rVes v 1

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Code: i211
Latin name: Yellow Jacket
Family: Vespula vulgaris
Common names: phospholipase A1, PLA1

Yellow Jacket

Recombinant allergens

  • rVes v 1
  • rVes v 5

Ves v 1

Allergen

Ves v 1 (1).  rVes v 1 is a CCD-free recombinant protein.

Biological function

A phospholipase.

Mw

Approximately 37 kDa.

Other allergens isolated

Allergens characterised to date include:

  • Ves v 1, a phospholipase. (1, 2, 3, 4, 5, 6, 7)
  • Ves v 2, a 43 kDa protein, a hyaluronidase. (2, 3, 4, 5, 8, 9, 10, 11)
  • Ves v 3, a dipeptidyl-peptidase. (2, 12, 13)
  • Ves v 5, a 100-105 kDa protein, also known as antigen 5 or Ag5. (2, 3, 4, 5, 10, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23)

Allergen description

Ves v 1, also known phospholipase A1, PLA1, is a 37 kDa protein. It is a phospholipase. Ves v 1 is one of three major allergens found in Yellow Jacket venom: Ves v 1 (phospholipase A1), Ves v 2 (hyaluronidase), and Ves v 5 (antigen 5). (21)

However, in addition to the presence of allergens, Hymenoptera venoms are rich sources of biologically active compounds which contain a complex mixture of amines, small peptides and high-molecular-weight proteins such as enzymes and toxins. (24) These other compounds may be relevant; for example, local reactions may result from biologically active peptides and polycationic peptides such as bradykinin-like peptides, chemotactic peptides and other components such as neurotoxic kinins and mastoparans. (24, 25, 26, 27)

Ves v 1, a 37 kDa protein, a phospholipase, is a triglyceride lipase. These are lipolytic enzymes that hydrolyse ester linkages of triglycerides. (28) Lipases are widely distributed in animals, plants and prokaryotes. Ves v 1, a phospholipase A1 (PLA1), comprises the whole of group 1 of vespid and ant venom allergens. These have no sequence similarity with bee venom phospholipase A2. (29, 30)

The Vespidae family includes hornets (genera Vespa and Dolichovespula), yellow jackets (genus Vespula) and the paper wasp (genus Polistes). 

Vespid phospholipases are homologous to porcine pancreatic lipase, among others (Table 1).(29)

Table 1: Examples of Phospholipase A1 have been isolated from various vespid and ant species.

Dol m 1

Dolichovespula maculate (bald-faced hornet)

(29, 31)

Pol a 1

Polistes annularis (paper wasp)

(30)

Pol d 1

Polistes dominulus (European paper wasp)

(32)

Poly p 1

Polybia paulista (neotropical social wasp)

(33)

Pro ca 38kD

Protortonia cacti (cochineal)

(34)

Sol i 1

Solenopsis invicta (red fire ant)

(35)

Sus s Lipase

Sus scrofa domestica (domestic pig)

(36)

Ves g 1

Vespula germanica (German yellow jacket)

(29)

Ves m 1

Vespula maculifrons (Eastern yellow jacket)

(37)

Ves v 1

Vespula vulgaris (yellow jacket)

(29)

Ves c 1

Vespa crabo (European hornet)

(38)

 

As most vespid-allergic patients show multiple reactions to more than one vespid venom, (39, 40) partial antigenic identity of the component proteins is suggested, (24) i.e. patients show a varying extent of cross-reactivity to related panallergens, e.g. Antigen 5's. (21)

Bees, fire ants and vespids each have unique as well as homologous venom allergens: one of the four known bee allergens is homologous to vespid hyaluronidases, with about 50% sequence identity. Two of the four known fire ant allergens are homologous to vespid antigen 5 and phospholipases.

