CN113238045B - Crmp2及抗crmp2抗体的应用 - Google Patents
Crmp2及抗crmp2抗体的应用 Download PDFInfo
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Abstract
本发明公开了CRMP2及抗CRMP2抗体的应用,具体为CRMP2和/或抗CRMP2抗体作为神经系统自身免疫性疾病标志物的应用,以及检测抗CRMP2抗体的试剂在制备神经系统自身免疫性疾病的检测、诊断、治疗或预后评估试剂中的应用。本发明通过研究发现CRMP2是一个新的脑炎/脑脊髓炎相关的自身抗体靶向分子标志物。CRMP2则可用于该疾病的明确诊断和为免疫治疗方案提供依据,并可通过检测该自身抗体的滴度变化监测治疗效果及判断预后及复发。
Description
技术领域
本发明属于生物医药技术领域,具体涉及CRMP2及抗CRMP2抗体的应用。
背景技术
神经系统自身免疫性疾病是自身免疫分子、免疫细胞识别了神经系统组织细胞自身成分(自身抗原)导致炎症等损伤所引起的一类疾病,可发生在中枢神经系统、周围神经系统及神经-肌肉接头处,包括:自身免疫性脑炎(autoimmune encephalitis,AE)、中枢性脱髓鞘疾病、自身免疫性周围神经病等。其中,AE最常见,临床表现为急性或者亚急性起病(<3个月),具备一个或者多个神经与精神症状或者临床综合征:1)边缘系统症状:近事记忆减退、癫痫发作、精神行为异常;2)脑炎综合征:弥漫性或者多灶性脑损害的临床表现;3)基底节和(或者)间脑/下丘脑受累的临床表现;4)精神障碍,且精神心理专科认为不符合非器质性疾病。主要累及青中年人群,致死率及致残率高。
目前已发现的神经元自身抗原有近20种。1985年开始发现的自身抗原主要针对神经元胞内抗体,例如抗Hu(ANNA-1)、Yo(PCA-1)、Rui(ANNA2)、PNMA2(Paraneoplasticantigen Ma2,副肿瘤抗原Ma2)等。2019年新发现精原细胞瘤相关的副肿瘤抗原Kelch-likeProtein 11。这类抗原主要是通过细胞免疫介导神经元不可逆损伤,这类AE患者常伴有肿瘤,又称为肿瘤相关AE,或称副肿瘤综合征。2007年美国宾夕法尼亚州Dalmau实验室在畸胎瘤患者的血清和脑脊液(cerebrospinal fluid,CSF)样品中首次发现第一个针对神经元表面受体AE自身抗体,即抗NMDAR(N-methyl-D-aspartate receptor,N-甲基-D-天冬氨酸受体)抗体,其病理机制是自身抗体通过结合NMDAR受体介导体液免疫反应,引起突触的NMDAR受体减少,从而引起相对可逆的神经元功能障碍,免疫治疗效果良好。近年来,越来越多的针对神经元细胞表面蛋白和突触蛋白的自身抗体介导的体液免疫导致一类全新的AE被鉴定,这类AE确诊后进行早期免疫治疗效果良好。这类AE对应的自身抗原(或蛋白)包括:(1)神经递质受体AMPAR(alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acidreceptor)、mGluR5(Metabotropic glutamate receptor 5)、GABAAR/GABABR(Gamma-Aminobutyric Acid A/B receptor)、GlyR1(甘氨酸受体)、D2R(多巴胺-2受体);(2)跨膜蛋白CASPR2(Contactin-associated protein-like 2)、DNER(Delta/Notch Like EGFRepeat Containing)、DDP6/DPPX(Dipeptidyl Peptidase Like 6)、DCC(Netrin1Receptor DCC)、IgLON5(IgLON Family Member 5)、Neurexin-3α;(3)分泌蛋白LGI1(Leucine Rich Glioma Inactivated 1);(4)以及细胞内蛋白GAD65(Glutamic AcidDecarboxylase 65)。与传统的副肿瘤综合征不同的是,AE可伴有或不伴有肿瘤的发生。已知肿瘤和病毒感染是激发因素之一。
2016年Graus等制定了AE的临床诊断和治疗专家共识。2017年中国脑炎专家根据国内AE临床特点形成了《中国自身免疫性脑炎诊治专家共识》,指出,这一新类型AE是一种致病性抗体兼诊断标记物可查的可治性且并不少见的脑炎,患者早期接受免疫治疗和非重症患者的预后较好。AE的诊断首先需要综合分析患者的临床表现、脑脊液检查、神经影像学和脑电图等辅助检查结果,确定其患有脑炎(AE疑似患者或可能的AE),继而进行已知AE相关的抗体检测予以诊断,抗体检测阳性并符合临床表现且排除其它病因的可能的AE即可明确诊断为针对某种已知自身抗原的AE,例如抗NMDAR脑炎。因此,对应抗体的阳性检出是AE确诊的必要条件,但不是充分条件。由于儿童的自身免疫性脑炎的临床表现与成人不同,难以鉴别特定的自身免疫性脑炎综合征,因此,自身抗体的检出对儿童自身免疫性脑炎的明确诊断显得非常重要。
随着共识的制定,AE抗体的阳性检出是确诊AE的必要条件。目前,AE特异抗体的检测主要采用基于表达特异抗原的细胞免疫荧光检测法(cell based assay,CBA法)。2014年中国医学科学院通过单荧光CBA法对284例不明原因脑炎患者的脑脊液进行抗NMDAR抗体检测,其中46例抗体阳性,发病比例为16.2%,说明抗NMDAR脑炎在我国并不罕见。因此,对不明病因脑炎病例进行抗NMDAR抗体检测是有必要的。2017年美国滨州大学中心用单荧光CBA法分析了750例疑似AE患者的最常见6种AE抗体(自免六项),在检出的4种AE抗体中,NMDAR抗体比例最高,为10.94%。我们对约4000例送检的疑似AE的样本进行检测,已知AE抗体总阳性检出率小于20%,早期诊断AE仍然是一个挑战。部分已知AE抗体检测阴性的患者的血清或脑脊液通过鼠脑组织的免疫组化检查结果为阳性,说明可能存在有未知抗体,这部分约占AE的60%~80%,因此,发现新的AE相关抗体及其靶向分子标志物,进一步阐释其致病性与致病机制,对于临床上更好地诊治自身免疫性脑炎具有重要意义。
AE的致病机理尚处于初期的研究阶段,不同自身抗体触发疾病的发生及临床表现有所不同。例如,抗NMDAR抗体与神经元NMDAR结合后,大大减少了突触的数量;而抗GABABR抗体抑制该受体活性,但对突触的密度并没有明显影响;抗LGI1和CASPR2抗体可干扰突触蛋白-蛋白相互作用;抗neurexin-3α抗体可改变突触的形成;抗IgLON5抗体可导致形成新形式的Tau蛋白病变。临床上,大部分患者表现为脑炎症状,也有表现为小脑综合征或慢性脑病症状。
肿瘤和病毒感染是AE的风险因素。抗NMDAR脑炎常伴有畸胎瘤,抗GABABR脑炎常伴有小细胞肺癌。肿瘤细胞可能分泌自身抗原从而激活了免疫系统而导致AE的发展,例如畸胎瘤类神经样组织细胞分泌NMDAR,发生AE比不发生AE的畸胎瘤患者的肿瘤组织炎症反应很高。但伴有Hodgkin淋巴瘤的DNER、mGluR1和mGluR5脑炎例外,肿瘤不产生任何AE相关的抗原。约20%的单纯疱疹病毒脑炎患者几周后可继发AE,主要以NMDAR为主,机理可能是病毒介导的颅内炎症反应促进自身抗原的产生,在神经系统外产生了自身免疫反应。然而,LG1脑炎及很多AE,特别是年轻患者,长期随访既没有肿瘤发现,也没有前期病毒感染的证据,说明的机制大部分并不清楚,AE的机制尚待进一步深入。
发明内容
本发明的目的在于提供一种新的抗体标志物并建立其检测体系,用于神经系统自身免疫性疾病的诊断和治疗。
本发明所采取的技术方案是:
本发明提供CRMP2作为神经系统自身免疫性疾病标志物的应用。
在本发明的一些实施方式中,所述CRMP2的氨基酸序列如SEQ ID NO:1~3任一项所示。
