Jug r 3
Allergen
Jug r 3 is a 9-kDa, non-specific lipid transport protein (nsLTP) recognized as the major allergen of walnut, that is resistant to both heat as well as pepsin digestion. This allergen belongs to the prolamin superfamily of proteins. The prevalence of allergy to walnut is reported in countries such as the US, France, Germany, Italy and Spain, with sensitization to Jug r 3 commonly reported in the Mediterranean, Italy and Spain. Patients sensitive to Jug r 3 allergen may develop severe reactions, such as food-induced contact urticaria, oral allergy syndrome, gastrointestinal symptoms, and even anaphylaxis. Jug r 3 has shown to exhibit cross-reactivity with other allergens, such as peach (Pru p 3), peanut (Ara h 9), hazelnut (Cor a 8), Pru ar 3 (apricot), cherry (Pru av 3) and almond (Pru du 3). This is observed as a result of structural similarity and shared IgE-binding epitopes between Jug r 3 and these allergens.
Epidemiology
Worldwide distribution
Allergy to walnut (Juglans spp.) is the most common immunoglobulin (IgE)-mediated sensitization reported in countries, such as the United States (US) and Europe.
In a cross-sectional, telephone survey conducted in the US, the prevalence of allergy to different tree nuts was determined. Reports found that the prevalence of walnut allergy was 20.33% (24 of 118 individuals), followed by cashew (6.8%), Brazil nut (6.8%), almond (5.9%) and pecan (5.9%).
A European survey (EuroPrevall analysis) was conducted among 4522 young adults in 13 countries to determine the overall prevalence of sensitization among various food allergens. According to the results, overall prevalence of allergy to walnut was reported to be 1.8%. Furthermore, the prevalence of walnut allergy, country wise was reported to be the highest in France (3.7%), which was followed by Germany (3.3%), Italy and Spain (3.1% each)
Jug r 3, a non-specific lipid transfer protein (nsLTP), is one of the major allergens identified in walnut, that belongs to the prolamin superfamily of proteins.
Several studies have reported that sensitization to specific walnut allergens among walnut-allergic patients vary based on the population heterogenicity and geographical location. High prevalence of IgE-reactivity to Jug r 1 allergen was observed among patients living in the US and the UK. Whereas, sensitivity to Jug r 3 has known to be more prevalent among the Mediterranean, Italian and Spanish individuals.
In a study conducted on 46 Italian patients allergic to walnut, Jug r 3 allergen was identified in serum IgE antibodies of 78.2% individuals (36 out of 46).
A EuroPrevall survey was conducted in 12 allergic clinics across different European locations, that included 531 individuals who reported of walnut allergy. Among these patients, 40.8% (211 out of 531) showed positive skin prick test (SPT) towards walnut and 13.9% (28/531) were sensitized to Jug r 3 allergen.
A prospective, single-centre, cohort study included 76 individuals who were walnut sensitized, among which 61 had allergy to walnut. Of these 61 individuals, 15% (9/61) showed high IgE-reactivity towards Jug r 3.
In an observational cohort study, conducted in UK among 35 individuals allergic to LTP, 86% (30 out of 35) reported positive IgE-reactivity towards Jug r 3 allergen.
Clinical Relevance
Disease Severity
Jug r 3 is one of the major allergens of walnut and is mainly associated with the risk of severe reactions (food-induced contact urticaria, oral allergy syndrome (OAS), gastrointestinal symptoms, and even anaphylaxis).
Some studies have been identified, that reported high sensitivity towards Jug r 3 allergen in walnut-allergic patients, leading to skin, respiratory and digestive disorders
In a study conducted among 46 walnut-allergic patients in Italy, the immunoblot assay revealed that 91.3% (42 out of 46) of individuals were found to be allergic to LTP. Furthermore, 78.2% of individuals (36 out of 46) showed IgE-reactivity towards a 9-kDa, i.e. Jug r 3 allergen.
