Impairment of immunity to
 Candida
 and
 Mycobacterium
 in humans with bi-allelic
 RORC
 mutations

Okada, Satoshi; Markle, Janet; Deenick, Elissa K.; Mele, Federico; Averbuch, Dina; Lagos, Macarena; Alzahrani, Mohammed; Al‐Muhsen, Saleh; Halwani, Rabih; Cindy, S.; Wong, Natalie; Soudais, Claire; Henderson, Lauren A.; Marzouqa, Hiyam; Shamma, Jamal; González, Marcela; Martı́nez-Barricarte, Rubén; Okada, Chizuru; Avery, Danielle T.; Latorre, Daniela; Deswarte, Caroline; Jabot–Hanin, Fabienne; Torrado, Egídio; Fountain, Jeffrey J.; Belkadi, Aziz; Itan, Yuval; Boisson, Bertrand; Migaud, Mélanie; Arlehamn, Cecilia S. Lindestam; Sette, Alessandro; Breton, Sylvain; McCluskey, James; Rossjohn, Jamie; Villartay, Jean‐Pierre de; Moshous, Despina; Hambleton, Sophie; Latour, Sylvain; Arkwright, Peter D.; Pïcard, Capucine; Lantz, Olivier; Engelhard, Dan; Kobayashi, Masao; Abel, Laurent; Cooper, Andrea M.; Notarangelo, Luigi D.; Boisson–Dupuis, Stéphanie; Puel, Anne; Sallusto, Federica; Bustamante, Jacinta; Tangye, Stuart G.; Casanova, Jean‐Laurent

doi:10.1126/science.aaa4282

Cited by 381 publications

(305 citation statements)

References 66 publications

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“…Patients with these mutations, who had long been known to be prone to thyroid autoimmunity, were recently found to display other infectious and autoimmune phenotypes (16,17,23,37,51). Another genetic etiology of syndromic CMCD has recently been described, with AR retinoic acid-related orphan receptors γ (ROR-γ/γT) deficiency in three kindreds with CMC and severe mycobacterial disease (53).…”

Section: Significancementioning

confidence: 99%

“…These patients display dysfunctional IL-17F and -17A/F (IL-17F mutations) or dysfunctional responses to IL-17A, -17A/F, and -17F (mutations in IL-17RA, -17RC, and ACT1). In patients with AD HIES (54)(55)(56)(57), AD STAT1 GOF (13, 18, 21, 27-29, 32, 35, 36, 38, 39, 41, 42, 45, 46, 49), or AR ROR-γ/γT deficiency (53), the development of IL-17A/F-producing T cells is impaired. Finally, patients with AR APS-1 have high titers of neutralizing auto-Abs against IL-17A and -17F (58,59).…”

Section: Significancementioning

confidence: 99%

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

Lévy

Okada

Béziat

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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152

134

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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.

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Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

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

Lévy

Okada

Béziat

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

152

134

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“…These patients also presented various other infectious and autoimmune features. Surprisingly, we identified biallelic mutations of RAR-related orphan receptor C (RORC) in patients with both CMC and mycobacterial disease (76). RORC encodes the isoforms and transcription factors ROR-γ and ROR-γT, which govern Th17 development in mice.…”

Section: Chronic Mucocutaneous Candidiasismentioning

confidence: 99%

Severe infectious diseases of childhood as monogenic inborn errors of immunity

Casanova

2015

Proc. Natl. Acad. Sci. U.S.A.

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202

163

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This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

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“…Immunity to Mycobacterium and Candida is impaired in these patients, explained by a defective IFN-γ response to Mycobacterium and the absence of IL-17A/F, respectively (15).…”

Section: Rorc Physiological Roles Have Been Identified In Rorc-deficimentioning

confidence: 99%

Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations

Guntermann

Piaia

Hamel³

et al. 2017

JCI Insight

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Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations

Cited by 381 publications

References 66 publications

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

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

Severe infectious diseases of childhood as monogenic inborn errors of immunity

Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations

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