在本发明的一些实施方式中,所述CRMP2的核苷酸序列如SEQ ID NO:4~6任一项所示。
本发明还提供抗CRMP2抗体作为神经系统自身免疫性疾病标志物的应用。
本发明还提供检测抗CRMP2抗体的试剂在制备神经系统自身免疫性疾病的检测、诊断、治疗或预后评估试剂中的应用。
在本发明的一些实施方式中,所述检测抗CRMP2抗体的方法选自CBA、免疫印迹、膜条法、ELISA、化学发光、放射免疫法、液相芯片法、侧向层析、电化学、流式细胞中的至少一种。
本发明还提供抑制抗CRMP2抗体表达或翻译的试剂在制备神经系统自身免疫性疾病药物中的应用。
在本发明的一些实施方式中,所述抑制抗CRMP2抗体表达或翻译的制剂包括:抗CRMP2抗体基因启动子抑制剂、抗CRMP2抗体基因转录抑制剂、抗CRMP2抗体蛋白合成抑制剂、抗CRMP2抗体基因的siRNA。
本发明还提供使抗CRMP2抗体活性降低或失活的制剂在制备神经系统自身免疫性疾病药物中的应用。
在本发明的一些实施方式中,使抗CRMP2抗体活性降低或失活的试剂包括:抑制抗CRMP2抗体活性的物质、或降解抗CRMP2抗体活性的物质、或降低抗CRMP2抗体蛋白水平的基因工具。
本发明还提供一种神经系统自身免疫性疾病辅助诊断试剂,该试剂含有检测抗CRMP2抗体表达量的试剂。
在本发明的一些实施方式中,所述检测的样本为脑脊液或血液。
在本发明的一些实施方式中,所述神经系统自身免疫性疾病为脑炎或脑脊髓炎。
本发明的有益效果是:
本发明通过研究发现CRMP2是一个新的脑炎或脑脊髓炎相关的自身抗体靶向分子标志物。根据该类疾病的命名规则,此新病称为抗CRMP2脑炎或脑脊髓炎,其累及部位或症状定位可以是大脑、小脑和/或脊髓。CRMP2则可用于该疾病的明确诊断和为免疫治疗方案提供依据,并可通过检测该自身抗体的滴度变化监测治疗效果及判断预后及复发。
附图说明
图1为pcDNA3.1+载体图谱。
图2为P1、P2、P3患者影像。
图3为P1患者脑脊液的脑片免疫组化检测。
图4为CRMP2标志物的鉴定。
图5为原代培养的小鼠大脑皮层神经元的P1患者血清的免疫荧光检测。
图6为P1、P3患者血清的CBA检测。
图7为P2患者治疗前后血清样本中抗CRMP2抗体的CBA检测。
图8为P2患者血清样本的膜条法检测。
图9为CRMP2的3种亚型序列比对结果。
图10为人、小鼠、大鼠、牛、猩猩、鸡的CRMP2蛋白序列比对。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述,以充分地理解本发明的目的、特征和效果。显然,所描述的实施例只是本发明的一部分实施例,而不是全部实施例,基于本发明的实施例,本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例,均属于本发明保护的范围。
其中已知CRMP2有3种蛋白亚型,序列如下:
亚型1:长度:677个氨基酸;种属:人(Homo sapiens),氨基酸序列如SEQ ID NO:1所示;亚型2:长度:572个氨基酸;种属:人(Homo sapiens),氨基酸序列如SEQ ID NO:2所示;亚型3:长度:536个氨基酸;种属:人(Homo sapiens),氨基酸序列如SEQ ID NO:3所示。
已知CRMP2有3种编码蛋白的转录本,对应上述3种蛋白亚型,序列如下:
转录本1:长度2034bp;种属:人(Homo sapiens),核苷酸序列如SEQ ID NO:4所示;转录本2:长度1719bp;种属:人(Homo sapiens),核苷酸序列如SEQ ID NO:5所示;转录本3:长度1611bp;种属:人(Homo sapiens),核苷酸序列如SEQ ID NO:6所示。
使用的pcDNA3.1-CRMP2质粒中CRMP2序列为转录本1,用以表达1型CRMP2蛋白,涵盖了3种转录本及3种亚型的全部序列,以便无遗漏的检测抗CRMP2抗体。其中pcDNA3.1-CRMP2载体图谱见图1。
pcDNA3.1-CRMP2质粒采用的真核表达载体为pcDNA3.1+,图谱如下:载体构建所用的酶切位点为BamH I(5’端)和EcoR I(3’端),中间为插入的CRMP2转录本1序列,具体序列如SEQ ID NO:7所示。
实施例1
本实施例中的3例患者编号分别为:P1、P2、P3。
P1为首例,利用其脑脊液和血液样本鉴定得到CRMP2;P2、P3为CBA法回顾性分析检测到的抗CRMP2抗体阳性病例。
P1、P2、P3均有头晕或头痛、视觉障碍、行走不稳病征;脑白质病变;免疫治疗有效;血液和/或脑脊液的大鼠脑片TBA检测阳性;抗CRMP2抗体检测阳性,其它AE相关抗体检测阴性。
P1、P3有语言障碍、双侧指鼻试验不准;P2具有胸腹部疼痛,脊髓病变。
P1脑脊液肺炎支原体检测阳性;P3脑脊液人疱疹病毒6型、肺炎克雷伯杆菌检测阳性;血乙型流感病毒IgM阳性。
其中P1、P2、P3这3例患者的具体临床资料见表1,影像资料见图2。
表1 3例抗CRMP2抗体阳性脑炎/脑脊髓炎患者的临床资料
注:1.1.自身免疫性脑炎抗体:抗NMDA/LGI1/GASPR-2/DABAB/AMPA1/AMPA2/IgLON5/DPPX/GIy1/DRD2/GAD65抗体;2.自身免疫性小脑相关抗体:抗DPYSL5/Homer3抗体;3.甲状腺相关抗体:促甲状腺素受体抗体、抗甲状腺过氧化物酶抗体、抗甲状腺球蛋白抗体;4.肿瘤抗原:糖类抗原(CA-125),非小细胞肺癌相关抗原,鳞状细胞癌相关抗原(SCC),血清胰腺和胃肠道肿瘤相关抗(CA242),胃癌相关抗原(CA-724),胃肠癌相关抗原(CA-199),癌胚抗原(CEA);5.血清自身免疫抗体:抗核抗体、抗双链DNA抗体、抗Jo-1抗体、抗ssB抗体、抗Sm抗体、抗UI-nRNP抗体、抗核糖体P蛋白抗体、抗增殖细胞核抗原抗体、抗线粒体抗体、抗着丝点抗体、抗PM-Scl抗体、抗SCL-70抗体、抗ssA抗体、抗核小体抗体、抗组蛋白抗体、抗重组Ro52抗体。
2.缩写:MRI:磁共振;mRS:改良Rankin量表。
实施例2
基于大鼠脑片的免疫组化实验是自身免疫性脑炎的常规检查,包括免疫酶化学法和免疫荧光法(亦称TBA法,tissue based assay)。
实施过程:将成年大鼠麻醉后心脏灌注PBS(磷酸盐缓冲液)以去除循环血液,取大脑(含海马区)进行矢状面冰冻切片,取小脑进行纵切,冷丙酮固定10分钟,晾干备用。用PBST溶液(含0.05%Tween-20的PBS)将切片洗3次,每次3分钟。
接下来分别进行免疫酶化学法和免疫荧光法进行检测:(1)进行免疫酶化学法:再用3%过氧化氢处理10分钟,PBST洗3次后进行下一步封闭,用10%羊血清/PBST溶液室温封闭1小时;(2)进行免疫荧光法:无需过氧化氢处理,用10%羊血清/PBST溶液室温封闭1小时。
两组封闭完后甩去封闭液,加入P1患者脑脊液,37℃孵育1小时。孵育完毕,用PBST洗3次,每次5分钟。
(1)进行免疫酶化学法:脑脊液孵育、洗涤后,加入1:5000倍稀释的辣根过氧化物酶(Horseradish Peroxidase,HRP)标记的羊抗人IgG二抗(bs-0297G-HRP,Bioss),37℃孵育30分钟,洗涤后滴加二氨基联苯胺(Diaminobenzidine,DAB)底物液,显色3-15分钟,漂洗后核复染,树脂封片,于DM3000显微镜(Leica,German)观察、采集图像。
(2)进行免疫荧光法:加入1:200倍稀释的绿色荧光标记的羊抗人IgG二抗(ab97003,Abcam),37℃孵育30分钟。然后用PBST洗3次,每次5分钟。防淬灭封片剂封片,IX73荧光显微镜(Olympus,Japan)观察结果、采集图像。
结果:检测结果见图3,其中图3中A图和C图为免疫酶化学检测结果。其中与阴性非自身免疫患者脑脊液染色比较结果见图3中A图,P1患者脑脊液脑片染色阳性见图3中C图。图3中B图和D图为免疫荧光检测结果,图3中B图为在大脑海马区的检测结果,图3中D图为在小脑浦肯野细胞的检测结果,可以看出均显示阳性。表明,P1患者脑脊液中含有针对脑神经元的自身抗体,P1患者为疑似AE。
