f355 Cyp c 1

Summary

Allergen

The major allergen of common carp (Cyprinus carpio) is a parvalbumin protein known as Cyp c 1. This 12-kDa sarcoplasmic protein is found in white muscle tissue and plays a role in muscle relaxation. Cyp c 1 is resistant to heat, enzymatic degradation, and chemical denaturation, contributing to its potent allergenic properties. Recombinant forms of Cyp c 1 (rCyp c 1) have been developed for research and diagnostic applications. The clinical manifestations of allergic reactions to Cyp c 1 include anaphylaxis, angioedema, contact urticaria, erythema, gastrointestinal symptoms, neurological symptoms, oral symptoms, respiratory reactions, and urticaria. Sensitization occurs primarily through ingestion, though exposure via inhalation or skin contact. Extensive IgE cross-reactivity is observed between Cyp c 1 and parvalbumins of other fish species such as cod, grass carp, and mackerel, attributed to their amino acid sequence homology. Additionally, Cyp c 1 shares structural homology with parvalbumins of amphibians and birds.

Epidemiology                   

Worldwide distribution

Common carp is among the heavily farmed and widely eaten fish species and is widely distributed across the globe, including regions in Asia, Europe, Africa, North America, and Australia (Sližienė et al. 2022).

Environmental characteristics            

Source and tissue

Parvalbumin Cyp c 1 is a small, 12 kDa sarcoplasmic protein found in the white muscle tissue of common carp. Parvalbumins usually contain 108–109 amino acid residues and play a critical role in muscle relaxation (Kumeta et al. 2017). The Cyp c 1 content in raw carp ranges from 2.5 to 5 mg/g and decreases slightly to 2.1 to 4.0 mg/g when cooked (Dijkema et al. 2022).

Risk factors

A genetic predisposition to food allergies, often linked to a family history of atopy, increases the likelihood of developing such allergies. Environmental factors also influence allergy risk beyond the perinatal stage. Cultural differences, including local dietary habits and infant feeding practices, significantly impact the development of specific food allergies (Lee et al. 2024). Postponing the inclusion of fish into the diet may increase the likelihood of developing fish allergies (Jonsson et al. 2017). Additionally, fish sensitization can occur through compromised skin barriers in individuals with a history of atopy and hand eczema (Klueber et al. 2019). The use of antacids and base powders, which elevate gastric pH, may also increase the risk of sensitization to food allergens (Pali-Scholl et al. 2010).

Fish allergies are primarily caused by parvalbumin, a 12 kDa sarcoplasmic protein present in the white muscle tissue of various fish species. In common carp, the parvalbumin responsible for allergic reactions is Cyp c 1 (Kumeta et al. 2017).

Clinical relevance

Disease severity

Fish is a common trigger for IgE-mediated food allergies (Zuidmeer-Jongejan et al. 2015). Symptoms can range from mild reactions, such as oral allergy syndrome, and skin reactions like angioedema, to gastrointestinal issues including nausea and vomiting. In severe cases, fish allergies can lead to anaphylaxis, characterized by respiratory and circulatory complications (Dijkema et al. 2022). A study examined 12 children with fish sensitization who experienced grade 2 to 4 reactions, as classified by Sampson's anaphylaxis grading system, following fish consumption. Testing with specific IgE confirmed that these children had IgE antibodies targeting codfish extract and/or the key codfish and carp allergens, Gad c 1 and Cyp c 1. The IgE levels for Cyp c 1 ranged from 2.08 kU_A/L to >100 kU_A/L (Douladiris et al. 2015).

The Cyp c 1 allergen has been associated with various allergic reactions, including anaphylaxis, angioedema, contact urticaria, erythema, gastrointestinal symptoms, neurological symptoms, oral symptoms, respiratory reactions, and urticaria (Leung et al. 2020).

Agabriel et al. (2010) documented the first case of exclusive sensitization to Cyp c1 in a child with persistent allergies to fish and chicken meat.

