CN107677835B - 一种ae-ipf的蛋白标记物及其应用 - Google Patents
一种ae-ipf的蛋白标记物及其应用 Download PDFInfo
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- CN107677835B CN107677835B CN201710881689.7A CN201710881689A CN107677835B CN 107677835 B CN107677835 B CN 107677835B CN 201710881689 A CN201710881689 A CN 201710881689A CN 107677835 B CN107677835 B CN 107677835B
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Abstract
本发明公开了一种AE‑IPF的蛋白标记物,所述蛋白标志物为干扰素基因刺激因子,其氨基酸序列如SEQ ID NO:1所示。本发明首次使用流式细胞技术,检测外周血单个核细胞中,尤其是巨噬细胞中STING蛋白的表达量,用于判断AE‑IPF的疾病的严重程度,并将与该蛋白标记物特异性结合的抗体应用于制备诊断产品中。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种AE-IPF的蛋白标记物及其应用。
背景技术
特发性肺纤维化(idiopathic pulmonary fibrosis,IPF)是特发性间质性肺炎的最常见的类型,其病理和/或影像表现为寻常性间质性肺炎的慢性进展性肺部疾病。IPF病因不明,预后极差,确诊后平均生存期仅为3-5年。IPF患者的自然病程及结局个体差异较大,部分患者呈快速进行性发展,有些甚至在病程中出现反复的急性加重。临床上将这种呼吸功能的急剧恶化称为特发性肺纤维化急性加重(acute exacerbation of idiopathicpulmonary fibrosis,AE-IPF)。AE-IPF是IPF的主要死亡原因,是影响IPF的总体生存期的瓶颈因素。在临床诊治过程中,及时判断患者病情的进展,尽早采取有效的干预措施,可以大大降低病人的病死率,从根本上改善这类致死性疾病的预后。但是现有针对AE-IPF的生物标记物的研究大多为小样本、单中心、回顾性研究,AE-IPF的生物标记物尚无统一的定论。寻找AE-IPF的生物标记物成为临床迫切需要解决的关键问题。
干扰素基因刺激因子(stimulator of interferon genes protein isoform 1,STING)是一类内质网的驻留蛋白,通过引起Ⅰ型干扰素的产生激发机体抗病毒天然免疫。人STING蛋白有379个氨基酸,氨基酸序列如SEQ ID NO:1所示。有文献报道,病毒感染与AE-IPF的发生发展关系密切,但STING在AE-IPF的作用尚未有相关报道。
STING蛋白的传统检测方法为蛋白质印迹(Western Blot)法,但该检测方法步骤繁琐、耗时费力,并且需要的临床样本多(肝素锂抗凝血15ml),大大限制了该方法在临床检测中的进一步推广。寻找更为特异、敏感、简便、可靠的方法检测STING蛋白的表达是也成为亟待解决的问题。
发明内容
本发明的目的是提供一种AE-IPF的蛋白标记物及其应用,使用流式细胞技术,检测外周血单个核细胞中,尤其是巨噬细胞中STING蛋白的表达量,用于判断AE-IPF的疾病的严重程度,并将与该蛋白标记物特异性结合的抗体应用于制备诊断产品中。
为达到上述目的,本发明提供了一种AE-IPF的蛋白标记物,所述蛋白标志物为干扰素基因刺激因子,其氨基酸序列如SEQ ID NO:1所示。
进一步的,所述干扰素基因刺激因子来源于外周血单个核细胞中。
更进一步的,所述干扰素基因刺激因子来源于外周血单个核细胞的巨噬细胞中。
本发明还提供了一种上述的AE-IPF的蛋白标记物在制备AE-IPF的诊断产品中的应用,该诊断产品包含与所述蛋白标记物特异性结合的抗体。
上述的AE-IPF的蛋白标记物在制备AE-IPF的诊断产品中的应用,其中,所述诊断产品为试剂盒、诊断试剂或生物芯片。
本发明还提供了一种上述的AE-IPF的蛋白标记物在制备判断AE-IPF预后的诊断产品中的应用,该诊断产品包含与所述蛋白标记物特异性结合的抗体。
上述的AE-IPF的蛋白标记物在制备判断AE-IPF预后的诊断产品中的应用,其中,所述诊断产品为试剂盒、诊断试剂或生物芯片。
本发明首次使用流式细胞技术,检测外周血单个核细胞中,尤其是巨噬细胞中STING蛋白的表达量,用于判断AE-IPF的疾病的严重程度,并将与该蛋白标记物特异性结合的抗体应用于制备诊断产品中。
附图说明
图1为AE-IPF组、稳定期IPF组和HC组STING的mRNA表达水平柱状图;
图2为AE-IPF组、稳定期IPF组和HC组PBMCs中的STING表达水平电泳图;
