Metabolomics Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11564, Saudi Arabia.
Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925(98), Riyadh 11461, Saudi Arabia.
Int J Mol Sci. 2023 Jan 26;24(3):2406. doi: 10.3390/ijms24032406.
Hyper-IgE Syndrome (HIES) is a heterogeneous group of primary immune-deficiency disorders characterized by elevated levels of IgE, eczema, and recurrent skin and lung infections. HIES that is autosomally dominant in the signal transducer and activator of transcription 3 (STAT3), and autosomal recessive mutations in phosphoglucomutase 3 (PGM3) have been reported in humans. An early diagnosis, based on clinical suspicion and immunological assessments, is challenging. Patients' metabolomics, proteomics, and cytokine profiles were compared to DOCK 8-deficient and atopic dermatitis patients. The PGM3 metabolomics profile identified significant dysregulation in hypotaurine, hypoxanthine, uridine, and ribothymidine. The eight proteins involved include bifunctional arginine demethylase and lysyl hydroxylase (JMJD1B), type 1 protein phosphatase inhibitor 4 (PPI 4), and platelet factor 4 which aligned with an increased level of the cytokine GCSF. Patients with STAT3 deficiency, on the other hand, showed significant dysregulation in eight metabolites, including an increase in protocatechuic acid, seven proteins including ceruloplasmin, and a plasma protease C1 inhibitor, in addition to cytokine VEGF being dysregulated. Using multi-omics profiling, we identified the dysregulation of endothelial growth factor (EGFR) and tumor necrosis factor (TNF) signaling pathways in PGM3 and STAT3 patients, respectively. Our findings may serve as a stepping stone for larger prospective HIES clinical cohorts to validate their future use as biomarkers.
高免疫球蛋白 E 综合征（HIES）是一组异质性的原发性免疫缺陷疾病，其特征是 IgE 水平升高、湿疹和反复的皮肤和肺部感染。在人类中，已经报道了信号转导和转录激活因子 3（STAT3）的常染色体显性突变和磷酸葡萄糖变位酶 3（PGM3）的常染色体隐性突变导致的 HIES。基于临床怀疑和免疫评估的早期诊断具有挑战性。将患者的代谢组学、蛋白质组学和细胞因子谱与 DOCK8 缺陷和特应性皮炎患者进行了比较。PGM3 的代谢组学图谱确定了 Hypotaurine、Hypoxanthine、Uridine 和 Ribothymidine 的显著失调。涉及的 8 种蛋白质包括双功能精氨酸脱甲基酶和赖氨酰羟化酶（JMJD1B）、1 型蛋白磷酸酶抑制剂 4（PPI4）和血小板因子 4，这与细胞因子 GCSF 的水平升高相一致。另一方面，STAT3 缺陷患者的八种代谢物出现显著失调，包括原儿茶酸增加，七种蛋白质包括铜蓝蛋白和血浆蛋白酶 C1 抑制剂，以及细胞因子 VEGF 失调。使用多组学分析，我们分别确定了 PGM3 和 STAT3 患者中内皮生长因子（EGFR）和肿瘤坏死因子（TNF）信号通路的失调。我们的发现可以为更大的前瞻性 HIES 临床队列提供一个基石，以验证它们未来作为生物标志物的用途。
