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

Abstract

House dust mites (Dermatophagoides spp.) are a common cause of allergy, known to trigger asthma attacks. The main dust-mite allergen, Der p 2, is found in high concentrations in mite faecal pellets. Der p 2 has structural homology with a component of the Toll-like-receptor signalling complex, and now that homology has been implicated in the mechanism by which such a strong allergic response is provoked. Der p 2 is shown to mimic the function of a Toll-like receptor complex protein, acting as an 'auto-adjuvant' and in effect tricking the immune system into believing that it is facing a bacterial infection. The common dust mite allergen Der p 2 is shown to replace MD-2 as the lipopolysaccharide-binding component and facilitates signalling through TLR4. It is suggested that Der p 2 tends to be targeted by adaptive immune responses because of its auto-adjuvant properties. 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.