CN113960315A - 一种诊断抗mda5阳性皮肌炎的分子标志物及其应用 - Google Patents
一种诊断抗mda5阳性皮肌炎的分子标志物及其应用 Download PDFInfo
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Abstract
本发明属于生物医药技术领域，具体涉及一种诊断抗MDA5阳性皮肌炎的分子标志物及其应用。一种分子标志物在制备用于诊断抗MDA5阳性皮肌炎的诊断试剂盒中的应用，所述的分子标志物为血清可溶性细胞间黏附分子‑1 ICAM‑1和血管细胞黏附分子‑1 VCAM‑1。实验证明皮肌炎患者ICAM‑1、VCAM‑1水平较正常人升高，并且抗MDA5抗体阳性皮肌炎血清二者水平高于抗MDA5抗体阴性组，ICAM‑1和VCAM‑1作为诊断抗MDA5阳性皮肌炎的标志物，解决了现有技术中抗MDA5抗体的检测方法复杂，试剂盒制作、标准品选择困难，免疫沉淀法操作复杂，无法在临床应用中普及的问题。早期发现升高的黏附分子水平有利于诊断抗MDA5抗体阳性皮肌炎，有利于指导下一步治疗，减少皮肌炎患者疾病恶化及死亡的风险。
Description
技术领域
本发明属于生物医药技术领域，具体涉及一种诊断抗MDA5阳性皮肌炎的分子标志物及其应用。
背景技术
特发性炎性肌病(idiopathic inflammatory myopathy，IIM)是一种以侵害骨骼肌为主的全身性疾病，临床特点为骨骼肌无力、皮肤病变、系统性器官损害以及有特异性抗体的产生。多发性肌炎(polymyositis，PM)和皮肌炎(dermatomyositis，DM)是最常见的两种类型。间质性肺病(interstitial lung disease，ILD)是PM/DM常见的一种并发症，是造成PM/DM患者死亡的主要原因，死亡率大约50%。其中，快速进展性间质性肺病(rapidlyprogressive interstitial lung disease，RP-ILD)死亡率更高，约占50-75%。RP-ILD定义为急性间质性肺炎，在数周或数月内出现呼吸困难或咳嗽加重。因此早期诊断及积极治疗RP-ILD，对改善患者预后至关重要。
日本学者Sato于2005年使用免疫沉淀法首次在CADM患者血清中发现了一种新型的抗体，是大约为140kd的多肽，称之为抗CADM-140抗体。Sato于2009年证实抗CADM-140抗体识别的靶抗原为细胞质蛋白黑色素瘤分化相关基因-5(melanoma differentiation-associated gene 5, MDA5)，该胞质内蛋白参与宿主对双链RNA病毒的免疫防御。抗MDA5抗体阳性皮肌炎发生RP-ILD的比率高于抗MDA5阴性皮肌炎，并且抗MDA5抗体是PM/DM预后不良的独立危险因素。因此，早期发现抗MDA5抗体并采用相应治疗方案，对改善患者预后也至关重要。
抗MDA5抗体检测有免疫沉淀法和酶联免疫吸附测定两种，免疫沉淀法是检测抗MDA5抗体的金标准，但是其劣势在于不能得出定量结果。因此，开发了使用重组MDA5蛋白作为抗原的酶联免疫吸附测定用于常规检测，标准曲线根据具有高滴度抗MDA5抗体的血清而获得。
黏附分子参与白细胞跨内皮迁移，白细胞黏附级联反应中主要参与作用的包括选择素家族、整合素家族、免疫球蛋白超家族。细胞间黏附分子-1(intercellular adhesionmolecule-1，ICAM-1)及血管细胞黏附分子-1(vascular cell adhesion molecule-1，VCAM-1)是免疫球蛋白超家族的主要成员，ICAM-1表达于活化的内皮细胞、白细胞、成纤维细胞、髓样细胞以及某些肿瘤细胞表面，VCAM-1表达于活化的内皮细胞，二者表达升高及血清游离的可溶性ICAM-1、VCAM-1水平升高与自身炎症性疾病和自身免疫性疾病有关，例如类风湿性关节炎、多发性硬化症、炎症性肠病等。ICAM-1和VCAM-1用于诊断抗MDA5阳性皮肌炎的分子标志物未见报道。彻底做到实际意义上的早期诊断以及早期有效治疗，进一步全面系统研究PM/DM的血清抗体全貌，找到用于PM/DM疾病诊断相关的标志物，是PM/DM疾病研究的重点及临床亟待解决的问题。
发明内容
