TY - JOUR
T1 - Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein
AU - Trompette, Aurelien
AU - Divanovic, Senad
AU - Visintin, Alberto
AU - Blanchard, Carine
AU - Hegde, Rashmi S.
AU - Madan, Rajat
AU - Thorne, Peter S.
AU - Wills-Karp, Marsha
AU - Gioannini, Theresa L.
AU - Weiss, Jerry P.
AU - Karp, Christopher L.
N1 - Funding Information:
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.).
PY - 2009/1/29
Y1 - 2009/1/29
N2 - Aeroallergy results from maladaptive immune responses to ubiquitous, otherwise innocuous environmental proteins. 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 complex. 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 proteins, 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.
AB - Aeroallergy results from maladaptive immune responses to ubiquitous, otherwise innocuous environmental proteins. 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 complex. 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 proteins, 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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U2 - 10.1038/nature07548
DO - 10.1038/nature07548
M3 - Article
C2 - 19060881
AN - SCOPUS:59049100417
SN - 0028-0836
VL - 457
SP - 585
EP - 588
JO - Nature
JF - Nature
IS - 7229
ER -