title: Low interleukin-17A production in response to fungal pathogens in patients with chronic granulomatous disease.
abstract: Patients with chronic granulomatous disease (CGD) cannot produce reactive oxygen species (ROS) due to a genetic defect in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system. Dysregulation of the L-tryptophan metabolism in mice with defects in NADPH oxidase, resulting in overproduction of interleukin (IL)-17, has been proposed to link ROS defects with hyperinflammation and susceptibility to pulmonary aspergillosis. In this study, we assessed the L-tryptophan metabolism and cytokine profiles in response to fungal pathogens in CGD patients. Peripheral blood mononuclear cells (PBMCs) from CGD patients showed increased production of IL-6, tumor necrosis factor-α, and interferon-γ upon stimulation with Aspergillus or Candida species, while IL-17A production was strikingly low compared with healthy controls. Indoleamine 2,3-dioxygenase expression was similar in PBMCs and neutrophils from CGD patients compared with healthy controls. Conversion of L-tryptophan to L-kynurenine, as measured by high-performance liquid chromatography, did not differ between CGD patients and healthy controls. Moreover, adding L-kynurenine to the cell cultures did not suppress fungal-induced IL-17A production. Although PBMCs of CGD patients produced more proinflammatory cytokines after stimulation, IL-17A production was strikingly low in response to fungal pathogens when compared with healthy controls. In addition, cells from CGD patients did not display a defective L-tryptophan metabolism.
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Sanne P
authors.initials: SP
authors.lastname: Smeekens
authors.forename: Stefanie S V
authors.initials: SS
authors.lastname: Henriet
authors.forename: Mark S
authors.initials: MS
authors.lastname: Gresnigt
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Peter W M
authors.initials: PW
authors.lastname: Hermans
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Adilia
authors.initials: A
authors.lastname: Warris
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001230:Aspergillus / Q000276:immunology*; D002176:Candida albicans / Q000276:immunology*; D002648:Child; D006105:Granulomatous Disease, Chronic / Q000276:immunology* / Q000382:microbiology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D014364:Tryptophan / Q000378:metabolism; D055815:Young Adult
chemical_list: C508717:IL17A protein, human; D018836:Inflammation Mediators; D020381:Interleukin-17; D007371:Interferon-gamma; D014364:Tryptophan