f233 Gal d 1

Summary

Hen’s egg (Gallus gallus domesticus) is a protein-rich food source and is usually consumed as raw, cooked, or processed. Egg white is rich in proteins and is regarded as highly allergenic. Gal d 1, also called ovomucoid, plays a crucial role in the pathogenesis of egg white-mediated allergic reactions. The egg has been considered one of the most common food allergy sources, particularly in infants and children, with the prevalence rate ranging between 1.3-1.6%. However, the prevalence of egg allergy in adults is less than 0.25%. Egg sensitization, having IgE antibodies to egg, is a prerequisite for egg allergy. Egg sensitization is more prevalent than egg allergy, and the prevalence rate has been reported to be up to 6% depending on age. The specific IgE test for egg white is commonly used as a start when investigating a patient with a suspicion of egg allergy. IgE tests for egg components, such as Gal d 1, are used to characterize the egg allergy. Most egg-allergic children can develop tolerance to egg proteins over time.

Gal d 1, a protein present in egg white, is considered a major allergenic protein molecule associated with allergic reactions among children. It is a stable protein (allergenicity remains intact), resistant to both heat and enzymatic digestion. An elevated level of Gal d 1 specific IgE (sIgE) has been reported to be correlated with persistent egg allergy. The level of IgE antibodies against Gal d 1 depends on if the patient is allergic to only raw eggs or to cooked eggs, which is a more serious form of egg allergy. Gal d 1 sIgE testing has been reported to aid in the differential diagnosis of the two forms of egg allergy (cooked vs. raw egg) and prognosis of egg allergy in patients. A lower level of sIgE against Gal d 1 has been reported to indicate a tolerance towards the boiled, cooked, or baked egg products. Hence, Gal d 1 sIgE in serum has been regarded as a beneficial tool for investigating persistent egg allergy and allergy towards heated eggs.

Epidemiology

Worldwide distributions

The egg has been reported as one of the common inducers of food allergy prevalent in industrialized countries (1). Moreover, egg allergy is found to be one of the most frequent childhood food allergies (IgE-mediated), with the prevalence rate ranging between 1.3-1.6% (2, 3). In egg, egg white is regarded as the primary source of allergens and comprises ovomucoid (Gal d 1), ovalbumin (Gal d 2), ovotransferrin (Gal d 3), and lysozyme (Gal d 4) (4). Gal d 1 (ovomucoid) is considered a major allergenic protein molecule, usually found to be associated with allergic reactions among children (5, 6). An Italy-based study reported 43.5% (20/46) of the egg-allergic children (0.7-15.1 years) possessing reactivity towards Gal d 1 (7).

Egg sensitization is more prevalent than egg allergy, and IgE antibodies have been detected already in very young age groups. Tedner et al. found in a Nordic population-based birth-cohort study the prevalence of egg sensitization among 3-month old infants to be 3.7% (41/1102), and among them, 0.8% was sensitized to Gal d 1 (8). Another birth cohort study in Japan found 0.8% of the children (at 9 years) to be sensitized towards Gal d 1 (9). Additionally, a Finland-based study on 185 egg-sensitized children (1-18 years; suspected egg allergy) reported Gal d 1 sensitization prevalence rate among 78% of the study population (10). An Australia-based study also studied Gal d 1 sensitization prevalence rate and including 297 egg-allergic and 97 egg sensitized but egg tolerant infants (11-20-months old). They reported Gal d 1 sensitization among 67.9% of the egg allergic infants and 32.1% of the egg sensitized but egg tolerant infants (11). 

Environmental Characteristics

Source and tissue

The International Union of Immunological Societies (IUIS) has listed Gal d 1, an ovomucoid protein, as a food allergen from Gallus gallus domesticus, hen’s egg white (12). Egg white comprises around 24 protein fractions, and Gal d 1 has been reported to contribute 10-11% of the total protein content in egg white (13, 14). Gal d 1 (ovomucoid) belongs to the kazal-type serine protease inhibitor protein family and functions as a trypsin inhibitor (15). It is a major allergen present in boiled eggs and other egg (heated) products (16)

Risk factors

An elevated level of ovomucoid specific IgE (sIgE) has been reported to be correlated with persistent egg allergy (4, 17, 18). Another study also found Gal d 1 sensitization among infants to be associated with an increased risk (2.5 times) of developing persistent egg allergy (11).

Moreover, as per a study, persistent eczema (early onset) is also claimed to be a probable risk factor for developing high-affinity ovomucoid-sIgE characteristics. The study further confirmed 47.8% (11/23) of infants with persistent eczema exhibited ovomucoid (Gal d 1) sIgE at 14 months (19).

Clinical Relevance

Disease severity

Egg white allergy has been reported as one of the most predominant IgE-mediated food allergies in infants and children (20). Individuals with suspected egg allergy might experience allergic reactions such as anaphylaxis, gastrointestinal (GI) reactions, skin reactions, respiratory reactions, and mucous membrane reactions after consumption of egg white (21).  

