Chronic Mucocutaneous Candidiasis in Humans With Inborn Errors of Interleukin-17 Immunity
PURPOSE OF THE STUDY.
Chronic mucocutaneous candidiasis disease (CMCD) is characterized by recurrent or persistent infections of the skin, nails, and oral and genital mucosa caused by Candida albicans and sometimes Staphylococcus. Previous studies have shown that interleukin 17 (IL-17) receptor-deficient mice were more susceptible to oropharyngeal candidiasis and staphylococcal infections of the skin. The purpose of this study was to assess if findings in the mouse model also applied to humans.
Candidate gene sequencing was performed on a child with C albicans in the neonatal period and Staphylococcus aureus dermatitis at 5 months of age and a family from Argentina with autosomal dominant pattern of CMCD inheritance. Sequences of IL-17–related genes and receptors from affected people were compared with those of family members and controls. Additional experiments were performed by incubating fibroblasts from an affected child with recombinant IL-17A and IL-17F homodimers and heterodimers.
The initial child was found to be homozygous for a mutation in the IL17RA gene that was not found in any of the controls. The IL-17RA protein was not detected on the surface of fibroblasts, CD4+ T cells, CD8+ T cells, or monocytes from the patient. The patient's fibroblasts did not respond to any of the 3 IL-17 cytokines. In the family studied, a heterozygous missense mutation was found in the IL17F gene. The mutant allele was found in 2 apparently healthy family members, which suggests incomplete clinical penetrance, and in all of the affected members of the kindred. This mutant protein was tested in a cell line and was nonfunctional.
Mutations in IL-17–family genes that cause functional deficiency of this pathway are associated with CMCD.
This is an excellent example of bench-to-bedside medicine and illustrates the utility of murine models of immunity in the search for causes of human disease. These findings provide definitive evidence that IL-17A and IL-17F are essential for protective immunity to C albicans and, to a lesser extent, S aureus in the nails, skin, and oral and genital mucosa and provide new opportunities for designing novel treatments for this chronic immunologic disorder. It is also important to consider that elevated levels of IL-17 have been associated with various chronic inflammatory conditions, which raises the possibility that anti–IL-17 treatment strategies now under development could lead to increased susceptibility to infections with C albicans or S aureus.
- Copyright © 2011 by the American Academy of Pediatrics