In a study conducted in Austria, serum samples were collected from 60 patients with at least one characteristic clinical symptom and confirmed history of type I fish allergy. All fish allergic patients exhibited IgE reactivity to rCyp c 1.01, which also triggered histamine release from basophils in a dose-dependent manner (Swoboda et al. 2002).

A multicenter cross-sectional observational survey on fish allergy was carried out at six allergy centers in Italy on 56 participants. Of these, 92.8% tested positive for at least one beta-parvalbumin, and 67.8% tested positive for Cyp c 1 (Villalta et al. 2022).

Cross-reactive molecules

In a study, 26 fish-allergic patients were included to investigate and compare the structural and immunological properties of natural and recombinant parvalbumins. Among them, 25 patients demonstrated IgE reactivity to recombinant carp parvalbumin as well as both native and recombinant cod parvalbumin. A 91% inhibition of IgE binding was observed for nGad m 1 and rGad m 1.02 (cod parvalbumin), while rCyp c 1.01 showed a 76% reduction. Additionally, rCyp c 1.01 inhibited IgE binding to rGad m 1.02 by 98%, while rGad m 1.02 reduced IgE binding to rCyp c 1.01 by 86% (Ma et al. 2008).

In another study, 69 patients with physician-diagnosed IgE-mediated grass carp allergy were recruited from four pediatric allergy referral centers to examine the molecular and immunological properties of grass carp parvalbumin in these patients. A strong correlation was noted between grass carp IgE levels and rCyp c 1. Specific IgE levels for rCyp c 1 ranged from 0.44 to 214 kU_A/L (Leung et al. 2020).

Prevention and therapy

Avoidance of fish is strongly recommended for individuals with fish allergies.

Allergen specific immunotherapy is currently not available.

Molecular aspects           

Biochemistry

Parvalbumins are the primary allergens in fish and are responsible for triggering 70%–100% of fish-related allergic reactions (Calamelli et al. 2019). Parvalbumins are known for their resistance to chemical denaturation, heat, and enzymatic digestion (Kumeta et al. 2017, Calamelli et al. 2019). rCyp c 1 is a recombinant carp parvalbumin that contains most of the IgE epitopes specific for fish (Douladiris et al. 2015).

A multicenter study investigated and compared the structural and immunological properties of natural and recombinant allergenic fish parvalbumins. A total of 26 fish allergic patients (children and adults) from the Netherlands, Spain, and Greece, were selected based on case histories and positive specific IgE tests. It was found that the IgE binding abilities of native and recombinant beta-parvalbumins from carp and cod (rCyp c 1, nGad m 1, and rGad m 1) were comparable in 19 out of 26 patient sera (Ma et al. 2008).

rCyp c 1 is a nearly spherical protein containing two functional calcium-binding domains. Calcium depletion significantly reduces the IgE binding of Cyp c 1 likely due to alterations of conformational IgE epitopes (Swoboda et al. 2002).

The molecular mass of rCyp c 1, determined through mass spectrometry, is 11.4 kDa (Swoboda et al. 2002).

Isoforms, epitopes, antibodies

As of December 11, 2024, two Cyp c 1 isoforms are designated as Cyp c 1.0101 and Cyp c 1.0201 (WHO/IUIS 2019).

Cross-reactivity due to structural similarity

Cyp c 1 is a primary fish allergen known for its extensive cross-reactivity with various fish species (Agabriel et al. 2010). Cyp c 1 encompasses the majority of cross-reactive IgE epitopes found within the homologous family of fish parvalbumins, including those from Baltic cod, chub mackerel, and Atlantic salmon (Zuidmeer-Jongejan et al. 2015, Sližienė et al. 2022, Stephen et al. 2017).