The tolerance towards hen’s egg has been reported to initiate with tolerance towards heated egg (boiled or cooked) followed by a gradual development of tolerance towards raw egg (17). As per a study, ovomucoid (a dominant protein) plays a crucial role in the pathogenesis of egg white-mediated allergic reactions. The study found 94.1% (16/17) patients had responded positively towards heated egg white but negatively to heated and ovomucoid-depleted egg white preparation (6). According to an oral food challenge (OFC) study, 95% (20/21) of Gal d 1-positive egg-allergic children reacted to raw egg, while 94% (44/47) of Gal d 1 negative children were tolerant to boiled egg (5).

A study involving 226 egg-allergic children (<6 years) reported the highest tolerance development (73%; 164/226) at 6 years of age. The egg-allergy-related conditions like AD, bronchial asthma, and anaphylaxis were evidently more frequent in patients with prolonged egg allergy. Moreover, infants with prolonged egg allergy had been found to have higher Gal d 1 (ovomucoid)-sIgE level in comparison to other infants without prolonged egg allergy (18). Additionally, the Gal d 1 sIgE level could also help differentiate egg-allergic children at risk for developing anaphylactic reactions towards egg (4). 

Cross-reactive molecules

A study reported cross-reactivity of the Gal d 1 (ovomucoid) found in hen’s egg white with egg white proteins from turkey, duck, goose, and seagull (22). 

Molecular Aspects

Biochemistry

Gal d 1 (ovomucoid) has been regarded as a predominant, extremely glycosylated allergenic protein molecule possessing trypsin inhibitor activity (13, 23). This protein's molecular weight has been reported to be around 28 kDa (14, 24). The polypeptide chain of Gal d 1 protein comprises 186 amino acids, which is further made up of three domains, each containing 60 amino acids. Among the three domains, the third domain has been claimed to be the most critical for allergenicity (24). Ovomucoid protein has also been found to contain around 20-25% of carbohydrates (24).

Ovomucoid is a stable protein that has been reported non-coagulable (on heating) and does not undergo denaturation on chemical treatment (14). Moreover, this protein's tertiary structure is considered highly stable due to the presence of disulfide bonds. Therefore, the allergenicity of Gal d 1 usually remains intact even after heating and enzymatic (proteinase) digestion (5).

Isoforms, epitopes, antibodies

Gal d 1.0101 has been identified as an isoallergen for Gal d 1 and has been listed in the IUIS database (12).

Gal d 1 is claimed as heat and protein digestion resistant due to the presence of linear epitopes, which undergo minute conformational alternations during heating or digestion (24). The IgE binding ability of this protein usually does not alter much on heating; however, the process of heating has been found to promote the digestibility of ovomucoid. Therefore, most egg-allergic children are found to be tolerant towards heated egg and baked egg products (5). 

Cross-reactivity due to structure similarity

Conformational homology between Gal d 1(ovomucoid) and antigenic determinant from ovoinhibitor (chicken) has been claimed to be responsible for cross-reactivity of ovoinhibitor with anti-ovomucoid antibodies (25).

Diagnostic Relevance

Disease Severity

Egg IgE has been claimed to be a predictor of egg allergy outcome and can be beneficial to counsel patients on prognosis (26). According to a case report study conducted by Philippe A. Eigenmann, two patients with negative follow-up food challenges to cooked eggs had subsequently developed anaphylactic reactions to raw eggs. This case report brought attention to the two different forms of egg allergy, cooked vs. raw egg allergy (27). Specific IgE testing to ovomucoid has been reported as an aid in the differential diagnosis of the two forms of egg allergy and prognosis of egg allergy in patients (17). The varying level of IgE antibodies against Gal d 1 (ovomucoid) depends on the form of the egg (raw, or cooked, or baked) consumed. A lower level of sIgE against Gal d 1 has been reported to indicate a tolerance towards the boiled, or cooked eggs, or baked egg products. As per a Japanese study, the positive decision and negative decision points for specific IgE to ovomucoid were found to be 10.8kU(A)/L and 1.2 kU(A)/L, respectively. These decision points have been found to be beneficial in guiding physicians to further decide the necessity of food challenges but depend on the clinical characteristics of the studied population. Therefore, the measurement of ovomucoid-sIgE can guide to clinically distinguish between reactivity towards heated and raw egg white (6, 13, 17, 20). Thus, periodic monitoring of the absolute values of sIgE antibody level towards ovomucoid and clinical history of egg allergy may help clinicians decide the further necessity of OFC test (17, 28, 29).

Persistent egg-allergic children have been found to possess significantly elevated IgE levels (against native and linearized epitopes of ovomucoid) compared to the transient allergic children (30). Therefore, Gal d 1 (ovomucoid) sIgE in serum has been regarded as a beneficial screening tool for persistent egg allergy (11, 30) and allergy towards heated eggs (even if the patients show a reaction to raw eggs) (16, 31).

Furthermore, a study reported Gal d 1 (ovomucoid) to be a better component in distinguishing egg allergy from asymptomatic sensitization (32). 

Exposure

The route of exposure for the Gal d 1 (ovomucoid) component found in egg white is through ingestion (33).

Compiled By

Author: Turacoz Healthcare Solutions

Reviewer: Dr Magnus Borres

Last reviewed: July  2021