CN110244053B - 用于诊断狼疮肾炎并肺动脉高压疾病的分子标志物及其用途 - Google Patents
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Abstract
本发明的目的是提供用于诊断狼疮肾炎并肺动脉高压疾病的分子标志物及其用途，利用补体因子H、补体Bb片段作为诊断或预测狼疮肾炎并肺动脉高压疾病的分子标志物能够简便、准确的诊断或预测狼疮肾炎患者是否合并肺动脉高压或其发病风险。相较于右心导管检查等侵入性检查手段，更加适合临床推广。
Description
技术领域
本发明涉及疾病分子标志物，特别涉及用于诊断狼疮肾炎并肺动脉高压疾病的分子标志物及其用途。
背景技术
系统性红斑狼疮(SLE)是我国最常见的自身免疫性疾病之一，肾脏是系统性红斑狼疮最容易累及的器官之一，狼疮肾炎(1upus nephritis，LN)是系统性红斑狼疮累及肾脏所引起的一种免疫复合物性肾炎，是最常见的继发性肾小球疾病。而肺动脉高压(PAH)指由各种原因引起的肺血管功能和或结构改变，以肺血管阻力进行性升高为特点，作为SLE常见且严重的并发症，是SLE患者预后不良的主要因素之一。
SLE-PAH致病机制的主要是血管内皮的功能障碍，血管的内皮不仅具有作为物理屏障的功能，还可以调节血管的舒张收缩，并且在促进凝血的功能及细胞间的相互作用上也发挥着重要的作用。肺动脉高压血管病变的初始阶段即可伴有内皮细胞的功能紊乱，涉及以下因素：1).由炎症反应引起的肺血管炎，伴低补体血症。2).主要由于肺血管内皮细胞和平滑肌细胞增生引起的肺血管病，原发病活动程度一般较低，与血管病变相关，原发病治疗可逆程度较低。3).主要由肺小血管血栓引起，如抗磷脂综合症等，也涉及补体系统功能失调等多方面原因。
现有技术中为了诊断患者是否存在肺动脉高压，需要进行侵入性检查，右心导管检查是确诊肺动脉高压的金标准，虽然右心导管检查能够准确获得肺循环及右心系统的血流动力学特征，但由于其侵入性其具有固有的缺陷。
补体系统属于天然免疫系统的第一道″防线″，共存在三种激活途径：经典途径、旁路途径及凝集素途径，共涉及已知的30余种血浆蛋白的参与。为了防止补体系统过度活化对机体本身造成的损伤，体内还存在众多补体成分的抑制剂对其活化进行精细的调节。因此，补体系统在机体免疫系统的调节过程中起到了重要的作用。
在系统性红斑狼疮的致病过程中，传统理论认为补体的免疫复合物激活经典途径是最主要的因素，但仍有许多临床特征不能得到可信的解释。进而有学者提出：免疫复合物在靶器官局部激活了补体的经典途径后，旁路途径的进一步激活，才使得C3a和C5a等炎症成分得到进一步的释放，进而导致″膜攻击复合物″的形成，最终造成靶器官损伤，因此，补体系统的旁路途径在系统性红斑狼疮的致病过程中具有重要的临床意义。
H因子作为补体旁路活化途径的主要调节蛋白，在防止补体旁路途径过度激活方面更是起着举足轻重的作用。H因子的编码基因位于1q32，其是由20个短的相同的重复片段(short consensus repeats，SCRs)结构域、1213个氨基酸残基组成的150kDa的糖蛋白，肝脏是其主要的合成器官。此外，肾脏系膜细胞、视网膜色素上皮细胞、血小板、外周单个核细胞、神经胶质细胞、成纤维细胞及内皮细胞等也可以表达。H因子两个主要的功能区域位于蛋白的两端：位于N端的SCR1-4主要是抑制旁路途径的C3转化酶(C3bBb)的形成、辅助I因子降解C3bBb，从而抑制补体旁路途径的过度活化；而位于C端的SCR19-20主要能够和宿主细胞表面的粘多糖相结合完成目标的识别，通过和这些位点的结合，协助H因子抑制宿主细胞表面补体旁路途径的过度激活。此外，H因子还可以和多种凋亡细胞的碎片、DNA、组蛋白等成分相结合，调节清除凋亡细胞。因此，H因子在调节补体系统参与天然免疫防御、抑制补体的过度活化，以及凋亡物质的清除中起着重要的″刹车制动″。
综上，出于简便、准确的诊断系统性红斑狼疮患者是否合并肺动脉高压的需要，仍然有需求寻找能够通过非侵入性检查如利用分子标志物来诊断和或作为靶标来治疗系统性红斑狼疮并肺动脉高压/狼疮肾炎并肺动脉高压。
发明内容
为解决现有技术的不足，本发明提供了一种狼疮肾炎并肺动脉高压疾病的分子标志物，所述标志物为补体因子H，相较于狼疮肾炎肺动脉压正常患者，补体因子H的表达水平显著降低。
进一步地，本发明还提供了一种狼疮肾炎并肺动脉高压疾病的分子标志物，所述标志物为补体Bb片段，相较于狼疮肾炎肺动脉压正常患者，补体Bb片段的表达水平显著升高。
进一步地，所述分子标志物为补体因子H和补体Bb片段。
本发明还提供一种分子标志物在诊断或预测狼疮肾炎并肺动脉高压疾病中的用途，所述用途为制备诊断试剂。
进一步地，所述分子标志物为补体因子H，相较于狼疮肾炎肺动脉压正常患者，补体因子H的表达水平显著降低。
进一步地，所述标志物为补体Bb片段，相较于狼疮肾炎肺动脉压正常患者，补体Bb片段的表达水平显著升高。
更进一步地，所述标志物为补体因子H和补体Bb片段。
更进一步地，所述诊断试剂还包括检测抗RNP抗体、抗心磷脂抗体、D-二聚体、和或血红蛋白的相关试剂。
本发明提供一种诊断试剂盒，所述试剂盒包括测定诊断或预测狼疮肾炎并肺动脉高压疾病的分子标志物的相关试剂。
进一步地，所述分子标志物为补体因子H。
进一步地，所述分子标志物为补体Bb片段。
更进一步地，所述分子标志物为补体因子H和补体Bb片段。
更进一步的，所述试剂盒还包括检测抗RNP抗体、抗心磷脂抗体、D-二聚体、和或血红蛋白的相关试剂。
本发明还提供一种诊断或预测狼疮肾炎并肺动脉高压疾病的方法，所述方法包括检测待诊断患者的分子标志物的表达水平，并与狼疮肾炎肺动脉压正常患者的分子标志物的表达水平比较，当分子标志物的表达水平有显著差异时，可诊断或预测为狼疮肾炎并肺动脉高压。
进一步地，所述分子标志物为补体因子H，相较于狼疮肾炎肺动脉压正常患者，补体因子H的表达水平显著降低。
进一步地，所述标志物为补体Bb片段，相较于狼疮肾炎肺动脉压正常患者，补体Bb片段的表达水平显著升高。
更进一步地，所述标志物为补体因子H和补体Bb片段。
更进一步的，所述方法还包括检测抗RNP抗体、抗心磷脂抗体、D-二聚体、和或血红蛋白的表达水平并与狼疮肾炎肺动脉压正常患者的表达水平比较。
更进一步地，所述补体H因子的表达水平小于等于241μg/ml表明狼疮肾炎患者合并肺动脉高压或具有合并肺动脉高压的高风险。
更进一步地，所述补体Bb片段的表达水平大于等于1.26μg/ml表明狼疮肾炎患者合并肺动脉高压或具有合并肺动脉高压的高风险。
有益效果
本发明明确了补体旁路途径在狼疮肾炎患者合并肺动脉高压疾病中具有重要的作用。
本发明发现了因子H、Bb能够作为狼疮肾炎并肺动脉高压疾病的分子标志物，相较于右心导管检查等侵入性检查方法，其能够准确、高效地诊断狼疮肾炎患者是否合并肺动脉高压或预测合并肺动脉高压患病风险。
附图说明
图1：患者登记入选流程图。
图2：LN-PAH患者肺部组织中补体途径活化相关组分的免疫荧光染色结果，所述组分包括Bb、C3d、以及C5b-9，对血管外主要成分层粘连蛋白进行共染色，图2A、图2B、图2C分别涉及Bb、C3d和C5b-9，图2D为Pearson相关系数评估的共区域化范围结果。
具体实施方式
在下文中更详细地描述了本发明以有助于对本发明的理解。
应当理解的是，在说明书和权利要求书中使用的术语或词语不应当理解为具有在字典中限定的含义，而应理解为在以下原则的基础上具有与其在本发明上下文中的含义一致的含义：术语的概念可以适当地由发明人为了对本发明的最佳说明而限定。
下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册中所述的条件，或按照制造厂商所建议的条件。
实施例1狼疮肾炎并肺动脉高压补体途径相关蛋白的差异表达
资料与方法
研究对象：
首先回顾性评估了2002年1月至2009年5月在北京大学第一医院就诊并经肾活检证实罹患狼疮肾炎的389例患者的病例，所述患者在住院期间经胸部超声心动图检查进行诊断，并通过肾脏病理观察评估所有类型的肾血管病变，包括血管免疫复合物沉积、动脉硬化、血栓性微血管病、非炎性坏死性血管病、真性血管炎。进而，依据图1的标准，选取狼疮肾炎合并肺动脉高压(LN-PAH)的24位患者进行了研究。其中狼疮肾炎的诊断是根据美国风湿病协会的标准进行的，PAH采用欧洲心脏病学会(ESC)2015年规定的标准，并排除先天性心脏病、门静脉高压、肺静脉闭塞、肺栓塞、慢性阻塞性肺病、左心功能衰竭病史。
方法：
将研究对象分为LN-PAH组(24例)和LN-non-PAH组(328例)及正常人群组(100例)。
检测LN-PAH组和LN-non-PAH组的临床指标，临床指标包括：年龄、性别、发热、颧部红斑、光过敏、脱发、口腔溃疡、关节炎、胸膜炎、雷诺现象、神经系统损害、贫血、白细胞减低、血小板减少、狼疮活动度评分。以上诊断、评估均按照标准方法进行操作。
检测LN-PAH组和LN-non-PAH组的实验室指标，实验室指标包括：血红蛋白、血肌酐、D二聚体、自身抗体谱相关指标。所述指标分析依据标准方法或依据试剂盒说明书进行操作。
检测LN-PAH组和LN-non-PAH组血浆中补体途径主要成分的表达情况，具体血浆中主要的补体成分的浓度通过酶联免疫分析进行了测定，包括补体片段C5a(QuidelCorporation，San Diego,CA)，C3a(Quidel Corporation,San Diego,CA)，Bb(QuidelCorporation,San Diego,CA)，可溶性C5b-9(SC5b-9，Quidel Corporation,San Diego,CA)，备解素properdin(Uscnk life science Inc,Wuhan,China)以及C3(QuidelCorporation,San Diego,CA)。所有补体成分均根据制造商说明进行测定。另外，血浆中C1q，MBL，C4BP的测定也依据标准方法进行测定。
血浆补体H因子水平的检测根据现有技术的实验方法作了如下改进：用pH9.6的0.05M碳酸盐缓冲液稀释山羊抗人H因子多克隆抗体(Calbiochem公司，德国)至10μg/ml，预先包被酶标板，4℃过夜孵育。将稀释好的H因子标准品、患者血浆样本分别加入反应孔，37℃孵育1h。洗板后加入小鼠抗人H因子单克隆抗体(Usbiological公司，美国)1∶500稀释，37℃孵育1h。洗板后加入碱性磷酸酶标记的羊抗鼠IgG(Sigma公司)，37℃孵育30min。最后加入碱性磷酸酶底物显色，用酶标仪在405nm波长下测定吸光度值。通过绘制标准曲线，依据标准品对血浆补体H因子水平进行定量。
免疫荧光测定：测定Bb、C3d和C5b-9在LN-PAH患者的肺部组织中的表达情况，具体为：取LN-PAH患者的肺组织，经固定-脱水-包埋后制成石蜡包块，以8um厚度切片，经脱蜡至水和抗原修复，以免疫荧光检测补体替代途径的激活产物Bb，终末共同途径产物C3d和补体激活终末复合物C5b-9在组织血管处的沉积，Confocal成像并进行灰度统计。
数据分析：
连续变量被描述为平均值±标准差(SD)或中位数(IQR，四分差)，组间差异通过使用方差检验和非参数检验的双因素分析。分类变量用百分比表示，并用卡方检验进行分析。哈迪-温伯格平衡使用x2拟合度进行分析。单变量和多变量采用逻辑回归分析评估生存率。结果采用95％置信区间的比率表示。数据统计分析采用SPSS 12.0软件计算。双尾p值小于0.05被认为具有统计学意义。
实验结果：