实施例3
利用免疫沉淀结合蛋白质谱鉴定P1患者脑脊液自身抗体针对的抗原。
实施过程:取约2月龄大鼠新鲜脑组织,加入1毫升蛋白裂解液(20mmol/L Tris-HCl,pH 7.4,150mmol/L NaCl,2mmol/L EDTA,1%TritonX-100,蛋白酶抑制剂),玻璃匀浆器匀浆1分钟,置于冰上裂解30分钟。4℃12000rpm离心15分钟,取上清液作为大鼠脑蛋白裂解液。将500微升蛋白裂解液与500微升P1患者脑脊液混合,4℃垂直混旋过夜。加入50微升预洗的蛋白A标记琼脂糖,4℃垂直混旋2小时。4℃、1000rpm离心、重悬,蛋白裂解液漂洗3次,然后加入1xSDS-PAGE样品缓冲液,煮沸5分钟洗脱蛋白复合物。制备的样品通过SDS-PAGE分离,分别做免疫印迹和考马斯亮蓝染色。大鼠脑片TBA检测阴性的脑脊液作为阴性对照。根据实验结果,选取疑似目的考马斯亮蓝染色条带(~70KDa),切胶,进行肽指纹质谱蛋白鉴定。结果见图4。其中图4中A图为免疫沉淀结果,图4中B图为考马斯亮蓝染色结果,其中免疫沉淀和考马斯亮蓝染色显示在约70KDa处可能为靶蛋白条带,将其切胶、质谱鉴定,鉴定到CRMP2的10余条多肽,其中图4中C图为其中一条多肽的二级质谱谱图,图4中D图为蛋白质谱鉴定到的多肽(下划线)在CRMP2蛋白上的分布,可以看出多肽的CRMP2蛋白覆盖度为40%,图4中D图下划虚线多肽对应图4中C图多肽。
实施例4
CRMP2定位于神经元的胞质、轴突和树突,抗CRMP2脑炎/脑脊髓炎患者的脑脊液和血清样本中的抗CRMP2抗体应可以与神经元结合,这是导致AE的重要机理。
实施过程:取18~19天的C57小鼠胚胎,分离其脑组织、制备皮层神经元细胞悬液,以3x106/孔的量铺24孔细胞培养板,板内预放细胞爬片,培养14天。培养完成后,用冰丙酮固定神经元10分钟。PBST洗涤3次3分钟、10%羊血清/PBST溶液室温封闭1小时后,加入患者或对照组血清(稀释度为1:20)和抗MAP2抗体(8707T,Cell Signaling Technology,稀释度为1:200),在4℃孵育过夜或37℃孵育1小时。反应完后PBST洗涤3次5分钟,然后加入红色荧光标记(Alexa594)的羊抗兔IgG(ab150092,Abcam)和绿色荧光标记(488)的羊抗人IgG(ab97003,Abcam)二抗37℃孵育30分钟。PBST洗涤3次5分钟,然后用含DAPI(4',6-Diamidino-2-Phenylindole,Dihydrochloride,4',6-二脒基-2-苯基吲哚)的封片剂封片。使用LSM 980激光共聚焦显微镜(zeiss,German)拍照。结果见图5。标尺为20μm。
从图5可以看出,P1患者血清染色神经元呈阳性,信号分布在神经元的胞质、树突和轴突上,与CRMP2的定位一致,符合抗CRMP2脑炎/脑脊髓炎特点。阴性对照血清无染色。
实施例5
基于293T细胞过表达靶抗原的免疫荧光(即CBA法)检测患者脑脊液和血清样本,是确诊自身免疫性脑炎/脑脊髓炎的重要途径。
实施过程:制备293T细胞爬片,待细胞长至50%~90%密度时,将pcDNA3.1-CRMP2真核表达质粒转染293T细胞,使293T细胞过表达CRMP2重组蛋白。PBS洗293T细胞3次,然后用丙酮固定5分钟,晾干。用PBST溶液将爬片洗3次,每次3分钟。用10%羊血清/PBST溶液室温封闭1小时,弃封闭液,加入P1或P3患者血清(1:20稀释),37度孵育1小时。孵育完毕,用PBST洗3次,每次5分钟。然后加入1:200倍稀释的绿色荧光标记的羊抗人IgG二抗(ab97003,Abcam),37度孵育30分钟。然后用PBST洗3次,每次5分钟。含DAPI的封片剂封片,使用LSM980激光共聚焦显微镜(zeiss,German)观察结果、采集图像。
本实施例在一抗同时加入抗CRMP2抗体(ab129082,Abcam,1:200稀释)做为阳性对照、二抗同时加入红色荧光标记的羊抗兔IgG二抗(ab150092,Abcam),进行免疫荧光共染色。本实施例以非自身免疫疾病患者血清为阴性对照。结果见图6。
从图6可以看出,本实施例成功于293T细胞过表达了CRMP2蛋白,P1、P3患者血清染色与CRMP2基本重叠。阴性对照血清无染色。表明P1、P3患者血清含抗CRMP2的自身免疫性抗体。
实施例6
通过免疫治疗降低或消除自身免疫性抗体,是治疗自身免疫性脑炎/脑脊髓炎的主要途径。
实施过程:3例患者经免疫治疗后均好转,见表1免疫治疗、预后。将P2患者治疗前和治疗后的血清进行抗CRMP2抗体的CBA检测,方法同实施例5。结果见图7。
从图7可以看出,P2患者治疗前血清的CBA染色阳性,且与CRMP2共定位,说明P2患者治疗前血清含抗CRMP2的自身免疫性抗体。治疗、恢复后,P2患者血清CBA染色阴性,表明P2患者治疗后血清抗CRMP2抗体消失。
实施例7
免疫印迹(亦称膜条法)是自身免疫抗体检测的另一方法。
实施过程:首先制备CRMP2蛋白。在10厘米细胞培养皿培养293T细胞至80%密度,利用EntransterTM-D4000(4000-2,Engreen)将pcDNA3.1-CRMP2真核表达质粒转染至293T细胞,继续培养293T细胞24小时~48小时,使其过表达CRMP2重组蛋白。然后,利用1毫升蛋白裂解液在4℃处理293T细胞30分钟。4℃12000rpm离心15分钟,收上清,获得含CRMP2的293T蛋白裂解液。加入5微克抗CRMP2抗体(ab129082,abcam),4℃垂直混旋过夜。加入50微升预洗的蛋白A标记琼脂糖,4℃垂直混旋2小时。4℃、1000rpm离心,去上清,蛋白裂解液重悬,然后重复离心和重悬以漂洗3次。最后一次离心后加入30微升的1xSDS-PAGE样品缓冲液重悬,煮沸5分钟以洗脱和纯化富集CRMP2蛋白。洗脱液经10%的SDS-PAGE分离、转印硝酸纤维素膜、5%脱脂奶粉/TBST室温封闭1小时、1:20稀释的P2患者脑脊液室温孵育2小时、TBST洗3次5分钟、1:5000稀释的HRP标记的羊抗人IgG室温孵育1小时、TBST洗3次5分钟、ECL底物显影,检测P2患者脑脊液中的抗CRMP2抗体。以正常兔IgG做为抗CRMP2抗体的阴性对照;以pcDNA3.1空载转染293T为CRMP2蛋白阴性对照。结果见图8。从图8可以看出,在目的CRMP2大小位置出现明显的条带,对应的阴性对照无条带,表明P2患者脑脊液中含抗CRMP2的抗体,同时表明免疫印迹(膜条法)可以用于该抗体的检测。
实施例8
CRMP2的3种亚型序列比对结果件图9,可以看出3种亚型在142至677位的氨基酸序列完全一致。因此实施例5、6、7中使用的pcDNA3.1-CRMP2质粒中CRMP2序列为转录本1,用以表达1型CRMP2蛋白,涵盖了3种转录本及3种亚型的全部序列,以便无遗漏的检测抗CRMP2抗体。
实施例9
对不同种属来源的CRMP2(别名DPYL2)蛋白序列进行同源性分析,结果见图10。从图10可以看出不同种属的CRMP2蛋白高度同源,同源性96.853%。可以利用不同种属的CRMP2蛋白检测人脑脊液或血清样本中的抗CRMP2抗体。
上述具体实施方式对本发明作了详细说明,但是本发明不限于上述实施例,在所属技术领域普通技术人员所具备的知识范围内,还可以在不脱离本发明宗旨的前提下作出各种变化。此外,在不冲突的情况下,本发明的实施例及实施例中的特征可以相互组合。
SEQUENCE LISTING
<110> 南方医科大学南方医院
<120> CRMP2及抗CRMP2抗体的应用
<130>
<160> 7
<170> PatentIn version 3.5
<210> 1
<211> 677
<212> PRT
<213> CRMP2
