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. 2016 Dec 20;113(51):E8277-E8285.
doi: 10.1073/pnas.1618300114. Epub 2016 Dec 7.

Genetic, Immunological, and Clinical Features of Patients With Bacterial and Fungal Infections Due to Inherited IL-17RA Deficiency

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Free PMC article

Genetic, Immunological, and Clinical Features of Patients With Bacterial and Fungal Infections Due to Inherited IL-17RA Deficiency

Romain Lévy et al. Proc Natl Acad Sci U S A. .
Free PMC article

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.

Keywords: candidiasis; genetics; immunodeficiency.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
The 12 kindreds with AR IL-17RA deficiency. (A) Pedigree of 12 families, with their genotypes. Kindred A has already been reported elsewhere (9). E? indicates individuals whose genetic status could not be evaluated; m, mutation. (B) Schematic diagram of the IL-17RA protein, with its extracellular (EC), transmembrane (TM), intracellular (IC), and SEFIR [SEF (similar expression to fibroblast growth factor genes) and IL-17R] domains and the positions affected by the mutations.
Fig. S1.
Fig. S1.
Immunophenotyping. (A) Frequency of naïve (CD45RA+CCR7+), central memory (CD45RACCR7+), effector memory (CD45RACCR7), and EMRA (CD45RA+CCR7) cells among the CD4+ and CD8+ T cells of patients (n = 5), healthy relatives (n = 6), and controls (n = 28). (B) Frequency of CD27+ memory cells in the B-cell compartment of patients (n = 5), healthy relatives (n = 6) and controls (n = 23). (C) Frequency of Treg (FoxP3+CD25+) among CD4+ T cells and frequency of γδ T cells (CD3+TCRγδ +) and mucosal-associated invariant T (CD161+Va7.2+) cells among the total CD3+ T cells of patients (n = 5), healthy relatives (n = 6), and controls (n = 23). (D) Frequency of T helper (Th) subsets within the CD4+ memory compartment of patients (n = 3), healthy relatives (n = 6), and controls (n = 28). Subsets were defined as follows: Tfh (CXCR5+), Th1 (CXCR5CXCR3+CCR4CCR6), Th2 (CXCR5CXCR3CCR4+CCR6), Th1* (CXCR5CXCR3+CCR4CCR6+), and Th17 (CXCR5CXCR3CCR4+CCR6+). (E) Immunophenotyping of NK cells showing total NK cell frequency in lymphocytes (Left), the frequency of CD56bright cells within the NK cell compartment (Center), and the terminal differentiation profile of the CD56dim compartment (Right), as assessed by the distribution of NKG2A and KIR on cells from patients (n = 5), healthy relatives (n = 6–8), and controls (n = 23). Horizontal bars represent the median value. Ctl, controls; Pat, patients; Rel, relatives.
Fig. 2.
Fig. 2.
IL-17RA expression. (A and B) IL-17RA expression in SV40-immortalized (A) and primary (B) fibroblasts from healthy controls and patients. (C) IL-17RA expression in T cells (CD3+), B cells (CD19+), natural killer cells (CD3CD56+), and monocytes (CD14+) from healthy controls and three patients. Isotype control, dashed lines; IL-17RA–specific antibody, solid lines.
Fig. 3.
Fig. 3.
Function of the mutant IL-17RA alleles. IL-6 and GRO-α fold induction measured in the supernatants of SV40-immortalized fibroblasts from two healthy controls and five patients, after 24 h of stimulation with IL-17A, -17F, -17A/F (100 ng/mL), or TNF-α (20 ng/mL), as assessed by ELISA. Means of three independent experiments are shown. Error bars represent the SD.
Fig. 4.
Fig. 4.
Complementation of IL-17RA deficiency. IL-6 production, measured by ELISA, in the supernatants of SV40-immortalized fibroblasts from a control, P1, and P5, after transfection with the empty pORF9mcs plasmid or the pORF9-hIL17RA plasmid, after 24 h of stimulation with IL-17A (100 ng/mL) alone or in combination with TNF-α (20 ng/mL) is shown. Means of three technical replicates are shown. Error bars represent the SD. One experiment representative of the three carried out is shown. NS, not stimulated.
