k220 Hev b 6.02, Latex

Summary

Hev b 6.02, also called hevein, is a major allergen from natural rubber latex (NRL) of particular importance in occupational latex allergy and latex-food syndrome (LFS). Hev b 6.02, naturally found in H. brasiliensis laticifers, locates to the B-serum phase of NRL after collection, treatment with ammonia and ultracentrifugation of the latex sap. Hev b 6.02 is the post-translational N-terminal mature form of prohevein (Hev b 6.01) and comprises most of its IgE-binding epitopes. Hev b 6.02 is a non-glycosylated, disulfide-bond stabilized lectin involved in antimicrobial plant defense thanks to its chitinase and ribonuclease activity.

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 6.02 is a major allergen in all categories of latex-allergic patients, i.e., occupational allergy, LFS, and to a lesser extent in those with a history of multiple surgical interventions (3-5). The prevalence of Hev b 6.02 sensitization in latex-allergic patients may reach 78% in healthcare workers (HCW) (6) and 58% in those with a history of multiple surgery (7). Conversely, the prevalence of Hev b 6.02 sensitization in spina bifida patients may be as low as 27% (8).

In an unselected population of 23,077 consecutive Italian subjects with a suspicion of airborne or food allergy, 1.3% displayed detectable IgE sensitization to Hev b 6 isoallergens, ranking 52 among 75 assayed allergenic molecules (9). In this study, Hev b 6 sensitization exhibited a statistically significant gender bias (women: 1.61% vs men 0.91%, p<0.001). Hev b 6.02 sensitization may be demonstrated in latex-sensitized, symptom-free patients, although with lower figures of prevalence and quantitative IgE levels (6, 10). 

Environmental Characteristics

Source and tissue

Hev b 6.02 is present in the lutoids of laticifer cells and hence in the latex sap collected from the trunk (11). After collection of the latex sap, ammonia treatment and ultracentrifugation, Hev b 6.02 is found mainly as a soluble allergen of the B-serum phase (11, 12). Hev b 6 (comprising isoallergens Hev b 6.01 and Hev b 6.02) is the most abundant allergenic molecule in NRL extracts, with an average of 75 nanomoles of Hev b 6 per milligram of total protein (13).

Risk factors

HLA class II haplotype may play a role in Hev b 6.02 sensitization and allergy in HCW, as suggested by an  increased frequency of the DQB1*0302 haplotype, alone or in association with DRB1*04, in association with Hev b 6.02 sensitization in latex-allergic HCW (4). 

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 (11). The following sections apply to adult and pediatric subjects alike (14).

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 in countries where appropriate prevention and diagnosis have been implemented, including the assessment of Hev b 6.02 sensitization in the diagnostic algorithm (3). A panel of major allergens comprising Hev b 6.02 alongside Hev b 5, Hev b 1, and Hev b 3 is advised as markers of genuine latex allergy, in order to identify clinically relevant NRL sensitization (11, 12, 15).

Clinical relevance in occupational latex allergy 

This type of latex allergy occurs in people who are occupationally exposed to NRL using and manufacturing (11, 16), and has also experienced a sharp decrease since the 1990s in countries where prevention measures have been implemented (3). Hev b 6.02 is a major allergen in this context, with Hev b 6.02 sensitization demonstrated in up to 78% of HCW (6). Hev b 6.02 sensitization is associated to frequent contact with NRL gloves and presents mainly with muco-cutaneous (urticaria, angio-edema) and oculo-respiratory (asthma, rhinoconjunctivitis) symptoms (5). Indeed, Hev b 6.02 may become aerosolized from gloves, or act through direct contact (11, 17). Hev b 6.02 assessment as part of the latex sensitization pattern contributes to stratification and prevention strategies (5, 18)

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 (12), although food-induced reactions may precede latex-associated ones (11). Such foods include the originally identified exotic fruit (banana, avocado) but have since extended to a large array of other plant foods (12, 19). Hev b 6.02 is widely recognized as a major contributor to LFS (11, 12). Hev b 6.02 sensitization is a frequent finding in patients with LFS who are sensitized to NRL extracts (10, 12), and has been reported in patients experiencing both latex glove anaphylaxis and allergy to fruit (20).