本发明的目的是提供一种诊断抗MDA5阳性皮肌炎的分子标志物及其应用。本发明研究发现皮肌炎患者血清可溶性ICAM-1、VCAM-1水平较正常人升高，并且抗MDA5抗体阳性皮肌炎血清二者水平高于抗MDA5抗体阴性组，血清可溶性细胞间黏附分子-1 ICAM-1和血管细胞黏附分子-1 VCAM-1作为诊断抗MDA5阳性皮肌炎的标志物，解决了现有技术中抗MDA5抗体的检测方法复杂，试剂盒制作、标准品选择困难，免疫沉淀法操作复杂，无法在临床应用中普及的问题。早期发现升高的黏附分子水平有利于诊断抗MDA5抗体阳性皮肌炎，有利于指导下一步治疗，减少皮肌炎患者疾病恶化及死亡的风险。
为实现上述目的，本发明采用以下技术方案。
一种分子标志物在制备用于诊断抗MDA5阳性皮肌炎的诊断试剂盒中的应用，所述的分子标志物为血清可溶性细胞间黏附分子-1 ICAM-1和血管细胞黏附分子-1 VCAM-1。
进一步地，所述的诊断为区分抗MDA5阳性皮肌炎与健康人群。
进一步地，血清可溶性细胞间黏附分子-1 ICAM-1和血管细胞黏附分子-1 VCAM-1使用酶联免疫吸附测定进行定量分析并预测抗MDA5抗体是否存在。
与现有技术相比，本发明具有以下有益效果。
血清可溶性细胞间黏附分子-1 ICAM-1和血管细胞黏附分子-1 VCAM-1诊断抗MDA5阳性皮肌炎的标志物，解决了现有技术中抗MDA5抗体的检测方法复杂，试剂盒制作、标准品选择困难，免疫沉淀法操作复杂，无法在临床应用中普及的问题。
抗MDA5抗体阳性皮肌炎的临床特征是严重皮肤和肺部受累而肌炎较轻或肌肉无累及。局部组织炎症如类风湿关节炎的滑膜组织、系统性红斑狼疮的肾组织、急性肺损伤的肺组织均可发现异常浸润的白细胞，以及黏附分子ICAM-1、VCAM-1的表达增加。因此，ICAM-1、VCAM-1水平可以预测皮肌炎患者局部组织受累程度进而协助诊断抗MDA5阳性皮肌炎。血清可溶性黏附分子使用酶联免疫吸附测定即可进行定量分析并预测抗MDA5抗体是否存在，诊断准确度较好。
血清可溶性黏附分子检测流程不复杂、检测结果应用酶标仪即可获得，试剂盒制作手段成熟易于购买，可以在临床应用中普及。早期发现升高的黏附分子水平有利于诊断抗MDA5抗体阳性皮肌炎，有利于指导下一步治疗，减少皮肌炎患者疾病恶化及死亡的风险。
附图说明
图1是血清可溶性ICAM-1、VCAM-1水平在健康对照和抗MDA5阳性、阴性皮肌炎中的变化。(A). 血清可溶性ICAM-1水平在抗MDA5阴性皮肌炎（n=18）中高于健康对照（n=21），在抗MDA5阳性皮肌炎（n=16）中高于健康对照以及抗MDA5阴性皮肌炎组。统计学方法采用单因素方差分析及Bonferroni校正t检验。(A). 血清可溶性VCAM-1水平在抗MDA5阴性皮肌炎（n=25）中高于健康对照（n=21），在抗MDA5阳性皮肌炎（n=20）中高于健康对照以及抗MDA5阴性皮肌炎组。统计学方法采用单因素方差分析及Bonferroni校正t检验。
图2是ROC曲线分析结果。其中A血清sICAM-1诊断阈值为243.4635 ng/ml时，鉴别抗MDA5抗体阳性皮肌炎的敏感性81.2%，特异性66.7%，曲线下面积为0.767，p=0.001。B血清sVCAM-1诊断阈值为730.4086 ng/ml时，鉴别抗MDA5抗体阳性皮肌炎的敏感性75%，特异性84%，曲线下面积为0.78，p<0.001。C sICAM-1和sVCAM-1联合鉴别抗MDA5抗体阳性皮肌炎的敏感性80%，特异性76.9%，曲线下面积为0.779，p=0.004。
具体实施方式
下面结合具体实施例和附图对本发明进一步阐述。
实施例1 皮肌炎患者血清可溶性ICAM-1、VCAM-1水平检测。
2017年10月至2019年12月就诊于中国医科大学附属第一医院风湿免疫科皮肌炎患者45例，根据是否存在抗MDA5抗体，分为抗MDA5阳性皮肌炎（25例）和抗MDA5阴性皮肌炎（20例）。同期性别和年龄匹配的健康对照21例。所有研究对象均于入选时采集静脉血5 ml，加入不含抗凝剂的真空玻璃管中，3000 r/min离心10 min，分离血清标本，采用酶联免疫吸附法（ELISA）试剂盒检测血清 sICAM-1、sVCAM-1水平，严格按试剂说明书操作。操作步骤如下，在包埋有ICAM-1（或VCAM-1）抗体的微孔板中分别加入100ul标准抗原，空白对照和稀释后的待测血清，随后每孔加入50ul生物素化的检测抗体，室温孵育2小时。