Chronic Mucocutaneous Candidiasis
Patients with CMC develop Candida infections of the mucous membranes, nails, and skin. Invasive infections are typically not seen.
Dectin-1 Deficiency - Dectin-1 and dectin-2 are fungal pattern recognition receptors expressed on macrophages, neutrophils and dendritic cells which recognize β-glucan, a cell wall component of Candida albicans. A homozygous nonsense mutation in Dectin-1 (Y238X) has been reported in 3 sisters from a single family who suffered from CMC but no other infectious complications. The mutation resulted in an inability of the Dectin-1 receptor to bind β-glucan and initiate downstream pro-inflammatory cytokine production. However, it should be noted that healthy Dectin-1 Y238X homozygotes and heterozygotes have also been discovered, suggesting this mutation may be a disease risk factor rather than a true causative gene for CMC.
CARD9 Deficiency - A homozygous nonsense mutation in CARD9 (Q295X) has been reported in 4 patients from a consanguineous family who suffered from CMC. The mutation resulted in the lack of CARD9 expression and low numbers of Th17 cells.
STAT3 Deficiency – Mutations in the STAT3 gene cause an autosomal dominant form of hyper IgE syndrome. In addition to invasive bacterial infections, patients also suffer from CMC.
DOCK8 Deficiency - DOCK8 deficiency results in an autosomal recessive form of hyper IgE syndrome. Similar to patients with STAT3 deficiency, there is impaired Th17 differentiation. In addition to bacterial infections and CMC, patients also suffer from severe viral skin infections.
IL-17F and IL17RA mutations - A heterozygous IL-17F mutation was reported in a multiplex family from Argentina with a dominant inheritance pattern of CMC. The missense mutation in the IL17F gene was found to impair IL-17F binding to the IL-17 receptor. Homozygous IL-17RA deficiency has been reported in a patient with consanguineous parents. The mutation resulted in a premature stop codon resulting in a complete absence of IL-17 receptor surface expression. The patient suffered from both Candida albicans and Staphylococcus aureus skin infections.
Gain of function STAT1 Mutations - AD gain of function mutations in STAT1 have been associated with CMC. The mutations result in reduced dephosphorylation of activated STAT1; this leads to increased accumulation of phosphorylated STAT1 in the nucleus and over-expression of cytokines such as IFN alpha/beta and IL-27 which inhibit Th17 differentiation.
APECED – This condition is characterized by CMC and polyendocrinopathy (adrenal insufficiency and hypoparathyroidism). A number of mechanisms for impaired fungal immunity in APECED have been reported. First, APECED patients have been shown to have elevated circulating neutralizing antibodies to the Th17 cytokines IL-17 and IL-22. Second, the AIRE protein appears to be involved in the dectin-1 signaling pathway by forming complexes with CARD9 and Syk.