k217 Hev b 3, Latex

Summary

Hev b 3 is an allergen from natural rubber latex (NRL). It is a major allergen in people allergic to NRL as a result of repeated mucosal contact with NRL and affected by a condition called spina bifida. Hev b 3 is a minor allergen in latex-allergic patients related to occupational exposure or latex-fruit syndromes. Hev b 3 is a non-glycosylated protein from H. brasiliensis laticifers, belonging to the small rubber particle protein (SRPP) family involved in NRL biosynthesis. Hev b 3 is biochemically and structurally related to Hev b 1, a rubber elongation factor. Following latex sap collection, treatment with ammonia and ultracentrifugation, Hev b 3 is found in the rubber phase, in association with the rubber latex particles. 

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 3 is a major allergen in latex-allergic patients with a history of multiple surgeries related to a condition called spina bifida (SB), a defect of neural tube closure requiring repeated surgical interventions, long-term use of catheters and overall frequent and prolonged mucosal contact with medical devices [3-5]. The median prevalence of Hev b 3 sensitization in these patients is 58%, with variations from 50 to 83% [3-6]. In patients having undergone multiple surgical interventions unrelated to a SB condition, as well as in latex-allergic patients with occupational exposure, such as healthcare workers (HCW), the prevalence of Hev b 3 sensitization is around 20% or lower [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 3 was 0.04%, ranking last of the 75 assayed allergenic molecules, and not observed as apparent monosensitization [7]. Hev b 3 sensitization in SB patients was reported in both latex-allergic patients and in those who had not experienced latex allergy [5, 6].

Environmental Characteristics

Source and tissue

Hev b 3 belongs to the REF/SRPP family [8, 9]. Hev b 3 is present in laticifer cells and hence in the latex sap collected from the trunk but has also been demonstrated in the leaves of H. brasiliensis [9]. After collection of the latex sap, ammonia treatment and ultracentrifugation, Hev b 3 is found mainly as an insoluble allergen of the rubber phase, present at the surface of small rubber particles [3, 10]. However, some small rubber particles and hence a minority of Hev b 3 are found in the C-serum, which contains mainly soluble proteins [10]. Proteases contained in the latex sap cleave Hev b 3 into multiple polypeptides of 5-24 kDa, which retain IgE reactivity [6, 10]. Apparent Hev b 3 abundance in NRL extracts depends on the method of preparation [11]. Hev b 3 has been reported as the second most abundant NRL allergen at 3.7 ng per mg of total protein, far behind Hev b 6 at 75 ng/mg [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 spina bifida 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 3 sensitization in the diagnostic algorithm [3, 13, 14].

As explained above, Hev b 3 sensitization is predominantly found in SB patients; however, this sensitization may occur in both latex-allergic and in asymptomatic SB patients [5, 6]. In contrast, other latex molecular allergens are better discriminants of latex allergy vs asymptomatic latex sensitization. As a result, a panel of major allergens comprising Hev b 3 alongside Hev b 5, Hev b 6, and Hev b 1 is advised in order to identify clinically relevant NRL sensitization [3, 13]. Once the clinical relevance is established, Hev b 3 sensitization in the context of a medical history of SB and/or multiple surgery allows the identification of mucosal contact-related latex allergy and the implementation of patient care guidelines including latex avoidance [3, 13, 14].

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, 13]. Hev b 3 is a minor allergen in this context, with Hev b 1 sensitization demonstrated in 2 to 10% of HCW [5, 15]. Indeed, Hev b 3 is an insoluble protein bound to rubber particles in latex products, and therefore will not become aerosolized [3, 5]. Hev b 3 assessment as part of the latex sensitization pattern contributes to stratification and prevention strategies [3, 4].

Clinical relevance in pollen and/or plant food allergy

Hev b 3 sensitization is uncommon in patients with pollen and/or plant food allergy who are sensitized to NRL extracts but has been reported in patients experiencing both latex glove anaphylaxis and allergy to fruit [5].

Disease severity and prediction

In patients sensitized to NRL extract, the demonstration of Hev b 3 sensitization is considered as a marker of genuine latex allergy [14].

Cross-reactive molecules

Hev b 3 shares a 47% sequence identity with Hev b 1, and 72% sequence similarity with Hev b 1, another rubber particle associated allergen [6]. 

Molecular Aspects

Biochemistry

Hev b 3 is an acidic protein with a molecular weight of 24 kDa, able to autoassemble into stable multimers after disruption of the laticifer cells [9]. 

Isoforms, epitopes, antibodies

As of October 9th, 2021, Hev b 3 possesses a single isoallergen officially published by the World Health Organization (WHO) and the International Union of Immunological Societies (IUIS) Allergen Nomenclature [16].

Cross-reactivity due to structural similarity

Serum IgE cross-reactivity in latex-allergic patients and the presence of shared B-cell but not T-cell epitopes between Hev b 3 and Hev b 1 are established [6, 17, 18]. Pre-incubation of serum from latex-allergic patients (SB and HCW) with Hev b 3 abolished 80% of IgE binding to Hev b 1 [18].

Diagnostic Relevance

Disease Severity

In the diagnostic context of latex allergy, sensitization to Hev b 3 is considered as a marker of high risk of perioperative anaphylaxis [3, 13, 14]. 

Cross-Reactivity

Hev b 3 cross-reactivity outside NRL has not been described [13]. 

Exposure

Hev b 3 sensitization is believed to occur during repeated mucosal contact with latex-containing medical products, preferentially during repeated perioperative exposure, as seen in SB patients [3]. As a rubber particle protein, Hev b 3 is mainly insoluble and does not become aerosolized except for powdered gloves, making respiratory exposure unlikely [3]. Hev b 3 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 [19], supporting continued exposure avoidance for latex-allergic patients.

Compiled By

Author: Joana Vitte

Reviewer: Dr. Christian  Fischer

Last reviewed:December 2021