洗板6次，随后加入l00ul的辣根过氧化物酶标记的链霉亲和素，室温孵育1小时。洗板6次，随后加入显色底物四甲基联苯胺（TMB），避光显色室温5-30 min。随后加入100ul终止液终止反应。于450 nm波长（参考波长570 nm）处测吸光度值。用标准抗原的吸光度及其相应的浓度值做出标准曲线，将待测血清的吸光度与标准曲线对比，计算出待测血清的浓度值。每个标准抗原及待测血清均做双孔取平均值。两指标浓度值均符合正态分布，结果用均数±标准差表示，统计学方法采用单因素方差分析及Bonferroni校正t检验进行多重比较，统计学分析软件应用SPSS 20.0，均为双侧检验，p<0.05被认为差异有统计学意义。抗MDA5抗体阳性皮肌炎患者血清可溶性ICAM-1、VCAM-1水平高于抗MDA5抗体阴性组，如图1所示。其中A血清可溶性ICAM-1水平在抗MDA5阴性皮肌炎（n=18）中高于健康对照（n=21），在抗MDA5阳性皮肌炎（n=16）中高于健康对照以及抗MDA5阴性皮肌炎组。B血清可溶性VCAM-1水平在抗MDA5阴性皮肌炎（n=25）中高于健康对照（n=21），在抗MDA5阳性皮肌炎（n=20）中高于健康对照以及抗MDA5阴性皮肌炎组。
实施例2血清可溶性黏附分子使用酶联免疫吸附测定即可进行定量分析并预测抗MDA5抗体是否存在。
通过绘制 ROC 曲线以分析实施例1中检测的血清sICAM-1、sVCAM-1水平对抗MDA5抗体阳性皮肌炎的预测价值。应用SPSS 20.0以及MedCalc 17.0进行绘图和统计学分析。使用二项分类Logistic回归分别输出sICAM-1、sVCAM-1以及sICAM-1联合sVCAM-1的预测概率，随后将三个预测概率与抗MDA5抗体进行ROC曲线分析。分析血清sICAM-1、sVCAM-1以及sICAM-1联合sVCAM-1诊断抗MDA5阳性皮肌炎的cut-off值及敏感性和特异性。曲线下面积在0.5-0.7之间表示诊断价值较低；在0.7-0.9之间表示诊断价值中等；0.9以上表示诊断价值较高。ROC曲线分析结果显示，如图2所示。其中A血清sICAM-1诊断阈值为243.4635 ng/ml时，鉴别抗MDA5抗体阳性皮肌炎的敏感性81.2%，特异性66.7%，曲线下面积为0.767，p=0.001。B血清sVCAM-1诊断阈值为730.4086 ng/ml时，鉴别抗MDA5抗体阳性皮肌炎的敏感性75%，特异性84%，曲线下面积为0.78，p<0.001。C sICAM-1和sVCAM-1联合鉴别抗MDA5抗体阳性皮肌炎的敏感性80%，特异性76.9%，曲线下面积为0.779，p=0.004。
Claims (3)
1.一种分子标志物在制备用于诊断抗MDA5阳性皮肌炎的诊断试剂盒中的应用，其特征在于，所述的分子标志物为血清可溶性细胞间黏附分子-1 ICAM-1和血管细胞黏附分子-1VCAM-1。
2.如权利要求1所述一种分子标志物在制备用于诊断抗MDA5阳性皮肌炎的诊断试剂盒中的应用，其特征在于，所述的诊断为区分抗MDA5阳性皮肌炎与健康人群。
3.如权利要求1所述一种分子标志物在制备用于诊断抗MDA5阳性皮肌炎的诊断试剂盒中的应用，其特征在于，血清可溶性细胞间黏附分子-1 ICAM-1和血管细胞黏附分子-1VCAM-1使用酶联免疫吸附测定进行定量分析并预测抗MDA5抗体是否存在。
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| CN116313071A (zh) * | 2023-01-16 | 2023-06-23 | 南方医科大学南方医院 | 一种预测初诊皮肌炎患者发生快速进展型间质性肺病的风险模型的构建方法 |
| CN116313071B (zh) * | 2023-01-16 | 2023-09-08 | 南方医科大学南方医院 | 一种预测初诊皮肌炎患者发生快速进展型间质性肺病的风险模型的构建方法 |
| CN116593700A (zh) * | 2023-05-24 | 2023-08-15 | 中日友好医院(中日友好临床医学研究所) | 一种用于鉴定抗mda5阳性皮肌炎患者的分子标记物 |
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