The parvalbumins Cyp c 1.01 and Cyp c 1.02 from common carp demonstrated the highest sequence similarity to the beta-parvalbumins of other bony fish species, such as silver hake, toadfish, whiting, chub, Atlantic salmon, and pike (Swoboda et al. 2002). Cyp c 1 from carp exhibits high cross-reactivity with cod parvalbumin Gad m 1 (77% sequence homology) and Gad c 1 (Sastre 2010, Moraes et al. 2014). Wolf-herring and grass carp parvalbumins also share 95.37% and 91.7% sequence similarity with Cyp c 1, respectively (Mohammadi et al. 2017, Leung et al. 2020).

Beta-parvalbumin from the amphibian African clawed frog shares 76% sequence similarity with Cyp c 1.01 and Cyp c 1.02. Map turtle parvalbumin and chicken parvalbumin also showed 73% and 71% sequence identity, respectively, with Cyp c 1.01 and Cyp c 1.02 (Swoboda et al. 2002).

Diagnostic relevance       

Disease severity

Fish allergy is typically diagnosed through detailed medical history alongside specific IgE testing and/or skin tests. If these methods are inconclusive, an open or, preferably, double-blind food challenge with the suspected fish is recommended (Dijkema et al. 2022). Fish-allergic patients exhibit diverse sensitization profiles to fish allergens. Parvalbumin serves as the main biomarker for fish allergy diagnosis (Wai et al. 2023).

A study examined 12 children with fish sensitization who experienced grade 2 to 4 reactions, as classified by Sampson's grading system, following fish consumption. Testing confirmed that these children had IgE antibodies targeting codfish extract and/or the key codfish and carp allergens, Gad c 1 and Cyp c 1. The IgE levels for Cyp c 1 ranged from 2.08 kU_A/L to >100 kU_A/L (Douladiris et al. 2015).

Cross-reactivity

Parvalbumins are IgE cross-reactive fish allergens. Purified rCyp c1 has been suggested as an effective tool for the serological diagnosis of fish allergies (Sližienė et al. 2022). In an immunoblot inhibition assay, rCyp c1 completely blocked IgE binding to natural carp parvalbumin, suggesting that the majority of IgE-binding epitopes in natural Cyp c 1 are also present in rCyp c1. Furthermore, it was observed that approximately 70% of the IgE epitopes in allergen extracts from various fish species are represented in rCyp c 1.01., suggesting that rCyp c 1 may serve as a diagnostic marker for IgE-mediated cross-sensitization across multiple fish species (Swoboda et al. 2002).

Exposure

Sensitization to fish allergens primarily occurs through ingestion via the gastrointestinal tract. Secondary sensitization can result from inhaling fish proteins, particularly in domestic or occupational settings, as well as through skin contact during fish handling, preparation, or cooking (Sharp et al. 2014).

Explained results

Allergen information

Cyp c 1 is a parvalbumin found in common carp responsible for causing allergies in fish-sensitized individuals. This 12-kDa sarcoplasmic protein, found in white muscle tissue, serves as the primary allergen in numerous fish species (Kumeta et al. 2017).

Clinical relevance

Fish are a common cause of IgE-mediated food allergies, with symptoms ranging from mild oral and skin reactions to severe anaphylaxis (Zuidmeer-Jongejan et al. 2015, Dijkema et al. 2022). Isolated sensitization to rCyp c 1 has been documented in a child with persistent fish and chicken allergies (Agabriel et al. 2010). Additionally, occupational asthma and rhinoconjunctivitis linked to rCyp c 1 have been reported in fish farm workers, primarily due to inhalation exposure to parvalbumin (Pérez Carral et al. 2010).

Cross-reactivity

Purified rCyp c 1 is a primary cross-reactive fish allergen and serves as a marker for diagnosing IgE-mediated fish allergies (Swoboda et al. 2002, Sližienė et al. 2022). Studies show strong IgE reactivity in fish-allergic patients, with significant inhibition of IgE binding between recombinant and native parvalbumins (Ma et al. 2008, Leung et al. 2020). The high sequence similarities between Cyp c 1 and parvalbumins from other fish species, as well as amphibians and reptiles, underline its broad cross-reactivity (Swoboda et al. 2002).

Author: Turacoz

Reviewer: Dr. Michael Spangfort