Author:
Lévy Romain,Okada Satoshi,Béziat Vivien,Moriya Kunihiko,Liu Caini,Chai Louis Yi Ann,Migaud Mélanie,Hauck Fabian,Al Ali Amein,Cyrus Cyril,Vatte Chittibabu,Patiroglu Turkan,Unal Ekrem,Ferneiny Marie,Hyakuna Nobuyuki,Nepesov Serdar,Oleastro Matias,Ikinciogullari Aydan,Dogu Figen,Asano Takaki,Ohara Osamu,Yun Ling,Della Mina Erika,Bronnimann Didier,Itan Yuval,Gothe Florian,Bustamante Jacinta,Boisson-Dupuis Stéphanie,Tahuil Natalia,Aytekin Caner,Salhi Aicha,Al Muhsen Saleh,Kobayashi Masao,Toubiana Julie,Abel Laurent,Li Xiaoxia,Camcioglu Yildiz,Celmeli Fatih,Klein Christoph,AlKhater Suzan A.,Casanova Jean-Laurent,Puel Anne
Abstract
Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensalCandidaspecies. 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 toCandidaandStaphylococcus, 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.
Funder
Agence Nationale de la Recherche
Jeffrey Modell Foundation
St. Giles Foundation
Japan Society for the Promotion of Science
Fulbright Commission
Japan Foundation for Pediatric Research
Societe Nationale de Medecine Interne
MOH | National Medical Research Council
National University Health System, Singapore
Else Kröner-Fresenius-Stiftung
Publisher
Proceedings of the National Academy of Sciences