Skip to main content
Log in

Proteases as Th2 adjuvants

  • Published:
Current Allergy and Asthma Reports Aims and scope Submit manuscript

Abstract

Several cysteine and serine protease allergens have been cloned from house dust mites, including Der p 1, Der p 3, Der p 6, and Der p 9. A significant body of evidence suggests that these allergens mimic helper T (Th) 2 cell adjuvants. Der p 1 cleaves CD23 from activated B cells and CD25 from T cells. Der p 1 proteolytically degrades tight junctions in lung epithelium and causes release of proinflammatory cytokines from bronchial epithelial cells, mast cells, and basophils. These synergistic effects of mite enzyme allergens may promote IgE synthesis and have direct inflammatory effects on lung epithelium, which could explain why mite allergens are associated with asthma. The crystal structures of the proenzyme and mature forms of Der p 1 have been determined, as have the structures of other indoor allergens that are not enzymes (eg, Der p 2, Fel d 1, and Bla g 2). Cockroach allergens are strongly associated with asthma in US inner cities, yet none of the cockroach allergens that have been cloned are proteolytic enzymes. Thus although mite proteases allergens may act as Th2 adjuvants, a paradoxical effect is that other allergens may elicit strong Th2 responses in the absence of enzyme activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Chua KY, Stewart GA, Thomas WR, et al.: Sequence analysis of cDNA coding for a major house dust mite allergen, Der p 1. Homology with cysteine proteases. J Exp Med 1988, 167:175–182.

    Article  PubMed  CAS  Google Scholar 

  2. Chapman MD, Pomés A, Breiteneder H, Ferreira F: Nomenclature and structural biology of allergens. J Allergy Clin Immunol 2007, 119:414–420.

    Article  PubMed  CAS  Google Scholar 

  3. Best EA, Stedman KE, Bozic CM, et al.: A recombinant group 1 house dust mite allergen, rDer f 1, with biological activities similar to those of the native allergen. Protein Expr Purif 2000, 20:462–471.

    Article  PubMed  CAS  Google Scholar 

  4. van Oort E, de Heer PG, van Leeuwen WA, et al.: Maturation of Pichia pastoris-derived recombinant pro-Der p 1 induced by deglycosylation and by the natural cysteine protease Der p 1 from house dust mite. Eur J Biochem 2002, 269:671–679.

    Article  PubMed  Google Scholar 

  5. Takai T, Kato T, Yasueda H, et al.: Analysis of the structure and allergenicity of recombinant pro-and mature Der p 1 and Der f 1: major conformational IgE epitopes blocked by prodomains. J Allergy Clin Immunol 2005, 115:555–563.

    Article  PubMed  CAS  Google Scholar 

  6. Meno K, Thorsted PB, Ipsen H, et al.: The crystal structure of recombinant proDer p 1, a major house dust mite proteolytic allergen. J Immunol 2005, 175:3835–3845.

    PubMed  CAS  Google Scholar 

  7. de Halleux S, Stura E, VanderElst L, et al.: Three-dimensional structure and IgE-binding properties of mature fully active Der p 1, a clinically relevant major allergen. J Allergy Clin Immunol 2006, 117:571–576.

    Article  PubMed  CAS  Google Scholar 

  8. Takai T, Kato T, Sakata Y, et al.: Recombinant Der p 1 and Der f 1 exhibit cysteine protease activity but no serine protease activity. Biochem Biophys Res Commun 2005, 328:944–952.

    Article  PubMed  CAS  Google Scholar 

  9. Nishiyama C, Yasuhara T, Yuuki T, Okumura Y: Cloning and expression in Escherichia coli of cDNA encoding house dust mite allergen Der f 3, serine protease from Dermatophagoides farinae. FEBS Lett 1995, 377:62–66.

    Article  PubMed  CAS  Google Scholar 

  10. Bennett BJ, Thomas WR: Cloning and sequencing of the group 6 allergen of Dermatophagoides pteronyssinus. Clin Exp Allergy 1996, 26:1150–1154.

