CN111175484A - 神经自身免疫性疾病的诊断 - Google Patents
神经自身免疫性疾病的诊断 Download PDFInfo
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- CN111175484A CN111175484A CN201910899318.0A CN201910899318A CN111175484A CN 111175484 A CN111175484 A CN 111175484A CN 201910899318 A CN201910899318 A CN 201910899318A CN 111175484 A CN111175484 A CN 111175484A
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Abstract
本发明涉及包括在来自患者的含有抗体的样品中检测结合DAGLA的自身抗体的步骤的用于诊断疾病的方法、含有DAGLA或其变体的固定化多肽、含有DAGLA或其变体的多肽用于疾病诊断的用途、分离的结合DAGLA的自身抗体、所述自身抗体用于疾病诊断的用途、用于分离结合DAGLA的自身抗体的方法、含有DAGLA或其变体的药物组合物或医疗装置、包含所述多肽或所述医疗装置的用于疾病诊断的试剂盒以及所述多肽或自身抗体用于制备试剂盒或医疗装置的用途。
Description
本发明涉及用于诊断疾病的方法(其包括在来自患者的包含抗体的样品中检测与DAGLA结合的自身抗体的步骤)、包含DAGLA或其变体的固定化多肽、包含DAGLA或其变体的多肽用于诊断疾病的用途、分离的与DAGLA结合的自身抗体、所述自身抗体用于诊断疾病的用途、用于分离结合DAGLA的自身抗体的方法、包含DAGLA或其变体的药物组合物或医疗装置、包含所述多肽或所述医疗装置的用于诊断疾病的试剂盒以及所述多肽或自身抗体用于制备试剂盒或医疗装置的用途。
开发用于神经学疾病的诊断系统是生物医学科学中的持续挑战,特别是因为遭遇的许多症状可由许多原因(包括遗传性疾病(genetically-inherited diseases)、药物滥用、营养不良、感染、损伤、精神疾病、免疫缺陷和癌症)所引起。
由于神经学疾病极少与临床症状的独特特征模式相关联,因此通常难以仅基于对受累患者的观察和检查或其医疗史来提供可靠的诊断。
早期诊断的重要性怎么强调都不为过。许多神经学疾病,最显著地阿尔茨海默氏病和帕金森病以及多发性硬化都无法治愈,但有可用于减缓其进展的药物。另外,某些罕见类型的癌症与神经学症状相关。诊断越早,利用系列可用疗法使患者充分受益的机会就越大。
在与自身抗体相关的神经学疾病的情况下更是如此。在某些情况下,特定可检测自身抗体与病况之间的联系足够强而允许立即诊断。
但即使不是这样,自身抗体的检测也可指示主治医生可用于改善患者病况的治疗手段。无论自身抗体的靶标的性质如何,都可使用多种广泛使用的免疫抑制剂。或者,可将单采血液成分术用于从患者的血液中去除自身抗体。在许多情况下,患者在神经学自身免疫性疾病(neurological autoimmune disease)的早期诊断和治疗后继续过正常生活。
基于自身抗体检测的诊断测定还可证实除与自身抗体相关的疾病外的疾病的诊断。如果事实证明血液样本缺乏特定的自身抗体,这可能有助于主治医生排除一系列可能性,从而缩小貌似合理的病况的范围。
与自身抗体的出现同时发生的神经学病况的实例包括视神经脊髓炎,一种特征在于视觉和脊髓功能丧失的疾病,以及抗NMDA受体脑炎,其与自主神经功能障碍、换气不足、小脑性共济失调、轻偏瘫、意识丧失或紧张症相关。虽然之前对自身抗体的参与和这些病况本身的性质了解很少,但由于有基于自身抗体检测的测定可供利用,现在可以高效地诊断和治疗许多这样的疾病。
因此,最重要的是开发新的方法来区分与自身抗体相关的神经学病况和与自身抗体无关的神经学病况。
本发明涉及针对DAGLA的自身抗体和基于其检测的诊断测定。就本发明人所知,在现有技术中尚未报道针对DAGLA的自身抗体的存在,更不用说它们的诊断有效性。许多公司已将与DAGLA结合的重组抗体商业化,例如LifeSpan Biosciences,Inc和Sigma。
本发明所要解决的问题是提供可用于支持自身免疫性疾病(优选地神经系统的自身免疫性疾病或与神经学疾病或神经学症状相关的自身免疫性疾病,更优选选自PNS、小脑炎、癫痫和硬化的自身免疫性疾病)的诊断和治疗的新型试剂、装置和方法。
本发明要解决的另一个问题是提供可用于区分自身免疫性疾病(特别是神经学自身免疫性疾病,更优选选自PNS、小脑炎、癫痫、共济失调、多发性神经病和/或多发性神经根病,以及硬化)与除自身免疫性疾病外的疾病(例如与神经学症状相关的感染),特别是用于确定最有希望的治疗方案(更具体地说是免疫抑制治疗是否适合)的新型试剂、装置和方法。
本发明要解决的问题可通过所附独立权利要求和从属权利要求的保护主题来解决。
在第一方面,所述问题通过用于诊断疾病的方法来解决,所述方法包括在来自患者的样品中检测与DAGLA结合的自身抗体的步骤。
在第二方面,所述问题通过包含DAGLA或其变体的固定化多肽来解决。
在第三方面,所述问题通过包含DAGLA或其变体的多肽用于诊断疾病的用途来解决,优选地包括在样品中检测与DAGLA结合的自身抗体的步骤。
在第四方面,所述问题通过将包含DAGLA或其变体的多肽用于治疗疾病来解决。
在第五方面,所述问题通过自身抗体(优选分离的针对DAGLA的自身抗体)来解决。
在第六方面,所述问题通过根据本发明的自身抗体用于诊断疾病的用途来解决。
在第七方面,所述问题通过用于分离与DAGLA结合的自身抗体的方法来解决,所述方法包括以下步骤:
a)在与复合物形成相容的条件下使包含所述自身抗体的样品与包含DAGLA或其变体的多肽接触,其中所述自身抗体结合所述多肽,
b)分离在步骤a)中形成的复合物,
c1)检测在步骤a)中形成的复合物或c2)解离在步骤b)中分离的复合物并将所述自身抗体与所述多肽分离。
在第八方面,所述问题通过包含含有DAGLA或其变体的多肽的药物组合物或医疗装置(优选诊断装置)来解决。
在第九方面,所述问题通过用于诊断疾病的试剂盒来解决,所述试剂盒包含含有DAGLA或其变体的多肽或包含含有DAGLA或其变体的多肽的医疗装置,其中优选地,所述试剂盒还包含用于检测包含所述多肽和结合DAGLA的抗体(优选与DAGLA结合的自身抗体)的复合物的工具,其中优选地,所述试剂盒还包含含有DAGLA或其变体的阳性对照或阴性对照。
在第十方面,所述问题通过包含DAGLA或其变体的多肽或与DAGLA结合的自身抗体或包含含有DAGLA或其变体的多肽的医疗装置在制造用于诊断疾病的试剂盒或医疗装置(优选诊断装置)中的用途来解决。
在一个优选实施方案中,所述疾病是PNS,优选与选自小脑炎、癫痫和硬化的病况相关。在另一个优选实施方案中,所述疾病选自PNS、小脑炎、癫痫、硬化和肿瘤,更优选PNS、小脑炎、癫痫和硬化。在一个优选实施方案中,所述疾病是癌症,优选来自包括胸癌(更优选肺癌或胸腺癌)的组,最优选来自包括小细胞肺癌、类癌和非小细胞肺癌;乳腺癌、妇科癌症和睾丸癌症;以及恶性血液病和实体瘤的组,优选来自包括淋巴瘤、白血病、黑色素瘤、泌尿道癌、胃肠癌、结肠癌、胃和食道癌、头颈癌、肉瘤和组织细胞增多症的组。
在一个优选实施方案中,样品是包含抗体的体液,优选选自全血、血浆、血清、脑脊液和唾液。
在一个优选实施方案中,使用选自免疫扩散技术、免疫电泳技术、光散射免疫测定、凝集技术、标记免疫测定(诸如选自包括放射性标记的免疫测定、酶免疫测定(更优选ELISA)、化学发光免疫测定(优选电化学发光免疫测定)和免疫荧光(优选间接免疫荧光)的组的标记免疫测定)的技术检测所述自身抗体或复合物。
在一个优选实施方案中,医疗装置选自玻璃载玻片(优选用于显微镜检查)、生物芯片、微量滴定板、侧向流动装置、测试条、膜(优选线印迹)、色谱柱和珠(优选磁珠或荧光珠)。
本发明基于本发明人的如下令人惊奇的发现,即在来自许多患有神经学病况的患者的样品中存在针对DAGLA的自身抗体,并且可以检测到,但在从健康受试者获得的样品中不能检测到。
此外,本发明基于本发明人的如下令人惊奇的发现,即可以通过检测针对DAGLA的自身抗体来诊断新的神经学疾病。
不希望受任何理论束缚,此类自身抗体的存在表明DAGLA和/或下游效应子的功能在具有此类自身抗体的患者中受损,从而造成神经学症状发生。
DAGLA(二酰基甘油脂肪酶α,120kDa,1.042个氨基酸)与DAGL-β一起是DAG脂肪酶(DAGL)家族的成员。
DAGL负责催化二酰基甘油(DAG)(细胞中研究最多的第二信使之一)水解成2-花生四烯酰甘油(2-AG)(体内内源性大麻素受体(eCB)的最丰富的配体)(Keimpema,E.等,(2013)Diacylglycerol lipaseαmanipulation reveals developmental roles forintercellular endocannabinoid signaling.Sci Rep.3:2093/doi:10.1038/srep02093)。DAGL依赖性eCB信号传导在发育期间调节轴突生长和导向,并且是成人大脑中新神经元的产生和迁移所必需的(Williams,E.J.等(1994)The production ofarachidonic acid can account for calcium channel activation in the secondmessenger pathway underlying neurite outgrowth stimulated by NCAM,N-cadherin,and L1.J.Neurochem.62:1231–1234/doi:10.1046/j.1471-4159.1994.62031231.x)。除了内源性大麻素系统之外,DAGL还通过在大脑和其他器官中合成2-AG来影响必需脂质花生四烯酸的水平(Reisenberg,M.等(2012)The diacylglycerol lipases:structure,regulation and roles in and beyond endocannabinoidsignalling.Phil.Trans.R.Soc.B:367,3264-3275/doi:10.1098/rstb.2011.0387)。
2-AG主要由其表达与2-AG的总生物合成和释放强烈相关的DAGLA同种型合成。DAGLA的表达模式从胚胎中的轴突束变为成人的脑室下区中的树突区和增殖神经干细胞(Bisogno,T.等(2003)Cloning of the first sn1-DAG lipases points to the spatialand temporal regulation of endocannabinoid signaling in the brain.J CellBiol.163(3):463-8/doi/10.1083/jcb.200305129)。
