Latex allergen components
Allergen related documents
Booklet: Native & Recombinant Allergen Components.
Allergy - Which allergens? Phadia AB, 2006.
Hevea brasiliensis
Available ImmunoCAP:
- k215 rHev b 1 (MBP fusion protein)
- k217 rHev b 3 (MBP fusion protein)
- k218 rHev b 5
- k219 rHev b 6.01 (MBP fusion protein)
- k220 rHev b 6.02 (MBP fusion protein)
- k221 rHev b 8 (MBP fusion protein)
- k222 rHev b 9 (MBP fusion protein)
- k224 rHev b 11 (MBP fusion protein)
Natural latex is a milky sap produced by over 2000 plants, whereas the Latex that is used industrially is derived almost exclusively from the rubber tree Hevea brasiliensis. Ammonia is added to the sap as a preservative at the time of harvesting. Processing of Natural latex results in Natural rubber latex (cis-1,4- polyisoprene). Many chemicals are added to Natural latex before, during and after processing, including antioxidants, emulsifiers, stabilisers and accelerators. Processing converts the sap into liquid Latex concentrate or solid dry rubber. Latex concentrate is used to make items such as gloves, condoms, balloons, catheters, baby pacifiers, and dental dams. Dry rubber is the essential ingredient in tires, tubing, hoses, footwear, automotive components, engineering parts, and adhesives. Latex concentrate contains about 1% total protein, of which a small fraction remains in the manufactured product. This protein is responsible for IgE-mediated reactions. Dry rubber, however, contains very little protein and therefore is much less immunogenic. Besides Latex protein, additives from the manufacturing process such as mercaptobenzothiazoles, carbamates, and thiurams may form haptens and act as allergens.
True Latex allergy develops from plant protein in the Latex sap itself, whereas concomitant allergies may also develop from the chemicals added during processing. An individual may have concomitant allergies, such as an IgE-mediated allergy to Latex proteins and a lymfocyte-mediated hypersensitivity to carbamates. Carbamates may be found in some non-Latex substitutes recommended for Latex-sensitive individuals. A third type of reaction is an irritant contact dermatitis, which is often associated with Latex but not caused by Latex itself, and may result, for example, from the alkaline pH found in many powdered gloves.
Natural rubber products must be distinguished from items manufactured with synthetic rubber, such as butyl rubber and neoprene (polymers of 2-chlorobutadiene), which pose no risk to persons sensitised to natural rubber proteins.
In general, the Latex serum obtained by centrifugation may be quite variable in its protein content, depending on the treatment of the Latex after collection from the rubber tree as well as on the considerable batch-to-batch variation in the protein content of the rubber tree sap due to genetic or environmental factors (1). Latex allergen content may vary widely even in the same product, with a variance of 3,000-fold having been documented for Latex gloves obtained from 10 separate manufacturers (2).
Rubber latex contains more than 200 proteins. Ultra-centrifugation of the fresh Latex sap results in as many as 9 fractions, of which 3 are most easily discerned: the rubber particle proteins, the C-serum and the bottom fraction (B-serum). Rubber particle proteins are water-insoluble. Most of the C-serum and B-serum proteins are water-soluble (1).
Rubber particle proteins
The rubber particle proteins comprise the rubber particles and 2 main insoluble proteins, which are extractable from the surface of the rubber particles. Two allergens have been identified, Hev b 1 and Hev b 3, both major allergens and strongly associated with Latex allergy in spina bifida (SB) patients (1).
C-serum proteins
Latex C-serum contains various proteins (more than 200 polypeptides), of which some are enzymes associated with rubber biosynthesis. Four characterised Latex allergens, Hev b 5, Hev b 7.02, Hev b 8, and Hev b 9, belong to the group of C-serum proteins, which are present in the cytosol fraction of the Latex. The most important allergen of this subgroup is Hev b 5, a heat-stable protein (1).
B-serum proteins
B-serum contains a smaller number of proteins, among which hevein is the most prominent and makes up more than 50% of the total soluble B-serum proteins. B-serum currently includes a group of 9 characterised Latex allergens (Hev b 2, Hev b 4, Hev b 6.01, Hev b 6.02, Hev b 6.03, Hev b 7.01, Hev b 10, Hev b 11, Hev b 13), which are extracytosolic proteins. With the exception of Hev b 7.01, all belong to the group of plant defense proteins. A tenth allergen belonging to this group is Hev b 12, a lipid transfer protein (1).