    Article  PubMed  CAS  Google Scholar 

  11. King C, Simpson RJ, Moritz RL, et al.: The isolation and characterization of a novel collagenolytic serine protease allergen (Der p 9) from the dust mite Dermatophagoides pteronyssinus. J Allergy Clin Immunol 1996, 98:739–747.

    Article  PubMed  CAS  Google Scholar 

  12. Flores I, Mora C, Rivera E, et al.: Cloning and molecular characterization of a cDNA from Blomia tropicalis homologous to dust mite group 3 allergens (trypsin-like proteases). Int Arch Allergy Immunol 2003, 130:12–16.

    Article  PubMed  CAS  Google Scholar 

  13. 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.

    Article  PubMed  CAS  Google Scholar 

  14. Schulz O, Laing P, Sewell HF, Shakib F: Der p I, a major allergen of the house dust mite, proteolytically cleaves the low-affinity receptor for human IgE (CD23). Eur J Immunol 1995, 25:3191–3194.

    Article  PubMed  CAS  Google Scholar 

  15. Shakib F, Schulz O, Sewell H: A mite subversive: cleavage of CD23 and CD25 by Der p 1 enhances allergenicity. Immunol Today 1998, 19:313–316.

    Article  PubMed  CAS  Google Scholar 

  16. Schulz O, Sewell HF, Shakib F: Proteolytic cleavage of CD25, the alpha subunit of the human T cell interleukin 2 receptor, by Der p 1, a major mite allergen with cysteine protease activity. J Exp Med 1998, 187:271–275.

    Article  PubMed  CAS  Google Scholar 

  17. King C, Brennan S, Thompson PJ, Stewart GA: Dust mite proteolytic allergens induce cytokine release from cultured airway epithelium. J Immunol 1998, 161:3645–3651.

    PubMed  CAS  Google Scholar 

  18. Tomee JF, van Weissenbruch R, de Monchy JG, Kauffman HF: Interactions between inhalant allergen extracts and airway epithelial cells: effect on cytokine production and cell detachment. J Allergy Clin Immunol 1998, 102:75–85.

    Article  PubMed  CAS  Google Scholar 

  19. Wan H, Winton HL, Soeller C, et al.: Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J Clin Invest 1999, 104:123–133.

    Article  PubMed  CAS  Google Scholar 

  20. Wan H, Winton HL, Soeller C, et al.: The transmembrane protein occludin of epithelial tight junctions is a functional target for serine peptidases from faecal pellets of Dermatophagoides pteronyssinus. Clin Exp Allergy 2001, 31:279–294.

    Article  PubMed  CAS  Google Scholar 

  21. Machado DC, Horton D, Harrop R, et al.: Potential allergens stimulate the release of mediators of the allergic response from cells of mast cell lineage in the absence of sensitization with antigen-specific IgE. Eur J Immunol 1996, 26:2972–2980.

    Article  PubMed  CAS  Google Scholar 

  22. Robinson C, Kalsheker NA, Srinivasan N, et al.: On the potential significance of the enzymatic activity of mite allergens to immunogenicity. Clues to structure and function revealed by molecular characterization. Clin Exp Allergy 1997, 27:10–21.

    Article  PubMed  CAS  Google Scholar 

  23. Sharma S, Lackie PM, Holgate ST: Uneasy breather: the implications of dust mite allergens. Clin Exp Allergy 2003, 33:163–165.

    Article  PubMed  CAS  Google Scholar 

  24. Asokananthan N, Graham PT, Stewart DJ, et al.: House dust mite allergens induce proinflammatory cytokines from respiratory epithelial cells: the cysteine protease allergen, Der p 1, activates protease-activated receptor (PAR)-2 and inactivates PAR-1. J Immunol 2002, 169:4572–4578.

