Pattern Recognition Pathways Leading to a Th2 Cytokine Bias in Allergic Bronchopulmonary Aspergillosis Patients

Clin Exp Allergy. 2015 Feb;45(2):423-37. doi: 10.1111/cea.12354.

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 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.

Keywords: Aspergillus fumigatus; allergic bronchopulmonary aspergillosis; interferon-γ; interleukin-13; interleukin-5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antibodies, Fungal / immunology
  • Aspergillosis, Allergic Bronchopulmonary / drug therapy
  • Aspergillosis, Allergic Bronchopulmonary / genetics
  • Aspergillosis, Allergic Bronchopulmonary / immunology*
  • Aspergillosis, Allergic Bronchopulmonary / metabolism*
  • Aspergillus / immunology
  • Case-Control Studies
  • Cytokines / metabolism*
  • Cytokines / pharmacology
  • Female
  • Humans
  • Immunoglobulin E / immunology
  • Immunoglobulin G / immunology
  • Lectins, C-Type / genetics
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Ligands
  • Macrophage-1 Antigen / metabolism
  • Male
  • Middle Aged
  • Mutation
  • Phagocytosis / immunology
  • Receptors, Pattern Recognition / antagonists & inhibitors
  • Receptors, Pattern Recognition / metabolism*
  • Signal Transduction*
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Th2 Cells / drug effects
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism*
  • Young Adult

Substances

  • Antibodies, Fungal
  • Cytokines
  • Immunoglobulin G
  • Lectins, C-Type
  • Ligands
  • Macrophage-1 Antigen
  • Receptors, Pattern Recognition
  • dectin 1
  • Immunoglobulin E