f448 Jug r 2

Allergen

Summary

Jug r 2 is a 7S globulin (vicilin) seed storage protein from English walnut (Juglans regia). It is a member of the cupin superfamily and notable for its heat and proteolytic stability. Jug r 2 acts as a primary sensitizing walnut allergen and a marker of genuine walnut allergy rather than pollen-related cross-reactivity. Sensitization to Jug r 2 is associated with systemic, often severe reactions, including anaphylaxis, and is especially relevant in patients with early-onset walnut allergy.

Epidemiology

Walnut is among the most clinically relevant causes of tree nut allergies worldwide. According to data from the EuroPrevall project, 3% of the adult European population is predicted to be sensitized to walnut, ranging from 0.1% in Iceland to 6% and 8% in Switzerland and Spain, respectively (Burney 2014). Sensitization to walnut among children across Europe ranges from 1.4% in Iceland to 9.5% in Switzerland (Lyons 2020).

In a systematic review and meta-analysis (Spolidoro 2024), walnut allergy and sensitization were assessed in 12 studies, of which 11 contributed data to the pooled sensitization analyses. Across these studies, the prevalence of walnut specific IgE sensitization was 4.1% and 2.7% for skin prick testing. In contrast, the pooled estimate for food challenge–confirmed walnut allergy was 0.02%, based on one available study.

According to telephone interviews with 4,855 randomly selected households in the United States, 62% of participants (51/82) who had information about their specific tree nut allergies, reported having walnut allergy (Sicherer 2003).

Data from the European Anaphylaxis Registry, collected between 2007 and 2015, showed that among children and adolescents with anaphylaxis to tree nuts, walnuts were one of the most significant triggers, accounting for 16% (42/256) of the cases (Grabenhenrich 2016).

Sensitization to Jug r 2 and other walnut storage proteins is associated with early-onset walnut allergy in childhood and correlates with severe reactions (Ballmer-Weber 2019, Lyons 2021).

In Ballmer-Weber et al. (2019), vicilin sensitization (Jug r 2 and Jug r 6) was consistently frequent across all European regions studied (Switzerland, Germany, Spain). Unlike other allergens with regionally skewed patterns—such as Jug r 3 (nsLTP), dominant in Spain, or Jug r 5 (PR-10), dominant in birch-endemic central Europe—the vicilin allergens Jug r 2/Jug r 6 showed no strong regional variation. This indicates that Jug r 2 and Jug r 6 act as primary sensitizers across regions with different climates and pollen exposure.

Environmental Characteristics

Source and Tissue

Jug r 2 is a seed storage protein expressed in the cotyledons of the walnut kernel, where it contributes to nutrient reserves during germination. It is a 7S globulin (vicilin) forming trimeric complexes (~145 kDa). Walnut belongs to the Juglandaceae family, and Jug r 2 shares conserved cupin motifs with homologous proteins in other nuts (Barre 2008, Scala 2018).

Risk Factors

Risk factors for Jug r 2 sensitization include early introduction of walnut, an atopic background or concurrent tree nut allergy, and IgE cross-reactivity via structurally related vicilins from closely related Juglandaceae species - such as black walnut (Jug n 2) and pecan (Car i 2) - which share high sequence identity with Jug r 2 (Costa 2014).

Clinical Relevance

Jug r 2 is a clinically important allergen linked to severe systemic reactions, including anaphylaxis (Teuber 1999, Pastorello 2004, Dubiela 2018, Hausmann 2023). In a prospective multicentre study of 115 European patients assessing walnut allergy severity and component resolved sensitization across age groups and regions, vicilin fractions containing Jug r 2 and Jug r 6 fragments correlated significantly with severe symptoms in children (Ballmer-Weber 2019). The same study also reported that sensitization to those vicilin fractions is closely associated with early-onset of walnut allergy.

The prevalence of Jug r 2 sensitization varies dependent on patient population. Early work by Teuber (1999) identified Jug r 2 as a major allergen, with IgE recognition in 60% (9/15) of patients from USA with severe systemic walnut allergy. In contrast, among an Italian cohort predominantly characterised by LTP-driven allergy, vicilin sensitization was detected in 22% (10/46) of patients (Pastorello 2004). Similarly, in a small group UK/Spain cohort with confirmed history of walnut allergy, 27% (3/11) showed IgE-reactivity to 7S globulin fragments (Downs 2014).

