期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：51
页码：E8277-E8285
DOI：10.1073/pnas.1618300114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceChronic mucocutaneous candidiasis (CMC) is defined as persistent or recurrent infections of the skin and/or mucosae by commensal fungi of the Candida genus. It is often seen in patients with T-cell deficiencies, whether inherited or acquired, who typically suffer from multiple infectious diseases. Rare patients are otherwise healthy and display isolated CMC, which often segregates as a Mendelian trait. In 2011, we described the first genetic cause of isolated CMC, with autosomal recessive (AR), complete IL-17 receptor A (IL-17RA) deficiency, in a single patient. We report here 21 patients from 12 unrelated kindreds, homozygous for 12 different mutant alleles that underlie AR IL-17RA deficiency. All patients have isolated CMC and their cells do not respond to IL-17A, -17F, and -17E/IL-25. Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensal Candida species. The first genetic etiology of isolated CMC--autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency--was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity to Candida and Staphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.