DAGLA中的遗传缺陷与人中的脊髓小脑性共济失调20型(SCA20)的发展潜在相关(Knight,M.A.等(2008)A duplication at chromosome 11q12.2-11q12.3 is associatedwith spinocerebellar ataxia type 20.Hum Mol Genet.17(24):3847-3853.doi:10.1093/hmg/ddn283)。脊髓小脑性共济失调是在临床和遗传上异质的一组小脑紊乱。由于小脑变性以及脑干和脊髓的可变受累,患者表现出步态的渐进性不协调以及通常手、言语和眼球运动的协调性差(Knight,M.A.等(2004)Dominantly inherited ataxia anddysphonia with dentate calcification:spinocerebellar ataxia type20.Brain.127:1172-1181/doi:10.1093/brain/awh139)。
DAGLA由以下部分组成:导致4个跨膜(4TM)螺旋结构域的短的细胞质N-末端序列,随后是具有催化结构域的规范α/β水解酶结构域,接着是长C-末端尾部结构域。4TM结构域在19个AA的末端序列中是保守的。4TM被短的无关环分隔,并且两个细胞外跨膜结构域代表糖基化的潜在位点。
在功能上,推测DAGLA促进酶在膜上的包装并且充当功能性复合物中的其他蛋白质的对接位点,并且形成调节DAG接近催化结构域并随后从细胞中的2-AG释放的通道。催化结构域由总共8个相互氢键合的β-折叠链组成,所述β-折叠链主要通过α-螺旋连接。特征性地,其具有催化性丝氨酸(AA 472)和天冬氨酸(AA 524)以及组氨酸(AA650),即所谓的催化三联体(Baggelaar,MP等(2013)Development of an Activity-Based Probe and InSilico Design Reveal Highly Selective Inhibitors for Diacylglycerol Lipase-alpha in Brain.Angw.Chem.Int.Ed.52:1-6/doi:10.1002/anie.201306295)。DAGLA的催化作用需要Ca2+作为必需辅助因子。另外,催化结构域包括调节环(约50-60AA长,位于第7与第8规范β-折叠片之间),其含有保守的10AA的聚脯氨酸特征基序(PLYPPGRIIH)。这可能用作帽或盖以保护疏水性催化腔免受水的影响(Miled,N.等(2003)Importance of thelid and cap domains for the catalytic activity of gastric lipases.CompBiochem Physiol B Biochem Mol Biol.136(1):131-8/doi:10.1016/S1096-4959(03)00183-0)。DAGLA的C末端是α与β同种型之间最具特征性的结构差异。DAGLA但非DAGL-β显示出长的细胞内序列。该DAGLA特异性尾部不直接促成催化活性,尽管已显示整合的共有基序(PPxxF)结合Homer蛋白的卷曲螺旋结构域(例如在mGluR相互作用中)。
本发明涉及包含选自DAGLA或与结合DAGLA的自身抗体具有反应性的其抗原性变体的哺乳动物(优选人)多肽的多肽。哺乳动物DAGLA包括来自人、猴、小鼠、大鼠、兔、豚鼠或猪(优选人)的同源物。
在一个更优选的实施方案中,DAGLA是由SEQ ID NO4、Q9Y4D2(α)(与SEQ ID NO4相同)、NP_631918.3(β同种型1)、NP_001136408.1(β同种型2),优选Q9Y4D2编码的多肽。由编码SEQ ID NO4的核酸组成的cDNA是SEQ ID NO1。在整个本申请中,引用的任何数据库代码是指Uniprot数据库,更具体地是本申请或其最早优先权申请的提交日期时的版本。
本发明的教导不仅可使用多肽,特别是包含多肽诸如DAGLA的天然序列的多肽或具有本申请中明确(例如通过功能、名称、序列或登录号)或隐含地提及的确切序列的核酸,而且还可使用此类多肽或核酸的变体来实施。
在一个优选实施方案中,如本文中所用,术语“变体”可以指提及的全长序列的至少一个片段,更具体地是指相对于全长序列在一个或两个末端被截短一个或多个氨基酸的一个或多个氨基酸序列或核酸序列。这种片段包含或编码具有原始序列或其变体的至少6个、7个、8个、10个、12个、15个、20个、25个、50个、75个、100个、150个或200个连续氨基酸的肽。变体的总长度可以是至少6个、7个、8个、9个、10个、11个、12个、20个、25个、30个、40个、50个、60个、70个、80个、90个、100个、200个、300个、400个、500个、750个、1000个或更多个氨基酸。
术语“变体”不仅涉及至少一个片段,而且还涉及包含与提及的参考氨基酸序列或其片段具有至少40%、50%、60%、70%、75%、80%、85%、90%、92%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列的多肽或其片段,其中除了对于生物活性(例如抗原与(自身)抗体结合的能力或多肽的折叠或结构)所必需的那些氨基酸外的氨基酸被缺失或取代,和/或以保守方式替换一个或多个此类必需氨基酸,和/或添加氨基酸,使得多肽的生物活性得以保留。现有技术包括可用于比对两个给定核酸或氨基酸序列并计算同一性程度的各种方法,参见例如Arthur Lesk(2008),Introduction to bioinformatics,OxfordUniversity Press,2008,第3版。在一个优选实施方案中,使用默认设置来利用ClustalW软件(Larkin,M.A.,Blackshields,G.,Brown,N.P.,Chenna,R.,McGettigan,P.A.,McWilliam,H.,Valentin,F.,Wallace,I.M.,Wilm,A.,Lopez,R.,Thompson,J.D.,Gibson,T.J.,Higgins,D.G.(2007).Clustal W和Clustal X 2.0版.Bioinformatics,23,2947-2948)。具有这种生物活性的优选变体或片段是SEQ ID NO26和SEQ ID NO28以及它们的His-标记的形式。
在一个优选实施方案中,变体是线性的未折叠的多肽,其任选是变性的。
在一个优选实施方案中,多肽及其变体可另外包含化学修饰,例如同位素标记或共价修饰,诸如糖基化、磷酸化、乙酰化、脱羧、瓜氨酸化、甲基化、羟基化等。本领域技术人员熟悉修饰多肽的方法。可以设计任何修饰,只要其不会消除变体的生物活性。
此外,变体还可通过与其他已知多肽或其变体融合产生,并且包含活性部分或结构域,所述活性部分或结构域优选地当与参考序列的活性部分比对时具有至少70%、75%、80%、85%、90%、92%、94%、95%、96%、97%、98或99%的序列同一性,其中如本文中所用,术语“活性部分”分别地指小于全长氨基酸序列的氨基酸序列,或者在核酸序列的情况下,编码小于全长氨基酸序列的核酸序列,和/或是天然序列的变体,但保留至少一定的生物活性。
在一个优选实施方案中,术语核酸的“变体”包括其互补链优选在严格条件下与参考或野生型核酸杂交的核酸。杂交反应的严格性可由本领域普通技术人员容易地确定,并且通常是取决于探针长度、洗涤温度和盐浓度的经验计算。通常,较长的探针需要较高的温度来进行正确的退火,而较短的探针则需要较低的温度来进行正确的退火。杂交通常取决于变性DNA与在低于其解链温度的环境中存在的互补链再退火的能力:探针与可杂交序列之间所需的同源性程度越高,则可使用的相对温度越高。因此,较高的相对温度倾向于使反应条件更严格,而较低的温度则倾向于使反应条件不太严格。关于杂交反应的严格性的其他细节和解释,参见Ausubel,F.M.(1995),Current Protocols in MolecularBiology.John Wiley&Sons,Inc.。此外,本领域技术人员可以遵循手册BoehringerMannheim GmbH(1993)The DIG System Users Guide for Filter Hybridization,Boehringer Mannheim GmbH,Mannheim,Germany中以及Liebl,W.,Ehrmann,M.,Ludwig,W.和Schleifer,K.H.(1991)International Journal of Systematic Bacteriology 41:255-260中关于如何通过杂交鉴定DNA序列所给出的说明。在一个优选实施方案中,对任何杂交应用严格条件,即仅当探针与靶序列具有70%或更多同一性时才发生杂交。相对于靶序列具有较低程度的同一性的探针可以杂交,但此类杂交体是不稳定的并且将在严格条件下在洗涤步骤中除去,例如将盐浓度降低至2x SSC,或任选地和随后地,降低至0.5x SSC,而温度按递增的优先顺序为约为50℃-68℃,约52℃-68℃,约54℃-68℃,约56℃-68℃,约58℃-68℃,约60℃-68℃,约62℃-68℃,约64℃-68℃,约66℃-68℃。在一个特别优选的实施方案中,温度为约64℃-68℃或约66℃-68℃。可以将盐的浓度调节至0.2x SSC或甚至0.1x SSC。可以分离相对于参考或野生型序列具有至少70%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%的同一性程度的核酸序列。在一个优选实施方案中,如本文中所用,术语核酸序列的变体是指按照遗传密码的简并性,与参考核酸序列编码相同的氨基酸序列及其变体的任何核酸序列。
多肽的变体具有生物活性。在一个优选实施方案中,这种生物学活性是与结合DAGLA的自身抗体特异性结合的能力,如在患有与这种自身抗体相关,优选与神经学疾病或病况(诸如PNS)相关的自身免疫性疾病的患者中发现的。例如,可以通过确定目标变体是否与来自自身抗体与野生型DAGLA结合的患者的样品的自身抗体结合(优选如通过本申请实验部分中描述的使用灵长类动物小脑的间接免疫荧光所测定的)来检查DAGLA的变体是否具有这种生物学活性。
