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

ABSTRACT: 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.

SUBMITTER: Levy R

PROVIDER: S-EPMC5187691 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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

Lévy Romain R Okada Satoshi S Béziat Vivien V Moriya Kunihiko K Liu Caini C Chai Louis Yi Ann LY Migaud Mélanie M Hauck Fabian F Al Ali Amein A Cyrus Cyril C Vatte Chittibabu C Patiroglu Turkan T Unal Ekrem E Ferneiny Marie M Hyakuna Nobuyuki N Nepesov Serdar S Oleastro Matias M Ikinciogullari Aydan A Dogu Figen F Asano Takaki T Ohara Osamu O Yun Ling L Della Mina Erika E Bronnimann Didier D Itan Yuval Y Gothe Florian F Bustamante Jacinta J Boisson-Dupuis Stéphanie S Tahuil Natalia N Aytekin Caner C Salhi Aicha A Al Muhsen Saleh S Kobayashi Masao M Toubiana Julie J Abel Laurent L Li Xiaoxia X Camcioglu Yildiz Y Celmeli Fatih F Klein Christoph C AlKhater Suzan A SA Casanova Jean-Laurent JL Puel Anne A

Proceedings of the National Academy of Sciences of the United States of America 20161207 51

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 c ...[more]

PMID: 27930337

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Project description:Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor β1 (IL-12Rβ1) deficiency. In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.

Dataset Information

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

Publications

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

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