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Met Glu Ala Leu Val Lys Asp His Gly Val Asn Ser Phe Leu Val Tyr
260 265 270
Met Ala Phe Lys Asp Arg Phe Gln Leu Thr Asp Cys Gln Ile Tyr Glu
275 280 285
Val Leu Ser Val Ile Arg Asp Ile Gly Ala Ile Ala Gln Val His Ala
290 295 300
Glu Asn Gly Asp Ile Ile Ala Glu Glu Gln Gln Arg Ile Leu Asp Leu
305 310 315 320
Gly Ile Thr Gly Pro Glu Gly His Val Leu Ser Arg Pro Glu Glu Val
325 330 335
Glu Ala Glu Ala Val Asn Arg Ala Ile Thr Ile Ala Asn Gln Thr Asn
340 345 350
Cys Pro Leu Tyr Ile Thr Lys Val Met Ser Lys Ser Ser Ala Glu Val
355 360 365
Ile Ala Gln Ala Arg Lys Lys Gly Thr Val Val Tyr Gly Glu Pro Ile
370 375 380
Thr Ala Ser Leu Gly Thr Asp Gly Ser His Tyr Trp Ser Lys Asn Trp
385 390 395 400
Ala Lys Ala Ala Ala Phe Val Thr Ser Pro Pro Leu Ser Pro Asp Pro
405 410 415
Thr Thr Pro Asp Phe Leu Asn Ser Leu Leu Ser Cys Gly Asp Leu Gln
420 425 430
Val Thr Gly Ser Ala His Cys Thr Phe Asn Thr Ala Gln Lys Ala Val
435 440 445
Gly Lys Asp Asn Phe Thr Leu Ile Pro Glu Gly Thr Asn Gly Thr Glu
450 455 460
Glu Arg Met Ser Val Ile Trp Asp Lys Ala Val Val Thr Gly Lys Met
465 470 475 480
Asp Glu Asn Gln Phe Val Ala Val Thr Ser Thr Asn Ala Ala Lys Val
485 490 495
Phe Asn Leu Tyr Pro Arg Lys Gly Arg Ile Ala Val Gly Ser Asp Ala
500 505 510
Asp Leu Val Ile Trp Asp Pro Asp Ser Val Lys Thr Ile Ser Ala Lys
515 520 525
Thr His Asn Ser Ser Leu Glu Tyr Asn Ile Phe Glu Gly Met Glu Cys
530 535 540
Arg Gly Ser Pro Leu Val Val Ile Ser Gln Gly Lys Ile Val Leu Glu
545 550 555 560
Asp Gly Thr Leu His Val Thr Glu Gly Ser Gly Arg Tyr Ile Pro Arg
565 570 575
Lys Pro Phe Pro Asp Phe Val Tyr Lys Arg Ile Lys Ala Arg Ser Arg
580 585 590
Leu Ala Glu Leu Arg Gly Val Pro Arg Gly Leu Tyr Asp Gly Pro Val
595 600 605
Cys Glu Val Ser Val Thr Pro Lys Thr Val Thr Pro Ala Ser Ser Ala
610 615 620
Lys Thr Ser Pro Ala Lys Gln Gln Ala Pro Pro Val Arg Asn Leu His
625 630 635 640
Gln Ser Gly Phe Ser Leu Ser Gly Ala Gln Ile Asp Asp Asn Ile Pro
645 650 655
Arg Arg Thr Thr Gln Arg Ile Val Ala Pro Pro Gly Gly Arg Ala Asn
660 665 670
Ile Thr Ser Leu Gly
675
<210> 2
<211> 572
<212> PRT
<213> CRMP2
<400> 2
Met Ser Tyr Gln Gly Lys Lys Asn Ile Pro Arg Ile Thr Ser Asp Arg
1 5 10 15
Leu Leu Ile Lys Gly Gly Lys Ile Val Asn Asp Asp Gln Ser Phe Tyr
20 25 30
Ala Asp Ile Tyr Met Glu Asp Gly Leu Ile Lys Gln Ile Gly Glu Asn
35 40 45
Leu Ile Val Pro Gly Gly Val Lys Thr Ile Glu Ala His Ser Arg Met
50 55 60
Val Ile Pro Gly Gly Ile Asp Val His Thr Arg Phe Gln Met Pro Asp
65 70 75 80
Gln Gly Met Thr Ser Ala Asp Asp Phe Phe Gln Gly Thr Lys Ala Ala
85 90 95
Leu Ala Gly Gly Thr Thr Met Ile Ile Asp His Val Val Pro Glu Pro
100 105 110
Gly Thr Ser Leu Leu Ala Ala Phe Asp Gln Trp Arg Glu Trp Ala Asp
115 120 125
Ser Lys Ser Cys Cys Asp Tyr Ser Leu His Val Asp Ile Ser Glu Trp
130 135 140
His Lys Gly Ile Gln Glu Glu Met Glu Ala Leu Val Lys Asp His Gly
145 150 155 160
Val Asn Ser Phe Leu Val Tyr Met Ala Phe Lys Asp Arg Phe Gln Leu
165 170 175
Thr Asp Cys Gln Ile Tyr Glu Val Leu Ser Val Ile Arg Asp Ile Gly
180 185 190
Ala Ile Ala Gln Val His Ala Glu Asn Gly Asp Ile Ile Ala Glu Glu
195 200 205
Gln Gln Arg Ile Leu Asp Leu Gly Ile Thr Gly Pro Glu Gly His Val
210 215 220
Leu Ser Arg Pro Glu Glu Val Glu Ala Glu Ala Val Asn Arg Ala Ile
225 230 235 240
Thr Ile Ala Asn Gln Thr Asn Cys Pro Leu Tyr Ile Thr Lys Val Met
245 250 255
Ser Lys Ser Ser Ala Glu Val Ile Ala Gln Ala Arg Lys Lys Gly Thr
260 265 270
