Jacob Minnie, Masood Afshan, Shinwari Zakiya, Abdel Jabbar Mai, Al-Mousa Hamoud, Arnaout Rand, AlSaud Bandar, Dasouki Majed, Alaiya Ayodele A, Abdel Rahman Anas M
Metabolomics Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
Front Allergy. 2021 Nov 29;2:774902. doi: 10.3389/falgy.2021.774902. eCollection 2021.
Dedicator of cytokinesis 8 deficiency is an autosomal recessive primary immune deficiency disease belonging to the group of hyperimmunoglobulinemia E syndrome (HIES). The clinical phenotype of dedicator of cytokinesis 8 (DOCK8) deficiency, characterized by allergic manifestations, increased infections, and increased IgE levels, overlaps with the clinical presentation of atopic dermatitis (AD). Despite the identification of metabolomics and cytokine biomarkers, distinguishing between the two conditions remains clinically challenging. The present study used a label-free untargeted proteomics approach using liquid-chromatography mass spectrometry with network pathway analysis to identify the differentially regulated serum proteins and the associated metabolic pathways altered between the groups. Serum samples from DOCK8 ( = 10), AD ( = 9) patients and healthy control (Ctrl) groups ( = 5) were analyzed. Based on the proteomics profile, the PLS-DA score plot between the three groups showed a clear group separation and sample clustering (2 = 0.957, 2 = 0.732). Significantly differentially abundant proteins ( < 0.05, FC cut off 2) were identified between DOCK8-deficient and AD groups relative to Ctrl ( = 105, and = 109) and between DOCK8-deficient and AD groups ( = 85). Venn diagram analysis revealed a differential regulation of 24 distinct proteins from among the 85 between DOCK8-deficient and AD groups, including claspin, haptoglobin-related protein, immunoglobulins, complement proteins, fibulin, and others. Receiver-operating characteristic curve (ROC) analysis identified claspin and haptoglobin-related protein, as potential biomarkers with the highest sensitivity and specificity (AUC = 1), capable of distinguishing between patients with DOCK8 deficiency and AD. Network pathway analysis between DOCK8-deficiency and AD groups revealed that the identified proteins centered around the dysregulation of ERK1/2 signaling pathway. Herein, proteomic profiling of DOCK8-deficiency and AD groups was carried out to determine alterations in the proteomic profiles and identify a panel of the potential proteomics biomarker with possible diagnostic applications. Distinguishing between DOCK8-deficiency and AD will help in the early initiation of treatment and preventing complications.
细胞分裂素8缺陷相关蛋白缺乏症是一种常染色体隐性原发性免疫缺陷疾病，属于高免疫球蛋白E综合征（HIES）。细胞分裂素8（DOCK8）缺陷的临床表型以过敏表现、感染增加和IgE水平升高为特征，与特应性皮炎（AD）的临床表现重叠。尽管已经确定了代谢组学和细胞因子生物标志物，但在临床上区分这两种疾病仍然具有挑战性。本研究采用无标记非靶向蛋白质组学方法，结合液相色谱质谱联用和网络通路分析，以鉴定两组之间差异调节的血清蛋白和相关代谢通路。分析了DOCK8组（n = 10）、AD组（n = 9）患者和健康对照组（Ctrl，n = 5）的血清样本。基于蛋白质组学图谱，三组之间的PLS-DA得分图显示出明显的组间分离和样本聚类（R2 = 0.957，Q2 = 0.732）。相对于Ctrl组（n = 105），在DOCK8缺陷组和AD组之间（n = 109）以及DOCK8缺陷组和AD组之间（n = 85）鉴定出显著差异丰富的蛋白质（p < 0.05，FC截止值为2）。维恩图分析显示，在DOCK8缺陷组和AD组之间的85种蛋白质中有24种不同蛋白质存在差异调节，包括 claspin、触珠蛋白相关蛋白、免疫球蛋白、补体蛋白、纤连蛋白等。受试者工作特征曲线（ROC）分析确定claspin和触珠蛋白相关蛋白是具有最高敏感性和特异性（AUC = 1）的潜在生物标志物，能够区分DOCK8缺陷患者和AD患者。DOCK8缺陷组和AD组之间的网络通路分析表明，鉴定出的蛋白质集中在ERK1/2信号通路的失调周围。在此，对DOCK8缺陷组和AD组进行了蛋白质组学分析，以确定蛋白质组学图谱的变化，并鉴定一组可能具有诊断应用价值的潜在蛋白质组学生物标志物。区分DOCK8缺陷和AD将有助于早期开始治疗并预防并发症。
