Yonsei Med J.  2011 May;52(3):393-400. 10.3349/ymj.2011.52.3.393.

Optimization of Allergen Standardization

• Jeong KY
• Hong CS
• Lee JS
• Park JW

• KMID: 1777010
• DOI: http://doi.org/10.3349/ymj.2011.52.3.393

Abstract

Preparation of high quality allergen extracts is essential for the diagnosis and immunotherapy of allergic disorders. Standardization of allergen extracts concerns determination of the allergen unit, development of reference material and measurement of the overall IgE binding capacity of an allergen extract. Recently, quantification of individual allergens has been the main focus of allergen standardization because the allergenicity of most allergen extracts is known to be mainly dependent on the content of a small number of allergen molecules. Therefore, characterization of major allergens will facilitate the standardization of allergens. In this article, we review the current state of allergen standardization. In addition, we briefly summarize the components of allergen extracts that should be under control for the optimization of allergen standardization, since its adjuvant-like activities could play an important role in allergic reactions even though the molecule itself does not bind to the IgE antibodies from subjects.

Keyword

Allergen extracts; natural adjuvant; polymorphism; standardization

MeSH Terms

Adjuvants, Immunologic/chemistry
Allergens/chemistry/*immunology/isolation & purification
Polymorphism, Genetic
Reference Standards
Republic of Korea

Figure

• 

  Fig. 1 (A) A Japanese hop, an annual climbing vine with 5-lobed leaves and covered with hooked hairs. The pollen of the Japanese hop is an important cause of seasonal rhinitis in Asia in August and September. (B) An adult male Chironomus kiiensis, a dominant species of non-biting midge in Korea. The emergence of a large number of non-biting midges often causes a nuisance as well as allergies.

Reference

1. Noon L. Prophylactic inoculation against hay fever. Lancet. 1911. 1:1572–1573.

2. Freeman J, Noon L. Further observation on the treatment of hay-fever by hypodermic inoculation of pollen vaccine. Lancet. 1911. 2:814–817.

3. Patterson ML, Slater JE. Characterization and comparison of commercially available German and American cockroach allergen extracts. Clin Exp Allergy. 2002. 32:721–727.

4. Larenas-Linnemann D, Cox LS. Immunotherapy and Allergy Diagnostics Committee of the American Academy of Allergy, Asthma and Immunology. European allergen extract units and potency: review of available information. Ann Allergy Asthma Immunol. 2008. 100:137–145.

5. Brunetto B, Tinghino R, Braschi MC, Antonicelli L, Pini C, Iacovacci P. Characterization and comparison of commercially available mite extracts for in vivo diagnosis. Allergy. 2010. 65:184–190.

6. Rossi R, Monasterolo G, Passalacqua G. The biological potency of different extracts for sublingual immunotherapy assessed by skin prick tests. Eur Ann Allergy Clin Immunol. 2010. 42:112–114.

7. Morrow KS, Slater JE. Regulatory aspects of allergen vaccines in the US. Clin Rev Allergy Immunol. 2001. 21:141–152.

8. Larsen JN, Dreborg S. Standardization of allergen extracts. Methods Mol Med. 2008. 138:133–145.

9. Burazer L, Milovanovic K, Milovanovic M, Vuckovic O, Velickovic TC, Gavrovic-Jankulovic M. Impact of Dermatophagoides pteronyssinus mite body raw material on house dust mite allergy diagnosis in a Serbian population. Med Vet Entomol. 2011. 25:77–83.

10. Weghofer M, Thomas WR, Kronqvist M, Mari A, Purohit A, Pauli G, et al. Variability of IgE reactivity profiles among European mite allergic patients. Eur J Clin Invest. 2008. 38:959–965.

11. May JC, Sih JT, Miller JR, Seligmann EB Jr. Optimization of parameters in protein nitrogen unit precipitation procedure for allergenic extracts. J Allergy Clin Immunol. 1979. 63:87–97.

