Allergo Journal

, Volume 21, Issue 4, pp 249–258

Potenzial, Fallstricke und aktueller Status der molekularen Diagnostik am Beispiel der Insektengiftallergie

Übersicht Review Article

Zusammenfassung

Die molekulare Allergiediagnostik ist in den letzten Jahren von einem weitestgehend akademischen Steckenpferd zu einem essenziellen Werkzeug der modernen Diagnostik gereift. So konnte in vielen Bereichen die Diagnostik auf der Basis des klassischen Extrakts, üblicherweise eines hochkomplexen Cocktails unterschiedlichster Moleküle, um eine Vielzahl seiner Einzelallergene erweitert werden, die eine Analyse wesentlich verlässlicher, aber auch ungleich vielschichtiger machen. In wenigen Gebieten tritt dabei der Fortschritt so klar zutage wie im Bereich der Hymenopterengiftallergien.

Hymenopterengiftallergien gehören aufgrund des hohen Risikos anaphylaktischer Reaktionen mit möglicherweise fatalen Folgen zu den schwersten Hypersensitivitäten. In Westeuropa gilt dies insbesondere für die Allergien auf die Gifte der Honigbiene und der gemeinen Wespe. Obgleich für eine Vielzahl von Allergenquellen die Zusammensetzung im Detail geklärt werden konnte, waren für Hymenopterengifte lange Zeit lediglich Major-Allergene charakterisiert.

Heutzutage ist eine deutlich größere Anzahl von Allergenen identifiziert und hinsichtlich ihrer Funktion, ihrer Natur und ihres allergenen Potenzials charakterisiert. Zudem erlauben fortschrittlichere Expressionsstrategien für die rekombinante Produktion von Giftallergenen eine Modifikation der Moleküle und versprechen damit Einblicke in unterschiedliche Arten der IgE-Reaktivität und des Sensibilisierungsmusters.

Damit kann das Wissen um die Allergene im Cocktail des Hymenopterengifts und ihre molekulare Nutzung helfen, die Diagnostik zu verbessern und Instrumente zur Evaluierung und Optimierung therapeutischer Strategien bereitstellen.

Schlüsselwörter

Allergenkomponenten Allergie Insektengift Kreuzreaktivität rekombinante Allergene Sensibilisierung 

Verwendete Abkürzungen

BAT

Basophilenaktivierungstest

CCD

Cross-reactive carbohydrate determinants

CRP

Kohlenhydratreiches Protein

DPP IV

Dipeptidylpeptidase IV

ELISA

Enzyme linked immunosorbent assay

Fuk

Fukose

GlcNAc

N-Acetylglukosamin

HRP

Meerrettichperoxidase

IgE

Immunglobulin E

IgG

Immunglobulin G

Man

Mannose

MRJP

Major royal jelly Protein

MUXF

Bromelain

MW

Molecular weight

PAGE

Polyacrylamid-Gelelektrophorese

PDGF

Platelet derived growth factor

sIgE

Spezifisches Immunglobulin E

TG

Trockengewicht

VEGF

Vascular endothelial growth factor

Perspectives, pittfalls and current status of molecular diagnosis in insect venom allergy

Summary

Molecular approaches in allergy diagnosis in the last years evolved from a merely academic exercise to an essential tool in modern diagnostics. Thereby, the classical diagnostics based on crude extracts, mostly a complex cocktail of a variety of different molecules, could be broadened by a plethora of single components rendering an analysis much more reliable, but also much more complex. In few areas the advancement is as evident as in hymenoptera venom allergy.

Hymenoptera venom allergy is one of the most severe hypersensitivities with regard to the high risk of anaphylactic conditions with potential fatal outcome. In Western Europe this relates primarily to allergies to venoms of the honeybee and the common yellow jacket. Although the composition of allergenic extracts has been resolved for a plethora of allergen sources in detail, only major allergens of hymenoptera venoms had been characterized.

Today an increasing number of allergens is identified, characterized regarding function and nature and assessed for allergenic potential. Moreover, advanced expression strategies for recombinant production of venom allergens allow for modification of the molecules and provide insight into different types of IgE reactivities and sensitization pattern.

