 was described in manioc [15], followed by Rosaceae fruit allergens such as apricot and peach [14]. To date, Man e 5 from manioc and Pru ar 5 from apricot are included in the IUIS/WHO official list of allergens as Hev b 5-like allergens [17, 18]. Among Italian (with low manioc consumption) latex-allergic patients with Hev b 5 sensitization, a prevalence of 40% was demonstrated for Man e 5 IgE binding [19]. Man e 5 was susceptible to pepsin degradation at acidic but not neutral pH and was not denatured by heat [19], confirming previous reports [19] of Hev b 5-associated LFS to both raw and boiled/cooked manioc, and possibly other plant foods. 

Disease severity and prediction

In patients sensitized to NRL extract, the demonstration of Hev b 5 sensitization is considered as a marker of genuine latex allergy [3, 13].

Clinical symptoms of Hev b 5-associated LFS include muco-cutaneous manifestations such as urticaria and angio-edema, but food anaphylaxis is quite frequent, reported in up to 30% of patients [14, 15, 19].

Cross-reactive molecules

Hev b 5 shares a sequence identity of 40% or higher with identified allergens from manioc (Man e 5), apricot (Pru ar 5), and cross-reactivity with other plant foods is suspected [14, 20].

Molecular Aspects

Biochemistry

Hev b 5 is an acidic structural protein with a molecular weight of 16 kDa [3, 11, 20]. 

Isoforms, epitopes, antibodies

As of October 9th, 2021, Hev b 5 possesses a single isoallergen officially published by the World Health Organization (WHO) and the International Union of Immunological Societies (IUIS) Allergen Nomenclature [21].

Cross-reactivity due to structural similarity

Cross-reactivity at the IgE binding level resulting in clinically relevant reactions has been reported for Hev b 5 homologs from manioc (Man e 5) et apricot (Pru ar 5) [14, 15, 19].

Diagnostic Relevance

Disease Severity

In the diagnostic context of latex allergy, sensitization to Hev b 5 is considered as a marker of genuine latex allergy, high risk of perioperative anaphylaxis, and high risk of a positive specific inhalation challenge with latex [3, 8, 9, 13]. 

Cross-Reactivity

Hev b 5 displays clinically relevant cross-reactivity with related allergens from certain plant foods, best described for manioc and apricot homologs Man e 5 and Pru ar 5 already included in the IUIS/WHO allergen list [9, 14, 15, 19].

Exposure

Hev b 5 sensitization is believed to occur during repeated occupational or mucosal contact with latex-containing products [3, 5]. Hev b 5 may become aerosolized, resulting in respiratory exposure [3]. Hev b 5 was still detectable in some but not all latex products investigated in a 2017 study, such as gloves, baby pacifiers, feeding bottle teats, and condoms [22], supporting continued exposure avoidance for latex-allergic patients.

Compiled By

Author: Joana Vitte

Reviewer: Dr. Christian Fischer

Last reviewed: February  2022