CN100476433C - 一种筛查系统性硬化症疑似患者血清的专用多肽 - Google Patents
一种筛查系统性硬化症疑似患者血清的专用多肽 Download PDFInfo
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Abstract
本发明公开了一种筛查系统性硬化症疑似患者血清的方法及其专用多肽。本发明的筛查系统性硬化症疑似患者血清专用多肽，是具有序列表中序列1和/或序列2的氨基酸残基序列的多肽。筛查系统性硬化症疑似患者血清的方法，是用具有序列表中序列1和/或序列2的氨基酸残基序列的多肽作为抗原，用ELISA方法检测待测血清中的抗具有序列表中序列1和/或序列2的氨基酸残基序列的多肽的抗体水平。如果待测血清中的酶底物显色反应的光密度值高于X+2SD，则待测血清为系统性硬化症疑似患者血清；所述X+2SD中，X为正常人血清中的酶底物显色反应的光密度平均值，2SD为正常人血清中的酶底物显色反应的光密度值的二倍标准差。
Description
技术领域
本发明涉及一种筛查系统性硬化症疑似患者血清的方法及其专用多肽。
背景技术
细胞内核糖核酸(RNA)与不同的蛋白质相结合形成不同类型的核糖核蛋白(RNP)。异质性细胞核糖核蛋白(hnRNP)是其中的一类。已发现真核细胞中的hnRNP有20余种，它们以字母顺序命名为hnRNP A-U(Krecic AM and SwansonMS.hnRNP complexes：composition，structure，and function，Curr Opin CellBiol 1999；11：363-371.Gorlach M，et al.The hnRNP proteins.Mol BiolRep1993；18：73-78.)。hnRNP I是近年来发现的hnRNP家族新成员。hnRNP I由557个氨基酸组成，分子量为59.632kDa。在过去的几十年中，已经发现多种RNP在风湿性疾病中具有抗原性，是多种风湿性疾病自身免疫反应的靶抗原。1996年，Montecucco克隆了hnRNP I的cDNA，在大肠杆菌表达出了其编码蛋白质，并纯化到了分子量为60kDa的蛋白质。他们用ELISA和免疫印迹法检测了101例结缔组织病患者和40例正常人血清，发现系统性硬化症(SSc)患者的阳性率明显高于其它疾病患者。他们由此得出结论，抗hnRNP I抗体升高对SSc患者具有特异性(Montecucco C，et al.Identification of autoantibodies to the I protein ofthe heterogenous nuclear ribonucleoprotein complex in patients withsystemic sclerosis.Arth Rheum 1996；39：1669-1676)。
临床上结缔组织病(包括SSc)的诊断除了临床症状和体症外，尚需实验室的检验指标作辅助。目前与SSc有关的实验室指标由ANA、抗U1RNP抗体、抗SSA抗体、抗SSB抗体、抗I与IV型胶原抗体、抗板层素抗体、抗Ku抗体、抗Th抗体、抗Scl 70抗体和抗着丝点抗体等。但其中只有Scl70抗体对SSc有一定的特异性。
发明内容
本发明的目的是提供一种筛查系统性硬化症疑似患者血清的方法及其专用多肽。
本发明所提供的筛查系统性硬化症疑似患者血清专用多肽，是具有序列表中序列1和/或序列2的氨基酸残基序列的多肽。
序列表中的序列1由29个氨基酸组成，名称为hnRNP I264-292；序列表中的序列2由21个氨基酸组成，名称为hnRNP I441-461。
上述筛查系统性硬化症疑似患者血清专用多肽可用于筛查系统性硬化症疑似患者血清。
在实际应用中，可以用hnRNP I264-292和/或hnRNP I441-461作为抗原，用ELISA方法检测待测血清中的抗hnRNP I264-292和/或hnRNP I441-461的抗体水平。如果待测血清中的酶底物显色反应的光密度值高于X+2SD，则待测血清为系统性硬化症疑似患者血清；所述X+2SD中，X为正常人血清中的酶底物显色反应的光密度平均值，2SD为正常人血清中的酶底物显色反应的光密度值的二倍标准差。
为了提高筛查效果，所述正常人血清最好为50-60例。
本发明创造性地用选自hnRNP I的两个多肽筛查系统性硬化症疑似患者血清，为系统性硬化症的诊断提供了一个新的检验指标。实验证实，抗hnRNP I264-292自身抗体和抗hnRNP I441-461自身抗体在系统性硬化症患者诊断中的敏感性分别为47.6％和38％，特异性分别为93.4％和91％。本发明的筛查系统性硬化症疑似患者血清专用多肽可用于系统性硬化症的辅助诊断。