12. Dreborg S. Precision of biological standardization of allergenic preparations. Allergy. 1992. 47:291–294.

13. Turkeltaub PC, Rastogi SC, Baer H, Anderson MC, Norman PS. A standardized quantitative skin-test assay of allergen potency and stability: studies on the allergen dose-response curve and effect of wheal, erythema, and patient selection on assay results. J Allergy Clin Immunol. 1982. 70:343–352.

14. Ibarrola I, Sanz ML, Gamboa PM, Mir A, Benahmed D, Ferrer A, et al. Biological characterization of glutaraldehyde-modified Parietaria judaica pollen extracts. Clin Exp Allergy. 2004. 34:303–309.

15. Grier TJ. Laboratory methods for allergen extract analysis and quality control. Clin Rev Allergy Immunol. 2001. 21:111–140.

16. Kleine Budde I, de Heer PG, van der Zee JS, Aalberse RC. The stripped basophil histamine release bioassay as a tool for the detection of allergen-specific IgE in serum. Int Arch Allergy Immunol. 2001. 126:277–285.

17. Kaul S, Lüttkopf D, Kastner B, Vogel L, Höltz G, Vieths S, et al. Mediator release assays based on human or murine immunoglobulin E in allergen standardization. Clin Exp Allergy. 2007. 37:141–150.

18. Ferreira F, Briza P, Inführ D, Schmidt G, Wallner M, Wopfner N, et al. Modified recombinant allergens for safer immunotherapy. Inflamm Allergy Drug Targets. 2006. 5:5–14.

19. Jeong KY, Hong CS, Yong TS. Recombinant allergens for diagnosis and immunotherapy of allergic disorders, with emphasis on cockroach allergy. Curr Protein Pept Sci. 2006. 7:57–71.

20. Dreborg S, Einarsson R. The major allergen content of allergenic preparations reflect their biological activity. Allergy. 1992. 47:418–423.

21. van Ree R. Indoor allergens: relevance of major allergen measurements and standardization. J Allergy Clin Immunol. 2007. 119:270–277.

22. Jutel M, Jaeger L, Suck R, Meyer H, Fiebig H, Cromwell O. Allergen-specific immunotherapy with recombinant grass pollen allergens. J Allergy Clin Immunol. 2005. 116:608–613.

23. Creticos PS, Schroeder JT, Hamilton RG, Balcer-Whaley SL, Khattignavong AP, Lindblad R, et al. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med. 2006. 355:1445–1455.

24. van Ree R, Dorpema JW, Vieths S. Allergy vaccines: a need for standardisation in mass units of major allergen. Pharmeuropa Bio. 2005. 2005:27–30.

25. van Ree R. CREATE Partnership. The CREATE project: EU support for the improvement of allergen standardization in Europe. Allergy. 2004. 59:571–574.

26. King TP, Hoffman D, Lowenstein H, Marsh DG, Platts-Mills TA, Thomas W. Allergen nomenclature. WHO/IUIS Allergen Nomenclature Subcommittee. Int Arch Allergy Immunol. 1994. 105:224–233.

27. van Ree R. Analytic aspects of the standardization of allergenic extracts. Allergy. 1997. 52:795–805.

28. Jeong KY, Yi MH, Jeong KJ, Lee H, Hong CS, Yong TS. Sequence diversity of the Bla g 4 cockroach allergen, homologous to lipocalins, from Blattella germanica. Int Arch Allergy Immunol. 2009. 148:339–345.

29. Smith WA, Hales BJ, Jarnicki AG, Thomas WR. Allergens of wild house dust mites: environmental Der p 1 and Der p 2 sequence polymorphisms. J Allergy Clin Immunol. 2001. 107:985–992.

30. Piboonpocanun S, Malainual N, Jirapongsananuruk O, Vichyanond P, Thomas WR. Genetic polymorphisms of major house dust mite allergens. Clin Exp Allergy. 2006. 36:510–516.

