Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein

This article has been updated

Abstract

Aeroallergy results from maladaptive immune responses to ubiquitous, otherwise innocuous environmental proteins1. Although the proteins targeted by aeroallergic responses represent a tiny fraction of the airborne proteins humans are exposed to, allergenicity is a quite public phenomenon—the same proteins typically behave as aeroallergens across the human population. Why particular proteins tend to act as allergens in susceptible hosts is a fundamental mechanistic question that remains largely unanswered. The main house-dust-mite allergen, Der p 2, has structural homology with MD-2 (also known as LY96), the lipopolysaccharide (LPS)-binding component of the Toll-like receptor (TLR) 4 signalling complex2,3,4. Here we show that Der p 2 also has functional homology, facilitating signalling through direct interactions with the TLR4 complex, and reconstituting LPS-driven TLR4 signalling in the absence of MD-2. Mirroring this, airway sensitization and challenge with Der p 2 led to experimental allergic asthma in wild type and MD-2-deficient, but not TLR4-deficient, mice. Our results indicate that Der p 2 tends to be targeted by adaptive immune responses because of its auto-adjuvant properties. The fact that other members of the MD-2-like lipid-binding family are allergens, and that most defined major allergens are thought to be lipid-binding proteins5, suggests that intrinsic adjuvant activity by such proteins and their accompanying lipid cargo may have some generality as a mechanism underlying the phenomenon of allergenicity.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Der p 2 reconstitutes and amplifies TLR4 signalling in the absence and presence of MD-2, respectively.
Figure 2: Der p 2 interacts directly with the TLR4 complex and with LPS.
Figure 3: TLR4-dependent induction of experimental allergic asthma by Der p 2.
Figure 4: Der p 2 induces experimental allergic asthma in the absence of MD-2.

Change history

  • 29 January 2009

    The AOP version of this paper contained incorrect labelling in Figure 2a and c. This was fixed for print on 29 January 2009.

References

  1. 1

    Wills-Karp, M. Immunologic basis of antigen-induced airway hyperresponsiveness. Annu. Rev. Immunol. 17, 255–281 (1999)

    CAS  Article  Google Scholar 

  2. 2

    Ohto, U. et al. Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa. Science 316, 1632–1634 (2007)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Derewenda, U. et al. The crystal structure of a major dust mite allergen Der p 2, and its biological implications. J. Mol. Biol. 318, 189–197 (2002)

    CAS  Article  Google Scholar 

  4. 4

    Kim, H. M. et al. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist eritoran. Cell 130, 906–917 (2007)

    CAS  Article  Google Scholar 

  5. 5

    Thomas, W. R. et al. Structural biology of allergens. Curr. Allergy Asthma Rep. 5, 388–393 (2005)

    CAS  Article  Google Scholar 

  6. 6

    Sokol, C. L. et al. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nature Immunol. 9, 310–318 (2008)

    CAS  Article  Google Scholar 

  7. 7

    Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nature Immunol. 5, 987–995 (2004)

    CAS  Article  Google Scholar 

  8. 8

    Sporri, R. & Reis e Sousa, C. Inflammatory mediators are insufficient for full dendritic cell activation and promote expansion of CD4+ T cell populations lacking helper function. Nature Immunol. 6, 163–170 (2005)

    Article  Google Scholar 

  9. 9

    Blander, J. M. & Medzhitov, R. Toll dependent selection of microbial antigens for presentation by dendritic cells. Nature 440, 808–812 (2006)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Maunsell, K. et al. Mites and house-dust allergy in bronchial asthma. Lancet 291, 1267–1270 (1968)

    Article  Google Scholar 

  11. 11

    Park, G. M. et al. Localization of a major allergen, Der p 2, in the gut and faecal pellets of Dermatophagoides pteronyssinus . Clin. Exp. Allergy 30, 1293–1297 (2000)

    CAS  Article  Google Scholar 

  12. 12

    Heymann, P. W. et al. Antigenic and structural analysis of group II allergens (Der f II and Der p II) from house dust mites (Dermatophagoides spp). J. Allergy Clin. Immunol. 83, 1055–1067 (1989)

    CAS  Article  Google Scholar 

  13. 13

    Inohara, N. & Nunez, G. ML—a conserved domain involved in innate immunity and lipid metabolism. Trends Biochem. Sci. 27, 219–221 (2002)

