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Fish allergy: parvalbumin and beyond

Fish allergy: parvalbumin and beyond. Kuehn Annette Molecular and Translational Allergology Department of Infection and Immunity, LIH, Luxembourg. Disclosure. Outline. In relation to this presentation, I declare that there are no conflicts of interest .

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Fish allergy: parvalbumin and beyond

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  1. Fish allergy: parvalbumin and beyond KuehnAnnette Molecular and Translational Allergology Department of Infection and Immunity, LIH, Luxembourg

  2. Disclosure Outline In relation to this presentation, I declare that there are no conflicts of interest. A conflict of interest is any situation in which a speaker or immediate family members have interests, and those may cause a conflict with the current presentation. Conflicts of interest do not preclude the delivery of the talk, but should be explicitly declared. These may include financial interests (eg. owning stocks of a related company, having received honoraria, consultancy fees), research interests (research support by grants or otherwise), organisational interests and gifts.

  3. Outline Outline 1. Fish allergy • fish production and consumption • prevalence, clinical pictures, diagnosis 2. Fish allergens • parvalbumins • enolases, aldolases and others 3. Component-resolved diagnosis of fish allergy

  4. Fish – a vital food Global fish consumption 1. Fish allergy • Nutritive value [1] • polyunsaturated  -3 fatty acids • vitamins and minerals • Consumption [2-4] • mean, 19 kg fish/capita/year • top-4 global: anchoveta, pollack, tuna, sardinella • top-4 EU: tuna, cod, salmon, pollack Important food fishes [1] Rehbein et al (2009). Wiley-Blackwell Publishing ISBN 978-1-4051-4162-8. [2] European Commission 2014. The EU fish market. [3] FAO (2007). FAO Fisheries Circular No. 972/4, Part 1 FIEP/C972/4. [4] Welch et al (2002). Public Health Nutr 5(6B):186-90.

  5. Fish allergy – clinical aspects Big-8 of food allergens [1, 2] 1. Fish allergy • Prevalence[1-4] • up to 1 % of the general population: self-report 2.2 %, skin test 0.6 %, sIgE 0.1 %, FC 0.1 % • variable in different regions • persistent food allergy • Symptoms [1, 2] • ingestion: mild reactions to severe • inhalation/contact: asthma, rhinitis, skin rash Fish allergy: country-specific variability [1] [1] Sharp and Lopata (2014). Clin Rev Allerg Immunol 46:258-71. [2] Kuehn et al (2014). Front Immunol 22;5:179. [3] Nwaru et al (2014). Allergy 69:992-1007. [4] Rona et al. (2007) J Allergy Clin Immunol 120:638-46.

  6. Fish allergy – clinicalphenotypes 1. Fish allergy • High cross-reactivity[1-3] • more than 60 % of the fish-allergic patients: skin test > 88 %, sIgE> 89 %, FC up to 70 % • Limited cross-reactivity[3] • case series (tuna/swordfish, pangasius/tilapia..) • No cross-reactivity[3] • case series (salmon, sole, cod..) Phenotypesbyclinicalhistoryand IgE-reactivity[3] [1] Bernhisel-Broadbent et al (1992). J Allergy Clin Immunol 89:730-7. [2] Helbling et al (1999). Ann Allergy Asthma Immunol 83:517-23. [3] Kuehn et al (2014). Front Immunol 22;5:179. [4] Kuehn et al (2013). Clin ExpAllergy 43:811-22.

  7. Fish allergy – clinicaldiagnosis 1. Fish allergy Decision tree for seafood challenge [1] • Clinicalhistory • Sera analysis, specific IgE [1-3] • 27 fish extracts, 2 allergens (Cyp c 1, Gad c 1) • predictive decision point (> 95 %) at 20 kUA/L • Skin testing [4] • 3-6 fish extracts/provider; PPV < 50 % • Food challenge [3] • ED10 27.3 mg, 2 patients reacted at 3 µg [1] Sharp and Lopata (2014). Clin Rev Allerg Immunol 46:258-71 [2] Sampson et al (2001). J Allergy Clin Immunol 107:891-6. [3] Ballmer-Weber et al (2015). J Allergy Clin Immunol 135:964-71. [4] Lee et al (2006). Annu Rev Nutr 26:539-65.