Fig. S2.
Fig. S2.
The p.D387N IL-17RA allele impairs IL-17RA/ACT1 interaction. HEK293 cells were transiently transfected with a plasmid encoding FLAG-tagged ACT1 together with plasmids encoding V5-tagged WT–IL-17RA or D387N–IL-17RA. Whole-cell lysates (WCL) were subjected to immunoprecipitation with anti-FLAG antibody. Western blot analysis was performed with anti-FLAG and -V5 antibodies.
Fig. S3.
Fig. S3.
Function of the mutant IL-17RA alleles. IL-6 and GRO-α production, measured by ELISA in the supernatants of SV40-immortalized (A) and primary fibroblasts (B) from two healthy controls and patients, after 24 h of stimulation with IL-17A, -17F, -17A/F (100 ng/mL), and TNF-α (20 ng/mL) alone or in combination. Means of three technical replicates are shown. Error bars represent the SD. (C) BD2 mRNA induction in SV40-immortalized fibroblasts from two healthy controls and from P1 and P5 after 24 h of stimulation with IL-17A (100 ng/mL) alone or with TNF-α (20 ng/mL). Means of three technical replicates are shown. Error bars represent the SD. Data are representative of two independent experiments. NS, not stimulated.
Fig. S4.
Fig. S4.
The p.D387N allele is loss of function for the response to IL-17E/IL-25. PBMCs from three controls, P5, P6, and two healthy relatives were cultured with thymic stromal lymphopoietin for 24 h, harvested, and stimulated with IL-2 and -17E/IL-25 for an additional 72 h. IL-5 was determined in the culture supernatants by ELISA. Error bars represent the SD. NS, not stimulated.
Fig. S5.
Fig. S5.
Complementation of IL-17RA deficiency. IL-17RA expression in SV40-immortalized fibroblasts from a control, P1, and P5 transfected with the empty pORF9mcs plasmid or the pORF9-hIL17RA plasmid. Isotype control, dashed lines; anti–IL-17RA antibody, solid lines.
Fig. S6.
Fig. S6.
GRO-α production, measured by ELISA, in the supernatants of SV40-immortalized fibroblasts from a control, P1, and P5 after transfection with the empty pORF9mcs plasmid or the pORF9-hIL17RA plasmid and stimulation for 24 h with IL-17A (100 ng/mL) alone or with TNF-α (20 ng/mL). Means of three technical replicates are shown. Error bars represent the SD. One experiment representative of the three carried out is shown. NS, not stimulated.
Fig. 5.
Fig. 5.
IL-17–producing T cells. (A) Percentages of memory CD4+ T cells producing IL-17A, -22, -17F, and IFN-γ, as determined ex vivo by flow cytometry, after 12 h of stimulation with PMA and ionomycin. Horizontal lines indicate the mean value. (B) IL-17A and -22 production, measured by ELISA, in the supernatants of whole blood after 24 h of stimulation with PMA and ionomycin. Horizontal lines indicate the mean value. These two experiments were conducted in parallel in 30 healthy controls, 8 healthy relatives, and 7 patients from kindreds C, D, E, and H. *P < 0.05; **P < 0.005; ***P < 0.0005 (two-tailed Mann–Whitney test).
Fig. S7.
Fig. S7.
Response to bacteria and yeasts in whole blood. Production of IL-17A, -6, and IFN-γ, measured by ELISA, in whole blood from four controls (black circles), four patients (red circles), and three healthy relatives (black triangles) after 3 d of stimulation is shown. Horizontal bars represent the mean value. BCG, Bacille de Calmette et Guérin; HKCA, heat-killed C. albicans; HKSA, heat-killed S. aureus; HKSC, heat-killed S. cerevisiae; LPS, lipopolysaccharide; NS, not stimulated; VSV, vesicular stomatitis virus.

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