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

作者：Trompette Aurelien; Divanovic Senad; Visintin Alberto; Blanchard Carine; Hegde Rashmi S; Madan Rajat; Thorne Peter S; Wills Karp Marsha; Gioannini Theresa L; Weiss Jerry P; Karp Christopher L^*

来源：Nature, 2009, 457(7229): 585-U91.

DOI：10.1038/nature07548

Aeroallergy results from maladaptive immune responses to ubiquitous, otherwise innocuous environmental proteins(1). 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(2-4). 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 proteins(5), 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.

• 出版日期2009-1-29