f426 Gad c 1

Summary

Gad c 1, the major allergen of Baltic cod (Gadus callarias), belongs to the beta lineage of the parvalbumin family. Similar to Cyp c 1 and other beta-parvalbumins including Gad m 1, its close homologue from Gadus morhua (Atlantic cod), Gad c 1 exerts its allergenicity mainly through fish ingestion, but also through inhalation during fish processing. Gad c 1 is mainly found in light fish muscle and contributes to calcium homeostasis during muscle relaxation. Gad c 1 is a heat-resistant allergen involved in cross-reactivity among bony fish species. The reader is invited to read the Cyp c 1 section for additional information on fish beta-parvalbumins.

Epidemiology

Worldwide distribution

Fish is a common cause of hypersensitivity involving mainly IgE-dependent but also IgE-independent mechanisms [1, 2]. In this chapter, we will focus on IgE-related fish allergy. In Europe, data collected from 2005 through 2009 as part of the EuroPrevall study showed self-reported allergy to fish in 3.6% of pediatric subjects (ranging 4th after cow’s milk, hen’s egg, and tomato), while IgE sensitization to fish was only found in 0.91% or less, and 0.53% or lower when considering an association of evocative symptoms and matching IgE sensitization, corresponding to probable allergy to fish [3]. The same cohort revealed that 3.1% of European adults self-reported allergy to fish, i.e. the 7th most prevalent food allergy, however, the prevalence of IgE sensitization varied between 0% in Lodz (Poland) and Sofia (Bulgaria) to 1.18% in Madrid (Spain), and the highest prevalence of probable allergy to fish, found in Madrid, was only 0.44% [4, 5]. In a European birth cohort evaluated at school age, white fish was consistently more prevalent than oily fish in terms of reported reactions, IgE sensitization, and probable fish allergy [6]. Worldwide, questionnaire-reported fish allergy is comprised between 0.01% (Israel) and 7% (Finland), while clinically confirmed fish allergy data, when available, peak at 1.2% -1.6% (Vietnam) [2, 7].

Environmental Characteristics

Source and tissue

Gad c 1 is a cytosolic protein, abundant in bony fish light muscle, but present in very low amounts in dark muscle [1]. It is absent from fish gelatin, which is made of hydrolyzed collagen, and from fish eggs, which do not contain any parvalbumin, while beta-parvalbumins have not been found in cartilaginous fish, nor in mammals [1, 2]. 

Risk factors

The main risk factor for developing sensitization to Gad c 1 is fish ingestion [1]. At the country level, the average annual consumption of fish per capita is not directly correlated with the prevalence of self-reported or confirmed fish allergy, however, it is assumed that fish allergy is more frequent in coastal regions [2]. A multicentric study from the US reported increased prevalence of fish allergy in African American children compared to White American ones [8].

Parvalbumins are pH-sensitive, therefore anti-acid treatments are associated with an increased risk of parvalbumin-related fish allergy [1].

In the occupational setting, parvalbumin is a component of bioaerosols generated during seafood processing activities [9].

Clinical Relevance

Sensitization to fish parvalbumin manifests as mild, moderate or severe symptoms, from oral syndrome to anaphylaxis [1]. 

Disease severity and prediction

In a Spanish retrospective cohort of 81 fish-allergic patients, levels of specific IgE to Gad c 1 were significantly higher at diagnosis than after acquisition of tolerance to at least one fish species (17 kUA/L versus 5 kUA/L, p 0.001) [10]

Cross-reactive molecules

Fish parvalbumins exhibit cross-reactivity that varies from one patient to another depending on the number of epitopes recognized by IgE from each patient [1]. Thus, three major patterns of IgE-dependent fish allergy are described: (1) extensive cross-reactivity related to cross-recognition of multiple epitopes; (2) limited cross-reactivity to a small number of fish species; (3) no cross-reactivity, due to epitope recognition limited to specific epitopes [1, 2].

Parvalbumin cross-reactivity extends beyond fish, with currently available examples being frog beta-parvalbumin, chicken, and crocodile [2, 11].

Molecular Aspects

Biochemistry

Gad c 1, the first allergenic parvalbumin which was identified in the 1970s, is a small protein of 12 kDa (113 aminoacids), acidic, able to form dimers or oligomers [1, 2, 12]. Similar to other parvalbumin family members, Gad c 1 binds two divalent metal ions, calcium or magnesium, thanks to two functional EF-hand domains, contributing to intracellular calcium homeostasis during muscle relaxation [2]. Gad c 1 is extremely heat-stable, explaining the lack of change in fish allergenicity following food processing, however, it is susceptible to proteolysis and acidic pH [1].

Isoforms, epitopes, antibodies

As of June 6, 2022, one isoallergen of Gad c 1 has been included in the World Health Organization (WHO) and International Union of Immunological Societies (IUIS) Allergen Nomenclature [13]. 

Cross-reactivity due to structural similarity

IgE cross-reactivity between parvalbumins is partly explained by their aminoacid sequence identity, and partly by the highly conserved protein structure and conformational epitopes [1]. IgE cross-reactivity has indeed been described for beta-parvalbumins sharing only 64% of aminoacid sequence identity [1, 2]. On the other hand, linear IgE epitopes on parvalbumins may contribute to species-specific sensitization and clinical reactivity [14].

Diagnostic Relevance

Gad c 1 is a marker allergen of genuine sensitization to fish. In patients with confirmed fish allergy and sensitization of similar magnitude to multiple fish species, comparable sensitization to parvalbumin suggests broad cross-reactivity [1]. 

Diagnosis of fish allergy 

Parvalbumins are the major allergens of bony fish [2]. The demonstration of Cyp c 1 or Gad c 1 sensitization in conjunction with skin tests or specific IgE to culprit fish extracts is part of the diagnosis of fish allergy [1].

Assessing beta-parvalbumin sensitization may improve the diagnostic performance, given that fish extracts lack standardization, with parvalbumin reportedly undetectable in a significant proportion of commercial extracts for skin testing [15].

Gad c 1 sensitization may be assessed using singleplex or multiplex approaches, which provide similar diagnostic performance [16].

Cross-Reactivity

In patients with convincing clinical history and specific IgE to culprit fish extract, beta-parvalbumin sensitization suggests cross-reactivity to other fish species; conversely, the lack of detectable beta-parvalbumin sensitization may be due to sensitization to other fish allergens and limited cross-reactivity to other fish species [1, 2]. Less frequently, beta-parvalbumin sensitization may be associated with monosensitization to a single epitope and thus a single fish species [2].

AIT Prescription

Seminal studies on therapeutic solutions were performed mostly with Cyp c 1 and are presented as such in this paragraph.

Hypoallergenic variants of Cyp c 1 were obtained by mutation of the calcium-binding EF-hand domains [17]. An alternative approach used proteomics in order to identify B-cell epitopes in parvalbumins from different fish species as putative vaccine candidates [18]. The preclinical development of a mutated Cyp c 1 for fish AIT was reported [19] and mechanisms of action on allergic symptoms were dissected in a murine model [20].

A recent study showed that beta-parvalbumins including Gad c 1 share common IgE epitopes, while IgG4 epitopes tend to be more patient-specific [14]. 

Exposure

The main route of exposure to Gad c 1 is through ingestion of G. callaris.

Compiled By

Author: Joana Vitte

Reviewer: Dr. Christian Fischer

Last reviewed: June 2022