当用于实施本发明的教导时,根据本发明的任何多肽可以以任何形式和任何纯化的程度提供,从包含以内源形式存在的所述多肽的液体样品、组织或细胞(更优选过表达所述多肽的细胞、此类细胞的粗制裂解物或富集的裂解物)至任选地基本上纯的纯化的和/或分离的多肽)。在一个优选实施方案中,所述多肽是天然多肽,其中如本文中所用,术语“天然多肽”是指折叠的多肽,更优选是指从组织或细胞,更优选从哺乳动物细胞或组织,任选地从非重组组织或细胞纯化的折叠的多肽。在另一个优选实施方案中,所述多肽是重组蛋白质,其中如本文中所用,术语“重组的”是指在生产过程的任何阶段使用基因工程方法(例如通过将编码所述多肽的核酸与用于细胞或组织中过表达的强启动子融合,或者通过对多肽本身的序列进行工程化)产生的多肽。本领域技术人员熟悉用于对核酸和编码的多肽进行工程化(例如,Sambrook,J.,Fritsch,E.F.和Maniatis,T.(1989),Molecular Cloning,CSH中或Brown T.A.(1986),Gene Cloning–an introduction,Chapman&Hall中描述的)以及用于产生和纯化天然或重组多肽(例如由GE Healthcare Life Sciences出版的手册“Strategies for Protein Purification”,“Antibody Purification”,“PurifyingChallenging Proteins”(2009/2010),以及Burgess,R.R.,Deutscher,M.P.(2009),Guideto Protein Purification中)的方法。在一个优选实施方案中,如果如通过SDS聚丙烯酰胺凝胶电泳然后通过考马斯蓝染色和目视检查所判断的,相应样品中至少60%、70%、80%、90%、95%或99%的多肽由所述多肽组成,则多肽是纯的。
如果本发明的多肽以组织形式提供,则优选地组织是哺乳动物组织,例如人、大鼠、灵长类动物、驴、小鼠、山羊、马、绵羊、猪或牛的组织,更优选脑组织,最优选小脑。如果使用细胞裂解物,优选地细胞裂解物包含与细胞表面相关的膜或实际上是富含膜的级分。如果所述多肽以重组细胞的形式提供,则优选地重组细胞是真核细胞,诸如酵母细胞,更优选来自多细胞真核细胞诸如植物、哺乳动物、青蛙或昆虫的细胞,最优选来自哺乳动物例如大鼠、人、灵长类动物、驴、小鼠、山羊、马、绵羊、猪或牛的细胞。
用于实施本发明教导的多肽(包括任何变体)优选被设计为使得其包含至少一个被与DAGLA结合的自身抗体识别的表位和/或与结合DAGLA的自身抗体特异性结合。与除针对DAGLA的自身抗体外的抗体相比,任何表位更优选地是仅被这种自身抗体识别的表位。在一个实施方案中,此类多肽包含6个、7个、8个、9个、10个、11个、12个、20个、25个、30个、40个、50个、60个、70个、80个、90个、100个或更多个,优选至少9个但不超过16个来自DAGLA的连续氨基酸的区段。本领域技术人员熟悉用于设计具有足够免疫原性的肽的指导,例如Jackson,D.C.,Fitzmaurice,C.J.,Brown,L.E.,Zeng,W.(1999),Preparation andproperties of totally synthetic immunogenes,Vaccine第18卷,3-4期,September1999,第355–361页;以及Black,M.,Trent,A.,Tirrell,M.和Olive,C.(2010),Advances inthe design and delivery of peptide subunit vaccines with a focus on Toll-likereceptor agonists,Expert Rev Vaccines,2010February;9(2):157–173中描述的指导。简言之,希望肽尽可能多地满足以下要求:(a)其具有高度亲水性,(b)其包含一个或多个选自天冬氨酸、脯氨酸、酪氨酸和苯丙氨酸的残基,(c)为了更高的特异性,其与其他已知的肽或多肽没有或几乎没有同源性,(d)其需要具有足够的可溶性,以及(e)除非出于特定的原因需要,否则其不包含糖基化或磷酸化位点。或者,可以遵循生物信息学方法,例如由Moreau,V.,Fleury,C.,Piquer,D.,Nguyen,C.,Novali,N.,Villard,S.,Laune,D.,Granier,C.和Molina,F.(2008),PEPOP:Computational design of immunogenicpeptides,BMC Bioinformatics 2008,9:71描述的生物信息学方法。合适的表位存在于SEQID NO 16和SEQ ID NO 22中。
当根据本发明使用时,本发明的多肽可以以任何种类的构象提供。例如,所述多肽可以是基本上解折叠的多肽、部分或完全折叠的多肽。在一个优选实施方案中,所述多肽在与本发明的自身抗体结合所必需的表位或者该蛋白质或其变体在其整体上采取天然蛋白质在其天然环境中所采取的折叠的意义上是折叠的。本领域技术人员熟悉适合于确定多肽是否折叠以及如果其是折叠的那么具有哪种结构的方法,例如有限蛋白质水解、NMR光谱学、CD光谱学或X射线晶体学(参见例如Banaszak L.J.(2008),Foundations ofStructural Biology,Academics Press,或Teng Q.(2013),Structural Biology:Practical Applications,Springer),优选使用CD光谱学。
本发明的多肽可以是融合蛋白,其包含除获自DAGLA的氨基酸序列外的氨基酸序列,特别是C-末端或N-末端标签,优选C-末端标签,如本文中所用,所述标签在一个优选实施方案中是具有一定生物学或物理功能并且可以例如用于纯化、固定、沉淀或鉴定本发明的多肽的具有功能的另外的序列基序或多肽。在一个更优选实施方案中,所述标签是能够与配体特异性结合的序列或结构域,例如选自His标签、硫氧还蛋白、麦芽糖结合蛋白、谷胱甘肽-S-转移酶、荧光标签(例如选自包括绿色荧光蛋白的组)的标签。
本发明的多肽可以是固定化多肽。在一个优选实施方案中,如本文中所用,术语“固定化”是指与不溶于水性溶液的固体载体结合(更优选通过共价键、静电相互作用、包封或截留(例如通过使球状多肽在凝胶中变性),或通过疏水相互作用,最优选通过一个或多个共价键)的分子。各种合适的载体,例如纸、聚苯乙烯、金属、硅或玻璃表面、微流体通道、膜、珠粒诸如磁珠、柱层析介质、生物芯片、聚丙烯酰胺凝胶等已描述于文献,例如Kim,D.,and Herr,A.E.(2013),Protein immobilization techniques for microfluidicassays,Biomicrofluidics7(4),041501中。这样,可以直接的方式(例如通过过滤、离心或倾析)将固定化分子与不溶性载体一起从水性溶液中分离出来。可以以可逆或不可逆的方式固定固定化分子。例如,如果分子通过可通过添加高浓度的盐来掩蔽的离子相互作用与载体相互作用,或者如果分子通过可裂解的共价键(诸如可通过添加含硫醇的试剂来裂解的二硫桥)结合,固定是可逆的。相反,如果分子通过不能在水性溶液中裂解的共价键(例如通过环氧化物基团与常用于将赖氨酸侧链偶联至亲和柱的胺基团的反应形成的键)系连于载体,则固定是不可逆的。可以例如通过以下方式间接固定蛋白质:固定对所述分子具有亲和力的抗体或其他实体,然后形成复合物以达到固定分子-抗体复合物的效果。固定分子的各种方法描述于文献例如Kim,D.,Herr和A.E.(2013),Protein immobilizsationtechniques for microfluidic assays,Biomicrofluidics7(4),041501中。另外,用于固定反应的各种试剂和试剂盒可以例如从Pierce Biotechnology商购获得。
必要的是,用于按照根据本发明的自身抗体的检测进行的诊断的样品包含抗体(也称为免疫球蛋白)。通常,体液样品包含全部的受试者免疫球蛋白的代表性组。然而,一旦提供,就可对样品进行进一步处理,所述处理可包括分级分离、离心、富集或分离受试者的全部免疫球蛋白或任何免疫球蛋白类别,这可影响各类免疫球蛋白的相对分布。
在整个本申请中描述的试剂、装置、方法和用途可用于疾病的诊断。在一个优选实施方案中,所述疾病是神经学疾病。在一个更优选的实施方案中,如本文中所用,术语“神经学疾病”是指与神经系统缺陷相关的任何疾病,在另一个优选实施方案中,如本文中所用,术语“PNS”(副肿瘤性神经综合征的缩写)是指由肿瘤的存在间接引起(例如,作为由肿瘤来源的细胞非正常产生的或以增加的浓度产生的物质(诸如激素或细胞因子)的产生释放,或者生物活性细胞的产生和释放的结果)的系统性病症。这种系统性病症(systemic order)可通过包括小脑炎、癫痫和硬化的各种病况揭示。PNS的任何表现都表明应该彻底检查患者是否存在肿瘤,尽管肿瘤可能太小而无法检测。
小脑炎可具有多种原因并且与下列疾病相关(因此其可使用本发明来诊断或与自身免疫性小脑炎相区分或区别):病毒感染(例如柯萨奇病毒、流感病毒、水痘带状疱疹病毒、EB病毒、轮状病毒或细小病毒的感染)、细菌感染(例如肺炎分枝杆菌(Mycobacteriumpneumoniae)或隐球菌属(Cryptococcus)的感染)、共济失调、自身免疫性小脑炎(例如与针对Neurochrondrin或Yo的自身抗体相关的)、药物过量(例如美沙酮或鸦片)、疫苗诱导的小脑炎。
癫痫可以具有多种原因并且与以下疾病相关(因此其可使用本发明诊断或与自身免疫性小脑炎相区分或区别):儿童的良性热性惊厥、特发性/隐源性癫痫发作、脑发育不全、症状性癫痫、头部创伤、中风、血管畸形、肿块病变、CNS感染、脑炎、心内膜炎(ceningitis)、囊尾蚴病、HIV脑病、低血糖症、低钠血症、高渗状态(hyperolsmolarstates)、低钙血症、尿毒症、肝性脑病、parophyria、药物毒性、药物戒断、全脑缺血、高血压性脑病、子痫、过热。
硬化可具有多种原因并且与以下疾病相关(因此其可使用本发明诊断或与自身免疫性小脑炎相区分或区别):Lou Gehrig病、动脉粥样硬化、肾病综合征、海马硬化症、硬化性苔藓和多发性硬化。
因此,本发明还可用于区分自身免疫性疾病与传染病,特别是区分神经元自身免疫性疾病与传染病。检测到针对DAGLA的自身抗体表明该疾病是自身免疫性疾病。
在一个优选实施方案中,如本文中所用,术语“诊断”是指目的在于获得有助于评估患者在过去、诊断时或将来是否患有或可能患有或比平均受试者或比较受试者(后者优选具有类似症状)更可能患有某一疾病或病症的信息,在于了解所述疾病如何进展或将来可能如何进展,或在于评估患者对某一治疗(例如免疫抑制药物的施用)的反应性的任何类型的程序。换句话说,术语“诊断”不仅包括诊断,而且还包括预测和/或监测疾病或病症的过程。
