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

Abstract

Aeroallergy results from maladaptive immune responses to ubiquitous, otherwise innocuous environmental proteins1. 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 remains largely unanswered. The major house dust mite allergen, Der p 2, has structural homology with MD-2, the lipopolysaccharide (LPS)-binding component of the Toll-like receptor (TLR)4 signalling complex2–4. Here we show that Der p 2 has functional homology as well, 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 suggest 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 a majority of 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.

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

“…Less is known which PRRs drive Th2-cell associated immune responses. Recent reports suggest that house dust mite allergens initiate asthmatic inflammation by signaling through the TLR4 receptor complex in part by LPS contamination [45,46]. Our data show that the T. brucei antigen MiTat1.5 sVSG-conditioned DCs to produce IL-6 and IL-1b, which is dependent on TLR4 and the adaptor molecule MyD88.…”

Requirement of MyD88 signaling in keratinocytes for Langerhans cell migration and initiation of atopic dermatitis‐like symptoms in mice

“…Both LCs and dDCs play a critical role in the pathophysiology of AD as they take up antigens in the skin and migrate to the sdLN where they contribute to T cell-dependent immune responses. Here, we show that migration of cutaneous DCs, such as LCs and dDCs, is dependent on MyD88 after application of OVA or Df mite extract, which is known to activate TLR signaling [45] in vivo. In addition, emigration of LCs after in vivo application of the hapten DNFB was also MyD88 dependent.…”

“…Here, we show that migration of cutaneous DCs, such as LCs and dDCs, is dependent on MyD88 after application of OVA or Df mite extract, which is known to activate TLR signaling [45] in vivo. In addition, emigration of LCs after in vivo application of the hapten DNFB was also MyD88 dependent.…”

Isoallergen Variations Contribute to the Overall Complexity of Effector Cell Degranulation: Effect Mediated through Differentiated IgE Affinity

“…Involvement in lipid transport has, however, been suggested due to its hydrophobic cavity (5). Recently, the allergenicity of Der p 2 was linked to its structural and functional homology with the TLR4 LPS-binding component MD-2 (6).…”