    PubMed  CAS  Google Scholar 

  25. Sun G, Stacey MA, Schmidt M, et al.: Interaction of mite allergens Der p3 and Der p9 with protease-activated receptor-2 expressed by lung epithelial cells. J Immunol 2001, 167:1014–1021.

    PubMed  CAS  Google Scholar 

  26. Sears MR, Greene JM, Willan AR, et al.: A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. N Engl J Med 2003, 349:1414–1422.

    Article  PubMed  CAS  Google Scholar 

  27. 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.

    Article  PubMed  CAS  Google Scholar 

  28. 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.

    Article  PubMed  CAS  Google Scholar 

  29. Gruber A, Mancek M, Wagner H, et al.: Structural model of MD-2 and functional role of its basic amino acid clusters involved in cellular lipopolysaccharide recognition. J Biol Chem 2004, 279:28475–28482.

    Article  PubMed  CAS  Google Scholar 

  30. Kikuchi Y, Takai T, Kuhara T, et al.: Crucial commitment of proteolytic activity of a purified recombinant major house dust mite allergen Der p1 to sensitization toward IgE and IgG responses. J Immunol 2006, 177:1609–1617.

    PubMed  CAS  Google Scholar 

  31. Chapman MD, Smith AM, Vailes LD, et al.: Recombinant allergens for diagnosis and therapy of allergic disease. J Allergy Clin Immunol 2000, 106:409–418.

    Article  PubMed  CAS  Google Scholar 

  32. Kaiser L, Gronlund H, Sandalova T, et al.: The crystal structure of the major cat allergen Fel d 1, a member of the secretoglobin family. J Biol Chem 2003, 278:37730–37735.

    Article  PubMed  CAS  Google Scholar 

  33. Morgan WJ, Crain EF, Gruchalla RS, et al.: Results of a home-based environmental intervention among urban children with asthma. N Engl J Med 2004, 351:1068–1080.

    Article  PubMed  CAS  Google Scholar 

  34. Gruchalla RS, Pongracic J, Plaut M, et al.: Inner City Asthma Study: relationships among sensitivity, allergen exposure, and asthma morbidity. J Allergy Clin Immunol 2005, 115:478–485.

    Article  PubMed  Google Scholar 

  35. Fan Y, Gore JC, Redding KO, et al.: Tissue localization and regulation by juvenile hormone of human allergen Bla g 4 from the German cockroach, Blattella germanica (L.). Insect Mol Biol 2005, 14:45–53.

    Article  PubMed  CAS  Google Scholar 

  36. Gore JC, Schal C: Cockroach allergen biology and mitigation in the indoor environment. Annu Rev Entomol 2007, 52:439–463.

    Article  PubMed  CAS  Google Scholar 

  37. Satinover SM, Reefer AJ, Pomés A, et al.: Specific IgE and IgG antibody-binding patterns to recombinant cockroach allergens. J Allergy Clin Immunol 2005, 115:803–809.

    Article  PubMed  CAS  Google Scholar 

  38. Pomés A, Chapman MD, Vailes LD, et al.: Cockroach allergen Bla g 2: structure, function, and implications for allergic sensitization. Am J Respir Crit Care Med 2002, 165:391–397.

    PubMed  Google Scholar 

  39. Wünschmann S, Gustchina A, Chapman MD, Pomés A: Cockroach allergen Bla g 2: an unusual aspartic proteinase. J Allergy Clin Immunol 2005, 116:140–145.

    Article  PubMed  CAS  Google Scholar 

  40. Gustchina A, Li M, Wünschmann S, et al.: Crystal structure of cockroach allergen Bla g 2, an unusual zinc binding aspartic protease with a novel mode of self-inhibition. J Mol Biol 2005, 348:433–444.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Martin D. Chapman PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chapman, M.D., Wünschmann, S. & Pomés, A. Proteases as Th2 adjuvants. Curr Allergy Asthma Rep 7, 363–367 (2007). https://doi.org/10.1007/s11882-007-0055-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11882-007-0055-6

Keywords

Navigation