    CAS  Article  Google Scholar 

  14. 14

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

    CAS  Article  Google Scholar 

  15. 15

    Williams, L. K. et al. The role of endotoxin and its receptors in allergic disease. Ann. Allergy Asthma Immunol. 94, 323–332 (2005)

    CAS  Article  Google Scholar 

  16. 16

    Divanovic, S. et al. Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nature Immunol. 6, 571–578 (2005)

    CAS  Article  Google Scholar 

  17. 17

    Kawasaki, K. et al. Identification of mouse MD-2 residues important for forming the cell surface TLR4-MD-2 complex recognized by anti-TLR4-MD-2 antibodies, and for conferring LPS and taxol responsiveness on mouse TLR4 by alanine-scanning mutagenesis. J. Immunol. 170, 413–420 (2003)

    CAS  Article  Google Scholar 

  18. 18

    Kennedy, M. N. et al. A complex of soluble MD-2 and lipopolysaccharide serves as an activating ligand for Toll-like receptor 4. J. Biol. Chem. 279, 34698–34704 (2004)

    CAS  Article  Google Scholar 

  19. 19

    Gioannini, T. L. et al. Isolation of an endotoxin-MD-2 complex that produces Toll-like receptor 4-dependent cell activation at picomolar concentrations. Proc. Natl Acad. Sci. USA 101, 4186–4191 (2004)

    ADS  CAS  Article  Google Scholar 

  20. 20

    Braun-Fahrlander, C. et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N. Engl. J. Med. 347, 869–877 (2002)

    Article  Google Scholar 

  21. 21

    Gehring, U. et al. House dust endotoxin and allergic sensitization in children. Am. J. Respir. Crit. Care Med. 166, 939–944 (2002)

    Article  Google Scholar 

  22. 22

    Riedler, J. et al. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 358, 1129–1133 (2001)

    CAS  Article  Google Scholar 

  23. 23

    Wills-Karp, M. et al. The germless theory of allergic disease: revisiting the hygiene hypothesis. Nature Rev. Immunol. 1, 69–75 (2001)

    CAS  Article  Google Scholar 

  24. 24

    Michel, O. et al. Effect of inhaled endotoxin on bronchial reactivity in asthmatic and normal subjects. J. Appl. Physiol. 66, 1059–1064 (1989)

    CAS  Article  Google Scholar 

  25. 25

    Tulic, M. K. et al. Modification of the inflammatory response to allergen challenge after exposure to bacterial lipopolysaccharide. Am. J. Respir. Cell Mol. Biol. 22, 604–612 (2000)

    CAS  Article  Google Scholar 

  26. 26

    Eisenbarth, S. C. et al. Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J. Exp. Med. 196, 1645–1651 (2002)

    CAS  Article  Google Scholar 

  27. 27

    Herrick, C. A. & Bottomly, K. To respond or not to respond: T cells in allergic asthma. Nature Rev. Immunol. 3, 405–412 (2003)

    CAS  Article  Google Scholar 

  28. 28

    Jia, H. P. et al. Endotoxin responsiveness of human airway epithelia is limited by low expression of MD-2. Am. J. Physiol. Lung Cell. Mol. Physiol. 287, L428–L437 (2004)

    CAS  Article  Google Scholar 

  29. 29

    Teghanemt, A. et al. Transfer of monomeric endotoxin from MD-2 to CD14: characterization and functional consequences. J. Biol. Chem. 282, 36250–36256 (2007)

    CAS  Article  Google Scholar 

  30. 30

    Wills-Karp, M. et al. Interleukin-13: central mediator of allergic asthma. Science 282, 2258–2261 (1998)

    ADS  CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank S. Vogel for re-purified LPS; E. Kurt-Jones and R. Finberg for HEK293 cells expressing TLR4 complex proteins, N. J. Gay for discussions, and L. Flick and J. Bohnert for technical assistance. This work was funded by grants from the Sandler Foundation for Asthma Research (C.L.K.), the National Institute of Allergy and Infectious Diseases (C.L.K., J.P.W.), and the Veteran’s Administration (T.L.G.).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Christopher L. Karp.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1- 9 with Legends. (PDF 1648 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Trompette, A., Divanovic, S., Visintin, A. et al. Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature 457, 585–588 (2009). https://doi.org/10.1038/nature07548

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing