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Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis.

Ling Y, Cypowyj S, Aytekin C, Galicchio M, Camcioglu Y, Nepesov S, Ikinciogullari A, Dogu F, Belkadi A, Levy R, Migaud M, Boisson B, Bolze A, Itan Y, Goudin N, Cottineau J, Picard C, Abel L, Bustamante J, Casanova JL, Puel A - J. Exp. Med. (2015)

Bottom Line: The defect is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers.However, in contrast to what is observed for the IL-17RA- and ACT1-deficient patients tested, the response to IL-17E (IL-25) is maintained in these IL-17RC-deficient patients.These experiments of nature indicate that human IL-17RC is essential for mucocutaneous immunity to C. albicans but is otherwise largely redundant.

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Affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, French Institute of Health and Medical Research (INSERM) U1163, 75015 Paris, France Imagine Institute, Paris Descartes University, 75015 Paris, France.

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Production of IL-6 and GRO-α by the patients’ fibroblasts in responses to IL-17 cytokines, after transfection with the WT or mutant IL17RC alleles. (A and B) IL-6 and GRO-α production by SV40-immortalized fibroblasts from a control, P1, P2, and an IL-17RA–deficient patient transfected with an empty vector (mock) or an IL-17RC vector encoding the WT or each one of the mutant (Q138*, R376*, or R378*) proteins, after 24 h of stimulation with 100 ng/ml IL-17A, as determined by ELISA on supernatants. NS, nonstimulated; NT, not transfected. Means ± SD (error bars) of three independent experiments are shown. Statistical analyses were performed by the nonparametric statistical test (Mann–Whitney test; **, P < 0.01). The experiments were repeated at least three times.
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fig7: Production of IL-6 and GRO-α by the patients’ fibroblasts in responses to IL-17 cytokines, after transfection with the WT or mutant IL17RC alleles. (A and B) IL-6 and GRO-α production by SV40-immortalized fibroblasts from a control, P1, P2, and an IL-17RA–deficient patient transfected with an empty vector (mock) or an IL-17RC vector encoding the WT or each one of the mutant (Q138*, R376*, or R378*) proteins, after 24 h of stimulation with 100 ng/ml IL-17A, as determined by ELISA on supernatants. NS, nonstimulated; NT, not transfected. Means ± SD (error bars) of three independent experiments are shown. Statistical analyses were performed by the nonparametric statistical test (Mann–Whitney test; **, P < 0.01). The experiments were repeated at least three times.

Mentions: We investigated whether the three IL17RC mutations identified had any functional consequences in terms of the response to IL-17 cytokines by testing the responses of the patients’ fibroblasts to various concentrations (10 and 100 ng/ml) of recombinant IL-17A and IL-17F homodimers and IL-17A/F heterodimers. Unlike fibroblasts from healthy controls, the patients’ fibroblasts did not respond to any of the three IL-17 dimers, whatever the concentration of cytokine used. These results were similar to those obtained for the IL-17RA–deficient patient carrying the homozygous Q284* mutation tested in parallel, in terms of IL-6 and GRO-α (growth-regulated oncogene-α) induction, as assessed by ELISA (Fig. 6, A and B). In contrast, the responses of the patients’ fibroblasts to IL-1β stimulation were within the same range as the controls. Transfection of the patients’ fibroblasts with a WT IL17RC construct, but not with an empty vector or with any of the three mutant constructs, restored the response to IL-17 cytokines in the patients’ fibroblasts (Fig. 7, A and B). In contrast, PBMCs from P2 and P3 stimulated with IL-17E/IL-25 in the presence of IL-2 produced IL-5 to levels in the control range, in contrast to what was observed for PBMCs from an IL-17RA–deficient patient. Thus, IL-17E/IL-25 signaling in humans is dependent on IL-17RA but not IL-17RC (Fig. 8). The three patients described here display a complete form of AR IL-17RC deficiency, with a lack of cellular responses to IL-17A and IL-17F homo- and heterodimers but normal responses to IL-17E/IL-25.


Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis.

