Mendelian traits causing susceptibility to mucocutaneous fungal infections in human subjects

J Allergy Clin Immunol. 2012 Feb;129(2):294-305; quiz 306-7. doi: 10.1016/j.jaci.2011.12.966.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Dermatomycoses / genetics*
  • Dermatomycoses / immunology
  • Genetic Predisposition to Disease
  • Humans
  • Immunologic Deficiency Syndromes / genetics*
  • Immunologic Deficiency Syndromes / immunology