Pattern recognition pathways leading to a Th2 cytokine bias in allergic bronchopulmonary aspergillosis patients.

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, ß-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 AND CLINICAL RELEVANCE: 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.