There is greater cross-reactivity between hornet and yellow jacket allergens than that between hornet (or yellow jacket) and wasp allergens. The order of cross-reaction of the three vespid allergens are hyaluronidase > antigen 5 > phospholipase. (4)

Hymenoptera venom allergy is usually an IgE-mediated allergic hypersensitivity of non-atopic origin. (41) The most frequent clinical patterns are: (i) large local reactions exceeding 10 cm in diameter and 24 hours in duration and (ii) rapid-onset (usually within 10 minutes after sting) generalised immediate-type hypersensitivity reactions such as pruritus, urticaria, angioedema, nausea, vomiting, diarrhoea, rhinoconjunctivitis, bronchospasm, hypotension, cardiovascular collapse and unconsciousness. (42, 43, 44, 45) Systemic reactions have been reported to occur in 0.8 to 5% of the general population. (46) These are mostly IgE-mediated and may be severe and even life-threatening, with 0.09 to 0.45 deaths per million within the general population. (47, 48)

Large doses of venom may result in unusual reactions such as haemolysis, coagulopathy, rhabdomyolysis, acute renal failure and hepatotoxicity. Aortic thrombosis and cerebral infarction has also been reported as a clinical symptom after massive wasp stings. (24, 42, 49, 50)

It is clear that knowledge of the composition of venoms and structure of allergens is a prerequisite for the accurate diagnosis and treatment of insect venom allergy. (51)

See Yellow Jacket i3 for clinical information and further details on Yellow Jacket allergy.

Estimates of the worldwide annual incidence of immunologic reactions to hymenopteran stings in the world population range from 0.3% to 3.0%, or nearly 100 million cases per year, ranging from local wheal-and-flare reactions to deaths from anaphylactic shock. In the United States, the annual incidence of allergic reactions to hymenopteran stings ranges between 0.4% and 4.0%, with 40 to 50 deaths a year. (52) Hymenoptera include the apids (bumblebee, honeybee, carpenter bee), vespids (hornets, wasps, yellow jackets), and formicids (fire ants, bulldog ants, bullet ants, etc.).

Skin tests and assessment of serum-specific IgE antibodies are used to diagnose venom allergy. Although determination of specific-serum IgE antibodies to Hymenoptera venoms is a very sensitive diagnostic test for venom allergy, unfortunately the test lacks absolute sensitivity and specificity. (53) Possible reasons for the inaccuracy of diagnostic tests with Hymenoptera venom (which may increase or decrease in sensitivity since last sting) (54, 55) include wide variability of venom amount applied with one sting, especially in vespids. (56, 57)

Less than 5% of history-positive individuals are negative in both skin and serum IgE if investigated within a year after a systemic reaction to Hymenoptera stings. Furthermore, up to 20% of individuals with no history of adverse reactions to Hymenoptera stings may react positively to either or both tests. (58) Test-positive individuals will develop a systemic reaction more frequently than test-negative individuals when re-stung; however, only some of the test-positive patients will react again. Additionally, some test-negative individuals may develop systemic reactions. (58, 59, 60)

The three allergens thought to be primarily responsible for IgE-mediated allergic reactions to yellow jacket are phospholipase A1 (Ves v 1), hyaluronidase (Ves v 2), and antigen 5 (Ves v 5). (5, 61, 62) Both Ves v 2 and Ves v 3 are glycoproteins prone to CCD reactivity with homologous allergens in honey bee venom. By contrast, Ves v 1 and Ves v 5 are non-glycosylated, and unique candidates for the diagnosis of yellow jacket venom allergy. (1)

Recombinant allergens may aid in the diagnosis of patients who have negative specific IgE responses to insect venom despite a history of severe clinical reactivity and a positive skin-test response. For example, an evaluation of the major allergens with either high abundance (e.g. honey bee Api m 1; yellow jacket Ves v 5) or low abundance (e.g. honey bee Api m 3; Api m 2) in patients receiving specific immunotherapy (SIT) with either honey bee (n=20) or vespid (n=22) venom extracts found that of the 8 patients who had been non-reactive to bee venom in classical serum IgE tests using whole venom extract (group A), no or rare serum IgE was found with the abundant major allergen Api m 1 (0/8) or the less abundant major allergen Api m 2 (2/8).

