Pattern recognition pathways leading to a Th2 cytokine bias in allergic bronchopulmonary aspergillosis patients. Issue 2 (February 2015)

• Record Type: Journal Article
• Authors: Becker, K. L.; Gresnigt, M. S.; Smeekens, S. P.; Jacobs, C. W.; Magis‐Escurra, C.; Jaeger, M.; Wang, X.; Lubbers, R.; Oosting, M.; Joosten, L. A. B.; Netea, M. G.; Reijers, M. H.; van de Veerdonk, F. L.
• Is Part Of: Clinical & experimental allergy. Volume 45:Issue 2(2015:Feb.)
• Page Start: 423
• Page End: 437
• Publication Date: 2015-02
• Subjects: Allergy -- Periodicals; Immunology -- Periodicals; 616.97
• DOI: 10.1111/cea.12354
• Languages: English
• ISSNs: 0954-7894

Abstract

<abstract abstract-type="main" id="cea12354-abs-0001"> <title>Summary</title> <sec id="cea12354-sec-0001" sec-type="section"> <title>Background</title> <p>Allergic bronchopulmonary aspergillosis (ABPA) is characterised by an exaggerated Th2 response to <italic>Aspergillus fumigatus</italic>, but the immunological pathways responsible for this effect are unknown.</p> </sec> <sec id="cea12354-sec-0002" sec-type="section"> <title>Objective</title> <p>The aim of this study was to decipher the pattern recognition receptors (PRRs) and cytokines involved in the <italic>Aspergillus‐</italic>specific Th2 response and to study <italic>Aspergillus</italic>‐induced responses in healthy controls and ABPA patients.</p> </sec> <sec id="cea12354-sec-0003" sec-type="section"> <title>Methods</title> <p>Peripheral blood mononuclear cells (PBMCs) were stimulated with heat‐killed <italic>Aspergillus</italic> 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.</p> </sec> <sec id="cea12354-sec-0004" sec-type="section"> <title>Results</title> <p> <italic>Aspergillus</italic> was the only pathogen that stimulated the Th2 cytokines IL‐5 and IL‐13, while Gram‐negative bacteria, Gram‐positive bacteria, <italic>Candida albicans, </italic> chitin, β‐glucan or Toll‐like receptor (TLR) ligands did not. Depletion of CD4<sup>+</sup> 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 <italic>Aspergillus</italic>‐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 <italic>Aspergillus</italic>‐induced IFNγ.</p> </sec> <sec id="cea12354-sec-0005" sec-type="section"> <title>Conclusions and Clinical Relevance</title> <p> <italic>Aspergillus</italic> conidia are unique in triggering Th2 responses in human PBMCs, through a CR3‐dependent pathway. ABPA patients display a significantly increased <italic>Aspergillus</italic>‐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.</p> </sec> </abstract>