title: Pattern recognition pathways leading to a Th2 cytokine bias in allergic bronchopulmonary aspergillosis patients.
abstract: BACKGROUND
  Allergic bronchopulmonary aspergillosis (ABPA) is characterised by an exaggerated Th2 response to Aspergillus fumigatus, but the immunological pathways responsible for this effect are unknown.
  
  
  OBJECTIVE
  The aim of this study was to decipher the pattern recognition receptors (PRRs) and cytokines involved in the Aspergillus-specific Th2 response and to study Aspergillus-induced responses in healthy controls and ABPA patients.
  
  
  METHODS
  Peripheral blood mononuclear cells (PBMCs) were stimulated with heat-killed Aspergillus conidia, various other pathogens, or PRR ligands. PRRs and cytokine pathways were blocked with PRR-blocking reagents, anti-TNF (Etanercept or Adalimumab), IL-1Ra (Anakinra) or IFNγ (IFN-gamma). ELISA and FACS were used to analyse cytokine responses.
  
  
  RESULTS
  Aspergillus was the only pathogen that stimulated the Th2 cytokines IL-5 and IL-13, while Gram-negative bacteria, Gram-positive bacteria, Candida albicans, chitin, β-glucan or Toll-like receptor (TLR) ligands did not. Depletion of CD4(+) cells abolished IL-13 production. Blocking complement receptor 3 (CR3) significantly reduced IL-5 and IL-13, while blocking TLR2, TLR4 or dectin-1 had no effect. ABPA patients displayed increased Aspergillus-induced IL-5 and IL-13 and decreased IFNγ production compared with healthy controls. All biological agents tested showed the capability to inhibit Th2 responses, but also decreased Aspergillus-induced IFNγ.
  
  
  CONCLUSIONS
  Aspergillus conidia are unique in triggering Th2 responses in human PBMCs, through a CR3-dependent pathway. ABPA patients display a significantly increased Aspergillus-induced Th2/Th1 ratio that can be modulated by biologicals. These data provide a rationale to explore IFNγ therapy in ABPA as a corticosteroid-sparing treatment option, by dampening Th2 responses and supplementing the IFNγ deficiency at the same time.
authors.affiliation: Department of Internal Medicine, Radboud University Nijmegen, Medical Centre and Nijmegen Institute for Infection, Inflammation, and Immunity (N4i), Nijmegen, The Netherlands.
authors.forename: K L
authors.initials: KL
authors.lastname: Becker
authors.forename: M S
authors.initials: MS
authors.lastname: Gresnigt
authors.forename: S P
authors.initials: SP
authors.lastname: Smeekens
authors.forename: C W
authors.initials: CW
authors.lastname: Jacobs
authors.forename: C
authors.initials: C
authors.lastname: Magis-Escurra
authors.forename: M
authors.initials: M
authors.lastname: Jaeger
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: R
authors.initials: R
authors.lastname: Lubbers
authors.forename: M
authors.initials: M
authors.lastname: Oosting
authors.forename: L A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: M G
authors.initials: MG
authors.lastname: Netea
authors.forename: M H
authors.initials: MH
authors.lastname: Reijers
authors.forename: F L
authors.initials: FL
authors.lastname: van de Veerdonk
mesh_terms: D000328:Adult; D000368:Aged; D000908:Antibodies, Fungal / Q000276:immunology; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D001230:Aspergillus / Q000276:immunology; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D037181:Lectins, C-Type / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010587:Phagocytosis / Q000276:immunology; D051192:Receptors, Pattern Recognition / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D055815:Young Adult; D000099181:Dectin-1
chemical_list: D000908:Antibodies, Fungal; D016207:Cytokines; D007073:Immunoglobulin E; D007074:Immunoglobulin G; D037181:Lectins, C-Type; D008024:Ligands; D016177:Macrophage-1 Antigen; D051192:Receptors, Pattern Recognition; D000099181:Dectin-1
keywords: Aspergillus fumigatus; allergic bronchopulmonary aspergillosis; interferon-γ; interleukin-13; interleukin-5