At the molecular level, Hev b 6.02 supports cross-reactivity with hevein-like domains which are found in class I and IV chitinases, widely distributed plant defense enzymes (19). Mus a 2 from banana, Tri a 18 from wheat, Pers a 1 from avocado, are examples of IUIS/WHO validated food chitinases  involved in LFS through cross-reactivity with Hev b 6.02 (19, 21).

Disease severity and prediction

In patients sensitized to NRL extract, the demonstration of sensitization to Hev b 6.02 (or to other Hev b 6 marker) is considered as a marker of genuine latex allergy (11, 15).

Clinical manifestations of of Hev b 6.02-associated latex allergy include muco-cutaneous manifestations such as urticaria and angio-edema, asthma, rhinoconjunctivitis, and perioperative hypersensitivity (5, 15).

Clinical relevance in occupational latex allergy

Cross-reactivity between NRL and Ficus benjamina has been reported, with 25% of latex-allergic HCW showing sensitization to F. benjamina and possible involvement of a hevein domain containing protein from F. benjamina, cross-reactive with Hev b 6.02 (22). A significant association between NRL and F. benjamina association was confirmed in an independent prospective study, however, the figures were much lower, with 10.6% of F. benjamina-sensitized patients also sensitized to NRL, and just one out of 11 with fruit allergy and sensitization to both NRL and F. benjamina demonstrating involvement of hevein (23). These differences may be attributed to a different study design, i.e. screening consecutive subjects with potential inhalant allergy rather than focusing on confirmed latex-allergic HCW. To date, no hevein domain containing allergen from F. benjamina has been registered with the IUIS/WHO Allergen Nomenclature.

Cross-reactive molecules

Hev b 6.02 shares clinically significant sequence similarity and cross-reactivity with identified allergens containing hevein-like domains, mainly class I and class IV chitinases, explaining an extended range of plant food cross-reactivity (19, 24). 

Molecular Aspects

Biochemistry

Hev b 6.02, also known as hevein, is an acidic protein of small molecular weight (4.7 kDa), resulting from the post-translational cleavage of prohevein Hev b 6.01 (11, 24). It is stabilized by four disulfide bonds, does not bear glycosylated groups, and is also categorized as a lectin since it binds and cleaves complex sugars such as chitin (19, 25)

Isoforms, epitopes, antibodies

As of October 9th, 2021, Hev b 6.02 is registered as one of the three Hev b 6 isoallergens 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 6.02 and hevein domain-containing homologs from banana (Mus a 2), avocado (Pers a 1), chestnut (Cas s 5), wheat (Tri a 18), kiwi, and other plant food chitinases (12, 19). Hev b 6.02 displays structural similarity and cross-reactivity with Hev b 11, a class I chitinase and a minor latex allergen (11, 19)..

Diagnostic Relevance

Disease Severity

In the diagnostic context of latex allergy, sensitization to Hev b 6.02 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 (6, 11, 12, 15). 

Cross-Reactivity

Hev b 6.02 displays clinically relevant cross-reactivity with related allergens from latex (Hev b 11) and certain plant foods, based on the similarity of the hevein domain ((12, 19). 

Exposure

Hev b 6.02 sensitization is believed to occur mainly through contact or inhalation while using or manufacturing NRL-containing products (11). Hev b 6.02 may become aerosolized, resulting in respiratory exposure (11). Hev b 6.02 was still detectable in some but not all latex products investigated in a 2017 study, such as medical and household gloves, condoms, and toy balloon (26), supporting continued exposure avoidance for latex-allergic patients.

Compiled By

Author: Joana Vitte

Reviewer: Dr. Christian  Fischer

Last reviewed:December 2021.