Impaired dendritic cell maturation and cytokine production in patients with chronic mucocutanous candidiasis with or without APECED.
Patients with chronic mucocutaneous candidiasis (CMC) suffer persistent infections with the yeast Candida. CMC includes patients with autoimmune regulator (AIRE) gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, and dendritic cells (DCs), as central orchestrators, may underlie pathogenic disease mechanisms. In 29 patients with CMC (13 with APECED) and controls, we generated monocyte-derived DCs, stimulated them with Candida albicans, Toll-like receptor-2/6 ligand and lipopolysaccharide to assess cytokine production [interleukin (IL)-12p70, IL-23, interferon (IFN)-gamma, IL-2, tumour necrosis factor (TNF)-alpha, IL-6, transforming growth factor-beta, IL-10, IL-5, IL-13] and cell-surface maturation marker expression (CD83, CD86, human leucocyte antigen D-related). In both APECED and non-APECED CMC patients, we demonstrate impairment of DC function as evidenced by altered cytokine expression profiles and DC maturation/activation: (1) both groups over-produce IL-2, IFN-gamma, TNF-alpha and IL-13 and demonstrate impaired DC maturation. (2) Only non-APECED patients showed markedly decreased Candida-stimulated production of IL-23 and markedly increased production of IL-6, suggesting impairment of the IL-6/IL-23/T helper type 17 axis. (3) In contrast, only APECED patients showed DC hyperactivation, which may underlie altered T cell responsiveness, autoimmunity and impaired response to Candida. We demonstrate different pathogenic mechanisms on the same immune response pathway underlying increased susceptibility to Candida infection in these patients.
Ryan
K R
KR
Institute for Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Hong
M
M
Arkwright
P D
PD
Gennery
A R
AR
Costigan
C
C
Dominguez
M
M
Denning
D
D
McConnell
V
V
Cant
A J
AJ
Abinun
M
M
Spickett
G P
GP
Lilic
D
D
D000293:Adolescent; D000328:Adult; D002178:Candidiasis, Chronic Mucocutaneous / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000276:immunology*; D004198:Disease Susceptibility; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053759:Interleukin-23 / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D016884:Polyendocrinopathies, Autoimmune / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D055815:Young Adult
D016207:Cytokines; D018836:Inflammation Mediators; D053759:Interleukin-23