title: Toll/IL-1 signaling is critical for house dust mite-specific helper T cell type 2 and type 17 [corrected] responses.
abstract: BACKGROUND
  One of the immunopathological features of allergic inflammation is the infiltration of helper T type 2 (Th2) cells to the site of disease. Activation of innate pattern recognition receptors such as Toll-like receptors (TLRs) plays a critical role in helper T type 1 cell differentiation, yet their contribution to the generation of Th2 responses to clinically relevant aeroallergens remains poorly defined.
  
  
  OBJECTIVE
  To determine the requirement for TLR2, TLR4, and the Toll/IL-1 receptor domain adaptor protein MyD88 in a murine model of allergic asthma.
  
  
  METHODS
  Wild-type and factor-deficient ((-/-)) mice were sensitized intranasally to the common allergen house dust mite (HDM) and challenged 2 weeks later on four consecutive days. Measurements of allergic airway inflammation, T-cell cytokine production, and airway hyperreactivity were performed 24 hours later.
  
  
  RESULTS
  Mice deficient in MyD88 were protected from the cardinal features of allergic asthma, including granulocytic inflammation, Th2 cytokine production and airway hyperreactivity. Although HDM activated NF-kappaB in TLR2- or TLR4-expressing HEK cells, only in TLR4(-/-) mice was the magnitude of allergic airway inflammation and hyperreactivity attenuated. The diminished Th2 response present in MyD88(-/-) and TLR4(-/-) mice was associated with fewer OX40 ligand-expressing myeloid dendritic cells in the draining lymph nodes during allergic sensitization. Finally, HDM-specific IL-17 production and airway neutrophilia were attenuated in MyD88(-/-) but not TLR4(-/-) mice.
  
  
  CONCLUSIONS
  Together, these data suggest that Th2- and Th17-mediated inflammation generated on inhalational HDM exposure is differentially regulated by the presence of microbial products and the activation of distinct MyD88-dependent pattern recognition receptors.
authors.affiliation: Centre for Asthma and Respiratory Diseases, School of Biomedical Sciences, University of Newcastle, NSW, 2300 Australia. simon.phipps@newcastle.edu.au
authors.forename: Simon
authors.initials: S
authors.lastname: Phipps
authors.forename: Chuan En
authors.initials: CE
authors.lastname: Lam
authors.forename: Gerard E
authors.initials: GE
authors.lastname: Kaiko
authors.forename: Shen Yun
authors.initials: SY
authors.lastname: Foo
authors.forename: Adam
authors.initials: A
authors.lastname: Collison
authors.forename: Joerg
authors.initials: J
authors.lastname: Mattes
authors.forename: Jessica
authors.initials: J
authors.lastname: Barry
authors.forename: Sophia
authors.initials: S
authors.lastname: Davidson
authors.forename: Kevin
authors.initials: K
authors.lastname: Oreo
authors.forename: Lauren
authors.initials: L
authors.lastname: Smith
authors.forename: Ashley
authors.initials: A
authors.lastname: Mansell
authors.forename: Klaus I
authors.initials: KI
authors.lastname: Matthaei
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001249:Asthma / Q000209:etiology / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000276:immunology; D000939:Epitopes; D020397:Goblet Cells / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology; D039981:Pyroglyphidae / Q000276:immunology*; D018121:Receptors, Cytokine / Q000096:biosynthesis / Q000276:immunology*; D018123:Receptors, Interleukin; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D051193:Toll-Like Receptors / Q000096:biosynthesis / Q000172:deficiency / Q000276:immunology*
chemical_list: D000939:Epitopes; C484747:Il27ra protein, mouse; D007074:Immunoglobulin G; D020381:Interleukin-17; D015848:Interleukin-5; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D051193:Toll-Like Receptors