Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 23561, Taiwan.
Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
BMC Med Inform Decis Mak. 2021 Feb 10;21(1):49. doi: 10.1186/s12911-020-01380-y.
Rheumatoid arthritis (RA) is an autoimmune disorder with systemic inflammation and may be induced by oxidative stress that affects an inflamed joint. Our objectives were to examine isotypes of autoantibodies against 4-hydroxy-2-nonenal (HNE) modifications in RA and associate them with increased levels of autoantibodies in RA patients.
Serum samples from 155 female patients [60 with RA, 35 with osteoarthritis (OA), and 60 healthy controls (HCs)] were obtained. Four novel differential HNE-modified peptide adducts, complement factor H (CFAH), haptoglobin (HPT), immunoglobulin (Ig) kappa chain C region (IGKC), and prothrombin (THRB), were re-analyzed using tandem mass spectrometric (MS/MS) spectra (ProteomeXchange: PXD004546) from RA patients vs. HCs. Further, we determined serum protein levels of CFAH, HPT, IGKC and THRB, HNE-protein adducts, and autoantibodies against unmodified and HNE-modified peptides. Significant correlations and odds ratios (ORs) were calculated.
Levels of HPT in RA patients were greatly higher than the levels in HCs. Levels of HNE-protein adducts and autoantibodies in RA patients were significantly greater than those of HCs. IgM anti-HPT HNE, IgM anti-IGKC, and IgM anti-IGKC HNE may be considered as diagnostic biomarkers for RA. Importantly, elevated levels of IgM anti-HPT HNE, IgM anti-IGKC, and IgG anti-THRB were positively correlated with the disease activity score in 28 joints for C-reactive protein (DAS28-CRP). Further, the ORs of RA development through IgM anti-HPT HNE (OR 5.235, p < 0.001), IgM anti-IGKC (OR 12.655, p < 0.001), and IgG anti-THRB (OR 5.761, p < 0.001) showed an increased risk. Lastly, we incorporated three machine learning models to differentiate RA from HC and OA, and performed feature selection to determine discriminative features. Experimental results showed that our proposed method achieved an area under the receiver operating characteristic curve of 0.92, which demonstrated that our selected autoantibodies combined with machine learning can efficiently detect RA.
This study discovered that some IgG- and IgM-NAAs and anti-HNE M-NAAs may be correlated with inflammation and disease activity in RA. Moreover, our findings suggested that IgM anti-HPT HNE, IgM anti-IGKC, and IgG anti-THRB may play heavy roles in RA development.
类风湿关节炎（RA）是一种具有全身炎症的自身免疫性疾病，可能是由影响炎症关节的氧化应激引起的。我们的目的是研究针对 4-羟基-2-壬烯醛（HNE）修饰的自身抗体的同种型在 RA 中的变化，并将其与 RA 患者中自身抗体水平的升高联系起来。
从 155 名女性患者（60 名 RA 患者、35 名骨关节炎（OA）患者和 60 名健康对照组（HC））中获得血清样本。使用串联质谱（MS/MS）图谱（ProteomeXchange：PXD004546）重新分析针对 4-羟基-2-壬烯醛（HNE）修饰的 4 种新型差异肽加合物，补体因子 H（CFAH）、触珠蛋白（HPT）、免疫球蛋白（Ig）κ 链 C 区（IGKC）和凝血酶原（THRB）。此外，我们还测定了 CFAH、HPT、IGKC 和 THRB 的血清蛋白水平、HNE-蛋白加合物和针对未修饰和 HNE 修饰肽的自身抗体。计算了显著相关性和优势比（ORs）。
RA 患者的 HPT 水平明显高于 HC。RA 患者的 HNE-蛋白加合物和自身抗体水平明显高于 HC。IgM 抗-HPT HNE、IgM 抗-IGKC 和 IgM 抗-IGKC HNE 可被视为 RA 的诊断生物标志物。重要的是，IgM 抗-HPT HNE、IgM 抗-IGKC 和 IgG 抗-THRB 的水平与 C 反应蛋白（DAS28-CRP）的 28 个关节的疾病活动评分呈正相关。此外，IgM 抗-HPT HNE（OR 5.235，p<0.001）、IgM 抗-IGKC（OR 12.655，p<0.001）和 IgG 抗-THRB（OR 5.761，p<0.001）的 RA 发病的 OR 显示出更高的风险。最后，我们将三种机器学习模型纳入区分 RA 与 HC 和 OA 的模型中，并进行了特征选择以确定有区别的特征。实验结果表明，我们提出的方法在接收者操作特征曲线下的面积为 0.92，这表明我们选择的自身抗体与机器学习相结合可以有效地检测 RA。
本研究发现，一些 IgG 和 IgM-NAAs 以及抗 HNE M-NAAs 可能与 RA 中的炎症和疾病活动有关。此外，我们的研究结果表明，IgM 抗-HPT HNE、IgM 抗-IGKC 和 IgG 抗-THRB 可能在 RA 发病中起重要作用。