在许多情况下,仅仅检测,换句话说,确定样品中是否存在可检测水平的所述抗体,足以用于诊断。如果可以检测到自身抗体,这将是有助于临床医生诊断的信息,并且表明患者患有疾病的可能性增加。在一个优选实施方案中,如果可以使用选自免疫沉淀、间接免疫荧光、ELISA或线印迹,优选间接免疫荧光的一种或多种方法检测到自身抗体,则认为其是可检测的。在一个优选实施方案中,可以测定血清中与可在平均健康受试者中发现的水平相比的抗体的相对浓度。虽然在许多情况下确定样品中是否存在或可检测自身抗体可能就足够了,但获得有助于诊断的信息所进行的方法可能涉及确定浓度是否为平均健康受试者中发现的浓度的至少2倍,优选至少5倍、10倍、20倍、25倍、50倍、100倍、200倍、500倍、1000倍、10000倍或100000倍。在一个优选实施方案中,使用选自半定量免疫沉淀、半定量半定量间接免疫荧光、ELISA或半定量线印迹中的一种或多种方法(优选ELISA)测定自身抗体的相对浓度。实验细节是在如本申请的实验部分中或如在本申请优先权日期可获得的教科书或实用手册中所述的。许多测定可以以竞争形式进行,其中DAGLA或其变体与第一抗体结合,所述第一抗体被第二抗体取代。例如,第一抗体可以是针对DAGLA的自身抗体,第二抗体可以是重组抗体,优选用可检测的标记物标记。
本领域技术人员将理解,临床医生通常不会仅基于单个诊断参数来判断患者是否患有或可能患有疾病、病况或病症,而是需要考虑其他方面,例如其他自身抗体、标志物的存在、血液参数、患者症状的临床评估或医学成像或其他非侵入性方法(诸如多导睡眠描记法)的结果,以得出确凿的诊断。参见Baenkler H.W.(2012),General aspects ofautoimmune diagnostics,in Renz,H.,Autoimmune diagnostics,2012,de Gruyter,第3页。诊断剂或方法的价值也可能存在于排除一种疾病的可能性,从而允许间接诊断另一种疾病。在一个优选实施方案中,整个本申请中提及的任何症状或疾病的含义符合本领域技术人员截止申请日期或优选地本申请的最早优先权日期时的理解(如教科书和科学出版物所证明的)。应该提及的是,单独使用本发明的方法或用途或产品不能用于达到明确的最终诊断。
因此,术语“诊断”优选地并不意味着根据本发明的诊断方法或试剂将是确定的并且足以在单个测试(更不用说参数)的基础上完成诊断,但可以指对所谓的“鉴别诊断”(即,基于一系列诊断参数考虑一系列可能病况的可能性的系统诊断程序)的贡献。因此,任选地用于确定患者是否患有疾病的本发明方法、多肽或用途可包括从患者(优选人患者)获得样品,确定所述样品中是否存在与DAGLA结合的自身抗体,其中通过使样品与本发明的多肽接触并优选地使用标记的第二抗体检测在所述多肽与所述自身抗体之间是否发生结合来进行所述测定,其中如果存在于样品中,则所述自身抗体与所述多肽结合,并且如果所述自身抗体经测定存在于样品中,则将患者诊断为患有所述神经学病症或更可能患有所述神经学病症。
术语“诊断”还可指用于区分与相似或相同症状相关的两种或更多种病况的方法或试剂。
术语“诊断”还可指用于为患者选择最有希望的治疗方案的方法或试剂。换句话说,该方法或试剂可涉及为受试者选择治疗方案。例如,自身抗体的检测可指示要选择免疫抑制疗法,其可以包括向患者施用一种或多种免疫抑制药物。
本发明涉及包含与本发明的多肽结合的抗体,优选自身抗体的复合物。可作为用于诊断疾病的方法的一部分使用这种复合物或检测这种复合物。如果要检测针对DAGLA的自身抗体,则可使用来自受试者的包含抗体的液体样品来实施该方法。这种液体样品可以是来自受试者的包含代表性抗体组的任何体液,优选来自受试者的包含一个免疫球蛋白类别的抗体的样品,所述抗体选自IgG、IgA和IgM类抗体,优选IgG,更优选IgG1和IgG2,更优选IgG1。例如,样品可以是脑脊髓液(CSF)、血液或血清、淋巴液、间质液,优选为血清或CSF,更优选血清。其优选是离体样品。
使包含抗体的液体样品与本发明的多肽接触的步骤可以通过在包含抗体的样品存在的情况下,在与包含相应多肽和与本发明的多肽结合的抗体(优选自身抗体)的复合物的形成相容的条件下孵育所述多肽的固定化形式来进行。随后可除去耗尽了与本发明的多肽结合的抗体的液体样品,然后进行一个或多个洗涤步骤。最后,可检测包含所述抗体和所述多肽的复合物。在一个优选实施方案中,术语“与复合物的形成相容的条件”是允许特异性抗原-抗体相互作用以构建包含所述多肽和所述抗体的复合物的条件。在一个优选实施方案中,此类条件可包括在25℃在PBS缓冲液中以1:100稀释的样品中孵育多肽30分钟。
在一个优选实施方案中,如本文中所用,术语“自身抗体”是指与产生所述自身抗体的动物(优选哺乳动物,更优选人)的内源性分子特异性结合的抗体,其中更优选地这种抗体的水平相较于与这种内源性分子特异性结合的任何其他抗体的平均水平有升高。在一个最优选实施方案中,自身抗体是与DAGLA结合的自身抗体。自身抗体可具有来自产生其的动物(优选人)的抗体恒定区的序列,但可变区能够与动物的内源性分子,更具体地DAGLA特异性结合。在一个优选实施方案中,从动物(优选人)的样品(优选组织、血清、血浆、血液或CSF)中分离和/或纯化自身抗体。自身抗体是来自所述动物的多克隆天然抗体,而不是合成或重组抗体。在一个优选实施方案中,自身抗体是与SEQ ID NO 26或SEQ ID NO 28(优选SEQ ID NO28)特异性结合的抗体。
根据本发明的方法优选是体外方法。
在一个优选实施方案中,用于根据本发明的预后、诊断、方法或测试试剂盒的复合物的检测包括使用选自免疫扩散技术、免疫电泳技术、光散射免疫测定、凝集技术、标记免疫测定(诸如来自包括放射性标记的免疫测定、酶免疫测定(优选ELISA)、化学发光免疫测定和免疫荧光(优选间接免疫荧光技术)的组的那些)的方法。本领域技术人员熟悉这些方法,所述方法也描述于现有技术中,例如Zane,H.D.(2001),Immunology–Theo-retical&Practical Concepts in Laboratory Medicine,W.B.Saunders Company,第14章。
或者,可使用包含含有本发明的多肽的组织的样品而非液体样品。组织样品优选来自表达内源性DAGLA的组织,优选来自相较于相应的生物体(优选人体)中的平均组织而言以升高的水平表达内源性DAGLA的组织。然后可将这种样品(其可以以固定在载体例如载玻片上(以用于显微镜分析)的组织切片形式存在)和与本发明的多肽结合的本发明的抗体(优选自身抗体)接触。优选标记抗体以允许区分与本发明的多肽结合的内源性抗体,使得可以检测以及任选地定量新形成的复合物。如果形成的复合物的量低于取自健康受试者的样品中发现的量,则已从其获取所检查的样品的受试者可能患有疾病。
可将证明包含抗体和本发明多肽的复合物的存在或不存在的任何数据与参考数据产生关联。例如,所述复合物的检测表明提供所分析的样品的患者已患有疾病,正患有疾病或在将来可能患有疾病。如果患者先前已被诊断并且再次运行获得诊断相关信息的方法,则可将在两次运行中检测到的复合物的量产生关联以弄清关于疾病进展和/或治疗成功的情况。在一个优选实施方案中,可以将证明复合物存在或不存在的任何信息或数据传达给患者或治疗该患者的医生,优选通过电话、以书面形式或通过互联网(例如以电子邮件或文本消息的形式)。
在另一个优选实施方案中,按照本发明教导的预后、诊断、方法或测试试剂盒包括间接免疫荧光的使用。本领域技术人员熟悉此类技术和合适样品的制备,其描述于现有技术(US4647543;Voigt,J.,Krause,C.,E,Saschenbrecker,S.,Hahn,M.,Danckwardt,M.,Feirer,C.,Ens,K,Fechner,K,Barth,E,Martinetz,T.和W.(2012),Automated Indirect Immunofluorescence Evaluation of AntinuclearAutoantibodies on HEp-2 Cells,”Clinical and Developmental Immunology,第2012卷,doi:10.1155/2012/65105;Bonilla,E.,Francis,L.,Allam,F.等,Immuno-fluorescence microscopy is superior to fluorescent beads for detection ofantinuclear antibody reactivity in systemic lupus erythematosus patients,Clinical Immunology,第124卷,第1期,第18–21页,2007)中。合适的试剂、装置和软件包可以例如从EUROIMMUN,Lübeck,Germany商购获得。
可以对样品进行测试以仅确定是否存在与DAGLA结合的自身抗体,但优选的是,诊断方法、测试、装置等包括确定针对一种或多种另外多肽(优选与神经学自身免疫性疾病相关)的自身抗体的存在,所述多肽优选选自,更优选全部来自包含以下的组:Hu、Yo、Ri、CV2、PNMA1、PNMA2、DNER/Tr、ARHGAP26、ITPR1、ATP1A3、NBC1、Neurochrondrin、CARPVIII、Zic4、Sox1、Ma、MAG、MP0、MBP、GAD65、双载蛋白(amphiphysin)、恢复蛋白、GABA A受体(EP13189172.3)、GABA B受体(EP2483417)、甘氨酸受体、桥尾蛋白(gephyrin)、IgLON5(US2016/0349275)、DPPX(US2015/0247847)、水通道蛋白-4、MOG、NMDA受体、AMPA受体、GRM1、GRM5、LGI1、VGCC以及mGluR1和CASPR2,优选将所述抗原固定在例如医疗装置(诸如线印迹)上。诊断相关标志物Neurochrondrin(EP15001186)、ITPR1(EP14003703.7)、NBC1(EP14003958.7)、ATP1A3(也称为人神经元Na(+)/K(+)ATP酶的α3亚基(EP14171561.5)、阀蛋白1/2(EP3101424)、NSF、STX1B以及VAMP2(EP17001205.8)和RGS8(EP17000666.2)(可另外检测针对其中的一种或多种(优选全部)的自身抗体)已在现有技术中有描述。
根据本发明的教导,提供了用于诊断疾病的与本发明的多肽结合的抗体,优选自身抗体。本领域技术人员熟悉纯化抗体的方法,例如Hermanson,G.T.,Mallia,A.K.和Smith,P.K.(1992),Immobilized Affinity Ligand Techniques,San Diego:AcademicPress中描述的方法。简言之,固定与目标抗体特异性结合的抗原(所述抗原是本发明的多肽),并将其用于通过亲和色谱从适当的来源纯化目标抗体。可将来自本发明人鉴定的患有神经学病症的患者的包含抗体的液体样品用作来源。