31. Ferreira F, Hirtenlehner K, Jilek A, Godnik-Cvar J, Breiteneder H, Grimm R, et al. Dissection of immunoglobulin E and T lymphocyte reactivity of isoforms of the major birch pollen allergen Bet v 1: potential use of hypoallergenic isoforms for immunotherapy. J Exp Med. 1996. 183:599–609.

32. Arquint O, Helbling A, Crameri R, Ferreira F, Breitenbach M, Pichler WJ. Reduced in vivo allergenicity of Bet v 1d isoform, a natural component of birch pollen. J Allergy Clin Immunol. 1999. 104:1239–1243.

33. Reyes-López CA, Pedraza-Escalona M, Mendoza G, Hernández-Santoyo A, Rodríguez-Romero A. A single amino acid substitution on the surface of a natural hevein isoform (Hev b 6.0202), confers different IgE recognition. FEBS Lett. 2006. 580:2483–2487.

34. Park JW, Kim KS, Jin HS, Kim CW, Kang DB, Choi SY, et al. Der p 2 isoallergens have different allergenicity, and quantification with 2-site ELISA using monoclonal antibodies is influenced by the isoallergens. Clin Exp Allergy. 2002. 32:1042–1047.

35. Jeong KY, Jin HS, Oh SH, Hong CS, Lee IY, Ree HI, et al. Monoclonal antibodies to recombinant Der f 2 and development of a two-site ELISA sensitive to major Der f 2 isoallergen in Korea. Allergy. 2002. 57:29–34.

36. Grier TJ, Hazelhurst DM, Duncan EA, West TK, Esch RE. Major allergen measurements: sources of variability, validation, quality assurance, and utility for laboratories, manufacturers, and clinics. Allergy Asthma Proc. 2002. 23:125–131.

37. Løwenstein H, Sparholt SH, Klysner SS, Ipsen H, Larsen JN. The significance of isoallergenic variations in present and future specific immunotherapy. Int Arch Allergy Immunol. 1995. 107:285–289.

38. Jacquet A. The Role of the House Dust Mite-Induced Innate Immunity in Development of Allergic Response. Int Arch Allergy Immunol. 2010. 155:95–105.

39. Osterlund C, Grönlund H, Gafvelin G, Bucht A. Non-Proteolytic Aeroallergens from Mites, Cat and Dog Exert Adjuvant-Like Activation of Bronchial Epithelial Cells. Int Arch Allergy Immunol. 2010. 155:111–118.

40. Willart MA, Lambrecht BN. The danger within: endogenous danger signals, atopy and asthma. Clin Exp Allergy. 2009. 39:12–19.

41. Liu AH. Endotoxin exposure in allergy and asthma: reconciling a paradox. J Allergy Clin Immunol. 2002. 109:379–392.

42. Michel O. Role of lipopolysaccharide (LPS) in asthma and other pulmonary conditions. J Endotoxin Res. 2003. 9:293–300.

43. Trompette A, Divanovic S, Visintin A, Blanchard C, Hegde RS, Madan R, et al. Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature. 2009. 457:585–588.

44. Doreswamy V, Peden DB. Modulation of asthma by endotoxin. Clin Exp Allergy. 2011. 41:9–19.

45. Tulic MK, Fiset PO, Manoukian JJ, Frenkiel S, Lavigne F, Eidelman DH, et al. Role of toll-like receptor 4 in protection by bacterial lipopolysaccharide in the nasal mucosa of atopic children but not adults. Lancet. 2004. 363:1689–1697.

46. Rylander R, Holt PG. (1→3)-beta-D-glucan and endotoxin modulate immune response to inhaled allergen. Mediators. Mediators Inflamm. 1998. 7:105–110.

47. Thorn J, Rylander R. Airways inflammation and glucan in a rowhouse area. Am J Respir Crit Care Med. 1998. 157:1798–1803.

48. Finkelman MA, Lempitski SJ, Slater JE. β-Glucans in standardized allergen extracts. J Endotoxin Res. 2006. 12:241–245.