Val Val Tyr Gly Glu Pro Ile Thr Ala Ser Leu Gly Thr Asp Gly Ser
275 280 285
His Tyr Trp Ser Lys Asn Trp Ala Lys Ala Ala Ala Phe Val Thr Ser
290 295 300
Pro Pro Leu Ser Pro Asp Pro Thr Thr Pro Asp Phe Leu Asn Ser Leu
305 310 315 320
Leu Ser Cys Gly Asp Leu Gln Val Thr Gly Ser Ala His Cys Thr Phe
325 330 335
Asn Thr Ala Gln Lys Ala Val Gly Lys Asp Asn Phe Thr Leu Ile Pro
340 345 350
Glu Gly Thr Asn Gly Thr Glu Glu Arg Met Ser Val Ile Trp Asp Lys
355 360 365
Ala Val Val Thr Gly Lys Met Asp Glu Asn Gln Phe Val Ala Val Thr
370 375 380
Ser Thr Asn Ala Ala Lys Val Phe Asn Leu Tyr Pro Arg Lys Gly Arg
385 390 395 400
Ile Ala Val Gly Ser Asp Ala Asp Leu Val Ile Trp Asp Pro Asp Ser
405 410 415
Val Lys Thr Ile Ser Ala Lys Thr His Asn Ser Ser Leu Glu Tyr Asn
420 425 430
Ile Phe Glu Gly Met Glu Cys Arg Gly Ser Pro Leu Val Val Ile Ser
435 440 445
Gln Gly Lys Ile Val Leu Glu Asp Gly Thr Leu His Val Thr Glu Gly
450 455 460
Ser Gly Arg Tyr Ile Pro Arg Lys Pro Phe Pro Asp Phe Val Tyr Lys
465 470 475 480
Arg Ile Lys Ala Arg Ser Arg Leu Ala Glu Leu Arg Gly Val Pro Arg
485 490 495
Gly Leu Tyr Asp Gly Pro Val Cys Glu Val Ser Val Thr Pro Lys Thr
500 505 510
Val Thr Pro Ala Ser Ser Ala Lys Thr Ser Pro Ala Lys Gln Gln Ala
515 520 525
Pro Pro Val Arg Asn Leu His Gln Ser Gly Phe Ser Leu Ser Gly Ala
530 535 540
Gln Ile Asp Asp Asn Ile Pro Arg Arg Thr Thr Gln Arg Ile Val Ala
545 550 555 560
Pro Pro Gly Gly Arg Ala Asn Ile Thr Ser Leu Gly
565 570
<210> 3
<211> 536
<212> PRT
<213> CRMP2
<400> 3
Met Glu Asp Gly Leu Ile Lys Gln Ile Gly Glu Asn Leu Ile Val Pro
1 5 10 15
Gly Gly Val Lys Thr Ile Glu Ala His Ser Arg Met Val Ile Pro Gly
20 25 30
Gly Ile Asp Val His Thr Arg Phe Gln Met Pro Asp Gln Gly Met Thr
35 40 45
Ser Ala Asp Asp Phe Phe Gln Gly Thr Lys Ala Ala Leu Ala Gly Gly
50 55 60
Thr Thr Met Ile Ile Asp His Val Val Pro Glu Pro Gly Thr Ser Leu
65 70 75 80
Leu Ala Ala Phe Asp Gln Trp Arg Glu Trp Ala Asp Ser Lys Ser Cys
85 90 95
Cys Asp Tyr Ser Leu His Val Asp Ile Ser Glu Trp His Lys Gly Ile
100 105 110
Gln Glu Glu Met Glu Ala Leu Val Lys Asp His Gly Val Asn Ser Phe
115 120 125
Leu Val Tyr Met Ala Phe Lys Asp Arg Phe Gln Leu Thr Asp Cys Gln
130 135 140
Ile Tyr Glu Val Leu Ser Val Ile Arg Asp Ile Gly Ala Ile Ala Gln
145 150 155 160
Val His Ala Glu Asn Gly Asp Ile Ile Ala Glu Glu Gln Gln Arg Ile
165 170 175
Leu Asp Leu Gly Ile Thr Gly Pro Glu Gly His Val Leu Ser Arg Pro
180 185 190
Glu Glu Val Glu Ala Glu Ala Val Asn Arg Ala Ile Thr Ile Ala Asn
195 200 205
Gln Thr Asn Cys Pro Leu Tyr Ile Thr Lys Val Met Ser Lys Ser Ser
210 215 220
Ala Glu Val Ile Ala Gln Ala Arg Lys Lys Gly Thr Val Val Tyr Gly
225 230 235 240
Glu Pro Ile Thr Ala Ser Leu Gly Thr Asp Gly Ser His Tyr Trp Ser
245 250 255
Lys Asn Trp Ala Lys Ala Ala Ala Phe Val Thr Ser Pro Pro Leu Ser
260 265 270
Pro Asp Pro Thr Thr Pro Asp Phe Leu Asn Ser Leu Leu Ser Cys Gly
275 280 285
Asp Leu Gln Val Thr Gly Ser Ala His Cys Thr Phe Asn Thr Ala Gln
290 295 300
Lys Ala Val Gly Lys Asp Asn Phe Thr Leu Ile Pro Glu Gly Thr Asn
305 310 315 320
Gly Thr Glu Glu Arg Met Ser Val Ile Trp Asp Lys Ala Val Val Thr
325 330 335
Gly Lys Met Asp Glu Asn Gln Phe Val Ala Val Thr Ser Thr Asn Ala
340 345 350
Ala Lys Val Phe Asn Leu Tyr Pro Arg Lys Gly Arg Ile Ala Val Gly
355 360 365
Ser Asp Ala Asp Leu Val Ile Trp Asp Pro Asp Ser Val Lys Thr Ile
370 375 380
Ser Ala Lys Thr His Asn Ser Ser Leu Glu Tyr Asn Ile Phe Glu Gly
385 390 395 400
