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].
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: extensive cross-reactivity related to cross-recognition of multiple epitopes; limited cross-reactivity to a small number of fish species; 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].
Diagnostics
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.
References
- Matricardi, P.M., et al., EAACI Molecular Allergology User's Guide. Pediatr Allergy Immunol, 2016. 27 Suppl 23: p. 1-250.
- Kalic, T., et al., Fish Allergy Around the World-Precise Diagnosis to Facilitate Patient Management. Front Allergy, 2021. 2: p. 732178.
- Lyons, S.A., et al., Prevalence of Food Sensitization and Food Allergy in Children Across Europe. J Allergy Clin Immunol Pract, 2020. 8(8): p. 2736-2746 e9.
- Lyons, S.A., et al., Food Allergy in Adults: Substantial Variation in Prevalence and Causative Foods Across Europe. J Allergy Clin Immunol Pract, 2019. 7(6): p. 1920-1928 e11.
- Burney, P.G., et al., The prevalence and distribution of food sensitization in European adults. Allergy, 2014. 69(3): p. 365-71.
- Grabenhenrich, L., et al., Frequency of food allergy in school-aged children in eight European countries-The EuroPrevall-iFAAM birth cohort. Allergy, 2020. 75(9): p. 2294-2308.
- Le, T.T.K., et al., The predominance of seafood allergy in Vietnamese adults: Results from the first population-based questionnaire survey. World Allergy Organ J, 2020. 13(3): p. 100102.
- Mahdavinia, M., et al., African American Children Are More Likely to Be Allergic to Shellfish and Finfish: Findings from FORWARD, a Multisite Cohort Study. J Allergy Clin Immunol Pract, 2021. 9(7): p. 2867-2873 e1.
- Bonlokke, J.H., et al., Exposures and Health Effects of Bioaerosols in Seafood Processing Workers - a Position Statement. J Agromedicine, 2019. 24(4): p. 441-448.
- Carvalho, S., et al., Role of Recombinant Parvalbumin Gad c 1 in the Diagnosis and Prognosis of Fish Allergy. J Investig Allergol Clin Immunol, 2020. 30(5): p. 340-345.
- Ruethers, T., et al., The first reptilian allergen and major allergen for fish-allergic patients: Crocodile beta-parvalbumin. Pediatr Allergy Immunol, 2022. 33(5): p. e13781.
- UniProtKB. UniProtKB Gad c 1 P02622 2022 2022 June 6]; Available from: https://www.uniprot.org/uniprot/P02622.
- IUIS/WHO. IUIS/WHO Gad c 1 (Gadus callarias) (Baltic cod). 2022 2022 June 6]; Available from: http://allergen.org/viewallergen.php?aid=334.
- Sharp, M.F., et al., IgE and IgG4 epitopes revealed on the major fish allergen Lat c 1. Mol Immunol, 2021. 131: p. 155-163.
- Ruethers, T., et al., Variability of allergens in commercial fish extracts for skin prick testing. Allergy, 2019. 74(7): p. 1352-1363.
- Vazquez-Cortes, S., et al., Diagnostic performance of single and multiplex IgE testing to recombinant parvalbumins in fish allergy. Ann Allergy Asthma Immunol, 2012. 109(5): p. 362-3.
- Swoboda, I., et al., A recombinant hypoallergenic parvalbumin mutant for immunotherapy of IgE-mediated fish allergy. J Immunol, 2007. 178(10): p. 6290-6.
- Carrera, M., et al., Molecular characterization of B-cell epitopes for the major fish allergen, parvalbumin, by shotgun proteomics, protein-based bioinformatics and IgE-reactive approaches. J Proteomics, 2019. 200: p. 123-133.
- Zuidmeer-Jongejan, L., et al., Development of a hypoallergenic recombinant parvalbumin for first-in-man subcutaneous immunotherapy of fish allergy. Int Arch Allergy Immunol, 2015. 166(1): p. 41-51.
- Freidl, R., et al., Blocking antibodies induced by immunization with a hypoallergenic parvalbumin mutant reduce allergic symptoms in a mouse model of fish allergy. J Allergy Clin Immunol, 2017. 139(6): p. 1897-1905 e1.