Mucocutaneous
candidiasis and dermatophyte
infections occur either in isolation or alongside other symptoms in patients with various
primary immunodeficiency diseases with diverse genetic defects, which result in impaired
IL-17 immunity,
IL-22 immunity, or both. In patients with
chronic mucocutaneous candidiasis, disease-associated polymorphisms in DECTIN1 act on the level of fungal recognition, whereas mutations in caspase recruitment domain-containing
protein 9 (CARD9) disturb the subsequent
spleen tyrosine kinase 2-CARD9/BCL10/MALT1-driven signaling cascade, impairing nuclear factor κB-mediated maturation of antigen-presenting cells and priming of naive T cells to differentiate into the T(H)17 cell lineage. T(H)17-priming
cytokines signal through the
transcription factor signal transducer and activator of transcription (STAT) 3, which in turn induces the T(H)17 lineage-determining
transcription factor retinoic acid-related orphan receptor γt. Dominant-negative mutations in STAT3 result in reduced numbers of T(H)17 cells, causing localized
candidiasis in patients with
hyper-IgE syndrome. In patients with
chronic mucocutaneous candidiasis, gain-of-function STAT1 mutations shift the cellular response toward T(H)17 cell-inhibiting
cytokines. T(H)17 cells secrete
IL-17 and
IL-22, which are
cytokines with potent antifungal properties, including production of
antimicrobial peptides and activation and recruitment of neutrophils. Neutrophils mediate microbial killing through phagocytosis, degranulation, and neutrophil extracellular traps. Mutations in IL17F and IL17R in patients with
chronic mucocutaneous candidiasis, as well as neutralizing
autoantibodies against
IL-17 and
IL-22 in patients with
autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, directly impair
IL-17 and
IL-22 immunity.