Jug r 6
Allergen
Summary
Jug r 6 is a 7S globulin (vicilin) seed storage protein abundant in walnut (Juglans regia) and a member of the cupin superfamily. Recently identified and characterized as a distinct walnut allergen, it expands the vicilin family beyond the previously described Jug r 2. Jug r 6 can improve detection and quantitation of walnut vicilin IgE and displays IgE cross-reactivity with vicilins from other nuts and seeds including hazelnut, pistachio and sesame.
Epidemiology
As part of the EuroPrevall outpatient surveys conducted in 12 European cities, standardized clinical evaluations were performed on 531 individuals reporting symptoms related to walnut consumption. Sensitization to all known walnut components was assessed in 202 of these individuals. Among them, IgE against Jug r 6 was detected in about 6% (12/202). The small number of subjects sensitized to Jug r 6 in this study made it difficult to accurately evaluate the geographical distribution across Europe. It should, however, be noted that in this population, the majority were sensitized to the Bet v 1-related PR-10 allergen Jug r 5, suggesting a dominance of birch pollen associated food allergy, and only around 10% were sensitized to the major walnut storage proteins Jug r 1, Jug r 2 and Jug r 4.
A study from Austria reported a somewhat higher prevalence of 26% sensitization to Jug r 6, among 77 patients classified by allergologists as clinically allergic to walnut. In the same study, IgE inhibition experiments showed that Jug r 6 displayed a significantly higher level of cross-reactivity to extracts of hazelnut, pistachio and sesame than did Jug r 2.
The relevance of vicilins Jug r 6 and Jug r 2 was assessed in sera from 185 children collected in the US and submitted by physicians for IgE testing to tree nuts. The positivity rate (≥ 0.35 kUA/L) for Jug r 6 IgE was 54%, with a median level of 1.9 kUA/L among the positive samples. For Jug r 2 IgE, the positivity rate was 64%, with a median level of 8.5 kUA/L. Additionally, among the 185 sera, there were 40 Jug r 1 negative sera of which 63% (25/40) tested positive to Jug r 2 and/or Jug r 6. Despite the lack of cohort case history and clinical observations, the data suggest that vicilins can play a significant role in sensitization to walnut and could be valuable additions to diagnostic IgE testing.
Route Of Exposure
Exposure occurs through ingestion of raw, roasted, or processed walnut products. In vitro experiments have shown that heating and digestion do not completely eliminate the IgE-binding capacity of Jug r 6. This suggests that Jug r 6 may retain some IgE reactivity in roasted and processed walnut products.
Clinical Relevance
Current evidence indicates that the prevalence of Jug r 6 sensitization is clinically relevant for a more complete picture of walnut vicilin sensitization and for identifying cross-reactive vicilin sensitization. This can aid in the management of walnut allergy and help assess the risk of clinical cross-reactions to other tree nuts and seeds.
Diagnostics
Jug r 6 is available for in vitro IgE testing, enabling a more complete detection and quantitation of IgE to walnut storage proteins and identification of cross-reactive vicilin sensitization among walnut-allergic patients.
Prevention And Therapy
There is currently no regulatory approved walnut oral immunotherapy available. Management involves avoidance of walnut and often cross-reactive nuts and seeds (especially hazelnut, pistachio, sesame), education, food labelling vigilance and epinephrine auto-injector prescription when indicated.
Walnut oral immunotherapy can induce desensitisation to walnut as well as cross-desensitisation to pecan and hazelnut in patients who have tree nut co-allergies. Desensitization was accompanied by an increase of IgG4 antibodies to walnut and its components Jug r 1, Jug r 3, Jug r 4, and vicilin fractions comprising predominantly the naturally occurring processing products of Jug r 6 and Jug r 2.
Cross-Reactivity
Inhibition experiments by Dubiela et al. (2018), showed the highest level of Jug r 6 cross-reactivity to Cor a 11 and hazelnut extract (up to 97% inhibition), followed by sesame and pistachio. In contrast, the cross-reactivity with Jug r 2 was relatively weak.
Comparison of amino acid sequence identity shows that Jug r 6 has higher similarity to the vicilins from hazelnut Cor a 11 (72%), sesame Ses i 3 (60%) and pistachio Pis v 3 (54%), than to Jug r 2 (44%).
Jug r 6 also show about 35% identity to the legume allergens Ara h 1 in peanut and Gly m 5 in soybean.
Explained Results
Allergen information
Jug r 6 is a 7S globulin (vicilin) recently identified and characterized as a distinct walnut allergen, expanding the vicilin family beyond the previously described Jug r 2.
Clinical relevance
Jug r 6 is clinically relevant for a more complete picture of walnut storage protein sensitization and for identifying cross-reactive vicilin sensitization.
Cross-reactivity
Jug r 6 displays IgE cross-reactivity with vicilins from other nuts and seeds such as hazelnut, pistachio and sesame.
References
- Dubiela P, Kabasser S, Smargiasso N, Geiselhart S, Bublin M, Hafner C, Mazzucchelli G, Hoffmann-Sommergruber K. Jug r 6 is the allergenic vicilin present in walnut responsible for IgE cross-reactivities to other tree nuts and seeds. Sci Rep. 2018;8:11366.
- Elizur A, Appel MY, Nachshon L, Levy MB, Epstein-Rigbi N, Pontoppidan B, Lidholm J, Goldberg MR. Walnut oral immunotherapy for desensitisation of walnut and additional tree nut allergies (Nut CRACKER): a single-centre, prospective cohort study. Lancet Child Adolesc Health. 2019;3312-321.
- Lidholm J, Mattsson L, Pontoppidan B, Valcour A. Vicilins – an overlooked group of storage protein allergens in walnut and hazelnut. EAACI Congress Glasgow 2025. Poster No. 000821.
- Lyons SA, Datema MR, Le TM, Asero R, Barreales L, Belohlavkova S, de Blay F, Clausen M, Dubakiene R, Fernández-Perez C, Fritsche P, Gislason D, Hoffmann-Sommergruber K, Jedrzejczak-Czechowicz M, Jongejan L, Kowalski ML, Kralimarkova TZ, Lidholm J, Papadopoulos NG, Pontoppidan B, Popov TA, Prado ND, Purohit A, Reig I, Seneviratne SL, Sinaniotis A, Vassilopoulou E, Versteeg SA, Vieths S, Zwinderman AH, Welsing PMJ, Mills ENC, Ballmer-Weber BK, Knulst AC, Fernández-Rivas M, Van Ree R. Walnut Allergy Across Europe: Distribution of Allergen Sensitization Patterns and Prediction of Severity. J Allergy Clin Immunol Pract. 2021;9:225-235.
- Smeekens JM, Bagley K, Kulis M. Tree nut allergies: Allergen homology, cross-reactivity, and implications for therapy. Clin Exp Allergy. 2018;48:762-772.