  8. Fish allergy – clinicaldiagnosis 1. Fish allergy Decision tree for seafood challenge [1] • Clinicalhistory • Sera analysis, specific IgE [1-3] • 27 fish extracts, 2 allergens (Cyp c 1, Gad c 1) • predictive decision point (> 95 %) at 20 kUA/L • Skin testing [4] • 3-6 fish extracts/provider; PPV < 50 % • Food challenge [3] • ED10 27.3 mg, 2 patients reacted at 3 µg extract-sIgE clinical reactivity [1] Sharp and Lopata (2014). Clin Rev Allerg Immunol 46:258-71 [2] Sampson et al (2001). J Allergy Clin Immunol 107:891-6. [3] Ballmer-Weber et al (2015). J Allergy Clin Immunol 135:964-71. [4] Lee et al (2006). Annu Rev Nutr 26:539-65.

  9. Parvalbumins as muscle proteins 2. Fish allergens Cod vs carpparvalbumin • Major fishallergen[1, 2] • 27 entries by allergen.org • sequence identities 65-75 % • Physiology  stable muscle protein (10-12 kDa) alpha-helical structure [3]  Ca2+-buffer/sensorprotein oligomers, isoforms and isotypes Cod parvalbumin: EF-hand family, ion binding characteristics [1] Sharp and Lopata(2014). Clinic Rev AllergImmunol 46:258-71. [2] Kuehn et al (2016). Allergologie. In press [3] Moraes et al (2014). Proteins 82:3032-42.

  10. Parvalbumins as fishpanallergens Epitopes in Ca2+-bindingregions 2. Fish allergens • Polysensibilization[1, 2] • clinical cross-reactivity (> 50%) • food and respiratoryallergens • In-vitro cross-reactivity[3-6] IgE-epitopes in highly conserved EF-hand-regions  IgE-epitopes in further regions identified  correlation: epitopes number and severity of reaction KnownIgEepitoperegions [1] Van Do et al (2005). J Allergy Clin Immunol 116: 1314-20. [2] Bernhisel-Broadbent et al (1992). J Allergy Clin Immunol 90: 622-9. [3] Kuehn et al (2012). AllergoJournal 21(1):16-18. [4] Untersmayr et al (2006). Mol Immunol 43(9):1454-61. [5] Swoboda I et al (2007). J Immunol 178(10):6290-6. [6] Perez-Gordo et al (2013). Mol Nutr Food Res 57(7):1283-90.

  11. Parvalbumins as fish-specificallergens ELISA: salmon parvalbumin-specificIgE [1] Salmon PV-specificepitope (red) [3] 2. Fish allergens • Salmonidparvalbumins[1-3] • clinical reactivity to salmon and trout • beta-1: selective IgE-epitope • beta-2: hypoallergenic • Catfish/angler parvalbumins [4] clinicalreactivity to pangasius  sIgE to pangasius/catfish/angler parvalbumins Immunoblot: angler parvalbumin-specific IgE [4] Species-specificepitope? [5] [1] Kuehn et al (2011). Allergy 66:299-301. [2] Perez-Gordo et al (2012). Int Arch Allergy Immunol 157:31-40. [3] Vazques-Cortes et al (2012). Ann Allergy Asthma Immunol 108:60-7. [4] Raith et al (2014). Ann Allergy Asthma Immunol 113(5):571-572. [5] Kuehn and Arumugam (2015). Unpublished data.

  12. Enolase/aldolase as muscle proteins 2. Fish allergens • New fishallergens[1] 6 entries by allergen.org sequence identity > 70% • Physiology[2] muscle protein(40-50 kDa)  glycolytic enzymes  putative isoforms less stable Salmon enolase and aldolase: TIM-barrel family, 8 α-helices, 8  -strands [3] [1] Kuehn et al (2013). Clin Exp Allergy 43:811-22. [2] Garfinkel et al (1985). Magnesium 4:60-72. [3] Kuehn and Arumugam (2015). Unpublished data.