Among the vespid venom-allergic patients, none showed serum IgE to the major vespid venom allergens Ves v 1, Ves v 2, or Ves v 5 in immunoblots, whereas one patient had demonstrable serum IgE against rVes v 5 (1/22). Therefore, due to the known low relative abundance of Api m 3 in native honey bee venom, rApi m 3 was a valuable tool in the diagnosis of honey bee venom allergy. The authors concluded that it was likely that diagnostic failures in vespid venom allergy are caused by serum-IgE reactivity against hitherto unidentified allergens in native vespid venom. (63)

Among patients with allergy to insect stings, double positivity in tests for IgE antibodies specific to honey bee and wasp (Vespula) venoms is a frequent diagnostic problem, and in particular makes selection of venom for immunotherapy problematic. Up to 50% of patients with allergic reactions to honey bee or Vespula stings are double-positive to both, i.e. they also have specific IgE to the other venom. (51, 64) This may be explained by true double sensitisation to both if the patient was stung by both honey bees and wasps, or by cross-reactivity between allergens of the two venoms, e.g. hyaluronidase and/or dipeptidylpeptidases, or between the carbohydrate epitopes (cross-reacting carbohydrate determinants (CCDs)) they share. (12, 64, 65, 66)

The relevance of CCDs in protein-directed cross-reactivity is controversial; whereas in Hymenoptera allergy it is thought to be clinically irrelevant, but diagnostically problematic. (1, 67, 68)

For example, a study examined the frequency of sensitisation to CCDs and their role in double positivity in a group of 100 patients allergic to vespula or honey bee stings and skin-prick test-positive to the respective venom. Serum IgE to bee venom, vespula venom and cross-reacting carbohydrate determinants (CCDs), and serum IgE to species-specific recombinant major allergens Api m1 (honey bee) and Ves v5 (Vespula) were assessed. Double positivity was observed in 59% of allergic patients. Serum lgE to Api m1 was detected in 97% of honey bee- and 17% of vespula-allergic patients. Serum lgE to Ves v 5 was demonstrated in 87% of Vespula- and 17% of honey bee-allergic patients. CCD serum IgE was present in 37% of all allergic patients and in 56% of those with double positivity, and was more frequent in bee venom- than in Vespula venom-allergic patients.

The authors concluded that double positivity of IgE to honey bee and Vespula venom was often caused by cross-reactions, particularly to CCDs, and that serum IgE to both Api m1 and Ves v5 indicates that true double sensitisation and immunotherapy with both venoms will be required. (64) Other researchers have reported similar findings. (69)

Honey bee venom phospholipase A2 and hyaluronidase are different from the Vespula enzymes, so there is little significant cross-reactivity. (70)

Therefore: as double positivity of IgE to honey bee and Vespula venom is often caused by cross-reactions, especially with CCDs, utilising a specific marker allergen may be of use to discern the difference. (64)

Such double positivity causes significant problems, including in the selection of venoms for immunotherapy: if double sensitisation is true for both venoms, this would indicate potential systemic allergic reactions to sting by both insect species, and immunotherapy with both venoms would be required. Species-specific recombinant major allergens may reduce the need for expensive inhibition tests required to demonstrate this, and would thus steer the choice of venoms for immunotherapy. (64)

In this instance, recombinant Ves v 1 (rVes v 1) may play a diagnostic role. In a study evaluating rVes v 1, of 20 double-positive patient sera, 15 showed reactivity to rVes v 1, 10 of which additionally had specific IgE to rVes v 5. Only 1 out of these 20 sera had serum IgE raised to rVes v 5 exclusively, while 2 sera exhibited additional reactivity to Api m 1. An overall diagnostic sensitivity of 80% could be achieved by use of two yellow jacket-venom allergens, compared to 50% when using rVes v 5 solely.

