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