Natural rubber latex-allergenic proteins include those involved in the biosynthesis of polyisoprene and the coagulation of Latex rubber elongation factor, small rubber particle protein, prohevein, and patatin. Structural and pathogenesis-related proteins include beta-1,3-glucanases, endochitinases (chitinase), hevamine, microhelix protein complex, proline-rich protein, profilins, enolases, and manganese superoxide dismutase (3). Other proteins isolated include proteasome subunit C5, malate dehydrogenase, and triosephosphate isomerase (4-5). Recently, a number of other proteins with allergenic activity have been isolated: Hev b Thioredoxin h, Hev b UDPGP (a UDP-glucose Pyrophosphorylase), Hev b Citrate-binding protein, Hev b Hevamine (a chitinase), Hev b IFR (an isoflavone reductase), and Hev b Rotamase (a cyclophilin) (6).
Latex allergy occurs more frequently among individuals heavily exposed to natural rubber latex (NRL) products, including healthcare workers (HCW), laboratory workers, food handlers, hairdressers, cleaning staff and rubber industry workers. Children with neural tube defects such as SB have a particularly high prevalence of Latex allergy. Latex-sensitive persons with spina bifida have been shown to react preferentially to Hev b 1 and Hev b 3 proteins, whereas Latex-sensitive healthcare workers are more apt to be sensitised to Hev b 5 and Hev b 6.
Latex allergy is perhaps more complex than many other allergies in that it stems not from a single protein, but from no fewer than 13 known Latex allergens, with no single allergen deemed to be dominant. Sources of NRL are of varying quality and difficult to standardise for diagnostic purposes. As most Latex-allergic patients are sensitised to more than one Latex allergen, a blend of a number of allergens allows the identification of a greater number of Latex-allergic patients (7). Recombinant allergens may therefore be of great value in composing an appropriate blend of for more exact diagnosis.
Hev b 1 and the homologous Hev b 3 are associated mainly with young SB patients, whereas Hev b 5, Hev b 6 and Hev b 7 are linked more to adult Latex-allergic patients (8). A recent review study reported that native Hev b 2, recombinant Hev b 5, native or recombinant Hev b 6, native Hev b 13, and possibly native Hev b 4 are the major allergens relevant to Latex-sensitised adults (7).
There has been a number of epidemiological studies of varying subject sizes, many attempting to determine which proteins behave as major allergens in different risk groups.
In a study evaluating sensitisation to Latex allergens in HCW with histories of Latex allergy, Hev b 2, Hev b 5, Hev b 6.01, and Hev b 13 produced positive skin reactions in more than 60% of subjects, with Hev b 1, 3, 4, and 7.01 eliciting reactions in less than 50%. Specificity of 7 Hev b allergens was 100% in identifying workers with confirmed NRL allergy, and 98% for Hev b 13 (9).
A study population of 38 Latex-allergic and 15 SB Latex-sensitised children showed that natural Hev b 1 was recognised by 82% and natural Hev b 3 by 79% of the SB Latex-allergic children. Fifteen (39.5%) of 38 Latex-allergic and 2 (13%) of 5 SB Latex-sensitised children demonstrated IgE binding to natural Hev b 7. Further studies including rHev b 7 demonstrated that Hev b 7 was a third SB-associated Latex allergen (10).
The relative propensities for IgE binding to individual Latex allergens, compared using sera from Latex-allergic patients, found that IgE antibody binding to Hev b 4, Hev b 7b, Hev b 5 and Hev b 2 occurred in 75, 61, 31 and 28% of the study group, respectively. Multiple allergen sensitisation was common: of the 31 sensitised patients, 23 (74%) had specific IgE directed against at least 2 Latex allergens, while 12 (39%) had IgE antibodies for at least 3 allergens. The data suggested that many patients might have acquired sensitivity to Hev b 2, Hev b 4 and Hev b 7b from Latex products. Sensitivity to Hev b 5 and to Hev b 7c were interrelated and thought to have been acquired from sources other than Latex products, i.e., from certain foods (11).
Using purified Latex allergens, Hev b 1, 2, 3, 4, 6 and 7, allergen-specific IgE was demonstrated in 32-65% of HCW and 54-100% of SB patients with Latex allergy. Using a combination of Hev b 2 and Hev b 7, 80% of HCW and 92% of SB patients with Latex allergy were identified by ELISA technique, but the combination gave lower positive rates when IgE antibody tests were used. The addition of Hev b 3 allowed the detection of allergen-specific IgE in all SB-Latex allergic patients (12).