49. Simonen-Jokinen T, Maisi P, Tervahartiala T, McGorum B, Pirie S, Sorsa T. Direct activation of gelatinase B (MMP-9) by hay dust suspension and different components of organic dust. Vet Immunol Immunopathol. 2006. 109:289–295.

50. Jeong KY, Kim C, Yong TS. Enzymatic activities of allergen extracts from three species of dust mites and cockroaches commonly found in Korean home. Korean J Parasitol. 2010. 48:151–155.

51. Thomas WR, Heinrich TK, Smith WA, Hales BJ. Pyroglyphid house dust mite allergens. Protein Pept Lett. 2007. 14:943–953.

52. Hewitt CR, Brown AP, Hart BJ, Pritchard DI. A major house dust mite allergen disrupts the immunoglobulin E network by selectively cleaving CD23: innate protection by antiproteases. J Exp Med. 1995. 182:1537–1544.

53. Ghaemmaghami AM, Robins A, Gough L, Sewell HF, Shakib F. Human T cell subset commitment determined by the intrinsic property of antigen: the proteolytic activity of the major mite allergen Der p 1 conditions T cells to produce more IL-4 and less IFN-gamma. Eur J Immunol. 2001. 31:1211–1216.

54. Smith PK, Harper JI. Serine proteases, their inhibitors and allergy. Allergy. 2006. 61:1441–1447.

55. Chapman MD, Wünschmann S, Pomés A. Proteases as Th2 adjuvants. Curr Allergy Asthma Rep. 2007. 7:363–367.

56. Gough L, Schulz O, Sewell HF, Shakib F. The cysteine protease activity of the major dust mite allergen Der p 1 selectively enhances the immunoglobulin E antibody response. J Exp Med. 1999. 190:1897–1902.

57. Gough L, Sewell HF, Shakib F. The proteolytic activity of the major dust mite allergen Der p 1 enhances the IgE antibody response to a bystander antigen. Clin Exp Allergy. 2001. 31:1594–1598.

58. Nagata S, Glovsky MM. Activation of human serum complement with allergens. I. Generation of C3a, C4a, and C5a and induction of human neutrophil aggregation. J Allergy Clin Immunol. 1987. 80:24–32.

59. Maruo K, Akaike T, Ono T, Okamoto T, Maeda H. Generation of anaphylatoxins through proteolytic processing of C3 and C5 by house dust mite protease. J Allergy Clin Immunol. 1997. 100:253–260.

60. Karp CL, Grupe A, Schadt E, Ewart SL, Keane-Moore M, Cuomo PJ, et al. Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Nat Immunol. 2000. 1:221–226.

61. Asokananthan N, Graham PT, Fink J, Knight DA, Bakker AJ, McWilliam AS, et al. Activation of protease-activated receptor (PAR)-1, PAR-2, and PAR-4 stimulates IL-6, IL-8, and prostaglandin E2 release from human respiratory epithelial cells. J Immunol. 2002. 168:3577–3585.

62. Miike S, Kita H. Human eosinophils are activated by cysteine proteases and release inflammatory mediators. J Allergy Clin Immunol. 2003. 111:704–713.

63. Sokol CL, Barton GM, Farr AG, Medzhitov R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Immunol. 2008. 9:310–318.

64. Kato T, Takai T, Mitsuishi K, Okumura K, Ogawa H. Cystatin A inhibits IL-8 production by keratinocytes stimulated with Der p 1 and Der f 1: biochemical skin barrier against mite cysteine proteases. J Allergy Clin Immunol. 2005. 116:169–176.

65. Ribas A, Martínez-Girón R. Protozoal forms in house-dust mites and respiratory allergy. Allergy Asthma Proc. 2006. 27:347–349.

66. Martínez-Girón R, Ribas A, Astudillo-González A. Flagellated protozoa in cockroaches and sputum: the unhygienic connection? Allergy Asthma Proc. 2007. 28:608–609.