具体实施方式
下述实施例中的实验方法，如无特别说明，均为常规方法。
实施例1、hnRNP I264-292和hnRNP I441-461在SSc患者诊断中的敏感性和特异性
1、筛查系统性硬化症疑似患者血清专用多肽的获得
根据抗体识别的是抗原分子中的B细胞表位的原则，用相应的软件(Wonderful生物信息学系统软件和DNAStar-Protein生物分析软件)对hnRNP I分子中的可能B细胞表位作了分析，发现hnRNP I氨基酸序列中的264-292(序列为NVKYNNDKSRDYTRPDLPSGDSQPSLDQT，名称为hnRNP I264-292)和441-461(序列为QLPREGQEDQGLTKDYGNSPL，名称为hnRNP I441-461)两个肽段可能是B细胞表位。由美国GENEMEDSYN公司合成hnRNP I264-292和hnRNP I441-461。
2、确定正常人血清的抗hnRNP I264-292和hnRNP I441-461自身抗体的正常值的上限
以hnRNP I264-292和hnRNP I441-461为抗原，用ELISA方法分别检测血清中的抗hnRNPI264-292和hnRNP I441-461自身抗体，具体方法如下：
1)包被：用pH9.6的包被缓冲液(Na2CO3 1.59g，NaHCO3 2.93g，加蒸馏水至1000ml，4℃保存)分别稀释合成的hnRNP I264-292和hnRNP I441-461至2μg/ml。96孔酶标板每孔加入100μl。置湿盒中，4℃过夜。
2)洗涤：弃去孔中的液体。用含0.05％Tween-20的PBS液(含0.05％Tween-20的PBS液的配制为NaCl 8.0g，KH2PO4 0.2g，Na2HPO4·12H2O 29g，KCl 0.2g，加蒸馏水至1000ml，pH7.4，再加Tween-20 0.5ml)洗涤酶标板3次。
3)加待测血清：用含10％(V/V)小牛血清的PBS液(PBS液的配制为NaCl 8.0g，KH2PO4 0.2g，Na2HPO4·12H2O 29g，KCl 0.2g，加蒸馏水至1000ml，pH7.4)稀释血清。每孔加100μl，设复孔。每板设2个空白对照孔，加入100μl含10％(V/V)小牛血清的PBS液(PBS液的配制为NaCl 8.0g，KH2PO4 0.2g，Na2HPO4·12H2O 29g，KCl 0.2g，加蒸馏水至1000ml，pH7.4)。37℃孵育2小时。弃去孔中的液体。酶标板洗涤3次。
4)加二抗：辣根过氧化物酶标记的鼠抗人IgG用含10％(V/V)小牛血清的PBS液(PBS液的配制为NaCl 8.0g，KH2PO4 0.2g，Na2HPO4·12H2O 29g，KCl 0.2g，加蒸馏水至1000ml，pH7.4)稀释。每孔加入100μl。37℃孵育2小时。弃去孔中液体。酶标板洗涤3次。
5)加底物液：底物为邻苯二胺(OPD)。底物液须新配制。取40mgOPD，溶于磷酸盐-柠檬酸缓冲液中(0.1mol/L柠檬酸24.3ml，0.2mol/L磷酸盐(Na2HPO4·12H2O)25.7ml，加水50ml，pH5.0)。用前加入30％(V/V)H2O2 0.15ml。配后即用，每孔加入100μl。37℃湿盒孵育15分钟。加入2mol/L H2SO4 25μl终止反应。
6)检测：用酶标仪在波长492mm的条件下测定光密度OD值。正常值上限经测定54例正常人血清确定。
正常人血清(献血员血清，满足献血条件)54例。用上述方法测得的OD值以单样本K-S检验分析符合正态分布(P＞0.05)。计算OD值的平均值(X)及标准差(SD)。以X+2SD为正常值的上限(表1)。表1表明，正常人血清中抗hnRNPI264-292自身抗体的正常值的上限为0.427，正常人血清中抗hnRNP I441-461自身抗体的正常值的上限为0.387。
表1 用ELISA法测定血清中抗hnRNP I264-292和hnRNP I441-461自身抗体的正常值的上限
| 血清份数 | 抗原 | OD(X±2SD) | Z(K-S试验) | P值 | 正常值的上限 |
| 5454 | hnRNP I<sub>264-292</sub>hnRNP I<sub>441-461</sub> | 0.249±0.0890.221±0.083 | 0.5810.554 | 0.8890.919 | 0.4270.387 |
3、多种结缔组织病患者血清抗hnRNP I264-292和hnRNP I441-461自身抗体的阳性率比较
按照步骤2的ELISA方法测定多种自身免疫性疾病患者血清抗hnRNP I264-292和hnRNP I441-461自身抗体。两者的OD值分别高于0.427和0.387为阳性(表2)。
