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

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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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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.


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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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Correspondence to Christopher L. Karp.

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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).

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