The obtained knowledge about the allergens in hymenoptera venom cocktails and their molecular use can help to improve current diagnostics for hymenoptera venom allergy and serve as tools for re-evaluation and improvement of current therapeutic strategies.

Key words

Allergen components allergy cross-reactivity insect venom recombinant allergens sensitization 

Literatur

  1. 1.
    Aalberse RC, Akkerdaas J, Ree R van. Cross-reactivity of IgE antibodies to allergens. Allergy 2001; 56: 478–490PubMedCrossRefGoogle Scholar
  2. 2.
    Arbesman CE, Reisman RE, Wypych JI. Allergenic potency of bee antigens measured by RAST inhibition. Clin Allergy 1976; 6: 587–595PubMedCrossRefGoogle Scholar
  3. 3.
    Blank S, Seismann H, Bockisch B, Braren I, Cifuentes L, McIntyre M, Ruhl D, Ring J, Bredehorst R, Ollert MW, Grunwald T, Spillner E. Identification, recombinant expression, and characterization of the 100 kDa high molecular weight hymenoptera venom allergens Api m 5 and Ves v 3. J Immunol 2010; 184: 5403–5413PubMedCrossRefGoogle Scholar
  4. 4.
    Blank S, Michel Y, Seismann H, Plum M, Greunke K, Grunwald T, Bredehorst R, Ollert M, Braren I, Spillner E. Evaluation of different glycoforms of honeybee venom major allergen phospholipase A2 (Api m 1) produced in insect cells. Protein Pept Lett 2011a; 18: 415–422PubMedCrossRefGoogle Scholar
  5. 5.
    Blank S, Seismann H, Michel Y, McIntyre M, Cifuentes L, Braren I, Grunwald T, Darsow U, Ring J, Bredehorst R, Ollert M, Spillner E. Api m 10, a genuine A. mellifera venom allergen, is clinically relevant but underrepresented in therapeutic extracts. Allergy 2011b; 66: 1322–1329PubMedCrossRefGoogle Scholar
  6. 6.
    Blank S, Bantleon F, McIntyre M, Ollert M, Spillner E. The major royal jelly proteins 8 and 9 (Api m 11) are glycosylated components of Apis mellifera venom with allergenic potential beyond carbohydrate based reactivity. Clin Exp Allergy 2012 (in press)Google Scholar
  7. 7.
    Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, Murphy BA, Satinover SM, Hosen J, Mauro D, Slebos RJ, Zhou Q, Gold D, Hatley T, Hicklin DJ, Platts-Mills TA. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med 2008; 358: 1109–1117PubMedCrossRefGoogle Scholar
  8. 8.
    Dudler T, Chen WQ, Wang S, Schneider T, Annand RR, Dempcy RO, Crameri R, Gmachl M, Suter M, Gelb MH. High-level expression in Escherichia coli and rapid purification of enzymatically active honey bee venom phospholipase A2. Biochim Biophys Acta 1992; 1165: 201–210PubMedGoogle Scholar
  9. 9.
    Gmachl M, Kreil G. Bee venom hyaluronidase is homologous to a membrane protein of mammalian sperm. Proc Natl Acad Sci U S A 1993; 90: 3569–3573PubMedCrossRefGoogle Scholar
  10. 10.
    Graaf DC de, Brunain M, Scharlaken B, Peiren N, Devreese B, Ebo DG, Stevens WJ, Desjardins CA, Werren JH, Jacobs FJ. Two novel proteins expressed by the venom glands of Apis mellifera and Nasonia vitripennis share an ancient C1q-like domain. Insect Mol Biol 2010; 19 Suppl 1: 1–10PubMedCrossRefGoogle Scholar
  11. 11.
    Grunwald T, Bockisch B, Spillner E, Ring J, Bredehorst R, Ollert MW. Molecular cloning and expression in insect cells of honeybee venom allergen acid phosphatase (Api m 3). J Allergy Clin Immunol 2006; 117: 848–854PubMedCrossRefGoogle Scholar
  12. 12.