表2各种结缔组织病患者血清抗hnRNP I264-292和hnRNP I441-461自身抗体的阳性率比较
| 疾病 | 例数 | hnRNP I<sub>264-292</sub>抗体阳性率 | hnRNP I<sub>441-461</sub>抗体阳性率 |
| 系统性硬化症(SSc)系统性红斑狼疮(SLE)原发性干燥综合症(pSS)混合性结缔组织病(MTCD)未分化结缔组织病(UCTD)类风湿关节炎(RA)其它结缔组织病正常人 | 42102261613263054 | 20/42(47.62％)8/102(7.84％)**1/26(3.85％)**3/16(18.75％)*1/13(3.85％)*0/26(0％)**1/30(3.33％)**0/54(0％)** | 16/42(38.10％)11/102(10.78％)**2/26(7.69％)**3/16(18.75％)*1/13(7.69％)*1/26(3.85％)**1/30(3.33％)**0/54(0％)** |
注：**，SSc与其它疾病的差异为P＜0.01
*SSc与其它疾病的差异为P＜0.05
在上述比较中，SSc的病例数为42，非SSc的病例数为223。把SSc和非SSc患者血清抗hnRNP I264-292和hnRNP I441-461自身抗体阳性和阴性的患者数分别列于表3和表4。
表3血清抗hnRNP I264-292自身抗体阳性和阴性的SSc和非SSc患者数
| hnRNP I<sub>264-292</sub>自身抗体 | SSc患者数 | 非SSc患者数 |
| 阳性阴性 | 20(a，即真阳性)22(c，即假阴性) | 14(b，即假阳性)199(d，即真阴性) |
表4血清抗hnRNP I441-461自身抗体阳性和阴性的SSc和非SSc患者数
| hnRNP I<sub>441-461</sub>自身抗体 | SSc患者数 | 非SSc患者数 |
| 阳性阴性 | 16(a)26(c) | 19(b)194(d) |
按下列公式计算出抗hnRNP I264-292和hnRNP I441-461自身抗体在SSc患者诊断中的敏感性和特异性：敏感性＝(a/a+c)×100％
特异性＝(d/b+d)×100％
阳性预测值＝(a/a+b)×100％
阴性预测值＝(d/c+d)×100％
抗hnRNP I264-292和hnRNP I441-461自身抗体在SSc患者中的敏感性和特异性结果如表5。
表5抗hnRNP I264-292和hnRNP I441-461自身抗体在SSc患者中的敏感性和特异性
| 自身抗体 | 敏感性 | 特异性 | 阳性预测值 | 阴性预测值 |
| 抗hnRNP I<sub>264-292</sub>抗hnRNP I<sub>441-461</sub> | 47.6％38％ | 93.4％91％ | 58.8％45.7％ | 90％88.2％ |
抗hnRNP I264-292和hnRNP I441-461自身抗体的相关性用卡方检测，pearson’s R值为0.823，P＜0.001，表明两者在统计学上显著相关(表6)。
| 抗hnRNP I<sub>264-292</sub>阳性病例数 | 抗hnRNP I<sub>441-461</sub>阴性病例数 | 总病例数 | |
| 抗hnRNP I<sub>264-292</sub>阳性病例数抗hnRNP I<sub>441-61</sub>阴性病例数总病例数 | 16016 | 42226 | 202242 |
序列表
<160>2
<210>1
<211>29
<212>PRT
<213>人工序列
<220>
<223>
<400>1
Asn Val Lys Tyr Asn Asn Asp Lys Ser Arg Asp Tyr Thr Arg Pro Asp
1 5 10 15
Leu Pro Ser Gly Asp Ser Gln Pro Ser Leu Asp Gln Thr
20 25
<210>2
<211>21
<212>PRT
<213>人工序列
<220>
<223>
<400>2
Gln Leu Pro Arg Glu Gly Gln Glu Asp Gln Gly Leu Thr Lys Asp Tyr
1 5 10 15
Gly Asn Ser Pro Leu
20
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1、筛查系统性硬化症疑似患者血清专用多肽，是具有序列表中序列1和/或序列2的氨基酸残基序列的多肽。
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