Allergic asthma is thought to arise from maladaptive, Th2-polarized immune responses to ubiquitous, otherwise innocuous environmental proteins. 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 has remained largely unanswered.
House dust mites are major sources of aeroallergens for patients with allergic asthma. Concentrated in mite fecal pellets, the major group 2 allergens, Der p 2 and Der f 2, are highly allergenic; among defined dust mite antigens, they have the highest rates of skin test positivity in atopic patients. Sequence homology places these allergens in the MD-2-related lipid-recognition (ML) domain family of proteins. Indeed, the crystal structures of MD-2 and Der p 2 exhibit considerable structural homology.
Our data indicate that: (a) Der p 2 has functional homology with MD-2 as well, facilitating signaling through direct interactions with the TLR4 complex, and reconstituting LPS-driven TLR4 signaling in the absence of MD-2; (b) Der p 2 facilitates LPS signaling in primary antigen presenting cells, with or without MD-2 being present; and (c) the in vivo allergenic activity of Der p 2 mirrors its in vitro functional and biochemical activity: Der p 2 efficiently drives airway Th2 inflammation in vivo in a TLR4-dependent manner, retaining this ability in the absence of MD-2. These data suggest that Der p 2 tends to be targeted by adaptive immune responses because of its auto-adjuvant properties. The fact that other ML domain family members are aeroallergens, and that more than 50% of defined major allergens are 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.