Of the remaining 4 patients, 2 had serum IgE to Api m 1 and 1 was reactive to the CCD marker MUXF-BSA only. Therefore, for 16 of the 20 patients (80%), a particular culprit venom could convincingly be assigned, whereas 2 patients showed a true double sensitisation. Only 1 patient showed no reactivity to either Ves v 1 or to Ves v 5. (This patient also showed no reactivity to other vespid proteins such as the hyluronidases Ves v 2a and b, or the dipeptidylpeptidase Ves v 3.)

In the yellow jacket-venom mono-sensitised group, 11 of 14 sera (79%) were reactive to rVes v 1, 7 of which exhibited additional serum IgE reactivity to rVes v 5. Two further patients showed serum IgE reactivity exclusively to rVes v 5. In summary, 13 of 14 (93%) had detectable serum IgE either to rVes v 1 or rVes v 5 or both, while 1 patient with low total yellow jacket-venom sIgE showed no reactivity. (1)

These data demonstrate that recombinant Ves v 1 is a necessity for assessing the sensitisation of individuals to yellow jacket venom, and its recombinant availability (complemented by Ves v 5 and Api m 1) allows for clear assignment of sensitisation patterns. (1)

Component Resolved Diagnosis (CRD) using recombinant allergens may be useful in various other scenarios. Only 30 to 50% of those with positive IgE tests will react to a subsequent sting by the same insect. (71) Sting-provocation tests during venom immunotherapy have shown that approximately 95% of patients allergic to vespid stings and 80-90% of those allergic to honey bee venom are completely protected from developing generalised allergic symptoms. (57, 71) CRD may be able to identify these individuals.

Furthermore, systemic allergic side-effects to immunotherapy injections may occur in 20 to 40% of patients during immunotherapy with honey bee venom, and 5 to 10% during immunotherapy with vespid venoms. (57) As a result of the recombinant venom allergens available today, and others in development, there is considerable potential for improvement of both diagnosis and immunotherapy of Hymenoptera-venom allergy. (72)

Diagnostic methods, e.g. skin- and serum-specific IgE, are based on natural yellow jacket extracts that contain both allergenic and non-allergenic proteins, and may contain major allergens in insufficient concentrations, or may be contaminated with unwanted components to which the patients are not allergic. Furthermore, important allergens may be lost during extraction because of (among other things) the activity of proteases co-purified with the allergens, or the protease nature of some of the allergens. (75)

A great variability and difficulty in standardisation exists because the extract composition depends on the origin of the raw material, and on the extraction, purification and storage procedures. (73) Recombinant allergens lead to standardised reagents that are biochemically characterised, and therefore to results that are comparable. Furthermore, recombinant allergens produced in E. coli lack carbohydrate determinants (CCDs), thereby eliminating the risk of false-positive results. (74)

The advantages of recombinant allergens include unlimited availability in their identical form, which allows for optimal standardisation; and the absence of contamination by traces of other allergens which might confound the true relevance of an individual allergen for the respective allergic disease. (75) Given also that the potency of natural allergens varies, (76) utilising recombinant allergens may allow more precise measurement and evaluation of IgE responses in certain instances, in particular for more appropriate diagnoses when used in Component Resolved Diagnosis (CRD), for exploring cross-reactivity, and for immunotherapy. (77)

Importantly, patients are not always able to provide the entomologic identification of the culprit responsible for a severe anaphylactic episode, precluding institution of the required life-saving venom-specific immunotherapy, and recombinant single allergens may be of benefit in such cases.

Therefore, as yellow jacket venom contains two non-glycosylated major allergens without significant cross-reactive homologues in other species, Ves v 1 and Ves v 5, and which have high IgE prevalence, (78) use of recombinant Ves v 1 and Ves v 5 provides a significant improvement in identification of the culprit venom, which is essential for choosing the appropriate immunotherapeutic strategy. Furthermore, recombinant Ves v 1 for routine diagnosis enables improved assessment of its true IgE prevalence and clinical relevance.

Compiled by Dr Harris Steinman, developer of Allergy Advisor, harris@zingsolutions.com

References

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As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.