根据本发明,提供了抗体,例如自身抗体,其能够与DAGLA特异性结合。反之亦然,DAGLA的变体与和DAGLA特异性结合的自身抗体特异性结合。在一个优选实施方案中,如本文中所用,术语“抗体”是指任何基于免疫球蛋白的结合部分,更优选包含至少一个免疫球蛋白重链和一个免疫球蛋白轻链的结合部分(包括但不限于单克隆和多克隆抗体以及抗体的变体,特别是片段),所述结合部分能够与相应的抗原结合,更优选与其特异性结合。在一个优选实施方案中,如本文中所用,术语“特异性结合”意指所述结合要强于特征在于1x10-5M,更优选1x 10-7M,更优选1x 10-8M,更优选1x 10-9M,更优选1x 10-10M,更优选1x 10- 11M,更优选1x 10-12M(如使用Biacore设备在25℃下在pH 7的PBS缓冲液中通过表面等离子体共振测定的)的解离常数的结合反应。抗体可以是异质的自身抗体制剂的一部分或可以是同质的自身抗体,其中异质制剂包含如可通过从人供体血清制备(例如通过亲和色谱,其使用固定化抗原以纯化能够与所述抗原结合的任何自身抗体)获得的多种不同的自身抗体种类。抗体可以是糖基化的或非糖基化的。抗体可以是重组和/或单克隆哺乳动物(优选不是人的动物)抗体。抗体可以是与SEQ ID NO 26或SEQ ID NO 28(优选SEQ ID NO28)特异性结合的抗体。本领域技术人员熟悉可用于鉴定、产生和纯化抗体及其变体的方法,例如EP 2423 226A2和其中的参考文献中描述的方法。优选地,抗体是纯化的和/或重组的。优选地,抗体与诊断上有用的载体结合。
本发明提供了一种用于分离与DAGLA结合的自身抗体的方法,其包括以下步骤:a)使包含所述抗体的样品与本发明的多肽接触以形成复合物,b)分离在步骤a)中形成的复合物,c)解离在步骤b)中分离的复合物,以及d)将所述抗体与本发明的多肽分离。来自本发明人鉴定的患有新型神经学病症的患者的样品可用作抗体来源。合适的方法描述于现有技术中,例如由GE Healthcare Life Sciences出版的手册“Affinity chromatography”,“Strategies for Protein Purification”and“Antibody Purification”(2009/2010)中和Philips,Terry,M.,Analytical techniques in immunochemistry,1992,MarcelDekker,Inc.中。
本发明提供了包含本发明多肽的药物组合物,所述组合物优选适合施用于受试者,优选哺乳动物受试者,更优选施用于人。这种药物组合物可包含药学上可接受的载体。药物组合物可以例如通过口服、肠胃外、通过吸入喷雾、局部、通过滴眼、经直肠、经鼻腔、经颊、经阴道或通过植入的储库施用,其中如本文中所用,术语“肠胃外”包括皮下、皮内、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、病灶内和颅内注射或输注技术。药物组合物可以以合适的剂型(例如胶囊、片剂和含水悬浮液和溶液),优选以无菌形式提供。其可用于治疗疾病的方法中,所述方法包括向受试者施用有效量的本发明的多肽。在一个优选实施方案中,本发明提供了包含本发明的多肽的疫苗(其任选地包含辅助剂诸如佐剂或缓冲剂),以及本发明的多肽用于制备疫苗的用途。
在本发明的范围内,提供了医学或诊断装置,其包含,优选涂覆有用于检测本发明的(自身)抗体和/或本发明的多肽的试剂。优选地,这种医学或诊断装置包含本发明的多肽,其形式允许以直接的方式使其与水性溶液,更优选液体人样品接触。特别地,可将本发明的多肽固定在载体表面上,所述载体优选选自玻璃板或载玻片、生物芯片、微量滴定板、珠粒(例如磁珠)、单采装置、色谱柱、膜等。示例性医疗装置包括线印迹、微量滴定板、用于显微镜检查的载玻片、珠粒(优选磁珠)和生物芯片。除了本发明的多肽以外,医学或诊断装置还可包含另外的多肽,例如阳性或阴性对照,诸如包含或不包含与目标多肽结合的抗体或与具有诊断价值的自身抗体结合的已知的其他抗原(特别是与和一种或多种相同或相似症状相关的其他疾病相关的抗原)的样品。
本发明的教导提供了优选用于诊断疾病的试剂盒。这种试剂盒可包括详细说明如何使用该试剂盒的说明书和用于使本发明的多肽与来自受试者(优选人受试者)的体液样品接触的工具(例如线印迹),其中将本发明的多肽固定在线印迹上。此外,试剂盒还可包含阳性对照,例如一批已知结合根据本发明的多肽(优选针对SEQ ID NO 26和/或SEQ IDNO28)的自身抗体或重组抗体,和阴性对照(例如,对本发明的多肽不具有可检测的亲和力的蛋白质诸如牛血清白蛋白)。最后,这种试剂盒可包含用于制备校准曲线的与DAGLA(优选SEQ ID NO26和/或SEQ ID NO28)结合的抗体的一种或多种标准溶液(也称为校准物)(优选具有已知的绝对或相对浓度)。优选地,试剂盒包括两种校准物,其中第一校准物的抗体浓度不超过第二校准物中所述抗体的浓度的50%、40%、30%、20%、10%、5%、2.5%或1%。在一个优选实施方案中,通过检测至少两种校准物(优选三种、四种或五种或更多种校准物)中的抗体浓度并获得每种校准物的浓度值,然后建立标准校准曲线,来校准包含诊断上有用的载体的装置。
在一个优选实施方案中,试剂盒包含用于检测与本发明的多肽结合的自身抗体(优选通过检测包含本发明的多肽和与本发明的多肽结合的抗体的复合物)的工具。此类工具优选是与所述复合物结合并修饰复合物或携带标记物以使复合物可检测的试剂。例如,所述工具可以是在除一抗识别的结合位点外的结合位点处与所述多肽结合或与一抗的恒定区结合的经标记的抗体。或者,所述工具可以是与自身抗体的恒定区结合的二抗,优选对哺乳动物IgG类抗体特异的二抗。用于检测这种复合物的多种方法和工具已描述于现有技术中,例如Philips,Terry,M.,Analytical techniques in immunochemistry,1992,Marcel Dekker,Inc.中。
DAGLA或其变体可以以包含和/或表达编码所述多肽的核酸的细胞的形式产生或提供。如果使用包含编码本发明的多肽或其变体的序列的核酸,则这种核酸可以是未修饰的核酸。在一个优选实施方案中,核酸是这样的核酸,其本身不存在于自然界中并且与天然核酸相比包含至少一种修饰,例如同位素含量或化学修饰,例如甲基化、序列修饰、表示合成来源的标记等。在一个优选实施方案中,所述核酸是重组核酸或核酸的一部分,并且在一个更优选的实施方案中,是载体的一部分,其中其可以与允许核酸表达(优选过表达)的启动子功能性连接。本领域技术人员熟悉各种合适的载体,其可以例如从Origene商购获得。例如,可使用编码具有C末端GFP的融合构建体的载体。细胞可以是真核细胞或原核细胞,优选真核细胞,诸如酵母细胞,更优选为哺乳动物细胞,更优选人细胞,诸如HEK293细胞。哺乳动物细胞的实例包括HEK293、CHO或COS-7细胞。包含编码本发明的多肽的核酸的细胞可以是重组细胞或分离的细胞,其中术语“分离的”意指富集细胞,使得与野生型的所述细胞的环境相比,存在更少的其他分化或种类的细胞或事实不存在此类其他细胞。在一个优选实施方案中,载体编码包含SEQ ID NO 26和/或SEQ ID NO28(优选SEQ ID NO28)的多肽。
在一个优选实施方案中,根据本发明的医疗装置,优选适用于显微镜检查的载玻片,包含来自包含表达(优选过表达)DAGLA或其变体的第一真核细胞、表达内源性DAGLA的真核(优选哺乳动物)组织诸如大鼠或灵长类动物小脑、第二真核细胞(其是与第一真核细胞相同类型的细胞,但不表达或过表达DAGLA)的组的一种或多种(优选所有)试剂。第一和第二真核细胞是源自分离的细胞系诸如HEK293的培养细胞。优选地,第一和第二细胞各自用共享相同骨架的载体转染,其中用于转染第一细胞的载体包含编码DAGLA或其变体的核酸,并且用于转染第二细胞的载体不包含DAGLA或其变体。第二细胞可用作阴性对照。试剂在医疗装置上可以是空间上分开的,使得它们可被独立地评估,而来自一种试剂的抗原不会污染另一种试剂。在一个更优选的实施方案中,第一和/或第二细胞是固定的细胞,例如使用甲醇或丙酮固定的。在现有技术中描述了用于固定细胞的方案。作为另外的试剂,可提供第二经标记的抗体(优选用荧光染料标记)。试剂和医疗装置可以是试剂盒的一部分。
在一个优选实施方案中,使用微量滴定板、膜、印迹诸如斑点印迹或线印迹来实施根据本发明的诊断方法。本领域技术人员熟悉线印迹的实验设置,这描述于现有技术(Raoult,D.和Dasch,G.A.(1989),The line blot:an immunoassay for monoclonal andother antibodies.Its application to the serotyping of gram-negativebacteria.J.Immunol.Methods,125(1-2),57-65;WO2013041540)中。如果医疗装置是线印迹,则其可包含固定在膜(优选呈测试条的形状)上的DAGLA或其变体。膜可包含一种或多种另外的抗原,其在空间上与DAGLA分开。膜可以包含指示样品诸如血液样品添加的对照条带,和/或指示二抗添加的对照条带。试剂盒可包含任何组分,优选全部来自包括线印迹、二抗和洗涤溶液的组。
在另一个优选实施方案中,医疗装置是包含至少8个孔的微量滴定板。至少一个孔直接或间接包被有DAGLA或其变体。提供至少3种,优选4种,更优选5种校准物,其包含确定浓度的针对DAGLA的抗体,并且可用于建立用于半定量分析的校准曲线。可提供包含酶促活性标记物的二抗。试剂盒可包含任何组分,优选全部来自包含微量滴定板、校准物、洗涤溶液和二抗的组。
在另一个优选实施方案中,医疗装置是直接或间接包被有DAGLA或其变体的珠粒。珠粒可选自磁珠和荧光珠。可提供包含能够化学发光或发荧光的标记物的二抗。可提供包含针对DAGLA的抗体的阳性对照。可提供至少3种,优选4种,更优选5种校准物,所述校准物包含确定浓度的针对DAGLA的抗体,并且可用于建立用于半定量分析的校准曲线。如果标记物能够产生化学发光,则可提供包含化学发光反应所需的其他组分的溶液。例如,如果标记物是酶,则溶液包含底物。如果标记物是能够产生化学发光的化合物诸如吖啶酯,则在溶液中提供反应所需的其他化合物。试剂盒可包含任何组分,优选全部来自包含珠粒、二抗、校准物、洗涤溶液和包含其他组分的溶液的组。
本发明的教导不仅可用于诊断,而且还可用于预防或治疗疾病,更具体地说,用于预防或治疗疾病的方法,其包括以下步骤:a)降低受试者的血液中与本发明的多肽结合的自身抗体的浓度,和/或b)施用一种或多种免疫抑制药物,所述免疫抑制药物优选选自利妥昔单抗、泼尼松、甲泼尼龙、环磷酰胺、吗替麦考酚酯、静脉注射免疫球蛋白、他克莫司、环孢菌素、甲氨蝶呤、硫唑嘌——和/或药物组合物。
