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

Aeroallergy results from maladaptive immune responses to ubiquitous, otherwise innocuous environmental proteins1. While the proteins so targeted 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 major house dust mite allergen, Der p 2, has structural homology with MD-2, the lipopolysaccharide (LPS)-binding component of the Toll-like receptor (TLR)4 signalling complex2–4. Here we show that Der p 2 has functional homology as well, 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 suggest 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 a majority of 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.