title: Toll-like receptor 4 signaling by intestinal microbes influences susceptibility to food allergy.
abstract: The mechanisms by which signaling by the innate immune system controls susceptibility to allergy are poorly understood. In this report, we show that intragastric administration of a food allergen with a mucosal adjuvant induces allergen-specific IgE, elevated plasma histamine levels, and anaphylactic symptoms in three different strains of mice lacking a functional receptor for bacterial LPS (Toll-like receptor 4 (TLR4)), but not in MHC-matched or congenic controls. Susceptibility to allergy correlates with a Th2-biased cytokine response in both the mucosal (mesenteric lymph node and Peyer's patch) and systemic (spleen) tissues of TLR4-mutant or -deficient mice. TLR4-mutant mice are not inherently impaired in their ability to regulate Th1 cytokine production because they respond to stimulation via TLR9. Coadministration of CpG oligodeoxynucleotides during sensitization of TLR4-mutant mice with allergen plus CT abrogates anaphylactic symptoms and Ag-specific IgE, and results in a Th1-polarized cytokine response. When the composition of the bacterial flora is reduced and altered by antibiotic administration (beginning at 2 wk of age), TLR4 wild-type mice become as susceptible to the induction of allergy as their TLR4-mutant counterparts. Both allergen-specific IgE and Th2 cytokine responses are reduced in antibiotic-treated mice in which the flora has been allowed to repopulate. Taken together, our results suggest that TLR4-dependent signals provided by the intestinal commensal flora inhibit the development of allergic responses to food Ags.
authors.affiliation: Mucosal Immunology Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Mohamed Elfatih H
authors.initials: ME
authors.lastname: Bashir
authors.forename: Steve
authors.initials: S
authors.lastname: Louie
authors.forename: Hai Ning
authors.initials: HN
authors.lastname: Shi
authors.forename: Cathryn
authors.initials: C
authors.lastname: Nagler-Anderson
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D010367:Arachis / Q000276:immunology; D004268:DNA-Binding Proteins / Q000502:physiology; D004198:Disease Susceptibility; D005260:Female; D005512:Food Hypersensitivity / Q000209:etiology*; D007073:Immunoglobulin E / Q000097:blood; D007422:Intestines / Q000382:microbiology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors
chemical_list: D000900:Anti-Bacterial Agents; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495370:Tlr9 protein, mouse; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D007073:Immunoglobulin E