CN117568463A - 滑膜npc2在类风湿关节炎的诊断、鉴别、预后评估与治疗中的应用 - Google Patents
滑膜npc2在类风湿关节炎的诊断、鉴别、预后评估与治疗中的应用 Download PDFInfo
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Abstract
本发明公开了滑膜NPC2在类风湿关节炎(RA)的诊断、鉴别、预后评估与治疗中的应用。本发明研究发现,RA滑膜高表达NPC2,且NPC2在RA滑膜的表达水平显著高于骨关节炎滑膜和非炎性关节病滑膜,表明滑膜NPC2可以用于RA的诊断和鉴别。同时,RA滑膜NPC2高表达组患者经治疗后的疾病缓解率显著低于RA滑膜NPC2低表达组患者,表明RA滑膜NPC2的表达水平与RA患者的治疗预后情况密切相关。此外,本发明还发现下调滑膜NPC2表达可以抑制滑膜炎症的发生发展,为RA靶向治疗提供了一种新的途径。综上,本发明的技术方案在RA的诊断、鉴别、预后评估与治疗方面具有重要的应用价值。
Description
技术领域
本发明属于生物医药领域。更具体地,涉及滑膜NPC2在类风湿关节炎的诊断、鉴别、预后评估与治疗中的应用。
背景技术
关节炎是指由炎症、感染、创伤或其他因素所致的关节及其周围组织的炎性病变,表现为关节红、肿、热、痛和功能障碍。关节炎病因复杂,常为多种疾病的早期表现,包括类风湿关节炎(rheumatoid arthritis,RA)、脊柱关节炎、痛风性关节炎、骨关节炎、结缔组织病相关性关节炎、感染相关性关节炎等。其中,RA是一种常见的关节炎,以进行性关节破坏为特征的自身免疫性疾病,在发病不久后即启动关节侵蚀,70%以上的RA患者有关节损伤破坏。RA的本质是慢性增生性滑膜炎形成血管翳,导致多关节破坏。RA多以缓慢而隐匿方式起病,如不及时治疗,可致畸致残,因此RA的早期诊断与治疗非常重要。
类风湿因子(RF)和抗环瓜氨酸肽(CCP)抗体是目前临床诊断RA的常见自身抗体,已被美国风湿学会/欧洲抗风湿联盟(ACR/EULAR2010)确定为RA诊断分类标准的重要部分。但临床研究发现:部分RA患者存在RF和抗CCP抗体阴性,导致此类患者在早期诊断方面比较困难。此外,RA与骨关节炎(osteoarthritis,OA)的临床症状较为相似,尤以血清阴性RA为甚,都以关节肿痛积液为主要特点,在临床上,RA容易与OA混淆,造成误诊,影响RA的及时和有效治疗。近年来,肌骨超声等技术被运用于RA的鉴别与诊断中,为RA的诊断及治疗方案选择提供参考依据。但肌骨超声也有一定的局限性,它无法穿透骨骼,视野受限,同时其检查效果与操作者的经验密切相关,对操作者的依赖程度高。
综上,现阶段仍然缺乏一种能够快速、精确、高效地诊断和鉴别RA的分子技术,用于RA靶向治疗和预后评估的分子也有待开发。
发明内容
本发明要解决的技术问题是克服现有技术的缺陷和不足,提供滑膜尼曼匹克C2型蛋白(Niemann-Pick C2,NPC2)在RA的诊断、鉴别、预后评估与治疗中的应用。
本发明的第一个目的是提供检测滑膜NPC2表达水平的试剂在制备RA诊断或预后评估产品中的应用。
本发明的第二个目的是提供检测滑膜NPC2表达水平的试剂在鉴别RA和其他关节炎或在制备鉴别RA和其他关节炎的产品中的应用。
本发明的第三个目的是提供一种RA诊断或预后评估试剂盒和一种鉴别RA和其他关节炎的试剂盒。
本发明的第四个目的是提供滑膜NPC2或滑膜NPC2表达抑制剂在制备RA治疗药物中的应用。
本发明的第五个目的是提供一种RA治疗药物。
本发明上述目的通过以下技术方案实现:
本发明经过前期大量研究发现,RA滑膜高表达NPC2基因,且RA滑膜的NPC2表达水平显著高于OA滑膜和非炎性关节病(orthopaedic arthropathies,Orth.A)滑膜,即NPC2在不同关节炎滑膜中表达存在差异。同时,本发明通过对基线滑膜NPC2高低表达的RA患者完成1年的前瞻性随访,发现NPC2高表达组在不同时间点的疾病缓解率均显著低于NPC2低表达组,表明RA滑膜组织NPC2的高表达与RA患者的预后不良相关。此外,本发明还通过siRNA下调NPC2表达,发现下调NPC2表达后,mTOR被抑制,炎症因子IL-1β及趋化因子MCP-1、CCL-5和CCL-12表达降低,抑制了滑膜炎症的发生发展,因此可通过干扰NPC2表达而实现RA治疗。
