Pattern recognition pathways leading to a Th2 cytokine bias in ABPA patients.
[allergic bronchopulmonary aspergillosis]
Allergic bronchopulmonary aspergillosis (ABPA) is characterized by an exaggerated Th2 response to Aspergillus fumigatus, but the immunological pathways responsible for this effect are unknown.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.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 analyze cytokine responses.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 receptors (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 to healthy controls. All biological agents tested showed the capability to inhibit Th2 responses, but also decreased Aspergillus-induced IFNγ.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. This article is protected by copyright. All rights reserved.