    Hemmer W, Focke M, Kolarich D, Dalik I, Gotz M, Jarisch R. Identification by immunoblot of venom glycoproteins displaying immunoglobulin E-binding N-glycans as cross-reactive allergens in honeybee and yellow jacket venom. Clin Exp Allergy 2004; 34: 460–469PubMedCrossRefGoogle Scholar
  13. 13.
    Henriksen A, King TP, Mirza O, Monsalve RI, Meno K, Ipsen H, Larsen JN, Gajhede M, Spangfort MD. Major venom allergen of yellow jackets, Ves v 5: structural characterization of a pathogenesis-related protein superfamily. Proteins 2001; 45: 438–448PubMedCrossRefGoogle Scholar
  14. 14.
    Hoffman DR, Shipman WH, Babin D. Allergens in bee venom II. Two new high molecular weight allergenic specificities. J Allergy Clin Immunol 1977; 59: 147–153PubMedCrossRefGoogle Scholar
  15. 15.
    Hofmann SC, Pfender N, Weckesser S, Blank S, Huss-Marp J, Spillner E, Jakob T. Detection of IgE to rApi m 1 and rVes v 5 is valuable but not sufficient to distinguish bee from wasp venom allergy (Reply). J Allergy Clin Immunol 2011; 128: 248CrossRefGoogle Scholar
  16. 16.
    Hofmann SC, Pfender N, Weckesser S, Huss-Marp J, Jakob T. Added value of IgE detection to rApi m 1 and rVes v 5 in patients with Hymenoptera venom allergy. J Allergy Clin Immunol 2011; 127: 265–267PubMedCrossRefGoogle Scholar
  17. 17.
    Jakob T, Ollert M. Rekombinante Insektengiftallergene — Nutzen in der Abgrenzung von Kreuzsensibilisierungen und echten Doppelsensibilisierungen. Allergo J 2011; 20: 22–23Google Scholar
  18. 18.
    Jappe U, Raulf-Heimsoth M, Hoffmann M, Burow G, Hubsch-Muller C, Enk A. In vitro hymenoptera venom allergy diagnosis: improved by screening for cross-reactive carbohydrate determinants and reciprocal inhibition. Allergy 2006; 61: 1220–1229PubMedCrossRefGoogle Scholar
  19. 19.
    Jin C, Hantusch B, Hemmer W, Stadlmann J, Altmann F. Affinity of IgE and IgG against cross-reactive carbohydrate determinants on plant and insect glycoproteins. J Allergy Clin Immunol 2008; 121: 185–190.e2PubMedCrossRefGoogle Scholar
  20. 20.
    Jin C, Focke M, Leonard R, Jarisch R, Altmann F, Hemmer W. Reassessing the role of hyaluronidase in yellow jacket venom allergy. J Allergy Clin Immunol 2010; 125: 184–190.e1PubMedCrossRefGoogle Scholar
  21. 21.
    Kettner A, Hughes GJ, Frutiger S, Astori M, Roggero M, Spertini F, Corradin G. Api m 6: a new bee venom allergen. J Allergy Clin Immunol 2001; 107: 914–920PubMedCrossRefGoogle Scholar
  22. 22.
    King TP, Alagon AC, Kuan J, Sobotka AK, Lichtenstein LM. Immunochemical studies of yellowjacket venom proteins. Mol Immunol. 1983; 20: 297–308PubMedCrossRefGoogle Scholar
  23. 23.
    King TP, Spangfort MD. Structure and biology of stinging insect venom allergens. Int Arch Allergy Immunol 2000; 123: 99–106PubMedCrossRefGoogle Scholar
  24. 24.
    Kolarich D, Leonard R, Hemmer W, Altmann F. The N-glycans of yellow jacket venom hyaluronidases and the protein sequence of its major isoform in Vespula vulgaris. Febs J 2005; 272: 5182–5190PubMedCrossRefGoogle Scholar
  25. 25.
    Kuchler K, Gmachl M, Sippl MJ, Kreil G. Analysis of the cDNA for phospholipase A2 from honeybee venom glands. The deduced amino acid sequence reveals homology to the corresponding vertebrate enzymes. Eur J Biochem. 1989; 184: 249–254PubMedCrossRefGoogle Scholar
  26. 26.