Met Glu Cys Arg Gly Ser Pro Leu Val Val Ile Ser Gln Gly Lys Ile
405 410 415
Val Leu Glu Asp Gly Thr Leu His Val Thr Glu Gly Ser Gly Arg Tyr
420 425 430
Ile Pro Arg Lys Pro Phe Pro Asp Phe Val Tyr Lys Arg Ile Lys Ala
435 440 445
Arg Ser Arg Leu Ala Glu Leu Arg Gly Val Pro Arg Gly Leu Tyr Asp
450 455 460
Gly Pro Val Cys Glu Val Ser Val Thr Pro Lys Thr Val Thr Pro Ala
465 470 475 480
Ser Ser Ala Lys Thr Ser Pro Ala Lys Gln Gln Ala Pro Pro Val Arg
485 490 495
Asn Leu His Gln Ser Gly Phe Ser Leu Ser Gly Ala Gln Ile Asp Asp
500 505 510
Asn Ile Pro Arg Arg Thr Thr Gln Arg Ile Val Ala Pro Pro Gly Gly
515 520 525
Arg Ala Asn Ile Thr Ser Leu Gly
530 535
<210> 4
<211> 2034
<212> DNA
<213> CRMP2
<400> 4
atggccgaga gaaagcaatc cgggaaggcg gcagaggacg aagaggtccc tgcttttttt 60
aaaaacctgg gctccggcag ccccaagccc cggcagaaat tctgtggcat gttctgcccg 120
gtggaagggt cctcggagaa caagaccatc gacttcgact cgctgtcggt gggccggggc 180
tcggggcagg tggtggctca gcagcgggac gtcgcccact tgggcccgga cccgcagccg 240
ccgtactcgc ggcagggccg gcgcgccggc ggagagccat ctgttgaatc gggccggaag 300
gtggagatcc ggagggcctc gggcaaagaa gccctgcaga acatcaacga ccagagcgat 360
cgtcttctga tcaaaggagg taaaattgtt aatgatgacc agtcgttcta tgcagacata 420
tacatggaag atgggttgat caagcaaata ggagaaaatc tgattgtgcc aggaggagtg 480
aagaccatcg aggcccactc ccggatggtg atccccggag gaattgacgt ccacactcgt 540
ttccagatgc ctgatcaggg aatgacgtct gctgatgatt tcttccaagg aaccaaggcg 600
gccctggctg ggggaaccac tatgatcatt gaccacgttg ttcctgagcc tgggacaagc 660
ctgctcgctg cctttgacca gtggagggaa tgggccgaca gcaagtcctg ctgtgactac 720
tctctgcatg tggacatcag tgagtggcat aagggcatcc aggaggagat ggaagcgctt 780
gtgaaggatc acggggtaaa ttccttcctc gtgtacatgg ctttcaaaga tcgcttccag 840
ctaacggatt gccagattta tgaagtactg agtgtgatcc gggatattgg cgccatagcc 900
caagtccacg cagaaaatgg cgacatcatt gcagaggagc agcagaggat cctggatctg 960
ggcatcacgg gccccgaggg acatgtgctg agccgacctg aggaggtcga ggccgaagcc 1020
gtgaatcgtg ccatcaccat cgccaaccag accaactgcc cgctgtatat caccaaggtg 1080
atgagcaaaa gctctgctga ggtcatcgcc caggcacgga agaagggaac tgtggtgtat 1140
ggcgagccca tcactgccag cttgggaacg gacggctccc attactggag caagaactgg 1200
gccaaggctg ctgcctttgt cacctcccca cccttgagcc ctgatccaac cactccagac 1260
tttctcaact ccttgctgtc ctgtggagac ctccaggtca cgggcagtgc ccattgcacg 1320
tttaacactg cccagaaggc tgtaggaaag gacaacttca ccctgattcc ggagggcacc 1380
aatggcactg aggagcggat gtccgtcatc tgggacaagg ctgtggtcac tgggaagatg 1440
gatgagaacc agtttgtggc tgtgaccagc accaatgcag ccaaagtctt caacctttac 1500
ccccggaaag gccgcattgc tgtgggatcc gatgccgacc tggtcatctg ggaccccgac 1560
agcgttaaaa ccatctctgc caagacacac aacagctctc tcgagtacaa catctttgaa 1620
ggcatggagt gccgcggctc cccactggtg gtcatcagcc aggggaagat tgtcctggag 1680
gacggcaccc tgcatgtcac cgaaggctct ggacgctaca ttccccggaa gcccttccct 1740
gattttgttt acaagcgtat caaggcaagg agcaggctgg ctgagctgag aggggttcct 1800
cgtggcctgt atgacggacc tgtgtgtgaa gtgtctgtga cgcccaagac agtcactcca 1860
gcctcctcgg ccaagacgtc tcctgccaag cagcaggccc cacctgtccg gaacctgcac 1920
cagtctggat tcagtttgtc tggtgctcag attgatgaca acattccccg ccgcaccacc 1980
cagcgtatcg tggcgccccc cggtggccgt gccaacatca ccagcctggg ctag 2034
<210> 5
<211> 1719
<212> DNA
<213> CRMP2
<400> 5
atgtcttatc aggggaagaa aaatattcca cgcatcacga gcgatcgtct tctgatcaaa 60
ggaggtaaaa ttgttaatga tgaccagtcg ttctatgcag acatatacat ggaagatggg 120
ttgatcaagc aaataggaga aaatctgatt gtgccaggag gagtgaagac catcgaggcc 180
cactcccgga tggtgatccc cggaggaatt gacgtccaca ctcgtttcca gatgcctgat 240