在一个优选实施方案中,本发明提供了用于检测针对DAGLA的自身抗体的试剂或与这种自身抗体结合的试剂,或编码DAGLA或变体的核酸或与编码DAGLA的核酸特异性杂交的核酸或包含所述核酸的载体或细胞在制备用于诊断疾病的试剂盒中的用途。
在一个优选实施方案中,根据本发明的任何方法或用途可以用于非诊断用途,即确定与DAGLA结合的自身抗体的存在以用于除诊断患者外的用途。例如,该方法或用途可以用于体外测试设计用于从患者血液中去除自身抗体的医疗装置的功效,其中对除患者血液外的液体进行所述测试。在将医疗装置用于患者后,可通过使包含针对DAGLA的抗体的溶液运行通过所述装置,然后使用根据本发明的方法确认已通过装置的溶液中存在较少的抗体或没有抗体(即显示该装置仍具有从溶液中除去抗体的能力)来检查其去除自身抗体的能力。
在另一个优选实施方案中,该方法可用于确认诊断测定的可靠性,并且可涉及检测溶液中的针对DAGLA的抗体,所述溶液不是来自患者的样品,但已知包含针对DAGLA的抗体(优选以已知的浓度)。或者,溶液可以是不包含所述抗体的阴性对照以检查背景。可将这种方法与诊断方法并行地、在其之后或在其之前运行。在一个优选实施方案中,根据本发明的任何方法或用途可以用于产生自身抗体谱,优选用于检测哺乳动物(优选人)的疾病。在一个优选实施方案中,任何方法或用途可以用于检测来自神经学疾病患者的样品中的疾病相关标志物。
在一个优选实施方案中,根据本发明的任何方法或用途可用于鉴定具有患神经学疾病和/或肿瘤或发展出神经学疾病和/或肿瘤的风险的受试者。
在一个优选实施方案中,本发明提供了用于分析来自患者的样品以检测针对DAGLA(优选SEQ ID NO26和/或SEQ ID NO28)的自身抗体从而表明疾病或发展出疾病的可能性增加的装置,其包括:
a.载体,其包含当样品与载体接触时从样品中捕获所述自身抗体的工具,
b.可检测工具,其能够在可检测工具与载体接触时与载体所捕获的抗体结合,其中所述可检测工具是能够与载体上捕获的抗体结合的经标记的二抗,
c.任选地,用于从载体和可检测工具中除去任何样品(优选通过洗涤)的工具;
d.检测装置,其用于检测可检测工具的存在并将结果转换成电信号,以及任选地,用于接收来自检测装置的电子信号并确定信号的水平是否表示患有或发展出疾病的可能性增加的装置,其中通过与在背景中检测到的信号水平或利用来自健康受试者的样品获得的输入参考值的比较,或通过将利用一个样品获得的信号水平与利用在较后时间点(优选至少一个月后)获得的第二样品获得的信号水平比较来进行所述确定。
图1显示使用大鼠和灵长类动物小脑的透化冷冻切片对患者P1至P5的血清进行间接免疫荧光测定的结果。观察到分子层的粒状染色。
图2显示使用患者血清从匀浆的大鼠小脑中免疫沉淀DAGLA,然后为使用患者血清作为抗体来源的蛋白质印迹分析(A1),考马斯染色的SDS PAGE(A2),使用与DAGLA结合的商业重组抗体的蛋白质印迹(A3)。此外,使用表达DAGLA的转染的HEK293细胞通过间接免疫荧光测试患者的样品。患者的血清与表达DAGLA的细胞反应(B1)。相反,模拟物转染的细胞未显示出任何特异性抗体结合(B2)。
图3显示使用用DAGLA预孵育或未用DAGLA预孵育的来自患者的自身抗体对大鼠和灵长类动物小脑进行免疫荧光测定的结果。通过用含有DAGLA(SEQ ID NO 4)的HEK293裂解物预孵育,可以消除患者的自身抗体对组织的反应(图3A)。当使用相当的来自模拟物转染的HEK293细胞的级分时,抗体结合不受影响。
使用患者血清和特异性多克隆抗DAGLA抗体(Sigma-Aldrich,Germany)对大鼠和灵长类动物小脑组织进行间接免疫荧光显示了分子层染色的精确重叠(图3B)。
图4显示使用人DAGLA的6个不同片段对包含针对DAGLA的自身抗体的八种阳性患者血清进行的ELISA分析。两个片段(583-1042和123-136)产生了阳性结果。
本申请包括一系列序列,更具体地是:
SEQ ID NO 1(编码人DAGLA的cDNA)
atgcccgggatcgtggtgttccggcggcgctggtctgtgggcagtgatgacctcgtcctaccagccatcttcctctttctcctgcataccacctggtttgtgatcctgtccgtggtgctcttcggcctggtctataacccgcacgaggcctgctccctgaacctggtggaccacggccgcggctacctgggcatcctgctgagctgcatgatcgctgagatggccatcatctggctgagcatgcgcgggggcatcctctacacggagccccgtgactccatgcagtacgtgctctacgtgcgcctggccatcctggtgatcgagttcatctacgccatcgtgggcatcgtctggctcactcagtactacacctcctgcaacgacctcactgccaagaatgtcaccctcggaatggttgtctgcaactgggtagtcatcctcagtgtgtgcatcactgtcctctgcgtcttcgaccccacgggccgcacctttgtcaagctgagagccaccaagaggaggcagcgtaacctgcggacctacaacctgcggcaccgcttagaggagggtcaagccaccagctggtcgcgccggctcaaagtgttcctctgctgcacgcggacgaaggactcccagtcagatgcctactcagaaatcgcctacctctttgcggagttcttccgggaccttgacattgtgccatccgacatcattgctggcctggtgctgctccggcagcggcagcgggccaagcgcaacgccgtgctggacgaggcaaacaatgacatcttggccttcctgtctgggatgccggtgaccagaaacaccaagtacctcgacctcaagaattcacaagagatgctccgctacaaagaggtctgctactacatgctctttgccctggctgcctacgggtggcccatgtacctgatgcggaagcccgcctgcggcctctgccaactggctcggtcctgctcgtgttgcctgtgtcctgcgaggccgcggttcgcccctggagtcaccatcgaggaagacaactgctgtggctgtaatgccattgccatccggcgccacttcctggacgagaacatgactgcggtggacatcgtctatacctcctgccatgatgcggtctatgaaacgcccttctacgtggcggtggaccatgacaagaagaaagtggtgatcagtatccgggggaccctgtcccccaaggatgccctgactgacctgacgggtgatgctgagcgcctccccgtggaggggcaccacggcacctggctgggccacaagggtatggtcctctcagctgagtacatcaagaagaaactggagcaggagatggtcctgtcccaggcctttgggcgagacctgggccgcggaaccaaacactacggcctgattgtggtgggccactccctgggcgcgggcactgctgccatcctctccttccttctgcgcccacagtatccgaccctcaagtgctttgcctactccccgccagggggcctgctgagtgaggatgcaatggagtattccaaggagttcgtgactgctgtggttctgggcaaagacctcgtccccaggattggcctctctcagctggaaggcttccgcagacagctcctggatgtcctgcagcgaagcaccaagcccaaatggcggatcatcgtgggggccaccaaatgcatccccaagtcggagctgcctgaggaggtagaggtgaccaccctggccagcacgcggctctggacccaccccagcgacctaactatagccctctcagccagcactccactctacccgcccggccgcatcatccacgtggtccacaaccaccctgcagagcagtgctgctgctgtgagcaggaggagcccacatactttgccatctggggcgacaacaaggccttcaatgaggtgatcatctcgccagccatgctgcatgagcacctgccctatgtggtcatggaggggctcaacaaggtgctggagaactacaacaaggggaagaccgctctgctctctgcagccaaggtcatggtgagccctaccgaggtggacctgactcctgagctcatcttccagcagcagccactccccacggggccgcccatgcccactggccttgccctggagctgccgactgcagaccaccgcaacagcagcgtcaggagcaagtcccagtctgagatgagcctggagggcttctcggaggggcggctgctgtcgccagtggttgcggcggcggcccgccaggacccggtggagctgctgctgctgtctacccaggagcggctggcggcggagctgcaggcccggcgggcaccactggccaccatggagagcctctcggacactgagtccctgtacagcttcgactcgcgccgctcctcaggcttccgcagcatccggggctcccccagcctccacgctgtgctggagcgtgatgaaggccacctcttctacattgaccctgccatccccgaggaaaacccatccctgagctcgcgcactgagctgctggcggccgacagcctgtccaagcactcacaggacacgcagcccctggaggcggccctgggcagtggcggcgtcactcctgagcggccccccagtgctgcggccaatgacgaggaggaagaggttggcggtgggggtggcgggccggcctcccgcggggagctggcgctgcacaatgggcgcctgggggactcgcccagtcctcaggtgctggaattcgccgagttcatcgacagcctcttcaacctggacagcaagagcagctccttccaagacctctactgcatggtggtgcccgagagccccaccagtgactacgctgagggccccaagtcccccagccagcaagagatcctgctccgtgcccagttcgagcccaacctggtgcccaagcccccacggctctttgccggctcagccgacccctcctcgggcatctcactctcgccctccttcccgctcagctcctcgggtgagctcatggacctgacgcccacgggcctcagtagccaggaatgcctggcggctgacaagatccggacttctacccccactggccacggagccagccccgccaagcaagatgagctggtcatctcagcacgctag