    Müller UR. Insektenstichallergie: Klinik, Diagnostik und Therapie. Stuttgart — New York: Gustav Fischer, 1988Google Scholar
  27. 27.
    Müller UR. Recombinant Hymenoptera venom allergens. Allergy 2002; 57: 570–576PubMedCrossRefGoogle Scholar
  28. 28.
    Müller UR. Recent developments and future strategies for immunotherapy of insect venom allergy. Curr Opin Allergy Clin Immunol 2003; 3: 299–303PubMedCrossRefGoogle Scholar
  29. 29.
    Müller UR, Johansen N, Petersen AB, Fromberg-Nielsen J, Haeberli G. Hymenoptera venom allergy: analysis of double positivity to honey bee and Vespula venom by estimation of IgE antibodies to species-specific major allergens Api m1 and Ves v5. Allergy 2009; 64: 543–548PubMedCrossRefGoogle Scholar
  30. 30.
    Peiren N, Vanrobaeys F, Graaf DC de, Devreese B, Van Beeumen J, Jacobs FJ. The protein composition of honeybee venom reconsidered by a proteomic approach. Biochim Biophys Acta 2005; 1752: 1–5PubMedGoogle Scholar
  31. 31.
    Schmidt M, Weimer ET, Sakell RH, Hoffman DR. Proteins in the hight molecular weight fraction of honeybee venom. J Allergy Clin Immunol 2005; 115: S107CrossRefGoogle Scholar
  32. 32.
    Seismann H, Blank S, Braren I, Greunke K, Cifuentes L, Grunwald T, Bredehorst R, Ollert M, Spillner E. Dissecting cross-reactivity in hymenoptera venom allergy by circumvention of alpha-1,3-core fucosylation. Mol Immunol 2010a; 47: 799–808PubMedCrossRefGoogle Scholar
  33. 33.
    Seismann H, Blank S, Cifuentes L, Braren I, Bredehorst R, Grunwald T, Ollert M, Spillner E. Recombinant phospholipase A1 (Ves v 1) from yellow jacket venom for improved diagnosis of hymenoptera venom hypersensitivity. Clin Mol Allergy 2010b; 8: 7PubMedCrossRefGoogle Scholar
  34. 34.
    Seppala U, Selby D, Monsalve R, King TP, Ebner C, Roepstorff P, Bohle B. Structural and immunological characterization of the N-glycans from the major yellow jacket allergen Ves v 2: the N-glycan structures are needed for the human antibody recognition. Mol Immunol 2009; 46: 2014–221PubMedCrossRefGoogle Scholar
  35. 35.
    Skov LK, Seppala U, Coen JJ, Crickmore N, King TP, Monsalve R, Kastrup JS, Spangfort MD, Gajhede M. Structure of recombinant Ves v 2 at 2.0 Angstrom resolution: structural analysis of an allergenic hyaluronidase from wasp venom. Acta Crystallogr D Biol Crystallogr 2006; 62: 595–604PubMedCrossRefGoogle Scholar
  36. 36.
    Soldatova LN, Crameri R, Gmachl M, Kemeny DM, Schmidt M, Weber M, Mueller UR. Superior biologic activity of the recombinant bee venom allergen hyaluronidase expressed in baculovirus-infected insect cells as compared with Escherichia coli. J Allergy Clin Immunol 1998; 101: 691–698PubMedCrossRefGoogle Scholar
  37. 37.
    Winningham KM, Fitch CD, Schmidt M, Hoffman DR. Hymenoptera venom protease allergens. J Allergy Clin Immunol 2004; 114: 928–933PubMedCrossRefGoogle Scholar

Copyright information

© Urban & Vogel 2012

Authors and Affiliations

  1. 1.Institut für Biochemie und Molekularbiologie, Universität HamburgHamburgDeutschland
  2. 2.Allergieabteilung und Forschergruppe Allergologie, Universitäts-Hautklinik, Universitätsklinikum FreiburgFreiburgDeutschland
  3. 3.Institut für Biochemie und Molekularbiologie Department Chemie, Universität HamburgHamburgDeutschland

Personalised recommendations