Small amounts of walnut can trigger severe reactions in patients’ monosensitized to Jug r 2 as illustrated by a recent case report (Hausmann 2023). The patient experienced anaphylaxis within 30 mins after ingestion of a salad from which a walnut topping had been removed. Walnut extract IgE was 4.98 kU_A/l and component testing showed Jug r 2–specific IgE of 8.58 kU_A/L. Specific IgE was <0.10 kU_A/L for Jug r 1, Jug r 3, Jug r 6, and 0.29 kU_A/L for Jug r 4.

Diagnostic Relevance

Component-resolved diagnosis using Jug r 2 can improve discrimination between primary walnut allergy and birch pollen–related cross-reactivity (Ballmer-Weber 2019). Specific IgE to Jug r 2 also appears to be a useful marker for identifying patients at increased risk of severe reactions (Pastorello 2004, Costa 2014, Ballmer-Weber 2019). In addition, Jug r 2 sensitization is associated with early-onset walnut allergy, with significantly higher sensitization rates in patients whose symptoms began in childhood (<14 years) (Ballmer-Weber 2019), providing valuable clinical information in the context of paediatric and early-onset disease.

Prevention and Therapy

There is currently no regulatory approved walnut oral immunotherapy available. Management involves avoidance of walnut and often cross-reactive nuts (especially pecan), education and epinephrine auto-injector prescription when indicated.

In a clinical study including 73 walnut allergic patients it was demonstrated that walnut oral immunotherapy can induce desensitisation to walnut as well as cross-desensitisation to pecan and, in some cases, hazelnut in patients who have tree nut co-allergies (Elizur 2019).

Molecular Aspects

Jug r 2 is a vicilin-type 7S globulin undergoing complex processing during protein maturation, the C-terminal cupin motif-containing domain forming homotrimer assemblies and the N-terminal part being cleaved into six separate hairpinin fragments (Downs 2014). The C-terminal part shares β-barrel cupin domains with other legume and nut vicilins (Barre 2008). Heat and digestion stability explain its persistence as a potent food allergen (Costa 2014, Geiselhart 2018).

The WHO/IUIS Allergen Nomenclature Sub-Committee records the full-length Jug r 2 allergen as Jug r 2.0102.

It also includes two entries corresponding to segments of the Jug r 2.0102 sequence: the N‑terminal hairpining domain (residues 27–367), and the cupin domain (residues 368–789).

In addition, the database lists Jug r 2.0101, which is annotated with an incomplete sequence, and an entry consisting of Jug r 2.0101 residues 1-173.

Cross-reactivity

Inhibition studies demonstrated that walnut pretreatment completely blocks IgE binding to pecan (Elizur 2020) indicating presence of shared epitopes that could lead to 7S globulin-mediated walnut-pecan clinical cross-reactivity. Walnut oral immunotherapy can induce cross-desensitisation to pecan and hazelnut in patients who have tree nut co-allergies (Elizur 2019). IgE cross-reactivity between Jug r 2 and pecan 7S globulin Car i 2, is expected based on their close to 70% amino acid sequence identity (Scala 2018) and presumed high similarity of molecular structures (Barre 2008).

Jug r 2 shares 44% amino acid identity with Jug r 6 vicilin and 30-70% identity with 7S globulins from other tree nuts, such as pecan (Car i 2), hazelnut (Cor a 11), pistachio (Pis v 3), and cashew (Ana o 1). It also shares identity with seeds, such as sesame (Ses i 3) and lupin (Lup an 1), and legumes, such as peanut (Ara h 1) and soybean (Gly m 5) (Dubiela 2018; Scala 2018).

The cupin domains of Jug r 2 and Cor a 16 share 72% sequence identity (personal communication Jonas Lidholm) indicating a strong likelihood for IgE cross-reactivity.

Exposure                                                                                                          

Exposure occurs through ingestion of raw, roasted, or processed walnut products. Jug r 2 is thermostable and resists degradation during cooking or digestion (Costa 2014), explaining reactions to trace amounts of walnut vicilins in baked or confectionery goods (Su 2004, Kim 2018).

Explained Results

Allergen information

Jug r 2 is a 7S globulin (vicilin) seed storage protein. It is heat- and digestion-stable and functions as a marker of genuine walnut allergy.

Clinical relevance

Jug r 2 sensitization is linked to severe systemic reactions and is closely associated with early-onset walnut allergy. Data suggests that Jug r 2 acts as a primary sensitizing walnut allergen across regions with climates and pollen exposure.

Cross-reactivity

Jug r 2 has close to 70% amino acid sequence identity with pecan vicilin Car i 2 that is expected to lead to clinical cross-reactivity. Jug r 2 also show around 40% identity with vicilins from other tree nuts, seeds and legumes.

Compiled by Dr. Michael Spangfort

Reviewed by Dr. Jonas Lidholm, December 2025