f323 Gal d 3, conalbumin/ ovotransferrin, Gallus domesticus egg

Summary

Gal d 3, a major allergen of hen’s egg white (Gallus domesticus), belongs to the transferrin family, involved in iron homeostasis and antimicrobial defense. Gal d 3 is sensitive to thermal and physico-chemical processing.

Epidemiology

Worldwide distribution

Hen’s egg is a staple human food. It is also a common cause of allergy, predominantly in pediatric populations and following egg white ingestion [1]. In Europe, data collected from 2005 through 2009 as part of the EuroPrevall study found self-reported allergy to hen’s egg  in 9.9% of pediatric subjects (second only to cow’s milk), IgE sensitization to hen’s egg in approximately 5%, and 1% or lower when considering an association of evocative symptoms and IgE sensitization, corresponding to probable allergy to hen’s egg [2]. The same study placed self-reported allergy to hen’s egg at the 4th place of most prevalent food allergy in European adults, however, IgE sensitization was detected in only 0.9%, and probable allergy to hen’s egg in 0.3% or less [3, 4]. 

Gal d 3 sensitization occurs in a majority of patients allergic to hen’s egg, up to 69% using affinity-purified Gal d 3 [5].

Environmental Characteristics

Source and tissue

Gal d 3 is present in hen’s egg white, accounting for 12% of its protein content, a level similar to that of ovomucoid Gal d 1  [1, 6]. Despite being a heat-sensitive protein, Gal d 3 was demonstrated in small amounts in cooked hen’s egg white [7].

Risk factors

The main risk factor for developing sensitization to Gal d 3 is exposure to raw or partially cooked hen’s egg [1]. 

Clinical Relevance

In hen’s egg allergic patients, sensitization to Gal d 3, an allergen sensitive to thermal and chemical processing, may be associated with symptoms induced by raw or incompletely cooked egg white, or even remain asymptomatic. However, egg allergic subjects are usually sensitized to multiple egg allergens, therefore clinical expression in Gal d 3-sensitized subjects may vary accordingly [1, 7, 8].

Disease severity and prediction

Gal d 3 sensitization usually coexists with sensitization to other allergens from hen’s egg white, explaining the lack of a statistically significant association with increased or decreased severity or persistence of this allergy [1, 8, 9]. Polysensitization to hen’s egg allergens, defined as detectable IgE to Gal d 1, Gal d 2, Gal d 3 and Gal d 4 was significantly more prevalent at baseline in children who did not achieve tolerance after 8 months of oral immunotherapy with raw egg [10]. These children also displayed significantly higher baseline levels of IgE to Gal d 3 [10].

Cross-reactive molecules

Given the frequent sensitization rate and the presence of numerous homologs, oral food challenges help define the spectrum of hen’s egg allergy and of its clinical cross-reactivity [1, 11]. In a Japanese cohort of hen’s egg allergic children, skin reactivity to both hen’s egg and quail’s egg (Coturnix japonica, a close relative of Gallus domestica belonging to Galliformes) found in 92% of patients was most often devoid of clinical relevance as assessed by a positive oral food challenge in only 45% of the patients [11]. Conversely, allergy to quail’s egg conalbumin with tolerance to hen’s egg Gal d 3 and isolated sensitization to quail’s egg conalbumin has been reported [12].

Molecular Aspects

Biochemistry

Gal d 3 was identified in hen’s egg white and named conalbumin in 1900, based on its higher thermal susceptibility compared to ovalbumin [13]. Gal d 3 is a relatively large monomeric protein with an isoelectric point of 6.0, comprising an aminoacid backbone of 686 aminoacids, stabilized by 15 disulfide bridges and decorated by glycosyl groups [6, 14]. Similar to other transferrin family members, Gal d 3 binds two iron atoms [6]. Gal d 3 exerts bacteriostatic, antifungal and antiviral effects, as well as antioxidant, immunomodulatory and cytotoxic actions [6]. Gal d 3 is the only egg white protein able to inhibit the growth of Salmonella enteritidis [14].

Isoforms, epitopes, antibodies

As of May 16, 2022, only one isoallergen of Gal d 3 has been included in the World Health Organization (WHO) and International Union of Immunological Societies (IUIS) Allergen Nomenclature [15]. 

Cross-reactivity due to structural similarity

Gal d 3 displays aminoacid sequence identity of 90% or higher with a limited number of egg and serum transferrins from other bird species, mainly from the same Galliformes order:  turkey (Meleagris gallopavo), peafowl (Pavo cristatus) and pheasant (Chrysolophus pictus) [16].  In vitro cross-reactivity of Gal d 3 with homologs from other species egg white varies as a function of phylogenetic distance, with more efficient IgE binding to closely related Galliformes species, such as turkey (M. gallopavo), while less IgE binding was observed with homologs from more distant orders, such as Anseriformes, e.g. duck and goose, or Charandriiformes, e.g. seagull [17]. Proteins cross-reactive with Gal d 3 were reported in hen’s egg yolk, and in chicken and hen meat and serum, although egg-allergic patients tolerated meat consumption [17].

Diagnostic Relevance

Cross-Reactivity

Gal d 3 displays in vitro cross-reactivity with homologs from egg white of other bird species, as well as various avian meat and serum, however, the clinical relevance might need to be assessed using oral food challenges [11].

AIT Prescription

In hen’s egg allergic patients, the distinction between sensitized and allergic, and between raw versus baked egg allergic patients relies primarily on the heat-resistant ovomucoid Gal d 1 [1].

Exposure

The main route of exposure to Gal d 3 is through egg white ingestion, but it may also happen in distinct circumstances, e.g. through inhalation of aerosolized hen’s egg allergens during the cooking process [1]. 

Compiled By

Author: Joana Vitte

Reviewer: Dr.Christian Fischer

Last reviewed: June 2022