A study comparing skin reactivity of 6 recombinant Latex allergens with NRL proteins in 31 Latex-allergic individuals found that rHev b 2, 3, 5, 6, 7, 8 were positive in at least one Latex-allergic patient. Sensitisation to the various recombinant allergens was similar to that shown by previous studies using the native proteins. The use of a combination of recombinant Latex allergens, Hev b 5, 6 and 7, diagnosed Latex allergy with 93% sensitivity and 100% specificity (13).
The IgE antibody pattern has also been shown to differ between children with Latex allergy who have not undergone surgery and those with a history of multiple operations. The major allergens in children with no history of surgery appear to be Hev b 6.01 and Hev b 6.02 and not Hev b 1, a finding similar to that reported for HCW with allergy to Latex (14).
Therefore, one or a combination of Latex recombinant allergens may be used to easily determine allergen sensitisation profiles in different groups of Latex-allergic patients. Natural and recombinant allergens may also be used for assessing the allergenic potential of glove samples. A study detected all 6 Latex allergens tested for in at least some of the glove samples; Hev b 5 and Hev b 13 were identified as the marker allergens that combined best to explain the variation in the glove allergenicity. The study concluded that the overall allergenic potential of Latex gloves could be estimated by using Hev b 5 and Hev b 13 as indicator allergens. The correlation between glove allergenicity and the level of these allergens was maintained for low-protein gloves (<200 microg/g) (15).
Immunological and clinical properties of characterised Latex allergens
|
Latex allergen |
Significance as Latex allergen |
Significance of cross-reactivity |
IgE-binding prevalence of the allergen |
Documented on k82 Latex ImmunoCAP |
|
Hev b 1 |
High (especially in spina bifida patients) |
Not observed yet |
HCW: 55/105 (52%)
SB: 56/69 (81%) |
++ |
|
Hev b 2 |
Medium |
Medium |
HCW: 20/31 (65%)
SB: 7/13 (54%) |
++ |
|
Hev b 3 |
High (especially in spina bifida patients) |
Not observed yet |
HCW: 13-20%
SB: 76-78% |
++ |
|
Hev b 4 |
Not determined |
Not observed yet |
No clear results |
nt |
|
Hev b 5 |
High in all risk groups: HCW, spina bifida, atopics |
Not observed yet
(structural homo-logy with a Kiwi fruit protein) |
HCW: 68-92%
SB: 33-66% |
++ |
|
Hev b 6.01 |
High in all risk groups: HCW, spina bifida, atopics |
High (especially with Banana, Kiwi, Avocado) |
LAP: 15/20 (75%)
LAP: 24/29 (83%) |
++ |
|
Hev b 6.02 |
High in all risk groups: HCW, spina bifida, atopics |
High (especially with Banana, Kiwi, Avocado, etc.; main IgE-binding epitope) |
LAP: 24/43 (56%)
HCW: 48/64 (75%)
SB: 3/11 (27%) |
++ |
|
Hev b 6.03 |
High in context with Hev b 6.01 |
High (structural homology to plant stress proteins) |
LAP: 3/20(15%)
LAP: 11/52(21%) |
|
|
Hev b 7.01 |
Low-Medium |
Unclear (structural homology to proteins from Potato and Tomato, but no cross-reactivity with Banana and Avocado |
LAP: 4/36 (11%)
LAP: 17/35 (49%) |
++ |
|
Hev b 7.02 |
Medium only in SB |
Unclear - see Hev b 7.01 |
SB: 15/30 (39.5%) |
++ |
|
Hev b 8 |
Low (profilin is a ubiquitous pan-allergen) |
Medium |
LAP: 2/19 (11%)
HCW: 20-24%
SB: 6-12% |
++ |
|
Hev b 9 |
Low |
Medium cross-reactivity with moulds |
LAP: 15/110 (15%) |
+ |
|
Hev b 10 |
Low |
Medium
cross-reactivity with moulds |
HCW: 0/20,
SB: 2/20
LAP: 4/15 (27%) |
++ |
|
Hev b 11 |
Low |
High cross-reactivity with fruit allergens, especially hevein-like sequences |
LAP: 10/57 (19%)
LAP (53 ???
