Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein (original) (raw)
Related papers
Nature Medicine, 2009
Barrier epithelial cells and airway dendritic cells (DC) make up the first line of defence against inhaled substances like house dust mite (HDM) allergen and endotoxin. We hypothesized that these cells need to communicate to cause allergic disease. Using irradiated chimeric mice, we demonstrate that TLR4 expression on radioresistant lung structural cells is required and sufficient for DC activation in the lung and for priming of effector T helper responses to HDM. TLR4 triggering on structural cells caused production of the innate proallergic cytokines thymic stromal lymphopoietin, granulocyte-macrophage colony stimulating factor, interleukin-25 and IL-33. The absence of TLR4 on structural cells, but not on hematopoietic cells, abolished HDM driven allergic airway inflammation. Finally, inhalation of a TLR4 antagonist to target exposed epithelial cells suppressed the salient features of asthma including bronchial hyperreactivity. Our data identify an innate immune function of airway epithelial cells that drives allergic inflammation via activation of mucosal DCs.
The structure of the dust mite allergen Der p 7 reveals similarities to innate immune proteins
Journal of Allergy and Clinical Immunology, 2010
Background-Sensitization to house dust mite allergens is strongly correlated with asthma. Der p 7 elicits strong IgE antibody and T-cell responses in mite allergic patients. However, the structure and biological function of this important allergen are unknown. Allergen function may contribute to allergenicity as shown for the protease activity of Group 1 mite allergens and the interaction with the innate immune system by Group 2 mite allergens. Objective-To determine the crystal structure of Der p 7 and to investigate its biological function. Methods-X-ray crystallography was utilized to determine the Der p 7 structure. NMR analysis and biochemical assays were used to examine the binding of Der p 7 to predicted ligands. Results-Der p 7 has an elongated structure with two 4-stranded anti-parallel β-sheets which wrap around a long C-terminal helix. The fold of Der p 7 is similar to lipopolysaccharide binding protein (LBP), which interacts with Toll-like receptors (TLRs) after binding lipopolysaccharide and other bacterially-derived lipid ligands. NMR and biochemical assays indicate that Der p 7 does not bind lipopolysaccharide but binds with weak affinity to the bacterial lipopeptide polymyxin B in the predicted binding site of Der p 7. Conclusions-Der p 7 binds a bacterially-derived lipid product, a common feature of some allergens. The finding that the Group 7 as well as the Group 2 mite allergens are structurally similar to different proteins in the TLR pathway further strengthens the connections between dust mites, innate immunity, and allergy.
Toll-like receptor 2 ligands inhibit TH2 responses to mite allergen
Journal of Allergy and Clinical Immunology, 2006
Background: There is intense interest in the interaction between microbial compounds and allergy. Although Toll-like receptor (TLR)-2 ligands derived from Gram-positive bacteria alter allergic sensitization in animal models, it is not clear what effect TLR2 ligands have on allergen-specific T-cell memory in human beings. Objective: To determine whether in vitro exposure to TLR2 ligands modifies the immune response to house dust mite allergen (HDM). Methods: Blood mononuclear cells were obtained from individuals both allergic (n 5 23) and not allergic (n 5 22) to HDM, and stimulated with HDM in the presence or absence of TLR2 ligands. Results: In subjects allergic to HDM, IL-5 and IL-13 responses to HDM were inhibited by heat-killed Staphylococcus aureus, staphylococcal lipoteichoic acid, and the synthetic lipoprotein Pam3CSK4 (P < .005; all stimuli). Although the whole staphylococcal bacteria increased IFN-g responses, the purified TLR2 ligands lipoteichoic acid and Pam3CSK4 inhibited HDM-specific IFN-g synthesis. In contrast, TLR2 ligands had minimal effects on responses to HDM in subjects without allergy. TLR2 ligands induced upregulation of HLA-DR expression but did not inhibit antigen uptake or processing by antigen-presenting cells. Conclusion: Toll-like receptor 2 ligands inhibit allergen-specific T H 2 responses in sensitized individuals. This effect appears to be mediated by the actions of TLR2 ligands on antigenpresenting cells, and at least for the purified TLR2 ligands does not involve the induction of a strong T H 1 immune response. Clinical implications: These findings provide an impetus for further preclinical studies examining the potential use of
Dual Role of Toll-like Receptors in Human and Experimental Asthma Models
Frontiers in Immunology
Asthma is a chronic airway inflammatory disease that is influenced by the interplay between genetic factors and exposure to environmental allergens, microbes, or microbial products where toll-like receptors (TLRs) play a pivotal role. TLRs recognize a wide range of microbial or endogenous molecules as well as airborne environmental allergens and act as adjuvants that influence positively or negatively allergic sensitization. TLRs are qualitatively and differentially expressed on hematopoietic and non-hematopoietic stromal or structural airway cells that when activated by TLRs agonists exert an immune-modulatory role in asthma development. Therefore, understanding mechanisms and pathways by which TLRs orchestrate asthma outcomes may offer new strategies to control the disease. Here, we aim to review and critically discuss the role of TLRs in human asthma and murine models of allergic airway inflammation, highlighting the complexity of TLRs function in development, exacerbation, or control of airway allergic inflammation.
