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].
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].
Diagnostics
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.
References
- Grogan, K., et al., Unravelling the link between global rubber price and tropical deforestation in Cambodia. Nat Plants, 2019. 5(1): p. 47-53.
- Warren-Thomas E, D.P., Edwards DP. , Increasing demand for natural rubber necessitates a robust sustainability initiative to mitigate impacts on tropical biodiversity. . Conservation Letters, 2015. 8(4): p. 230-241.
- Matricardi, P.M., et al., EAACI Molecular Allergology User's Guide. Pediatr Allergy Immunol, 2016. 27 Suppl 23: p. 1-250.
- Steering Committee, A. and M. Review Panel, A WAO - ARIA - GA(2)LEN consensus document on molecular-based allergy diagnosis (PAMD@): Update 2020. World Allergy Organ J, 2020. 13(2): p. 100091.
- Raulf-Heimsoth, M., et al., Quantitative analysis of immunoglobulin E reactivity profiles in patients allergic or sensitized to natural rubber latex (Hevea brasiliensis). Clin Exp Allergy, 2007. 37(11): p. 1657-67.
- Scala, E., et al., Cross-sectional survey on immunoglobulin E reactivity in 23,077 subjects using an allergenic molecule-based microarray detection system. Clin Exp Allergy, 2010. 40(6): p. 911-21.
- Brandi, S.L., L.K. Poulsen, and L.H. Garvey, The Clinical Relevance of Natural Rubber Latex-Specific IgE in Patients Sensitized to Timothy Grass Pollen. Int Arch Allergy Immunol, 2019. 178(4): p. 345-354.
- Vandenplas, O., et al., The role of allergen components for the diagnosis of latex-induced occupational asthma. Allergy, 2016. 71(6): p. 840-9.
- Ebo, D.G., C.H. Bridts, and H.P. Rihs, Hevea latex-associated allergies: piecing together the puzzle of the latex IgE reactivity profile. Expert Rev Mol Diagn, 2020. 20(4): p. 367-373.
- Yeang, H.Y., et al., Allergen concentration in natural rubber latex. Clin Exp Allergy, 2006. 36(8): p. 1078-86.
- Raulf, M., Allergen component analysis as a tool in the diagnosis and management of occupational allergy. Mol Immunol, 2018. 100: p. 21-27.
- Niggemann, B. and H. Breiteneder, Latex allergy in children. Int Arch Allergy Immunol, 2000. 121(2): p. 98-107.
- Cardona, V. and I.J. Ansotegui, Component-resolved diagnosis in anaphylaxis. Curr Opin Allergy Clin Immunol, 2016. 16(3): p. 244-9.
- Giangrieco, I., et al., ENEA, a peach and apricot IgE-binding protein cross-reacting with the latex major allergen Hev b 5. Mol Immunol, 2019. 112: p. 347-357.
- Santos, K.S., et al., Allergic reactions to manioc (Manihot esculenta Crantz): identification of novel allergens with potential involvement in latex-fruit syndrome. J Allergy Clin Immunol, 2011. 128(6): p. 1367-9.
- Sompornrattanaphan, M., et al., Severe anaphylaxis after pelvic examination: a case report of dual latex and chlorhexidine allergies. Allergy Asthma Clin Immunol, 2019. 15: p. 19.
- IUIS/WHO. IUIS/WHO Allergen Nomenclature: apricot. 21/10/2021]; Available from: http://allergen.org/search.php?allergenname=&allergensource=apricot&TaxSource=&TaxOrder=&foodallerg=all&bioname=.
- IUIS/WHO. IUIS/WHO Allergen Nomenclature: manioc. 21/10/2021http://allergen.org/viewallergen.php?aid=726].
- Santos, K.S., et al., Novel allergens from ancient foods: Man e 5 from manioc (Manihot esculenta Crantz) cross reacts with Hev b 5 from latex. Mol Nutr Food Res, 2013. 57(6): p. 1100-9.
- UniProt. UniProtKB - Q39967 (ALL5_HEVBR) Hev b 5. 21/10/2021]; Available from: https://www.uniprot.org/uniprot/Q39967.
- IUIS/WHO. IUIS/WHO Allergen Nomenclature: latex. [cited 2021 18 October 2021]; Available from: http://allergen.org/search.php?allergenname=&allergensource=latex&TaxSource=&TaxOrder=&foodallerg=all&bioname=.
- von der Gathen, Y., et al., Quantification of protein and latex allergen content of various natural rubber latex products. Allergol Select, 2017. 1(2): p. 109-119.