67. Yao G. Bronchopulmonary infection with Lophomonas blattarum: two cases report and literature review. J Med Coll PLA. 2008. 23:176–182.

68. Martínez-Girón R, van Woerden HC. Is the dust mite allergen Der p1 protozoal in origin? Scand J Immunol. 2009. 70:75–76.

69. Peregrine PC. Host dietary changes and the hindgut fauna of cockroaches. Int J Parasitol. 1974. 4:645–656.

70. Im J, Jeon JH, Cho MK, Woo SS, Kang SS, Yun CH, et al. Induction of IL-8 expression by bacterial flagellin is mediated through lipid raft formation and intracellular TLR5 activation in A549 cells. Mol Immunol. 2009. 47:614–622.

71. Le TA, Takai T, Vu AT, Kinoshita H, Chen X, Ikeda S, et al. Flagellin Induces the Expression of Thymic Stromal Lymphopoietin in Human Keratinocytes via Toll-Like Receptor 5. Int Arch Allergy Immunol. 2010. 155:31–37.

72. Zhu Z, Zheng T, Homer RJ, Kim YK, Chen NY, Cohn L, et al. Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science. 2004. 304:1678–1682.

73. Elias JA, Homer RJ, Hamid Q, Lee CG. Chitinases and chitinase-like proteins in T(H)2 inflammation and asthma. J Allergy Clin Immunol. 2005. 116:497–500.

74. Schubert MS. A superantigen hypothesis for the pathogenesis of chronic hypertrophic rhinosinusitis, allergic fungal sinusitis, and related disorders. Ann Allergy Asthma Immunol. 2001. 87:181–188.

75. Hochrein H, Schlatter B, O'Keeffe M, Wagner C, Schmitz F, Schiemann M, et al. Herpes simplex virus type-1 induces IFN-alpha production via Toll-like receptor 9-dependent and -independent pathways. Proc Natl Acad Sci U S A. 2004. 101:11416–11421.

76. Lazarczyk M, Grzela K, Grzela T. Immunostimulatory oligonucleotides in therapy of allergic diseases. Expert Opin Biol Ther. 2005. 5:525–536.

77. Valerio CR, Murray P, Arlian LG, Slater JE. Bacterial 16S ribosomal DNA in house dust mite cultures. J Allergy Clin Immunol. 2005. 116:1296–1300.

78. Huffnagle GB. The microbiota and allergies/asthma. PLoS Pathog. 2010. 6:e1000549.

79. Huang YJ, Nelson CE, Brodie EL, Desantis TZ, Baek MS, Liu J, et al. Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma. J Allergy Clin Immunol. 2011. 127:372–381.

80. Jackson DJ, Johnston SL. The role of viruses in acute exacerbations of asthma. J Allergy Clin Immunol. 2010. 125:1178–1187.

81. Park JW, Ko SH, Kim CW, Jeoung BJ, Hong CS. Identification and characterization of the major allergen of the Humulus japonicus pollen. Clin Exp Allergy. 1999. 29:1080–1086.

82. Kim YK, Kim YY. Spider-mite allergy and asthma in fruit growers. Curr Opin Allergy Clin Immunol. 2002. 2:103–107.

83. Jeong KY, Yum HY, Lee IY, Ree HI, Hong CS, Kim DS, et al. Molecular cloning and characterization of tropomyosin, a major allergen of Chironomus kiiensis, a dominant species of nonbiting midges in Korea. Clin Diagn Lab Immunol. 2004. 11:320–324.

84. Kim CW, Choi SY, Park JW, Hong CS. Respiratory allergy to the indoor ant (Monomorium pharaonis) not related to sting allergy. Ann Allergy Asthma Immunol. 2005. 94:301–306.

85. Yun YY, Ko SH, Park JW, Hong CS. Anaphylaxis to venom of the Pachycondyla species ant. J Allergy Clin Immunol. 1999. 104:879–882.