Interferon-gamma Production Defects Characterize Immune Responses in Patients with Chronic Pulmonary Aspergillosis

BACKGROUND Chronic pulmonary aspergillosis (CPA) usually develops in patients with pre-existing lung damage. However, little is known about potential underlying immune defects that might predispose patients to developing this debilitating condition. METHODS We performed immunological analyses in 21 patients with CPA and 14 healthy controls. Polymorphonuclear granulocytes (PMNs) and peripheral blood mononuclear cells (PBMCs) were isolated from venous blood. We measured reactive oxygen species (ROS) production and Aspergillus fumigatus killing capacity in PMNs and cytokine production by PBMCs in response to multiple stimuli after 24 hours (TNF-α, IL-1β, IL-6 and IL-1RA) and 7 days (IFN-γ, IL-17 and IL-22) by enzyme-linked immunosorbent assay. RESULTS Patients demonstrated no defects in PMN ROS production and A. fumigatus killing capacity as compared to controls. PBMC production of TNF-α, IL-1β and IL-6 did not differ significantly between both groups in response to all but one stimulus. However, IL-1RA production was significantly higher in patients in response to several stimuli. Patients demonstrated deficient IFN-γ production in response to several stimuli and a decreased IL-17 response to phytohaemagglutinin.Co-stimulation with A. fumigatus and M. avium leads to a synergistic TNF-α response in healthy controls, but synergism was lost in patients with CPA. CONCLUSIONS The impaired IFN-γ and (more restricted) IL-17 response found in patients with CPA indicate an adaptive immunity/lymphocyte defect. Patients produce higher concentrations of the anti-inflammatory cytokine IL-1RA and demonstrate loss of synergistic TNF-α production after co-stimulation with A. fumigatus and M. avium. No significant innate immune response defects were found in patients with CPA.