Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

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Levy R., Okada S., Beziat V., Moriya K., Liu C., Chai L. Y. A., ...Daha Fazla

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, cilt.113, sa.51, 2016 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 113 Sayı: 51
  • Basım Tarihi: 2016
  • Doi Numarası: 10.1073/pnas.1618300114
  • Dergi Adı: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Anahtar Kelimeler: genetics, immunodeficiency, candidiasis, CHRONIC MUCOCUTANEOUS CANDIDIASIS, GAIN-OF-FUNCTION, FUNCTION STAT1 MUTATIONS, PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY, FUNCTION SIGNAL TRANSDUCER, HYPER-IGE SYNDROME, RECEPTOR-BETA-1 DEFICIENCY, INBORN-ERRORS, DOMINANT GAIN, IFN-GAMMA
  • Erciyes Üniversitesi Adresli: Evet

Özet

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.