In an observational cohort study, conducted in UK among 35 LTP-allergic individuals, the most common allergic symptoms patients suffered were eczema, food allergy, asthma, and allergic rhinitis (hay fever). These symptoms were mostly provoked due to consumption of raw or cooked food source, containing LTPs. Furthermore, among 35 individuals with LTP allergy, 83% (29/35) of patients showed positive SPT to walnut, and 86% (30 out of 35) reported positive IgE-reactivity towards Jug r 3 allergen.
Cross-reactive Molecules
Jug r 3, a major allergen of walnut has reported to show cross-reactivity with fruits/seeds of Rosaceae family, such as peach (Pru p 3), cherry (Pru av 3) and almond (Pru du 3), and other foods containing LTPs, such as peanut (Ara h 9) and hazelnut (Cor a 8).
Significant correlation has been observed between Jug r 3 (walnut) and Cor a 8 (hazelnut), suggesting co-sensitization and probable cross-reactivity between these nut allergens, due to shared protein epitopes.
High sequence identity and cross-reactivity between allergens of walnut and peach has been reported. This evidence is supported by a study conducted among 66 nut-allergic patients (walnut, peanut and hazelnut), where 69.7% (46/66) were allergic to peach. Furthermore, of the 44 patients allergic to walnut, 84% (n=37) were sensitized to Jug r 3, of 39 patients allergic to peanut, 66.6% (n=26) were sensitized to Ara h 9, and of 36 patients allergic to hazelnut, 80.5% (n=29) were sensitized to Cor a 8. Furthermore, positive specific-IgE against Pru p 3 was observed among 100% of patients allergic to walnut, 87.2% to peanut and 97.2% to hazelnut. This finding confirms high cross-reactivity between peach allergen and other nut LTPs, especially walnut.
Strong correlation of Jug r 3 with other LTP-containing legumes, like lentil (p=0.80) and pollens, like Chenopodium, mugwort, and plane tree (p=0.76–0.86) has been observed through IgE-reactivity testing in a European study. However, further investigations are needed to identify cross-reactivity and co-sensitization among these LTP allergens.
Diagnostics
Disease severity
Testing with walnut component allergens has been reported to enhance the prediction capability of severity due to walnut allergy in walnut-sensitive patients. However, Jug r 3 IgE-reactivity may not be considered as a suitable predictor of walnut allergy severity, since differences in sensitization rates to Jug r 3 has been observed in a diverse population, geographically.
Cross-reactivity
Peach allergy (Pru p 3) may serve as a diagnostic marker for walnut allergy (Jug r 3) in Mediterranean areas.
AIT Prescription
There is currently no licensed allergen immunotherapy product for the treatment of Jug r 3-induced food allergy.
Exposure
The main route of exposure is through ingestion.
Cross-Reactivity
A similarity in the amino-acid sequence of Jug r 3 is observed with allergens of Rosaceae fruits/seeds, like Pru du 3 (almond), Pru ar 3 (apricot), Pru av 3 (cherry), and Pru p 3 (peach), and various other foods containing LTPs, like hazelnut (Cor a 8) and peanut (Ara h 9), which may suggest IgE cross-reactivity among them. This cross-reactivity has reported to cause severe allergic reactions among individuals, after consuming botanically different plant-based foods. Of interest, tree nuts, such as walnut and hazelnut have reported to trigger severe allergic reactions, as a result of cross-reactivity with Rosaceae members.
In a study conducted in Italy, extensive cross-reactivity between Jug r 3 and allergens from Rosaceae members, such as peach (Pru p 3) and apricot (Pru ar 3) was reported. It was found that Jug r 3 exhibited a high degree of sequence similarity (~80%) with peach as well as apricot.
Sequence similarity of Jug r 3 with Cor a 8 (60%), Pru av 3 (59%), Ara h 9 (57%), and Pru du 3 (53%) was also identified, which indicated a high cross-reactivity between these allergens.
A strong correlation between LTP of walnut (Jug r 3) and hazelnut (Cor a 8) (correlation coefficient = 0.74) has been observed, that suggests cross-reactivity, due to presence of similar IgE-recognized epitopes on these allergens.