HCW (5SB): 17/58 (29%) |
++ |
|
Hev b 12 |
Low |
Medium
pan-allergen; cross-reactivity with fruits |
LAP: 9/37 (24%) |
|
|
Hev b 13 |
High |
Not determined yet |
HCWs by SPT: 39/62 (63%) |
nt |
IUIS nomenclature
LAP = Latex-allergic patients
HCW = healthcare workers
SB = spina bifida patients
++ Satisfactory amounts on k82 Latex ImmunoCAP
+ Acceptable but low amounts on k82 Latex ImmunoCAP
* Testing in progress
nt Not tested/not available
From: Rihs H-P, Raulf-Heimsoth M. Natural rubber latex allergens: Characterization and evaluation of their allergenic capacity. New Horizons, Pharmacia Diagnostics AB 2003; No 3.
References:
- Rihs H-P, Raulf-Heimsoth M. Natural rubber latex allergens: Characterization and evaluation of their allergenic capacity. New Horizons, Pharmacia Diagnostics AB 2003;No 3
- Yunginger JW, Jones, RT, Fransway AF, Kelso JM, et al. Extractable latex allergens and proteins in disposable medical gloves and other other rubber products. J Allergy Clin Immunol 1994;93:836-842
- Sussman GL, Beezhold DH, Kurup VP. Allergens and natural rubber proteins. J Allergy Clin Immunol 2002;110(2 Pt 2):S033-9
- Posch A, Chen Z, Dunn MJ, Wheeler CH, Petersen A, Leubner-Metzger G, Baur X. Latex allergen database. Electrophoresis 1997;18(15):2803-10.
- Posch A, Chen Z, Wheeler C, Dunn MJ, Raulf-Heimsoth M, Baur X. Characterization and identification of latex allergens by two-dimensional electrophoresis and protein microsequencing. J Allergy Clin Immunol 1997;99(3):385-395
- Yagami T, Haishima Y, Tsuchiya T, Tomitaka-Yagami A, Kano H, Matsunaga K. Proteomic analysis of putative latex allergens. Int Arch Allergy Immunol 2004;135(1):3-11
- Yeang HY. Natural rubber latex allergens: new developments. Curr Opin Allergy Clin Immunol 2004;4(2):99-104.
- Salcedo G, Diaz-Perales A, Sanchez-Monge R. The role of plant panallergens in sensitization to natural rubber latex. Curr Opin Allergy Clin Immunol 2001;1(2):177-83
- Bernstein DI, Biagini RE, Karnani R, Hamilton R, Murphy K, Bernstein C, Arif SA, Berendts B, Yeang HY. In vivo sensitization to purified Hevea brasiliensis proteins in health care workers sensitized to natural rubber latex. J Allergy Clin Immunol 2003;111(3):610-6
- Wagner B, Buck D, Hafner C, Sowka S, Niggemann B, Scheiner O, Breiteneder H. Hev b 7 is a Hevea brasiliensis protein associated with latex allergy in children with spina bifida. J Allergy Clin Immunol 2001;108(4):621-7
- Yeang HY, Chow KS, Yusof F, Arif SA, Chew NP, Loke YH. Appraisal of latex glove proteins in the induction of sensitivity to multiple latex allergens. J Investig Allergol Clin Immunol 2000;10(4):215-22
- Kurup VP, Yeang HY, Sussman GL, Bansal NK, Beezhold DH, Kelly KJ, Hoffman DR, Williams B, Fink JN. Detection of immunoglobulin antibodies in the sera of patients using purified latex allergens. Clin Exp Allergy 2000;30(3):359-69.
- Yip L, Hickey V, Wagner B, Liss G, Slater J, Breiteneder H, Sussman G, Beezhold D. Skin prick test reactivity to recombinant latex allergens. Int Arch Allergy Immunol 2000;121(4):292-9.
- Ylitalo L, Alenius H, Turjanmaa K, Palosuo T, Reunala T. IgE antibodies to prohevein, hevein, and rubber elongation factor in children with latex allergy. J Allergy Clin Immunol 1998;102(4 Pt 1):659-64
- Yeang HY, Arif SA, Raulf-Heimsoth M, Loke YH, Sander I, Sulong SH, Lau CH, Hamilton RG. Hev b 5 and Hev b 13 as allergen markers to estimate the allergenic potency of latex gloves. J Allergy Clin Immunol 2004;114(3):593-8