Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein
By Aurélien Trompette, Senad Divanovic, A. Visintin, C. Blanchard, R. Hegde, R. Madan, P. Thorne, M. Wills-Karp, T. Gioannini, J. P. Weiss and 1 more. Nature, 2008
788 citations recorded by the source corpus.
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.
Subfields: Dermatology, Immunology and Allergy, Physiology
View Paper: https://www.semanticscholar.org/paper/982fa07e12e00d4ada877e7d39a857690f5c7349
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In Physiology
Citations in the corpus
- Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4 (2012, background): “It is therefore tempting to speculate that their ability to stimulate TLR4 contributes to their allergenicity, as has been shown recently for the main house dust mite allergen Der p2 (Trompette et al., 2009).”
- DAMPening Inflammation by Modulating TLR Signalling (2010, background): “Interestingly, in the absence of MD-2, the LPS-dependent TLR4 signalling can be reconstituted by the mite dust allergen Der p 2, which has structural and functional homology with MD-2 and mimics the activity of MD-2 by presenting LPS to TLR4 [58, 59].”
- EAACI Molecular Allergology User's Guide (2016, background): “These features include (i) the ability to bind lipids and to activate Toll-like receptors – shown for Der p 2 from house dust mite (126) and for Fel d 1 from cat (127); (ii) the presence of glycosylation and thus the ability to bind to Ctype lectin receptors – shown for allergen from house dust mite”
- House dust mite allergen induces asthma via TLR4 triggering of airway structural cells (2009, background): “Here we address this issue by studying key aspects of airway DC biology after inhalation of the TLR4 ligand LPS, found predominantly in the wall of Gram-negative organisms, as well as after inhalation of HDM, a ubiquitous indoor allergen contaminated with LPS from colonizing bacteria and environment”
- How are TH2-type immune responses initiated and amplified? (2010, background): “Interestingly, the main HDM allergen, Der p 2, is structurally homologous to MD2 (also known as LY96), a molecule that is required for LPS binding to TLR4 (Ref”
- Inflammatory dendritic cells—not basophils—are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen (2010, background): “We favor a model in which basophils amplify Th2 immunity to HDM, initiated by DCs and instructed by innate signaling through TLR4 and Myd88 signaling and C-type lectin signaling on epithelial cells and dendritic cells (Hammad et al., 2009; Nathan et al., 2009; Trompette et al., 2009).”