Ling Y, Cypowyj S, Aytekin C, Galicchio M, Camcioglu Y, Nepesov S, Ikinciogullari A, Dogu F, Belkadi A, Levy R, Migaud M, Boisson B, Bolze A, Itan Y, Goudin N, Cottineau J, Picard C, Abel L, Bustamante J, Casanova JL, Puel A - J. Exp. Med. (2015)

Production of IL-6 and GRO-α by the patients’ fibroblasts in responses to IL-17 cytokines, after transfection with the WT or mutant IL17RC alleles. (A and B) IL-6 and GRO-α production by SV40-immortalized fibroblasts from a control, P1, P2, and an IL-17RA–deficient patient transfected with an empty vector (mock) or an IL-17RC vector encoding the WT or each one of the mutant (Q138*, R376*, or R378*) proteins, after 24 h of stimulation with 100 ng/ml IL-17A, as determined by ELISA on supernatants. NS, nonstimulated; NT, not transfected. Means ± SD (error bars) of three independent experiments are shown. Statistical analyses were performed by the nonparametric statistical test (Mann–Whitney test; **, P < 0.01). The experiments were repeated at least three times.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC4419340&req=5

fig7: Production of IL-6 and GRO-α by the patients’ fibroblasts in responses to IL-17 cytokines, after transfection with the WT or mutant IL17RC alleles. (A and B) IL-6 and GRO-α production by SV40-immortalized fibroblasts from a control, P1, P2, and an IL-17RA–deficient patient transfected with an empty vector (mock) or an IL-17RC vector encoding the WT or each one of the mutant (Q138*, R376*, or R378*) proteins, after 24 h of stimulation with 100 ng/ml IL-17A, as determined by ELISA on supernatants. NS, nonstimulated; NT, not transfected. Means ± SD (error bars) of three independent experiments are shown. Statistical analyses were performed by the nonparametric statistical test (Mann–Whitney test; **, P < 0.01). The experiments were repeated at least three times.
Mentions: We investigated whether the three IL17RC mutations identified had any functional consequences in terms of the response to IL-17 cytokines by testing the responses of the patients’ fibroblasts to various concentrations (10 and 100 ng/ml) of recombinant IL-17A and IL-17F homodimers and IL-17A/F heterodimers. Unlike fibroblasts from healthy controls, the patients’ fibroblasts did not respond to any of the three IL-17 dimers, whatever the concentration of cytokine used. These results were similar to those obtained for the IL-17RA–deficient patient carrying the homozygous Q284* mutation tested in parallel, in terms of IL-6 and GRO-α (growth-regulated oncogene-α) induction, as assessed by ELISA (Fig. 6, A and B). In contrast, the responses of the patients’ fibroblasts to IL-1β stimulation were within the same range as the controls. Transfection of the patients’ fibroblasts with a WT IL17RC construct, but not with an empty vector or with any of the three mutant constructs, restored the response to IL-17 cytokines in the patients’ fibroblasts (Fig. 7, A and B). In contrast, PBMCs from P2 and P3 stimulated with IL-17E/IL-25 in the presence of IL-2 produced IL-5 to levels in the control range, in contrast to what was observed for PBMCs from an IL-17RA–deficient patient. Thus, IL-17E/IL-25 signaling in humans is dependent on IL-17RA but not IL-17RC (Fig. 8). The three patients described here display a complete form of AR IL-17RC deficiency, with a lack of cellular responses to IL-17A and IL-17F homo- and heterodimers but normal responses to IL-17E/IL-25.

Bottom Line: The defect is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers.However, in contrast to what is observed for the IL-17RA- and ACT1-deficient patients tested, the response to IL-17E (IL-25) is maintained in these IL-17RC-deficient patients.These experiments of nature indicate that human IL-17RC is essential for mucocutaneous immunity to C. albicans but is otherwise largely redundant.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, French Institute of Health and Medical Research (INSERM) U1163, 75015 Paris, France Imagine Institute, Paris Descartes University, 75015 Paris, France.

Show MeSH
Related in: MedlinePlus