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

Nature. 2009 Jan 29;457(7229):585-8. doi: 10.1038/nature07548. Epub 2008 Dec 7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Air
  • Allergens / chemistry
  • Allergens / genetics
  • Allergens / immunology*
  • Allergens / metabolism*
  • Animals
  • Antigens, Dermatophagoides / chemistry
  • Antigens, Dermatophagoides / genetics
  • Antigens, Dermatophagoides / immunology*
  • Antigens, Dermatophagoides / metabolism*
  • Arthropod Proteins
  • Asthma / genetics
  • Asthma / immunology
  • Cell Line
  • Disease Models, Animal
  • Female
  • Humans
  • Lipopolysaccharides / immunology
  • Lymphocyte Antigen 96 / chemistry
  • Lymphocyte Antigen 96 / deficiency
  • Lymphocyte Antigen 96 / genetics
  • Lymphocyte Antigen 96 / immunology
  • Lymphocyte Antigen 96 / metabolism
  • Mice
  • Molecular Mimicry / immunology*
  • Protein Binding
  • Toll-Like Receptor 4 / deficiency
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology*
  • Toll-Like Receptor 4 / metabolism*


  • Allergens
  • Antigens, Dermatophagoides
  • Arthropod Proteins
  • Dermatophagoides pteronyssinus antigen p 2
  • Lipopolysaccharides
  • Lymphocyte Antigen 96
  • Toll-Like Receptor 4