Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein.
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.
Trompette
Aurelien
A
Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
Divanovic
Senad
S
Visintin
Alberto
A
Blanchard
Carine
C
Hegde
Rashmi S
RS
Madan
Rajat
R
Thorne
Peter S
PS
Wills-Karp
Marsha
M
Gioannini
Theresa L
TL
Weiss
Jerry P
JP
Karp
Christopher L
CL
D000388:Air; D000485:Allergens / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D060829:Arthropod Proteins; D001249:Asthma / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D051218:Lymphocyte Antigen 96 / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018716:Molecular Mimicry / Q000276:immunology*; D011485:Protein Binding; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
D000485:Allergens; D039741:Antigens, Dermatophagoides; D060829:Arthropod Proteins; C451163:Dermatophagoides pteronyssinus antigen p 2; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D051197:Toll-Like Receptor 4