图3为AE-IPF组、稳定期IPF组和HC组PBMCs中的STING表达水平柱状图;
图4为AE-IPF治疗前后STING表达水平变化电泳图;
图5为AE-IPF治疗前后病情变化与STING表达水平的关系图;
图6为STING的表达水平与PaO2的关系图;
图7为PBMCs的T细胞、B细胞和巨噬细胞中STING的流式细胞分析示意图;
图8为PBMCs的T细胞中STING的平均荧光强度分析示意图;
图9为PBMCs的B细胞中STING的平均荧光强度分析示意图;
图10为PBMCs的巨噬细胞中STING的平均荧光强度分析示意图。
具体实施方式
以下结合附图通过具体实施例对本发明作进一步的描述,这些实施例仅用于说明本发明,并不是对本发明保护范围的限制。
本发明提供了一种AE-IPF的蛋白标记物,所述蛋白标志物为干扰素基因刺激因子,其氨基酸序列如SEQ ID NO:1所示。
进一步的,所述干扰素基因刺激因子来源于外周血单个核细胞中。
更进一步的,所述干扰素基因刺激因子来源于外周血单个核细胞的巨噬细胞中。
本发明还提供了一种上述的AE-IPF的蛋白标记物在制备AE-IPF的诊断产品中的应用,该诊断产品包含与所述蛋白标记物特异性结合的抗体。
上述的AE-IPF的蛋白标记物在制备AE-IPF的诊断产品中的应用,其中,所述诊断产品为试剂盒、诊断试剂或生物芯片。
本发明还提供了一种上述的AE-IPF的蛋白标记物在制备判断AE-IPF预后的诊断产品中的应用,该诊断产品包含与所述蛋白标记物特异性结合的抗体。
上述的AE-IPF的蛋白标记物在制备判断AE-IPF预后的诊断产品中的应用,其中,所述诊断产品为试剂盒、诊断试剂或生物芯片。
以下通过一个具体实施例具体阐述上述蛋白标记物的确认及其应用:
1.收集健康志愿者(HC)、稳定期IPF和AE-IPF患者的外周血单个核细胞(peripheral-blood mononuclear cells,PBMCs),提取PBMCs的mRNA,使用实时定量荧光PCR(real-time PCR)方法检测STING mRNA的表达,结果如图1所示。发现健康志愿者、稳定期IPF患者和AE-IPF患者STING的mRNA水平无明显差异。
2.收集健康志愿者(HC)、稳定期IPF和AE-IPF患者的外周单个核细胞(peripheral-blood mononuclear cells,PBMCs),提取PBMCs的总蛋白,使用Western Blot方法检测STING蛋白的表达(β-Actin作为内参),结果如图2和图3所示。发现与健康志愿者、稳定期IPF患者相比,AE-IPF患者PBMCs中的STING的蛋白水平明显下降,大约是健康志愿者、稳定期IPF患者的20分之一。
3.为了观察STING在AE-IPF疾病过程中的动态变化,收集10例AE-IPF患者治疗前后的系列标本。治疗后(Post-T)好转的标准为:与治疗前(Pre-T)相比,患者的呼吸系统症状改善,和(或)影像学病灶吸收≥10%,和(或)动脉血氧分压(PaO2)升高≥10%。治疗后恶化的标准为:与治疗前相比,患者的呼吸系统症状加重,和(或)影像学病灶持续扩大,和(或)动脉血氧分压(PaO2)持续下降。使用Western Blot方法检测治疗前后STING蛋白的表达,结果如图4和图5所示。发现治疗前所有患者STING的表达均明显减少,治疗后病情好转的患者STING的表达有一定程度的恢复,而病情恶化的患者STING持续在低水平。对STING的表达与PaO2进行皮尔逊(Pearson)相关性分析,结果如图6所示。结果显示STING的表达与PaO2的水平呈明显正相关(R2=0.8405,p<0.0001)。
4.使用流式细胞法检测AE-IPF组、稳定期IPF组和HC组的PBMCs亚群的STING蛋白的表达。
流式细胞技术(flow cytometry,FCM)是利用流式细胞仪进行的一种单细胞定量分析和分选技术。其工作原理是在细胞分子水平上通过单克隆抗体对单个细胞或其他生物粒子进行多参数、快速的定量分析。它可以高速分析上万个细胞,并能同时从一个细胞中测得多个参数,具有速度快、精度高、准确性好的优点,是当代最先进的细胞定量分析技术之一。
实验步骤:
(1)提取PBMCs
使用蔗糖-梯度离心法收集AE-IPF组、稳定期IPF组和HC组PBMCs,操作步骤如下:
a)取50mL离心管,将新鲜肝素锂抗凝全血12.5mL,用PBS稀释至25mL;
b)取50mL离心管,管内加入12.5mL LymphoprepTM分离液上;
c)将稀释后的血液混匀,小心平铺于LymphoprepTM分离液上;
d)将铺好的离心管以上升600g,下降0g,20℃离心25min;
e)离心后,将中间层的单个核细胞吸出后转移至空15mL离心管中;
f)将离心管中的液体用PBS稀释到10mL,然后250-300g,20℃离心10min;
g)弃上清,各离心管加入10mL PBS后吹打混匀细胞,再次250-300g,20℃离心10min;
h)弃上清,离心管中留下的细胞即是PBMCs。
(2)STING的流式细胞检测