因此,本发明申请保护以下产品和应用:
本发明申请保护检测滑膜NPC2表达水平的试剂在制备RA诊断或预后评估产品中的应用。
本发明申请保护检测滑膜NPC2表达水平的试剂在鉴别RA和其他关节炎或在制备鉴别RA和其他关节炎的产品中的应用。
所述RA诊断或鉴别的依据为:NPC2表达水平高的为RA。
具体地,所述其他关节炎包括骨关节炎。
本发明申请保护一种RA诊断或预后评估试剂盒,以及一种鉴别RA和其他关节炎的试剂盒,所述试剂盒含有检测滑膜NPC2表达水平的试剂。
作为可实施方案,所述检测NPC2表达水平的试剂可以是现有技术中可用于检测滑膜NPC2表达水平的技术所用到的试剂及试剂组合。比如NPC2检测引物/引物组、荧光标记的结合NPC2的探针、结合NPC2的小分子化合物、结合NPC2的生物大分子。
具体地,所述生物大分子包括抗体或抗体功能片段、荧光标记的抗体或抗体功能片段、RNA结合蛋白或其功能片段、荧光标记的RNA结合蛋或其功能片段。
比如,本发明实施例中使用免疫组化染色检测技术检测NPC2表达量,以及利用Anti-Niemann Pick C2抗体(abcam,ab218192)检测NPC2表达量,则所述检测NPC2表达水平的试剂即为免疫组化染色检测技术所需试剂或Anti-Niemann Pick C2抗体(abcam,ab218192)。
作为一种优选的实施方案,在本发明的技术方案中,可利用免疫组化染色技术检测NPC2表达水平,则RA诊断或鉴别的标准为:对待测患者滑膜组织样本进行免疫组化染色,统计滑膜NPC2阳性细胞比例评分与染色强度评分的乘积为滑膜NPC2表达评分;待测患者滑膜组织样本的滑膜NPC2表达评分高的判断为RA;具体标准是:滑膜NPC2表达评分≥1.6,则为RA样本。
另外,本发明申请保护滑膜NPC2或滑膜NPC2表达抑制剂在制备RA治疗药物中的应用。
本发明还申请保护含有滑膜NPC2表达抑制剂的RA治疗药物。
具体地,所述治疗为抑制滑膜炎症的发生发展。
更具体地,所述治疗为抑制mTOR、炎症因子IL-1β和趋化因子MCP-1、CCL-5和CCL-12表达。
作为一种可实施方案,所述滑膜NPC2表达抑制剂为siNPC2(下调NPC2表达的siRNA)。
作为一种可实施方案,所述siNPC2的靶序列如下任一或任几:
siNPC2(1):CTACCTGAATAAACTACCA(SEQ ID NO.1),
siNPC2(2):AGTGGCAACTTCAGGATGA(SEQ ID NO.2),
siNPC2(3):GCCCTATCCAAAAAGACAA(SEQ ID NO.3)。
优选地,所述siNPC2的靶序列为siNPC2(2)。
本发明具有以下有益效果:
1.本发明研究发现了NPC2在RA滑膜组织高表达,而在OA滑膜和Orth.A滑膜组织的表达水平较低,表明滑膜NPC2可以用于RA的诊断,同时还可以用于鉴别临床症状较为相似的RA和OA。
2.本发明对20例RA患者完成1年随访,发现基线滑膜NPC2高表达组患者在接受治疗后,疾病缓解率均显著低于NPC2低表达组患者,表明RA滑膜NPC2的高表达与RA患者的预后不良相关。因此,滑膜NPC2可以用于RA的预后评估。
3.本发明还通过siRNA下调NPC2表达,发现下调NPC2表达后,mTOR被抑制,炎症因子IL-1β及趋化因子MCP-1、CCL-5和CCL-12表达降低。以上结果表明,滑膜NPC2可以作为RA的治疗靶点,临床上可以通过抑制滑膜NPC2的表达实现对RA的治疗。
4.本发明的RA诊断方案特异性和敏感性好,尤其是特异性达100%,显著高于现有技术。目前临床上普遍使用且对RA诊断价值最高的自身抗体是类风湿因子(RF)和抗环瓜氨酸多肽(CCP)抗体,Meta分析显示,对RA诊断,RF的特异性为85%,敏感性为69%;抗CCP抗体的特异性>90%,但敏感性为50%~80%。
附图说明
