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.
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Wills-Karp, M. Immunologic basis of antigen-induced airway hyperresponsiveness. Annu. Rev. Immunol. 17, 255–281 (1999)
Ohto, U. et al. Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa. Science 316, 1632–1634 (2007)
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)
Kim, H. M. et al. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist eritoran. Cell 130, 906–917 (2007)
Thomas, W. R. et al. Structural biology of allergens. Curr. Allergy Asthma Rep. 5, 388–393 (2005)
Sokol, C. L. et al. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nature Immunol. 9, 310–318 (2008)
Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nature Immunol. 5, 987–995 (2004)
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)
Blander, J. M. & Medzhitov, R. Toll dependent selection of microbial antigens for presentation by dendritic cells. Nature 440, 808–812 (2006)
Maunsell, K. et al. Mites and house-dust allergy in bronchial asthma. Lancet 291, 1267–1270 (1968)
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)
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)
Inohara, N. & Nunez, G. ML—a conserved domain involved in innate immunity and lipid metabolism. Trends Biochem. Sci. 27, 219–221 (2002)
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)
Williams, L. K. et al. The role of endotoxin and its receptors in allergic disease. Ann. Allergy Asthma Immunol. 94, 323–332 (2005)
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)
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)
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)
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)
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)
Gehring, U. et al. House dust endotoxin and allergic sensitization in children. Am. J. Respir. Crit. Care Med. 166, 939–944 (2002)
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)
Wills-Karp, M. et al. The germless theory of allergic disease: revisiting the hygiene hypothesis. Nature Rev. Immunol. 1, 69–75 (2001)
Michel, O. et al. Effect of inhaled endotoxin on bronchial reactivity in asthmatic and normal subjects. J. Appl. Physiol. 66, 1059–1064 (1989)
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)
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)
Herrick, C. A. & Bottomly, K. To respond or not to respond: T cells in allergic asthma. Nature Rev. Immunol. 3, 405–412 (2003)
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)
Teghanemt, A. et al. Transfer of monomeric endotoxin from MD-2 to CD14: characterization and functional consequences. J. Biol. Chem. 282, 36250–36256 (2007)
Wills-Karp, M. et al. Interleukin-13: central mediator of allergic asthma. Science 282, 2258–2261 (1998)
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.).
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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
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