SEQ ID NO 2[用于扩增cDNA的有义DAGLA引物]
ATACGTCTCACATGCCCGGGATCGTGGTGTTCCGG
SEQ ID NO 3[用于扩增cDNA的反义DAGLA-Stop引物]
ATACGTCTCCTCGAGCTAGCGTGCTGAGATGACCAGCTC
SEQ ID NO 4(在HEK293中表达的DAGLA)
MPGIVVFRRRWSVGSDDLVLPAIFLFLLHTTWFVILSVVLFGLVYNPHEACSLNLVDHGRGYLGILLSCMIAEMAIIWLSMRGGILYTEPRDSMQYVLYVRLAILVIEFIYAIVGIVWLTQYYTSCNDLTAKNVTLGMVVCNWVVILSVCITVLCVFDPTGRTFVKLRATKRRQRNLRTYNLRHRLEEGQATSWSRRLKVFLCCTRTKDSQSDAYSEIAYLFAEFFRDLDIVPSDIIAGLVLLRQRQRAKRNAVLDEANNDILAFLSGMPVTRNTKYLDLKNSQEMLRYKEVCYYMLFALAAYGWPMYLMRKPACGLCQLARSCSCCLCPARPRFAPGVTIEEDNCCGCNAIAIRRHFLDENMTAVDIVYTSCHDAVYETPFYVAVDHDKKKVVISIRGTLSPKDALTDLTGDAERLPVEGHHGTWLGHKGMVLSAEYIKKKLEQEMVLSQAFGRDLGRGTKHYGLIVVGHSLGAGTAAILSFLLRPQYPTLKCFAYSPPGGLLSEDAMEYSKEFVTAVVLGKDLVPRIGLSQLEGFRRQLLDVLQRSTKPKWRIIVGATKCIPKSELPEEVEVTTLASTRLWTHPSDLTIALSASTPLYPPGRIIHVVHNHPAEQCCCCEQEEPTYFAIWGDNKAFNEVIISPAMLHEHLPYVVMEGLNKVLENYNKGKTALLSAAKVMVSPTEVDLTPELIFQQQPLPTGPPMPTGLALELPTADHRNSSVRSKSQSEMSLEGFSEGRLLSPVVAAAARQDPVELLLLSTQERLAAELQARRAPLATMESLSDTESLYSFDSRRSSGFRSIRGSPSLHAVLERDEGHLFYIDPAIPEENPSLSSRTELLAADSLSKHSQDTQPLEAALGSGGVTPERPPSAAANDEEEEVGGGGGGPASRGELALHNGRLGDSPSPQVLEFAEFIDSLFNLDSKSSSFQDLYCMVVPESPTSDYAEGPKSPSQQEILLRAQFEPNLVPKPPRLFAGSADPSSGISLSPSFPLSSSGELMDLTPTGLSSQECLAADKIRTSTPTGHGASPAKQDELVISAR
SEQ ID NO 5[用于克隆DAGLA片段的有义DAGLA[1-22]引物]
CATGCCCGGGATCGTGGTGTTCCGGCGGCGCTGGTCTGTGGGCAGTGATGACCTCGTCCTACCAGCCTAATGA
SEQ ID NO 6[用于克隆DAGLA片段的反义DAGLA[1-22]引物]
TCGATCATTAGGCTGGTAGGACGAGGTCATCACTGCCCACAGACCAGCGCCGCCGGAACACCACGATCCCGGG
SEQ ID NO 7[用于克隆DAGLA片段的有义DAGLA[44-60]引物]
CATGGTCTATAACCCGCACGAGGCCTGCTCCCTGAACCTGGTGGACCACGGCCGCTAATGA
SEQ ID NO 8[用于克隆DAGLA片段的反义DAGLA[44-60]引物]
TCGATCATTAGCGGCCGTGGTCCACCAGGTTCAGGGAGCAGGCCTCGTGCGGGTTATAGAC
SEQ ID NO 9[用于克隆DAGLA片段的有义DAGLA[81-101]引物]
CATGCGCGGGGGCATCCTCTACACGGAGCCCCGTGACTCCATGCAGTACGTGCTCTACGTGCGCTAATGA
SEQ ID NO 10[用于克隆DAGLA片段的反义DAGLA[81-101]引物]
TCGATCATTAGCGCACGTAGAGCACGTACTGCATGGAGTCACGGGGCTCCGTGTAGAGGATGCCCCCGCG
SEQ ID NO 11[用于克隆DAGLA片段的有义DAGLA[123-136]引物]
CATGTACACCTCCTGCAACGACCTCACTGCCAAGAATGTCACCCTCTAATGA
SEQ ID NO 12[用于克隆DAGLA片段的反义DAGLA[123-136]引物]
TCGATCATTAGAGGGTGACATTCTTGGCAGTGAGGTCGTTGCAGGAGGTGTA
SEQ ID NO 13(H8-GST-DAGLA[1-22])
MSHHHHHHHHMSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKLEVLFQGPAMPGIVVFRRRWSVGSDDLVLPA
SEQ ID NO 14(H8-GST-DAGLA[44-60])
MSHHHHHHHHMSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKLEVLFQGPAMVYNPHEACSLNLVDHGR
SEQ ID NO 15(H8-GST-DAGLA[81-101])
MSHHHHHHHHMSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKLEVLFQGPAMRGGILYTEPRDSMQYVLYVR
SEQ ID NO 16(H8-GST-DAGLA[123-136])
MSHHHHHHHHMSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKLEVLFQGPAMYTSCNDLTAKNVTL
SEQ ID NO 17[有义DAGLA[158-598]]
ATACGTCTCGCATGGACCCCACGGGCCGCACCTTTGTCAAG
SEQ ID NO 18[反义DAGLA[158-598]]
TATCGTCTCGTCGATCATTATGGAGTGCTGGCTGAGAGGGCTATAG
SEQ ID NO 19[有义DAGLA[583-1042]]
ATACGTCTCGCATGTGGACCCACCCCAGCGACCTAACTATAGC
SEQ ID NO 20[反义DAGLA[583-1042]]
TATCGTCTCGTCGATCATTAGCGTGCTGAGATGACCAGCTCATCTTG
SEQ ID NO 21(H8-DAGLA[158-598])
MSHHHHHHHHSMDPTGRTFVKLRATKRRQRNLRTYNLRHRLEEGQATSWSRRLKVFLCCTRTKDSQSDAYSEIAYLFAEFFRDLDIVPSDIIAGLVLLRQRQRAKRNAVLDEANNDILAFLSGMPVTRNTKYLDLKNSQEMLRYKEVCYYMLFALAAYGWPMYLMRKPACGLCQLARSCSCCLCPARPRFAPGVTIEEDNCCGCNAIAIRRHFLDENMTAVDIVYTSCHDAVYETPFYVAVDHDKKKVVISIRGTLSPKDALTDLTGDAERLPVEGHHGTWLGHKGMVLSAEYIKKKLEQEMVLSQAFGRDLGRGTKHYGLIVVGHSLGAGTAAILSFLLRPQYPTLKCFAYSPPGGLLSEDAMEYSKEFVTAVVLGKDLVPRIGLSQLEGFRRQLLDVLQRSTKPKWRIIVGATKCIPKSELPEEVEVTTLASTRLWTHPSDLTIALSASTP
SEQ ID NO 22(H8-DAGLA[583-1042])
MSHHHHHHHHSMWTHPSDLTIALSASTPLYPPGRIIHVVHNHPAEQCCCCEQEEPTYFAIWGDNKAFNEVIISPAMLHEHLPYVVMEGLNKVLENYNKGKTALLSAAKVMVSPTEVDLTPELIFQQQPLPTGPPMPTGLALELPTADHRNSSVRSKSQSEMSLEGFSEGRLLSPVVAAAARQDPVELLLLSTQERLAAELQARRAPLATMESLSDTESLYSFDSRRSSGFRSIRGSPSLHAVLERDEGHLFYIDPAIPEENPSLSSRTELLAADSLSKHSQDTQPLEAALGSGGVTPERPPSAAANDEEEEVGGGGGGPASRGELALHNGRLGDSPSPQVLEFAEFIDSLFNLDSKSSSFQDLYCMVVPESPTSDYAEGPKSPSQQEILLRAQFEPNLVPKPPRLFAGSADPSSGISLSPSFPLSSSGELMDLTPTGLSSQECLAADKIRTSTPTGHGASPAKQDELVISAR
SEQ ID NO 23(H8-GST-DAGLA[1-22])
MPGIVVFRRRWSVGSDDLVLPA
SEQ ID NO 24(H8-GST-DAGLA[44-60])
VYNPHEACSLNLVDHGR
SEQ ID NO 25(H8-GST-DAGLA[81-101])
MRGGILYTEPRDSMQYVLYVR
SEQ ID NO 26(H8-GST-DAGLA[123-136]),与患者血清具有反应性
YTSCNDLTAKNVTL
SEQ ID NO 27(DAGLA[158-598])
TGRTFVKLRATKRRQRNLRTYNLRHRLEEGQATSWSRRLKVFLCCTRTKDSQSDAYSEIAYLFAEFFRDLDIVPSDIIAGLVLLRQRQRAKRNAVLDEANNDILAFLSGMPVTRNTKYLDLKNSQEMLRYKEVCYYMLFALAAYGWPMYLMRKPACGLCQLARSCSCCLCPARPRFAPGVTIEEDNCCGCNAIAIRRHFLDENMTAVDIVYTSCHDAVYETPFYVAVDHDKKKVVISIRGTLSPKDALTDLTGDAERLPVEGHHGTWLGHKGMVLSAEYIKKKLEQEMVLSQAFGRDLGRGTKHYGLIVVGHSLGAGTAAILSFLLRPQYPTLKCFAYSPPGGLLSEDAMEYSKEFVTAVVLGKDLVPRIGLSQLEGFRRQLLDVLQRSTKPKWRIIVGATKCIPKSELPEEVEVTTLASTRLWTHPSDLTIALSASTPPD