LN-PAH患者组的24位患者中，2位是男性、22位是女性，实验进行时的平均年龄为35.29±15.13岁；LN-non-PAN患者组的328位患者中，53位是男性、275位是女性，实验进行时的平均年龄为32.83±11.30；LN-PAH患者组和LN-non-PAH患者组在年龄和性别方面没有显著差异(p值均为0.758)。
其中LN-PAH患者组的具体相关信息如表1所示。
表1：狼疮合并肺动脉高压患者相关信息
LN-PAH组患者和LN-non-PAH组患者的临床评价数据和实验室检查结果分别如表2和表3所示。
表2：狼疮合并肺动脉高压患者与狼疮肺动脉压正常患者临床数据比较
表3：狠疮合并肺动脉高压患者与狠疮肺动脉压正常患者实验室数据比较
由表2可知，相较于LN-non-PAH患者组，LN-PAH患者组具有更多的血小板减少症状(p＜0.001)，更低的颧部红斑(p＝0.01)、脱发(p＝0.017)和关节炎(p＝0.03)症状，说明上述症状与肺动脉高压的发生并不同步。
狼疮合并肺动脉高压患者与狼疮肺动脉压正常患者的补体水平比较结果见表4。
表4：狼疮合并肺动脉高压患者与狼疮肺动脉压正常患者补体水平比较
由表4可知，正常人群中的血清甘露糖凝集素、C3a、C5a和可溶性C5b-9的水平分别为1532±1020ng/ml、100.87±70.55ng/ml、9.32±7.88ng/ml和467.41±545.23ng/ml。
相较于正常人群，LN-PAH患者和LN-non-PAH患者的血清甘露糖凝集素、C3a、C5a和可溶性C5b-9的水平均具有显著升高(p值分别为P＜0.01、P＜0.01、P＜0.01、P＜0.01)。
C1q作为经典补体活化途径的第一个组分，其在LN-PAH患者中的表达水平与LN-non-PAH患者中的表达水平没有显著差异(p＝0.206)。
甘露糖凝集素是凝集素补体活化途径的诱导物，同样，在LN-PAH患者中的表达水平与LN-non-PAH患者中的表达水平也没有显著差异(p＝0.874)。
C4BP是补体活化的主要液相抑制蛋白，其能够通过增强经典/凝集素途径的C3转化酶C4b2a的衰竭来起到抑制作用，还能通过增强旁路途径C3转化酶C3bBb的衰竭来起到抑制作用。在LN-PAH患者中C4BP的表达水平与LN-non-PAH患者中的表达水平没有显著差异(p＝0.308)。
上述实验结果说明并不能通过经典途径和凝集素途径相关成分来区分LN-PAH患者和LN-non-PAH患者，也并不能通过经典途径和凝集素途径相关成分来诊断或预测狼疮患者合并肺动脉高压的风险。
备解素在旁路途径C3转化酶稳定中起到关键作用，Bb是旁路途径中因子B的活性片段，而补体因子H是一种丰富的血浆补体调节因子，其能抑制C3转化酶的形成和促进C3转化酶的衰竭、以及作为补体因子I的共因子来失活C3b，通过上述功能，补体因子H能够抑制旁路途径的活化。
通过测定血浆中Bb、备解素和因子H的表达水平能够得知旁路途径是否得到活化。结果显示(参见表4)，在LN-PAH患者中Bb的表达水平与LN-non-PAH患者中的表达水平相比有显著升高(1.26±0.758μg/ml vs.0.74±0.186μg/ml,p＝0.049)；在LN-PAH患者中因子H的表达水平与LN-non-PAH患者中的表达水平相比有显著降低(241.00±116.502μg/mlvs.417.13±188.017μg/ml,p＝0.024)，而在LN-PAH患者中备解素的表达水平与LN-non-PAH患者中的表达水平没有显著差异(p＝0.102)。
上述结果说明在LN-PAH患者中，补体旁路途径发生了过度活化，其主要通过Bb的过表达以及因子H表达水平的降低而实现的。
补体经典途径的活化主要体现在将C3转化为C3a和C3b，进而形成C5转化酶多分子酶，其能够将C5切割为C5a和C5b，最终的补体复合物C5b-9由于补体系统的激活而使C5b与C9装配而获得，因此，研究了C3、C3a、C5a和可溶性C5b-9，其能够反映在循环系统中的补体活化情况。