图1:滑膜NPC2表达水平及其与治疗预后的相关性。图A:免疫组化染色检测Orth.A、OA和RA患者滑膜NPC2的表达水平;图B:Orth.A、OA和RA患者滑膜NPC2的表达水平比较;图C:不同基线滑膜NPC2表达水平的RA患者接受治疗后的缓解率比较(*P<0.05)。
图2:多重免疫荧光染色检测NPC2在RA滑膜的细胞定位。
图3:RA滑膜和Orth.A滑膜NPC2蛋白水平检测。图A:Western Blot检测滑膜组织NPC2的蛋白水平;图B:Western Blot检测体外培养的成纤维样滑膜细胞(fibroblastsynoviocytes,FLS)中NPC2的蛋白水平。
图4:下调NPC2的表达水平对RA滑膜炎症发生发展的影响。图A:siRNA转染下调RA-FLS中NPC2的表达,NC:siNC(siRNA对照),si1:靶序列为siNPC2(1)的siRNA,si2:靶序列为siNPC2(2)的siRNA,si3:靶序列为siNPC2(3)的siRNA;图B:下调NPC2的表达水平对RA-FLS细胞炎症因子和趋化因子的影响,siNC:siRNA对照,siNPC2:靶序列为siNPC2(2)的siRNA(*P<0.05)。
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明,以下实施例所用试剂和材料均为市购。
以下实施例中提及的患者来源为:来自中山大学孙逸仙纪念医院临床病例;病例中含有符合2010年美国风湿病协会(ACR)/欧洲风湿病协会(EULAR)关于早期RA分类标准的RA患者,符合1986年ACR制定的膝OA分类标准的OA患者,以及符合相应诊断(包括半月板损伤、交叉韧带损伤、骨折)的Orth.A患者。
以下实施例中所用滑膜组织来源于患者的膝关节。
以下实施例中所用RA-FLS细胞来源为RA膝关节滑膜组织分离培养的原代细胞。具体分离步骤如下:
(1)将获取的滑膜组织置于无菌5mL EP管中,加入1mL I型胶原酶(工作浓度为2mg/mL)和等体积的DMEM完全培养基(含10% FBS),放入恒温摇床中(37℃,300rpm)中消化2h;
(2)1000rpm离心5min,去上清,加入1mL DMEM完全培养基重悬细胞,转移至T25细胞培养瓶,放入培养箱倒置培养过夜;
(3)第二天,将培养瓶倒正,继续加入少量DMEM完全培养基(没过组织即可),培养2-3天,待组织完全贴壁后,更换4-5mL DMEM完全培养基;
(4)每2~4天更换1次培养基,待RA-FLS生长至融合度为70%~80%时进行细胞传代:加入1mL 0.25%胰酶-0.02% EDTA消化2min,镜下观察细胞收缩、变圆、完全悬浮后加入3mL DMEM完全培养基终止消化,转移至15mL离心管中,1000rpm离心5min;用DMEM完全培养基重悬细胞,按1:3比例进行传代培养。
实施例1滑膜NPC2的差异表达
我们首先通过免疫组化染色检测了20例RA患者(其中包括3例血清阴性的RA患者)、10例OA患者及10例Orth.A患者滑膜组织NPC2的表达,结果发现,NPC2主要在RA滑膜衬里层及衬里下层的成纤维样滑膜细胞(fibroblast synoviocytes,FLS)中表达(图1中A图),且RA滑膜NPC2阳性细胞比例、染色强度及NPC2表达评分(阳性细胞比例评分×染色强度评分)均显著高于OA滑膜和Orth.A滑膜(图1中B图)。
根据Orth.A滑膜NPC2表达评分的95%百分位数上限确定NPC2的正常参考值,正常参考值=表达评分的平均值+1.96×标准差,得到NPC2表达评分的正常参考值为<1.6。以滑膜NPC2表达评分=1.6作为截断值,根据ROC曲线分析,计算得出滑膜NPC2表达评分在诊断RA和非RA(OA和Orth.A)时ROC曲线的曲线下面积为0.942,诊断特异性为100.0%(特异性=真阴性病例数/实际为阴性的病例数),敏感性为70.0%(敏感性=真阳性病例数/实际为阳性的病例数)。
我们进一步通过多重免疫荧光染色结合激光共聚焦检测,发现RA滑膜NPC2主要表达在FAPα阳性的FLS中(图2)。Western Blot检测证实RA滑膜组织及体外培养的RA-FLS中NPC2表达水平均显著高于Orth.A(图3中A图和B图)。