cagggaatga cgtctgctga tgatttcttc caaggaacca aggcggccct ggctggggga 300
accactatga tcattgacca cgttgttcct gagcctggga caagcctgct cgctgccttt 360
gaccagtgga gggaatgggc cgacagcaag tcctgctgtg actactctct gcatgtggac 420
atcagtgagt ggcataaggg catccaggag gagatggaag cgcttgtgaa ggatcacggg 480
gtaaattcct tcctcgtgta catggctttc aaagatcgct tccagctaac ggattgccag 540
atttatgaag tactgagtgt gatccgggat attggcgcca tagcccaagt ccacgcagaa 600
aatggcgaca tcattgcaga ggagcagcag aggatcctgg atctgggcat cacgggcccc 660
gagggacatg tgctgagccg acctgaggag gtcgaggccg aagccgtgaa tcgtgccatc 720
accatcgcca accagaccaa ctgcccgctg tatatcacca aggtgatgag caaaagctct 780
gctgaggtca tcgcccaggc acggaagaag ggaactgtgg tgtatggcga gcccatcact 840
gccagcttgg gaacggacgg ctcccattac tggagcaaga actgggccaa ggctgctgcc 900
tttgtcacct ccccaccctt gagccctgat ccaaccactc cagactttct caactccttg 960
ctgtcctgtg gagacctcca ggtcacgggc agtgcccatt gcacgtttaa cactgcccag 1020
aaggctgtag gaaaggacaa cttcaccctg attccggagg gcaccaatgg cactgaggag 1080
cggatgtccg tcatctggga caaggctgtg gtcactggga agatggatga gaaccagttt 1140
gtggctgtga ccagcaccaa tgcagccaaa gtcttcaacc tttacccccg gaaaggccgc 1200
attgctgtgg gatccgatgc cgacctggtc atctgggacc ccgacagcgt taaaaccatc 1260
tctgccaaga cacacaacag ctctctcgag tacaacatct ttgaaggcat ggagtgccgc 1320
ggctccccac tggtggtcat cagccagggg aagattgtcc tggaggacgg caccctgcat 1380
gtcaccgaag gctctggacg ctacattccc cggaagccct tccctgattt tgtttacaag 1440
cgtatcaagg caaggagcag gctggctgag ctgagagggg ttcctcgtgg cctgtatgac 1500
ggacctgtgt gtgaagtgtc tgtgacgccc aagacagtca ctccagcctc ctcggccaag 1560
acgtctcctg ccaagcagca ggccccacct gtccggaacc tgcaccagtc tggattcagt 1620
ttgtctggtg ctcagattga tgacaacatt ccccgccgca ccacccagcg tatcgtggcg 1680
ccccccggtg gccgtgccaa catcaccagc ctgggctag 1719
<210> 6
<211> 1611
<212> DNA
<213> CRMP2
<400> 6
atggaagatg ggttgatcaa gcaaatagga gaaaatctga ttgtgccagg aggagtgaag 60
accatcgagg cccactcccg gatggtgatc cccggaggaa ttgacgtcca cactcgtttc 120
cagatgcctg atcagggaat gacgtctgct gatgatttct tccaaggaac caaggcggcc 180
ctggctgggg gaaccactat gatcattgac cacgttgttc ctgagcctgg gacaagcctg 240
ctcgctgcct ttgaccagtg gagggaatgg gccgacagca agtcctgctg tgactactct 300
ctgcatgtgg acatcagtga gtggcataag ggcatccagg aggagatgga agcgcttgtg 360
aaggatcacg gggtaaattc cttcctcgtg tacatggctt tcaaagatcg cttccagcta 420
acggattgcc agatttatga agtactgagt gtgatccggg atattggcgc catagcccaa 480
gtccacgcag aaaatggcga catcattgca gaggagcagc agaggatcct ggatctgggc 540
atcacgggcc ccgagggaca tgtgctgagc cgacctgagg aggtcgaggc cgaagccgtg 600
aatcgtgcca tcaccatcgc caaccagacc aactgcccgc tgtatatcac caaggtgatg 660
agcaaaagct ctgctgaggt catcgcccag gcacggaaga agggaactgt ggtgtatggc 720
gagcccatca ctgccagctt gggaacggac ggctcccatt actggagcaa gaactgggcc 780
aaggctgctg cctttgtcac ctccccaccc ttgagccctg atccaaccac tccagacttt 840
ctcaactcct tgctgtcctg tggagacctc caggtcacgg gcagtgccca ttgcacgttt 900
aacactgccc agaaggctgt aggaaaggac aacttcaccc tgattccgga gggcaccaat 960
ggcactgagg agcggatgtc cgtcatctgg gacaaggctg tggtcactgg gaagatggat 1020
gagaaccagt ttgtggctgt gaccagcacc aatgcagcca aagtcttcaa cctttacccc 1080
cggaaaggcc gcattgctgt gggatccgat gccgacctgg tcatctggga ccccgacagc 1140
gttaaaacca tctctgccaa gacacacaac agctctctcg agtacaacat ctttgaaggc 1200
atggagtgcc gcggctcccc actggtggtc atcagccagg ggaagattgt cctggaggac 1260
ggcaccctgc atgtcaccga aggctctgga cgctacattc cccggaagcc cttccctgat 1320
tttgtttaca agcgtatcaa ggcaaggagc aggctggctg agctgagagg ggttcctcgt 1380