结果显示，在LN-PAH患者中C3、C3a、C5a和可溶性C5b-9的表达水平与LN-non-PAH患者中的表达水平没有显著差异，表明补体经典途径在两组患者中的活化程度没有显著差异。
为了进一步证实补体途径相关组分在LN-PAH患者的肺部组织定位及表达情况，通过免疫荧光检测法对C3d、C5b-9和Bb的沉积情况进行了检测，结果显示(参见图2)，作为经典补体途径的标志物的C3d、C5b-9以及作为旁路补体途径的特异性标志物的Bb片段在肺部组织中均是阳性的，结合前述LN-PAH患者与LN-non-PAH患者中C3d、C5b-9、Bb的表达差异，进一步证实了在LN-PAH患者中存在补体旁路途径的过度活化。
血管损伤是SLE的一个常见特征，而狼疮并肺动脉高压被认为是由其血管内皮引起的病变。SLE血管病变的一个公认假设是血管内皮上的免疫复合物触发炎症反应，包括激活补体级联反应，形成C5b-9膜补体攻击进而最终破坏血管基底膜和发生炎性细胞浸润。
补体途径在LN-PAH中的机制是矛盾的，一方面，早期经典或替代途径补体成分的遗传纯合子缺陷使患者易患狼疮，另一方面，补体过度活化导致炎症和组织损伤。
以前的研究仅证实了旁路补体途径的活化能够反应SLE活性、血管病变尤其是以合并血栓性微血管病变为主的血管病变的严重程度。调节旁路补体途径的过度活化能够有效的抑制SLE的发生和进展。
而本申请发现Bb、C3d和C5b-9表达水平的升高以及因子H含量的降低表明旁路补体途径活化在LN-PAH起到重要作用，且Bb、C3d、C5b-9在LN-PAH患者的肺部组织中是有沉积的。
因此，可通过检测血浆中Bb、因子H的表达水平来诊断狼疮肾炎患者是否合并肺动脉高压的或预测合并肺动脉高压患病风险。
实施例2利用补体途径差异蛋白诊断狼疮肾炎并肺动脉高压
选取北京大学第一医院新收治的狼疮肾炎患者7例利用补体H因子、补体Bb片段作为分子标志物诊断其是否并肺动脉高压，同时利用右心导管检查结果作为对照。
检测结果如表5所示：
| 患者 | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 因子H(μg/ml) | 253.00 | 326.12 | 469.56 | 500.78 | 189.65 | 385.46 | 156.27 |
| Bb(μg/ml) | 1.20 | 0.72 | 0.69 | 0.61 | 1.29 | 0.69 | 2.11 |
| 右心导管检查检测(+/-) | + | - | - | - | + | - | + |
结果显示，利用补体因子H、补体Bb片段作为分子标志物能够准确地诊断或预测狼疮肾炎患者是否合并肺动脉高压疾病。
以上所述仅是本发明的优选实施方式，应当指出：对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (4)
1.检测分子标志物表达水平的试剂或分子标志物在用于制备诊断或预测狼疮肾炎并肺动脉高压疾病的试剂中的用途，其特征在于：所述分子标志物为补体因子H，相较于狼疮肾炎肺动脉压正常患者，补体因子H的表达水平显著降低。
2.根据权利要求1所述的用途，其特征在于：所述分子标记物为补体Bb片段，相较于狼疮肾炎肺动脉压正常患者，补体Bb片段的表达水平显著升高。
3.根据权利要求1所述的用途，其特征在于：所述分子标记物为补体因子H和补体Bb片段，相较于狼疮肾炎肺动脉压正常患者，补体因子H的表达水平显著降低，且补体Bb片段的表达水平显著升高。
4.根据权利要求1-3任一项所述的用途，其特征在于：所述试剂还包括检测抗RNP抗体、抗心磷脂抗体、D-二聚体和血红蛋白的相关组分。
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