  13. Enolase/aldolase as cross-reactiveallergens ELISA: IgE cross-inhibition with enolases 2. Fish allergens • Polysensibilization[1, 2] • sIgE in >50 % of poly-sensitized patients • IgE cross-reactivity: cod, salmon, tuna • further cross-reactivity likely • ubiquitous enzymes • Allergenicpotency[3] skin reactivity at 5-10 g allergen/ml [1] Kuehn et al (2013). Clin Exp Allergy 43:811-22. [2] Kuehn et al (2014). Ann Allergy Asthma Immunol 113:670-671. [3] Kuehn et al (2015). Unpublished data.

  14. Enolase/aldolase as fish-specificallergens 2. Fish allergens • Cod enolase and aldolase[1] • clinicalreactivity to cod(2 patients: OAS, E, AE, U) • no sIgE to cod parvalbumin (CAP) • sIgE to cod enolase and aldolase IgE-blot: cod extract IgE-ELISA: purified allergens [1] Kuehn et al (2014). Ann Allergy Asthma Immunol 113:670-671.

  15. Collagenhelix(2 1-, 1 2-chain) Fish gelatin 2. Fish allergens • Literature[1-3] • 2studies: onlyfishgelatin-sIgE • 3/30 patients: SPT positive; 1/3 patients: OAS at 7.7 g gelatin (DBFC) • Anaphylaxis to fishgelatin[4] 3-4 g fishgelatin: AE, U, A  skin test and IgE test pos. withfishgelatin • Occupationalallergy to fishgelatin[5] Substitute for mammaliangelatin Immunoblot: Collagen (A.)/gelatin-specificIgE (B.) [4] [1] Sakaguchi et al (2001). J Allergy Clin Imunol 106:579-84. [2] Andre et al (2003). Int Arch Allergy Immunol 130:17-24. [3] Hansen et al (2004). Food Chem Toxicol 42:2037-44. [4] Kuehn et al (2009). J Allergy Clin Immunol 123:708-9. [5] Renaudin et al (2010). Rev Fr Allergol 50:364.

  16. Fish allergens in component-resolveddiagnosis 3. Component-resolved diagnosis • Fish muscle • parvalbumin (Gad m 1 etc) [1] • enolase (Gad m 2 etc) [2] • aldolase (Gad m 3 etc) [2] • fishgelatin[2,3] • tropomyosin (Ore m 4) [4] • Fish eggs • vitellogenin (Onc k 5) [5] IgE-based fish allergy diagnosis: Food and occupational allergy Diagnosticsignificanceunclear [1] De Martino et al (1990). J Allergy Clin Immunol 86:909. [2] Kuehn et al (2013). Clin Exp Allergy 43:811-22. [3] Kuehn et al (2009). J Allergy Clin Immunol 123:708-9. [4] Renaudin et al (2010). Rev Fr Allergol 50:364. [5] Liu et al (2013). Clin Exp Allergy 43:365-77. [6] Shimizu et al (2014). Int Immunol 26:139-47.

  17. CRD-study in fish allergy (I) 3. Component-resolved diagnosis • Recruitment of 62 fish-allergic patients [1-2] • 26 children, 36 adults • clinical history, SPT, sIgE to fish extracts Clinical symptoms Self-report: clinicalreactivity ImmunoCAP: IgE to total extract ‚Single fish‘ 10 % ‚Specific fish‘ 19 % ‚Fish‘ 71 % Mild to severe symptoms 29 %: mono-/oligo-sensitized 1/3 of the patients: neg. or very low titer [1] Kuehn et al (2013). Clin Exp Allergy 43:811-22. [2] Kuehn et al (2014).Rev Fr d'Allergol 54:51-60.

  18. CRD-study in fish allergy (II) 3. Component-resolved diagnosis • IgE profilingwith 62 fish-allergic patients [1-2] IgE to .. .. three parvalbumins .. salmonparvalbumin .. otherallergens 58 % 15 % 27 % [1] Kuehn et al (2013). Clin Exp Allergy 43:811-22. [2] Kuehn et al (2014).Rev Fr d'Allergol 54:51-60.

  19. CRD-study in fish allergy (II) 3. Component-resolved diagnosis • IgE profilingwith 62 fish-allergic patients [1-2] IgE to .. .. three parvalbumins .. salmonparvalbumin .. otherallergens 58 % 15 % 27 % 54 % • Clinical reaction to multiple fish • Mild to severe [1] Kuehn et al (2013). Clin Exp Allergy 43:811-22. [2] Kuehn et al (2014).Rev Fr d'Allergol 54:51-60.