a)将步骤(1)获得的细胞沉淀用1mL FACS洗涤,1500rpm,20℃,3min离心;
b)将获得的细胞沉淀加入300μL FACS重悬,平均分为3管,分别为T细胞(T cells)+STING、B细胞(B cells)+STING、巨噬细胞(Macrophage)+STING;
另外设置阴性对照管4管,分别为不着色(non-staining)、抗体CD4-FITC、抗体CD19-PE和抗体CD14-FITC;
c)加入表面抗体1μL:T cell:CD4-FITC;B cell:CD19-PE;Macrophage:CD14-FITC;
d)室温、避光20min,加入1mL FACS洗涤,1500rpm,3min,20℃离心,弃上清;
e)加入100μL固定液,固定20min;
f)加入1mL破膜液混匀,1500rpm,20℃,3min离心,弃上清;
g)加入100μL破膜液重悬细胞,加入STING抗体1μL;室温、避光30min;
h)每管加入1mLFACS洗涤,1500rpm,20℃,3min离心,弃上清;
i)加入二抗(Ig-APC)3μL,20℃,3min离心,弃上清;
j)获得沉淀后用1mL FACS洗涤,1500rpm,20℃,3min离心;
k)200μL FACS重悬,样品进行流式细胞检测,结果如图7、图8、图9和图10所示。
实验结果:
1)AE-IPF组PBMCs中巨噬细胞STING的表达与稳定期IPF组和HC组相比明显下降;
2)AE-IPF组PBMCs中T细胞STING的表达与稳定期IPF组和HC组相比略有下降,但差别无统计学意义;
3)AE-IPF组PBMCs中B细胞STING的表达与稳定期IPF组和HC组相比无统计学差异。
在一本发明AE-IPF的蛋白标记物在诊断试剂上的应用的具体实施例中,
将STING抗体1μL加入提取的PBMCs中,并对PBMCs细胞进行胞内抗原的标记,进而通过流式细胞检测技术检测STING这一新的疾病标记物用于疾病AE-IPF的诊断。
综上所述,本发明首次使用流式细胞技术,检测外周血单个核细胞中,尤其是巨噬细胞中STING蛋白的表达量,用于判断AE-IPF的疾病的严重程度,并将与该蛋白标记物特异性结合的抗体应用于制备诊断产品中。
本发明利用流式细胞技术,检测外周血细胞中,尤其巨噬细胞中STING蛋白的表达量。与传统的Western Blot方法相比,流式细胞技术将进一步提高检测的特异度和灵敏度,缩短检测周期,样本需要量少(肝素锂抗凝血5mL)。
尽管本发明的内容已经通过上述优选实施例作了详细介绍,但应当认识到上述的描述不应被认为是对本发明的限制。在本领域技术人员阅读了上述内容后,对于本发明的多种修改和替代都将是显而易见的。因此,本发明的保护范围应由所附的权利要求来限定。
SEQUENCE LISTING
<110> 上海市肺科医院
<120> 一种AE-IPF的蛋白标记物及其应用
<130> 2017
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 379
<212> PRT
<213> 人种(Homo sapiens)
<400> 1
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Claims (8)
1.一种AE-IPF的蛋白标记物在制备AE-IPF的诊断产品中的应用,其特征在于,所述蛋白标记物为干扰素基因刺激因子,其氨基酸序列如SEQ IDNO:1所示;该诊断产品包含与所述蛋白标记物特异性结合的抗体。
2.如权利要求1所述的AE-IPF的蛋白标记物在制备AE-IPF的诊断产品中的应用,其特征在于,所述诊断产品为试剂盒、诊断试剂或生物芯片。
3.如权利要求1所述的AE-IPF的蛋白标记物在制备AE-IPF的诊断产品中的应用,其特征在于,所述干扰素基因刺激因子来源于外周血单个核细胞中。
4.如权利要求1所述的AE-IPF的蛋白标记物在制备AE-IPF的诊断产品中的应用,其特征在于,所述干扰素基因刺激因子来源于外周血单个核细胞的巨噬细胞中。
5.一种AE-IPF的蛋白标记物在制备判断AE-IPF预后的诊断产品中的应用,其特征在于,所述蛋白标记物为干扰素基因刺激因子,其氨基酸序列如SEQ ID NO:1所示;该诊断产品包含与所述蛋白标记物特异性结合的抗体。
6.如权利要求5所述的AE-IPF的蛋白标记物在制备判断AE-IPF预后的诊断产品中的应用,其特征在于,所述诊断产品为试剂盒、诊断试剂或生物芯片。
7.如权利要求5所述的AE-IPF的蛋白标记物在制备判断AE-IPF预后的诊断产品中的应用,其特征在于,所述干扰素基因刺激因子来源于外周血单个核细胞中。
8.如权利要求5所述的AE-IPF的蛋白标记物在制备判断AE-IPF预后的诊断产品中的应用,其特征在于,所述干扰素基因刺激因子来源于外周血单个核细胞的巨噬细胞中。
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