IL-17 receptor A and adenosine deaminase 2 deficiency in siblings with recurrent infections and chronic inflammation

Fellmann, Florence; Angelini, Federica; Wassenberg, Jacqueline; Perreau, Matthieu; Ramirez, Natalia Arenas; Simon, Gregoire; Boyman, Onur; Demaria, Olivier; Christen‐Zaech, Stéphanie; Hohl, Daniel; Belfiore, Marco; Scheven-Gête, Annette von; Gilliet, Michel; Bochud, Pierre–Yves; Perrin, Yannick; Popovic, Maya Beck; Bart, Pierre‐Alexandre; Beckmann, Jacques S.; Martinet, Danielle; Hofer, Michaël

doi:10.1016/j.jaci.2015.07.053

Cited by 57 publications

(48 citation statements)

References 26 publications

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“…The detection of surface IL-17RA should not, therefore, exclude a diagnosis of IL-17RA deficiency, as previously shown for other cytokine receptors, such as IFN-γR1 (66-69), IFN-γR2 (70,71), IL-12Rβ1 (72,73), and IL-10RA (74,75). IL-17RA deficiency has recently been reported in two siblings from Sri Lanka (60). These siblings are homozygous for a large chromosomal deletion, also encompassing CECR1 (encoding ADA2) and XKR3 (encoding X Kell blood group-related 3).…”

Section: Discussionmentioning

confidence: 89%

“…Staphylococcal skin disease is frequently observed in patients with ACT1 and IL-17RA deficiencies, but has not been reported in patients with IL-17F and -17RC deficiencies (9)(10)(11)60). This observation suggests that staphylococcal disease may be partly due to an impairment of IL-17E/IL-25 responses, which normally require IL-17RA and ACT1, but neither IL-17F nor IL-17RC.…”

Section: Significancementioning

confidence: 97%

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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.

150

127

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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: Discussionmentioning

confidence: 89%

Section: Significancementioning

confidence: 97%

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.

150

127

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“…The patient, born to consanguineous Moroccan parents, presented early-onset (at one month) CMC and cutaneous Staphylococcus aureus infection (at five months), and was homozygous for a nonsense (Q284*) mutation of IL17RA . A large homozygous deletion encompassing IL17RA and ADA2 , encoding adenosine deaminase 2, was subsequently identified in two siblings from Sri Lanka with CMC, S. aureus skin infection, and chronic inflammation [25]. Since 2011, AR IL-17RA deficiency, resulting from diverse homozygous nonsense (R66*, Q86*, Q284*, and Y384*), missense (D387N), frameshift indel (H38Afs*15, C57Yfs*5, L90Cfs*30, P257Rfs*16, N440Rfs*50, and Y591Sfs*29), splice site (c.163+1G>A) mutations, and large deletions (770 kb at 22q11.1 ), has been reported in 23 patients from 13 unrelated kindreds originating from Morocco, Turkey, Japan, Saudi Arabia, Algeria, Argentina, and Sri Lanka [25,26].…”

Section: Chronic Mucocutaneous Candidiasis: Inborn Errors Of Il-17 Immentioning

confidence: 99%

“…All patients displayed early-onset (before 6 months of age) CMC affecting mucosal sites (oral thrush and anogenital candidiasis), the skin, scalp, and nails. In addition, 16 of these patients presented staphylococcal skin diseases (abscesses, folliculitis, furunculosis, and crusted pustules on the face and scalp, sometimes spreading to the shoulders and arms), and 10 patients were prone to recurrent infections of the respiratory tract, including otitis, sinusitis, bronchitis, and lobar pneumonia [25,26]. Consistent with the first report, fibroblasts derived from the skin of the patients did not respond to IL-17A and IL-17F homodimers and heterodimers, whereas no response to IL-25 was detected in their leukocytes, including cells from the patient carrying the only missense D387N mutation with a receptor detectable by flow cytometry at the surface of fibroblasts and monocytes [23,26,27].…”

Section: Chronic Mucocutaneous Candidiasis: Inborn Errors Of Il-17 Immentioning

confidence: 99%

Inborn errors of immunity underlying fungal diseases in otherwise healthy individuals

Vinh

Casanova³

et al. 2017

Current Opinion in Microbiology

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It has been estimated that there are at least 1.5 million fungal species, mostly present in the environment, but only a few of these fungi cause human disease. Most fungal diseases are self-healing and benign, but some are chronic or life-threatening. Acquired and inherited defects of immunity, including breaches of mucocutaneous barriers and circulating leukocyte deficiencies, account for most severe modern-day mycoses. Other types of infection typically accompany these fungal infections. More rarely, severe fungal diseases can strike otherwise healthy individuals. Historical reports of fungi causing chronic peripheral (e.g. affecting the nails, skin, hair) infections, and invasive disease (e.g. brain, lungs, liver), in otherwise healthy patients, can be traced back to the mid-20th century. These fungi typically cause endemic, but not epidemic diseases, are more likely to underlie sporadic than familial cases, and only threaten a small proportion of infected individuals. The basis of this “idiosyncratic” susceptibility has long remained unexplained, but it has recently become apparent that “idiopathic” fungal diseases, in children, teenagers, and even adults, may be caused by single-gene inborn errors of immunity. The study of these unusual primary immunodeficiencies (PIDs) has led to the identification of molecules and cells playing a crucial role in human host defenses against certain fungi at particular anatomic sites. A picture is emerging of inborn errors of IL-17 immunity selectively underlying chronic mucocutaneous candidiasis, with little inter-individual variability, and of inborn errors of CARD9 immunity underlying various life-threatening invasive fungal diseases, differing between patients.

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“…Biallelic CECR1 mutations have also been found in patients presenting with anemia, thrombocytopenia, and splenomegaly, leading to the initial clinical diagnosis of Diamond-Blackfan anemia or storage disease 37 . Recently a biallelic 770-kb deletion of chromosome 22q11.1 encompassing both CECR1 and IL17RA (encoding the IL-17 receptor A) was reported in two siblings with a history of both mucocutaneous infection and early-onset systemic vasculitis 38 . This finding, taken together with the 28-kb deletion in the CECR1 locus reported by Zhou et al 27 , indicates the importance of structural genomic analysis in the genetic diagnosis of DADA2.…”

Section: Deficiency Of Ada2 (Dada2)mentioning

confidence: 99%

Genomics, Biology, and Human Illness

Oda

Kastner

2017

Rheumatic Disease Clinics of North America

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SYNOPSIS The monogenic autoinflammatory diseases are a group of illnesses with prominent rheumatic manifestations that are characterized by genetically-determined recurrent sterile inflammation, and are thus inborn errors of innate immunity. Molecular targeted therapies against inflammatory cytokines such as IL-1 and TNF and intracellular cytokine signaling pathways have proven effective in many cases. Emerging next generation sequencing technologies have accelerated the identification of previously unreported genes causing autoinflammatory diseases. In this review we will cover several of the prominent recent advances in the field of autoinflammatory diseases, including gene discoveries, the elucidation of new pathogenic mechanisms, and the development of effective targeted therapies.

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IL-17 receptor A and adenosine deaminase 2 deficiency in siblings with recurrent infections and chronic inflammation

Cited by 57 publications

References 26 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

Inborn errors of immunity underlying fungal diseases in otherwise healthy individuals

Genomics, Biology, and Human Illness

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