ggcctgtatg acggacctgt gtgtgaagtg tctgtgacgc ccaagacagt cactccagcc 1440
tcctcggcca agacgtctcc tgccaagcag caggccccac ctgtccggaa cctgcaccag 1500
tctggattca gtttgtctgg tgctcagatt gatgacaaca ttccccgccg caccacccag 1560
cgtatcgtgg cgccccccgg tggccgtgcc aacatcacca gcctgggcta g 1611
<210> 7
<211> 2046
<212> DNA
<213> 人工序列
<400> 7
ggatccatgg ccgagagaaa gcaatccggg aaggcggcag aggacgaaga ggtccctgct 60
ttttttaaaa acctgggctc cggcagcccc aagccccggc agaaattctg tggcatgttc 120
tgcccggtgg aagggtcctc ggagaacaag accatcgact tcgactcgct gtcggtgggc 180
cggggctcgg ggcaggtggt ggctcagcag cgggacgtcg cccacttggg cccggacccg 240
cagccgccgt actcgcggca gggccggcgc gccggcggag agccatctgt tgaatcgggc 300
cggaaggtgg agatccggag ggcctcgggc aaagaagccc tgcagaacat caacgaccag 360
agcgatcgtc ttctgatcaa aggaggtaaa attgttaatg atgaccagtc gttctatgca 420
gacatataca tggaagatgg gttgatcaag caaataggag aaaatctgat tgtgccagga 480
ggagtgaaga ccatcgaggc ccactcccgg atggtgatcc ccggaggaat tgacgtccac 540
actcgtttcc agatgcctga tcagggaatg acgtctgctg atgatttctt ccaaggaacc 600
aaggcggccc tggctggggg aaccactatg atcattgacc acgttgttcc tgagcctggg 660
acaagcctgc tcgctgcctt tgaccagtgg agggaatggg ccgacagcaa gtcctgctgt 720
gactactctc tgcatgtgga catcagtgag tggcataagg gcatccagga ggagatggaa 780
gcgcttgtga aggatcacgg ggtaaattcc ttcctcgtgt acatggcttt caaagatcgc 840
ttccagctaa cggattgcca gatttatgaa gtactgagtg tgatccggga tattggcgcc 900
atagcccaag tccacgcaga aaatggcgac atcattgcag aggagcagca gaggatcctg 960
gatctgggca tcacgggccc cgagggacat gtgctgagcc gacctgagga ggtcgaggcc 1020
gaagccgtga atcgtgccat caccatcgcc aaccagacca actgcccgct gtatatcacc 1080
aaggtgatga gcaaaagctc tgctgaggtc atcgcccagg cacggaagaa gggaactgtg 1140
gtgtatggcg agcccatcac tgccagcttg ggaacggacg gctcccatta ctggagcaag 1200
aactgggcca aggctgctgc ctttgtcacc tccccaccct tgagccctga tccaaccact 1260
ccagactttc tcaactcctt gctgtcctgt ggagacctcc aggtcacggg cagtgcccat 1320
tgcacgttta acactgccca gaaggctgta ggaaaggaca acttcaccct gattccggag 1380
ggcaccaatg gcactgagga gcggatgtcc gtcatctggg acaaggctgt ggtcactggg 1440
aagatggatg agaaccagtt tgtggctgtg accagcacca atgcagccaa agtcttcaac 1500
ctttaccccc ggaaaggccg cattgctgtg ggatccgatg ccgacctggt catctgggac 1560
cccgacagcg ttaaaaccat ctctgccaag acacacaaca gctctctcga gtacaacatc 1620
tttgaaggca tggagtgccg cggctcccca ctggtggtca tcagccaggg gaagattgtc 1680
ctggaggacg gcaccctgca tgtcaccgaa ggctctggac gctacattcc ccggaagccc 1740
ttccctgatt ttgtttacaa gcgtatcaag gcaaggagca ggctggctga gctgagaggg 1800
gttcctcgtg gcctgtatga cggacctgtg tgtgaagtgt ctgtgacgcc caagacagtc 1860
actccagcct cctcggccaa gacgtctcct gccaagcagc aggccccacc tgtccggaac 1920
ctgcaccagt ctggattcag tttgtctggt gctcagattg atgacaacat tccccgccgc 1980
accacccagc gtatcgtggc gccccccggt ggccgtgcca acatcaccag cctgggctag 2040
gaattc 2046
Claims (2)
1.检测抗CRMP2抗体的试剂在制备神经系统自身免疫性疾病的检测、诊断、治疗或预后评估试剂中的应用;所述神经系统自身免疫性疾病为脑炎或脑脊髓炎。
2.根据权利要求1所述的应用,其特征在于,所述检测抗CRMP2抗体的方法选自CBA、免疫印迹、膜条法、ELISA、化学发光、放射免疫法、液相芯片法、侧向层析、电化学、流式细胞中的至少一种。
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EP21939076.2A EP4332577A1 (en) | 2021-04-27 | 2021-12-16 | Applications of crmp2 and anti-crmp2 antibodies |
PCT/CN2021/138864 WO2022227617A1 (zh) | 2021-04-27 | 2021-12-16 | Crmp2及抗crmp2抗体的应用 |
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CN114019161B (zh) * | 2021-11-08 | 2022-08-09 | 陕西脉元生物科技有限公司 | 抗camk2a自身抗体的试剂在制备诊断神经系统症状相关疾病的试剂盒中的应用 |
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