References
- Sicherer SH, Muñoz-Furlong A, Burks AW, Sampson HA. Prevalence of peanut and tree nut allergy in the US determined by a random digit dial telephone survey. Journal of Allergy and Clinical Immunology. 1999;103(4):559-62.
- Burney P, Summers C, Chinn S, Hooper R, Van Ree R, Lidholm J. Prevalence and distribution of sensitization to foods in the European Community Respiratory Health Survey: a EuroPrevall analysis. Allergy. 2010;65(9):1182-8.
- Dubiela P, Del Conte R, Cantini F, Borowski T, Aina R, Radauer C, et al. Impact of lipid binding on the tertiary structure and allergenic potential of Jug r 3, the non-specific lipid transfer protein from walnut. Scientific reports. 2019;9(1):1-11.
- Teuber SS, Dandekar AM, Peterson WR, Sellers CL. Cloning and sequencing of a gene encoding a 2S albumin seed storage protein precursor from English walnut (Juglans regia), a major food allergen. J Allergy Clin Immunol. 1998;101(6 Pt 1):807-14.
- Mew R, Borres M, Sjölander S, du Toit G. A retrospect study into the utility of allergen components in walnut allergy. Pediatr Allergy Immunol. 2016;27(7):750-2.
- Elizur A, Appel MY, Nachshon L, Levy MB, Epstein-Rigbi N, Pontoppidan B, et al. Clinical and molecular characterization of walnut and pecan allergy (NUT CRACKER study). The Journal of Allergy and Clinical Immunology: In Practice. 2020;8(1):157-65. e2.
- Lyons SA, Datema MR, Le T-M, Asero R, Barreales L, Belohlavkova S, et al. Walnut Allergy Across Europe: Distribution of Allergen Sensitization Patterns and Prediction of Severity. The Journal of Allergy and Clinical Immunology: In Practice. 2020.
- Pastorello EA, Farioli L, Pravettoni V, Robino AM, Scibilia J, Fortunato D, et al. Lipid transfer protein and vicilin are important walnut allergens in patients not allergic to pollen. Journal of Allergy and Clinical Immunology. 2004;114(4):908-14.
- Ballmer-Weber BK, Lidholm J, Lange L, Pascal M, Lang C, Gernert S, et al. Allergen recognition patterns in walnut allergy are age dependent and correlate with the severity of allergic reactions. The Journal of Allergy and Clinical Immunology: In Practice. 2019;7(5):1560-7. e6.
- Skypala IJ, Cecchi L, Shamji MH, Scala E, Till S. Lipid Transfer Protein allergy in the United Kingdom: Characterization and comparison with a matched Italian cohort. Allergy. 2019;74(7):1340-51.
- Costa J, Carrapatoso I, Oliveira M, Mafra I. Walnut allergens: molecular characterization, detection and clinical relevance. Clinical & Experimental Allergy. 2014;44(3):319-41.
- Asero R, Piantanida M, Pravettoni V. Allergy to LTP: to eat or not to eat sensitizing foods? A follow-up study. European annals of allergy and clinical immunology. 2018;50(4):156-62.
- Valcour A, Lidholm J, Borres M, Hamilton RG. Sensitization Profiles to Hazelnut Allergens across the United States of America. Journal of Allergy and Clinical Immunology. 2019;143(2):AB238.
- Goikoetxea M, D'Amelio C, Martínez-Aranguren R, Gamboa P, Garcia B, Gómez F, et al. Is microarray analysis really useful and sufficient to diagnose nut allergy in the mediterranean area? J investig allergol clin immunol. 2016:31-9.
- Dubiela P, Aina R, Polak D, Geiselhart S, Humeniuk P, Bohle B, et al. Enhanced Pru p 3 IgE-binding activity by selective free fatty acid-interaction. Journal of Allergy and Clinical Immunology. 2017;140(6):1728-31. e10.