以上结果表明,NPC2在不同关节炎滑膜的表达存在差异,RA滑膜NPC2表达水平显著高于OA滑膜和Orth.A滑膜;包括对于血清阴性RA,RA滑膜NPC2表达水平也是显著高于OA滑膜和Orth.A滑膜。因此,滑膜NPC2不仅可以作为RA的诊断靶点,同时还可以用于鉴别临床症状较为相似的RA和OA。以及确定了诊断鉴别的标准为:滑膜NPC2表达评分≥1.6则为RA。
实施例2滑膜NPC2的表达水平与RA患者预后的相关性
对实施例1中的20例RA患者完成1年的前瞻性随访。根据滑膜NPC2表达评分的正常参考值为<1.6,将RA患者分为低NPC2表达组(表达评分<1.6,n=6)和高NPC2表达组(表达评分≥1.6,n=14)。
再将所有患者按照2013/2016年EULAR建议的“治疗-目标”策略进行治疗,经统计,按照治疗方案分为了如下三组:
组一:12例(包括7例NPC2高表达,5例NPC2低表达)接受糖皮质激素+传统改善病情抗风湿药(甲氨蝶呤、来氟米特、羟氯喹等)治疗;
组二:6例(包括5例NPC2高表达,1例NPC2低表达)接受糖皮质激素+传统改善病情抗风湿药(甲氨蝶呤、来氟米特、羟氯喹等)+生物制剂(TNF抑制剂、IL-6抑制剂等)治疗;
组三:2例(包括2例NPC2高表达,0例NPC2低表达)接受传统改善病情抗风湿药(甲氨蝶呤、来氟米特、羟氯喹等)治疗。
根据RA临床疾病活动指数(CDAI)≤2.8定义缓解,并进一步通过Logistic回归分析校正基线混杂因素(性别、年龄、病程、类风湿因子(RF)、抗环瓜氨酸肽抗体(ACPA)、红细胞沉降率(ESR)、C-反应蛋白(CRP)、临床疾病活动指数(CDAI)、中国版斯坦福健康评估问卷-残疾指数(HAQ-DI)和治疗用药(包括糖皮质激素、传统改善病情抗风湿药、生物制剂等))。
统计分析表明,三组治疗方案下,NPC2高表达患者的缓解率均显著低于NPC2低表达患者。NPC2高表达患者在接受治疗后3个月、6个月、9个月和12个月的缓解率(分别为7.1%、7.1%、14.3%和21.4%)显著低于NPC2低表达患者(3个月、6个月、9个月和12个月的缓解率分别为50.0%、66.7%、83.3%和83.3%)(图1中C图)。
以上结果表明,RA基线滑膜NPC2表达评分是治疗12个月内病情不缓解的独立危险因素(OR:2.305,95%CI:1.102~4.823,P=0.027)。通过检测RA滑膜的表达水平,可以评估RA患者的治疗预后情况。
实施例3NPC2的表达水平对RA滑膜炎症发生发展的影响
我们通过前期大量研究发现,富含炎症细胞的RA滑膜中FLS的NPC2表达水平显著高于炎症细胞较少的RA滑膜FLS,提示RA滑膜NPC2表达水平与RA滑膜炎症有关。为进一步深入研究滑膜NPC2的表达水平与RA滑膜炎症的关系,我们通过siRNA体外转染原代培养的RA-FLS下调NPC2表达,检测下调NPC2后炎症通路相关基因的表达情况。具体步骤如下:
(一)下调NPC2表达水平
(1)按6×105个/孔的密度将RA-FLS接种于6孔板,观察其汇合度至70%时,进行后续细胞转染。
(2)使用250μL Opti-MEM减血清培养基稀释5μL Lipofectamine RNAiMAX试剂,同时用250μL Opti-MEM减血清培养基稀释5μL浓度为20μM的siRNA,将两者混匀后置于室温孵育15分钟
(3)向待转染的6孔板中每孔加入1.5mL不加双抗的Opti-MEM减血清培养基,10分钟后每孔加入500μL步骤(2)中混匀的转染液。
(4)隔天后给予换液,并持续培养至第4天。
(5)收集细胞裂解液,用柱式动物组织/细胞总蛋白抽提试剂盒(雅梅,PC201)提取细胞总蛋白,用于后续的Western Blot检测。
(6)使用Anti-Niemann Pick C2抗体(abcam,ab218192)标记NPC2,Western Blot验证siRNA体外转染原代培养的RA-FLS后是否下调NPC2表达。
上述步骤所使用的NPC2 siRNA靶序列如表1所示。
表1siRNA靶序列
