1. Division of Molecular Immunology,
2. Division of Allergy and Immunology,
3. Division of Developmental Biology, and,
4. Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA
5. Division of Infectious Diseases & Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01606, USA
6. Department of Occupational and Environmental Health, and,
7. Inflammation Program, Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52241, USA
8. Veteran's Affairs Medical Center, Iowa City, Iowa 52247, USA

Correspondence to: Christopher L. Karp¹ Correspondence and requests for materials should be addressed to C.L.K. (Email: chris.karp@chmcc.org).

Abstract

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 complex^{2, 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.

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.