The active contribution of Toll-like receptors to allergic airway inflammation
International Immunopharmacology, 2011
Epithelia lining the respiratory tract represent a major portal of entry for microorganisms and allergens and are equipped with innate and adaptive immune signaling receptors for host protection. These include Toll-like receptors (TLRs) that recognize microbial components and evoke diverse responses in cells of the respiratory system. TLR stimulation by microorganismderived molecules activates antigen presenting cells, control T helper (Th) 1, Th2, and Th17 immune cell differentiation, cytokine production by mast cells, and activation of eosinophils. It is clear that TLR are involved in the pathophysiology of allergic airway diseases such as asthma. Dendritic cells (DCs), a kind of antigen presenting cells, which play a key role in the induction of allergic airway inflammation, are privileged targets for pathogen associated molecular patterns (PAMPs). During the allergic responses, engagement of TLRs on DCs determines the Th2 polarization of the T cells. TLR signaling in mast cells increases the release of IL-5, and TLR activation of airway epithelial cells forces the generation of proallergic Th2 type of cytokines. Although these responses aim to protect the host, they may also result in inflammatory tissue damage in the airway. Under certain conditions, stimulation of TLRs, in particular, TLR9, may reduce Th2-dependent allergic inflammation by induction of Th1 responses. Therefore, understanding the complex regulatory roles of TLRs in the pathogenesis of allergic airway inflammation should facilitate the development of preventive and therapeutic measures for asthmatic patients.
Nature Medicine, 2012
Allergic asthma is a complex disease characterized by eosinophilic pulmonary inflammation, mucus production and reversible airway obstruction 1 . Exposure to indoor allergens is a clear risk factor for asthma, but this disease is also associated with high household levels of total and Gramnegative bacteria 2 . The ability of bacterial products to act as adjuvants 3 suggests they might promote asthma by priming allergic sensitization to inhaled allergens. In support of this idea, house dust extracts (HDEs) can activate antigen presenting dendritic cells (DC) in vitro and promote allergic sensitization to inhaled innocuous proteinsin vivo 4 . It is unknown which
Toll-like receptors and immune response in allergic disease
Clinical Reviews in Allergy & Immunology, 2004
Allergic reactions are dominated by the preferential development of specific Th2 responses against innocuous antigens in atopic individuals. This can reflect alterations in innate immune mechanisms. Toll-like receptors (TLRs) have evolved as key molecules in innate and adaptive immunity. Their activation by structurally distinct exogenous or endogenous ligands present at the cell microenvironment plays a critical role in antimicrobial defense. The global view is that TLR activation induces antigen-presenting cells to produce cytokines that favor Th1-type immune responses, suggesting that it might prevent the development of deleterious Th2 responses in allergy. On the basis of epidemiological studies and recent data, it has been established that TLRs play a role in the development of Th2 responses. However, more information is needed to fully understand the mechanism of TLR involvement and the implication of immune cells that express TLRs in the Th1/Th2 cytokine profiles. Several TLRs, such as TLR9, TLR7, and TLR8, can be considered as good target candidates. Some TLR ligands, such as CpG DNA, are effective adjuvants, strong inducers of both IL-5 and eosinophilia downregulation. They are also potential links to allergen epitopes that could provide new allergen-specific immunotherapy regimens for the treatment of allergic disorders.
Lipopolysaccharide binding of the mite allergen Der f 2
Genes to Cells, 2009
Lipid-binding properties and ⁄ or involvement with host defense are often found in allergen proteins, implying that these intrinsic biological functions likely contribute to the allergenicity of allergens. The group 2 major mite allergens, Der f 2 and Der p 2, show structural homology with MD-2, the lipopolysaccharide (LPS)-binding component of the Toll-like receptor (TLR) 4 signalling complex. Elucidation of the ligand-binding properties of group 2 mite allergens and identification of interaction sites by structural studies are important to explore the relationship between allergenicity and biological function. Here, we report a ligand-fishing approach in which His-tagged Der f 2 was incubated with sonicated stable isotope-labelled Escherichia coli as a potential ligand source, followed by isolation of Der f 2-bound material by a HisTrap column and NMR analysis. We found that Der f 2 binds to LPS with a nanomolar affinity and, using fluorescence and gel filtration assays that LPS binds to Der f 2 in a molar ratio of 1 : 1. We mapped the LPS-binding interface of Der f 2 by NMR perturbation studies, which suggested that LPS binds Der f 2 between the two large b-sheets, similar to its binding to MD-2, the LPS-binding component of the innate immunity receptor TLR4.