靶序列名称 | 靶序列 | 序列编号 |
siNPC2(1) | CTACCTGAATAAACTACCA | SEQ ID NO.1 |
siNPC2(2) | AGTGGCAACTTCAGGATGA | SEQ ID NO.2 |
siNPC2(3) | GCCCTATCCAAAAAGACAA | SEQ ID NO.3 |
同时设置siNC对照组,siNC购自锐博生物,货号为siN0000001-1-5。
结果如图4中A图所示,本研究设计的3条siNPC2均能下调RA-FLS的NPC2表达,其中,靶序列为siNPC2(2)的siRNA下调NPC2表达的效率最高。
(二)炎症相关因子的检测
收集经靶序列为siNPC2(2)的siRNA转染的细胞,提取细胞总RNA,通过qRT-PCR检测下游炎症通路相关基因(mTOR、IL-1β、MCP-1、CCL-5和CCL-12)的mRNA水平,发现下调NPC2表达后,mTOR被抑制,炎症因子IL-1β及趋化因子MCP-1、CCL-5和CCL-12表达降低(图4中B图)。
上述结果表明,通过抑制滑膜NPC2的表达水平,可以抑制RA滑膜炎症的发生发展,进而可以用于RA的治疗。
实施例4临床验证
22例来自中山大学孙逸仙纪念医院的关节病临床病例作为验证队列,分别按照本发明诊断方案,以及现有常规诊断标准进行诊断。
具体地,本发明诊断方案:利用免疫组化染色技术检测滑膜NPC2表达水平,具体是对患者滑膜组织样本进行免疫组化染色,统计滑膜NPC2阳性细胞比例评分与染色强度评分的乘积为滑膜NPC2表达评分。如滑膜NPC2表达评分≥1.6,则为RA。
现有常规诊断标准:2010年美国风湿病协会(ACR)/欧洲风湿病协会(EULAR)关于早期RA分类标准。
结果显示,22例临床病例中,滑膜NPC2表达评分≥1.6共8例,滑膜NPC2表达评分<1.6共14例。
根据本发明诊断方案及现有诊断标准,滑膜NPC2表达评分≥1.6的8例均为RA病例。此8例诊断结果与按照现有常规诊断标准的诊断结果一致。
而滑膜NPC2表达评分<1.6的14例中,按照现有常规诊断标准,其中3例为RA病例,11例为非RA病例。
ROC曲线分析提示,在验证队列中,滑膜NPC2表达评分在诊断RA和非RA时ROC曲线的曲线下面积为0.971,诊断特异性为100.0%,敏感性为72.7%,准确性为86.4%(准确性=真阳性病例数和真阴性病例数之和/总检测病例数,用于表示诊断试验结果与金标准符合的程度,反映该诊断方案正确诊断患者与排除非患者的能力)。
综上研究显示,本发明提供了以滑膜NPC2表达水平为依据的RA诊断方案,并明确了诊断标准,临床诊断特异性达100%,敏感性超过70%,具有很高的临床应用价值。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
1.检测滑膜NPC2表达水平的试剂在制备类风湿关节炎诊断或预后评估产品中的应用。
2.检测滑膜NPC2表达水平的试剂在鉴别类风湿关节炎和其他关节炎中的应用。
3.检测滑膜NPC2表达水平的试剂在制备鉴别类风湿关节炎和其他关节炎的产品中的应用。
4.一种类风湿关节炎诊断或预后评估试剂盒,其特征在于,所述试剂盒含有检测滑膜NPC2表达水平的试剂。
5.一种鉴别类风湿关节炎和其他关节炎的试剂盒,其特征在于,所述试剂盒含有检测滑膜NPC2表达水平的试剂。
6.根据权利要求2~3任一所述应用或权利要求5所述试剂盒,其特征在于,其他关节炎包括骨关节炎。
7.根据权利要求1~3任一所述应用或权利要求4~5任一所述试剂盒,其特征在于,所述诊断或鉴别的依据为:滑膜NPC2表达水平高的为类风湿关节炎。
8.滑膜NPC2或滑膜NPC2表达抑制剂在制备类风湿关节炎治疗药物中的应用。
9.一种类风湿关节炎治疗药物,其特征在于,含有滑膜NPC2表达抑制剂。
10.根据权利要求8所述应用或权利要求9所述药物,其特征在于,所述滑膜NPC2表达抑制剂为siNPC2,所述siNPC2的靶序列如SEQ ID NO.1~3任一或任几所示。
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