title: Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen.
abstract: Allergic asthma is an inflammatory lung disease initiated and directed by T helper cells type 2 (Th2). The mechanism involved in generation of Th2 responses to inert inhaled antigens, however, is unknown. Epidemiological evidence suggests that exposure to lipopolysaccharide (LPS) or other microbial products can influence the development and severity of asthma. However, the mechanism by which LPS influences asthma pathogenesis remains undefined. Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 (Th1) responses, it is unclear if TLRs are needed for Th2 priming. Here, we report that low level inhaled LPS signaling through TLR4 is necessary to induce Th2 responses to inhaled antigens in a mouse model of allergic sensitization. The mechanism by which LPS signaling results in Th2 sensitization involves the activation of antigen-containing dendritic cells. In contrast to low levels, inhalation of high levels of LPS with antigen results in Th1 responses. These studies suggest that the level of LPS exposure can determine the type of inflammatory response generated and provide a potential mechanistic explanation of epidemiological data on endotoxin exposure and asthma prevalence.
authors.affiliation: Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Eisenbarth
authors.forename: Damani A
authors.initials: DA
authors.lastname: Piggott
authors.forename: James W
authors.initials: JW
authors.lastname: Huleatt
authors.forename: Irene
authors.initials: I
authors.lastname: Visintin
authors.forename: Christina A
authors.initials: CA
authors.lastname: Herrick
authors.forename: Kim
authors.initials: K
authors.lastname: Bottomly
mesh_terms: D000818:Animals; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D001249:Asthma / Q000276:immunology / Q000378:metabolism; D018893:Bronchoalveolar Lavage; D003713:Dendritic Cells / Q000378:metabolism; D004195:Disease Models, Animal; D029721:Drosophila Proteins; D005805:Genes, MHC Class I; D006680:HLA Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007114:Immunization; D019570:Inhalation Exposure; D018664:Interleukin-12 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology*; D008168:Lung / Q000166:cytology / Q000473:pathology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000276:immunology*; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D000941:Antigens; D029721:Drosophila Proteins; D006680:HLA Antigens; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D018664:Interleukin-12