f456 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) (Lyons 2021). 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 (Dubiela 2018). 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 (Dubiela 2018).

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 (Lidholm 2025). The positivity rate (≥ 0.35 kU_A/L) for Jug r 6 IgE was 54%, with a median level of 1.9 kU_A/L among the positive samples. For Jug r 2 IgE, the positivity rate was 64%, with a median level of 8.5 kU_A/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 (Lidholm 2025).

Environmental Characteristics

Source and Tissue

Jug r 6 is a 7S globulin seed storage vicilin expressed in the cotyledonary tissues of Juglans regia kernels. The native form is a trimeric complex (~135 kDa) of glycosylated monomers (~47–50 kDa). Jug r 6 is ~7-fold more abundant than Jug r 2 in walnut kernels (Dubiela 2018) which may increase probability for exposure and sensitization.

Risk Factors

Risk factors for Jug r 6 sensitization include early introduction of walnut, an atopic background or concurrent tree nut allergy, and IgE cross-reactivity via structurally related vicilins from especially hazelnut, pistachio, and sesame (Dubiela 2018).

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 (Dubiela 2018, Lyons 2021, Lidholm 2025). This can aid in the management of walnut allergy and help assess the risk of clinical cross-reactions to other tree nuts and seeds.

Diagnostic Relevance

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 (Elizar 2019). 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 (Elizur 2019).

Molecular Aspects

Jug r 6 is a 7S globulin (vicilin) with a cupin domain, having a molecular mass of 47–50 kDa and existing as a native trimer of approximately 136 kDa. It is predicted to undergo N-glycosylation, exhibits intermediate thermal stability, and is highly susceptible to gastric digestion (Dubiela 2018).

Jug r 6 allergen is listed as Jug r 6.0101 in the IUIS allergen database WHO/IUIS Allergen Nomenclature Sub-Committee.

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%) (Dubiela 2018, Smeekens 2018).

Jug r 6 also show about 35% identity to the legume allergens Ara h 1 in peanut and Gly m 5 in soybean (Smeekens 2018).

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 (Dubiela 2018). This suggests that Jug r 6 may retain some IgE reactivity in roasted and processed walnut products.

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.

Compiled by Dr. Michael Spangfort

Reviewed by Dr. Jonas Lidholm, December 2025.