  20. CRD-study in fish allergy (II) 3. Component-resolved diagnosis • IgE profilingwith 62 fish-allergic patients [1-2] IgE to .. .. three parvalbumins .. salmonparvalbumin .. otherallergens 58 % 15 % 27 % 54 % • Clinical reaction to multiple fish • Mild to severe • Clinical reaction to salmon • Mild [1] Kuehn et al (2013). Clin Exp Allergy 43:811-22. [2] Kuehn et al (2014).Rev Fr d'Allergol 54:51-60.

  21. CRD-study in fish allergy (II) 3. Component-resolved diagnosis • IgE profilingwith 62 fish-allergic patients [1-2] IgE to .. .. three parvalbumins .. salmonparvalbumin .. otherallergens 58 % 15 % 27 % 54 % 65 % • Clinical reaction to multiple fish • Mild to severe • Clinical reaction to salmon • Mild • Clinical reaction to specific fish • Mild to severe [1] Kuehn et al (2013). Clin Exp Allergy 43:811-22. [2] Kuehn et al (2014).Rev Fr d'Allergol 54:51-60.

  22. Determination of fish-specific allergies [3] • salmonids • cod • pangasius • other fishes (allergens unknown) CRD-study in fish allergy (III) 3. Component-resolved diagnosis • Highersensitivity in CRD [1, 2] ImmunoCAP (grey) vs IgE ELISA (color) Parvalbumins Enolases Aldolases [1] Kuehn et al (2013). Clin Exp Allergy 43:811-22. [2] Kuehn et al (2014).Rev Fr d'Allergol 54:51-60. [3] Kuehn et al (2016). Allergologie. In press

  23. Determination of fish-specific allergies [3] • salmonids • cod • pangasius • other fishes (allergens unknown) CRD-study in fish allergy (III) 3. Component-resolved diagnosis • Highersensitivity in CRD [1, 2] ImmunoCAP (grey) vs IgE ELISA (color) parvalbumins enolases aldolases IgE-reactivity  clinical reactivity! [1] Kuehn et al (2013). Clin Exp Allergy 43:811-22. [2] Kuehn et al (2014).Rev Fr d'Allergol 54:51-60. [3] Kuehn et al (2016). Allergologie. In press

  24. Diagnostic allergen panel 3. Component-resolved diagnosis IgE to cod/carpparvalbumin • Fish allergens for IgE-diagnosis + - IgE to cod/salmon/tunaenolase/aldolase IgE to fishgelatin IgE to salmonparvalbumin IgE to codenolase/aldolase Variable allergenicity: foodprocessing Variable allergenicity: allergen content Variable allergenicity: foodprocessing Food and occupationalallergen Clinical cross-reactivity Clinical mono-sensitivity (salmonids) Clinical mono-sensitivity(codfish)

  25. Conclusions • Diagnostic challenge: differentphenotypes, patients withfish poly-/oligo-/monosensitivity specificin-vitroassays to meetthisclinicalneed • CRD: • clinical reactivity not necessarily linked to parvalbumin • variable allergenicity of fish allergens • improvement of IgE-based diagnosis by using a panel of allergens

  26. Luxembourg: LIH C Hilger T Graf T Scheuermann C Binsfeld D Revets K Arumugam M Ollert Centre Hospitalier: M Morisset F Hentges F Morel C Lehners Germany: University Hospital Tübingen: J Fischer C Sparla Technische Universität München: T Biedermann Belgium: CHU Brugmann V Doyen Norway: University Hospital of North Norway: M Sørensen, C Klingenberg Denmark: Odense Research Center for Anaphylaxis: A Pahlow-Mose, C Bindslev-Jensen France: Hôpitaux Universitaires de Strasbourg C Metz-Favre F de Blay G Pauli Centre Hospitalier Lyon-Sud: F Villard-Truc, S Gomez-André, V Jubin, F Bienvenu Centre Hospitalier Reims: JM Perotin-Collard French Society of Allergology, Working group ‘Molecular Allergens’: H Chabane, P Auriole, C Braun, C Chepin, A Foessel, L Guenard, P Krieger, JM Renaudin, JF Tuyeras Thanks to all clinicalpartners and collaborators.

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