Abstract

Candidiasis is characterized by susceptibility to recurrent or persistent infections caused by Candida spp., typically Candida albicans, of cutaneous and mucosal surfaces. In this report, function and frequency of Th17 cells as well as genetics of patients susceptible to mucocutaneous candidiasis were studied. For patients, T-cell proliferation tests in response to Candida antigen, Th17 cell proportions, and STAT1 phosphorylation were evaluated through flow cytometry. Expression of IL17A, IL17F and IL22 genes were measured by real-time quantitative PCR. At the same time, whole exome sequencing was performed for all patients. We identified two heterozygous substitutions, one: c.821G > A (p. R274Q) was found in a multiplex family with three individuals affected, the second one: c.812A > C (p. Q271P) was found in a sporadic case. Both mutations are located in the coiled-coil domain (CCD) of STAT1. The frequency of Th17 cells, IL17A, IL17F, and IL22 gene expression in patients’ peripheral blood mononuclear cells (PBMCs), and T-cell proliferation to Candida antigens were significantly reduced in the patients as compared to healthy controls. An increased STAT1 phosphorylation was observed in patients’ PBMCs upon interferon (IFN)-γ stimulation as compared to healthy controls. We report two different but neighboring heterozygous mutations, located in exon 10 of the STAT1 gene, in four Iranian patients with CMC, one of whom also had hypothyroidism. These mutations were associated with impaired T cell proliferation to Candida antigen, low Th17 cell proportions, and increased STAT1 phosphorylation upon IFN-γ. We suggest that interfering with STAT1 phosphorylation might be a promising way for potential therapeutic measurements for such patients.

中文翻译：

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两个常染色体显性遗传性慢性皮肤黏膜念珠菌病伊朗家族的两个 STAT1 功能获得性突变的功能分析

摘要

念珠菌病的特征是对皮肤和粘膜表面念珠菌属（通常为白色念珠菌）引起的复发性或持续性感染的易感性。在这份报告中，研究了 Th17 细胞的功能和频率以及易患皮肤粘膜念珠菌病的患者的遗传学。对于患者，通过流式细胞术评估了响应念珠菌抗原的T 细胞增殖测试、Th17 细胞比例和 STAT1 磷酸化。表达IL-17A，IL-17F和IL-22通过实时定量PCR测量基因。同时，对所有患者进行全外显子组测序。我们确定了两个杂合子替换，一个：c.821G > A (p. R274Q) 在一个有 3 个受影响的个体的多重家族中被发现，第二个：c.812A > C (p. Q271P) 在一个散发病例中被发现。这两个突变都位于 STAT1 的卷曲螺旋结构域 (CCD)。Th17细胞、IL17A、IL17F和IL22基因在患者外周血单核细胞（PBMC）中的表达频率，以及T细胞对念珠菌的增殖与健康对照相比，患者体内的抗原显着减少。与健康对照相比，在干扰素 (IFN)-γ 刺激后患者的 PBMC 中观察到 STAT1 磷酸化增加。我们报告了四名伊朗 CMC 患者的STAT1基因外显子 10 中的两种不同但相邻的杂合突变，其中一名患者还患有甲状腺功能减退症。这些突变与对念珠菌抗原的T 细胞增殖受损、Th17 细胞比例低以及 IFN-γ 后 STAT1 磷酸化增加有关。我们建议干扰 STAT1 磷酸化可能是对此类患者进行潜在治疗测量的有前途的方法。