SEQ ID NO 28(DAGLA[583-1042]),与患者血清具有反应性
WTHPSDLTIALSASTPLYPPGRIIHVVHNHPAEQCCCCEQEEPTYFAIWGDNKAFNEVIISPAMLHEHLPYVVMEGLNKVLENYNKGKTALLSAAKVMVSPTEVDLTPELIFQQQPLPTGPPMPTGLALELPTADHRNSSVRSKSQSEMSLEGFSEGRLLSPVVAAAARQDPVELLLLSTQERLAAELQARRAPLATMESLSDTESLYSFDSRRSSGFRSIRGSPSLHAVLERDEGHLFYIDPAIPEENPSLSSRTELLAADSLSKHSQDTQPLEAALGSGGVTPERPPSAAANDEEEEVGGGGGGPASRGELALHNGRLGDSPSPQVLEFAEFIDSLFNLDSKSSSFQDLYCMVVPESPTSDYAEGPKSPSQQEILLRAQFEPNLVPKPPRLFAGSADPSSGISLSPSFPLSSSGELMDLTPTGLSSQECLAADKIRTSTPTGHGASPAKQDELVISAR
通过以下非限制性实施例进一步说明本发明,从所述实施例中可以获得本发明的其他特征、实施方案、方面和有利方面。
实施例
概述
方法:5名患有神经学疾病的患者(P1-P5)接受血清学调查。为此,通过间接免疫荧光试验(IFA)和免疫印迹对来自全部五名患者的血清进行了全面的自身抗体筛选。用小脑裂解物进行免疫沉淀随后采用质谱法(MS)来鉴定自身抗原,其通过用针对相应靶抗原的单特异性动物抗体的蛋白质印迹(WB)以及通过在HEK293细胞中重组表达并且在免疫测定中使用重组蛋白来进行验证。此外,将具有神经学症状和确定的抗神经自身抗体的患者的血清、具有与P1至P5相似的染色模式而没有已知的自身抗体反应性的血清以及阴性对照血清就抗-DAGLA抗体进行筛选。在大肠杆菌(E.coli)中重组表达DAGLA蛋白的六个不同片段。使用抗-DAGLA阳性患者血清和健康对照在ELISA中分析经纯化的蛋白质。
结果:来自P1到P5的血清的IFA筛选显示了与啮齿动物和猴小脑中的分子层的IgG反应性。浦肯野细胞(purkinje cell)的树突被染色,而浦肯野细胞胞体无反应。此外,用一组30种重组表达的已建立的神经自身抗原未发现IgG反应性。如通过考马斯染色SDS-PAGE、随后通过MALDI-TOF质谱法检测的,P1至P5的血清能使Sn1-特异性二酰基甘油脂肪酶α(DAGLA)免疫沉淀。当使用针对DAGLA的单特异性动物抗体通过蛋白质印迹分析免疫沉淀物时,抗-DAGLA显示出与P1至P5的免疫沉淀物的反应性,而在五种对照血清的免疫沉淀物中没有反应性。但是,在P1至P5的血清以及在小脑中具有相似染色模式的另外7名患者(P6至P12)的血清中,用重组蛋白通过RC-IFA可以检测到抗-DAGLA抗体。对在IIFT中与神经组织无特异性反应的健康对照血清(n=51)的筛选显示没有抗-DAGLA阳性的样品。使用人DAGLA蛋白的重组表达片段的ELISA表明抗-DAGLA阳性血清主要与c-末端细胞内片段有反应性。
已有来自两名具有抗-DAGLA自身抗体的患者的临床数据可供利用。P11患有小脑炎,P12患有癫痫和海马硬化。
患者:
对照组包括51名健康供者和40名具有神经学症状和确定的抗神经自身抗体(3x抗-CASPR2、5x抗-NMDAR、5x抗-LGI1、5x抗-Hu、2x抗-Hu/抗-Ri 3x抗-Ri、2x抗-Yo/抗-Ri、3x抗-Yo、5x抗-AQP4、5x抗-GAD65、2x抗-GABAB受体)的患者。
间接免疫荧光试验(IFA)
使用具有脑组织(大鼠的海马,大鼠和猴的小脑)冷冻切片的生物芯片阵列的载玻片联合分别表达30种不同脑抗原(Hu、Yo、Ri、CV2、PNMA2、ITPR1、Homer 3、CARP VIII、ARHGAP26、ZIC4、DNER/Tr、GAD65、GAD67、双载蛋白、恢复蛋白、GABAB受体、甘氨酸受体、DPPX、IgLON5、谷氨酸受体(NMDA、AMPA、mGluR1、mGluR5、GLURD2型)、LGI1、CASPR2、AQP4(M1和M23)、MOG、ATP1A3、NCDN(EUROIMMUN、FA 111a-1003-51、FA 1112-1003-50、FA-1128-1003-50、FA112d-1003-1、FA 112m-1003-50、FA 1151-1003-50、Miske R,Hahn S,Rosenkranz T,Müller M,Dettmann IM,Mindorf S,Denno Y,Brakopp S,Scharf M,TeegenB,Probst C,Melzer N,Meinck HM,Terborg C,W,Komorowski L.,2016,Autoantibodies against glutamate receptorδ2after allogenic stem celltransplantation.Neurol Neuroimmunol Neuroinflamm.,3(4):e255;Scharf M,Miske R,Heidenreich F,Giess R,Landwehr P,IM,Begemann N,Denno Y,Tiede S,C,Schlumberger W,Unger M,Teegen B, W,Probst C,KomorowskiL,2015,Neuronal Na+/K+ATPase is an autoantibody target in paraneoplasticneurologic syndrome,Neurology;84(16):1673-9;Miske R,Gross CC,Scharf M,Golombeck KS,Hartwig M,Bhatia U,Schulte-Mecklenbeck A, K,Strippel C, L,Synofzik M,Lohmann H,Dettmann IM,Deppe M,Mindorf S,Warnecke T,DennoY,Teegen B,Probst C,Brakopp S,Wandinger KP,Wiendl H,W,Meuth SG,Komorowski L,Melzer N,2016,Neurochondrin is a neuronal target antigen inautoimmune cerebellar degeneration,Neurol Neuroimmunol Neuroinflamm.;4(1):e307))的重组HEK293细胞进行IFA。将每个生物芯片马赛克与70μL经PBS稀释的样品在室温下孵育30分钟,用PBS-Tween洗涤并浸入PBS-Tween中5分钟。在第二步中,应用Alexa488标记的山羊抗人IgG(Jackson Research,Suffolk,United Kingdom)或异硫氰酸荧光素(FITC)标记的山羊抗人IgG(EUROIMMUN Medizinische Labordiagnostika AG,Lübeck)并在室温下孵育30分钟。用一股PBS-Tween再次洗涤载玻片,然后浸入PBS-Tween中5分钟。将载玻片包埋在经PBS缓冲的包含DABCO的甘油(每个视野大约20μL)中,并通过荧光显微镜观察。包括阳性对照和阴性对照。基于转染细胞中的荧光强度直接与未转染细胞和对照样品比较,将样品分类为阳性或阴性。终点滴度是指显示可见荧光的最后稀释度。
使用EUROSTARII显微镜(EUROIMMUN Medizinische Labordiagnostika AG,Lübeck,Germany)由两名独立观察者评估结果。如果没有另外说明,试剂从Merck,Darmstadt,Germany或Sigma-Aldrich,Heidelberg,Germany获得。
免疫印迹
将经免疫沉淀的小脑裂解物与包含25mmol/L二硫苏糖醇的NuPage LDS样品缓冲液(ThermoFisher Scientific,Schwerte,Germany)在70℃孵育10分钟,随后进行SDS-PAGE(NuPAGE,ThermoFisher Scientific,Schwerte,Germany)。按照制造商的说明书,通过用转移缓冲液(ThermoFisher Scientific)进行槽式印迹将分离的蛋白质电转移至硝酸纤维素膜上。用Universal Blot Buffer plus(EUROIMMUN Medizinische Labordiagnostika AG,Lübeck)封闭膜15分钟,并在Universal Blot Buffer plus中与患者或对照血清(稀释度1:200)或针对DAGLA的单特异性兔抗体(Sigma Aldrich,HPA062497,1:2000)孵育3h,随后用Universal Blot Buffer(EUROIMMUN Medizinische Labordiagnostika AG,Lübeck)进行3次洗涤步骤,用抗人-IgG-AP(EUROIMMUN Medizinische Labordiagnostika AG,Lübeck,1:10)或抗兔-IgG-AP(1:2000)在Universal Blot Buffer plus中进行第二次孵育30分钟,3个洗涤步骤,并用NBT/BCIP底物(EUROIMMUN Medizinische Labordiagnostika AG,Lübeck)进行染色。如果没有另外说明,试剂从Merck,Darmstadt,Germany或Sigma-Aldrich,Heidelberg,Germany获得。
鉴定抗原
解剖来自大鼠的小脑并在液氮中骤冷。在4℃下用Miccra D-8(Roth,Karlsruhe,Germany)和手动匀浆器(Sartorius,Germany)将组织在包含蛋白酶抑制剂(Complete mini,Roche Diagnostics,Penzberg,Germany)的增溶缓冲液(100mmol/Ltris-HCl pH 7.4、150mmol/L氯化钠、2.5mmol/L乙二胺四乙酸、0.5%(w/v)脱氧胆酸钠、1%(w/v)Triton X-100)中匀浆。将组织裂解物以21000×g在4℃下离心15分钟,并将澄清的上清液与患者的血清(1:16.7稀释)在4℃下孵育过夜。然后将样品与蛋白G Dynabeads(ThermoFisher Scientific,Dreieich,Germany)在4℃下孵育3小时以捕获免疫复合物。将珠子用PBS洗涤3次,并用包含25mmol/L二硫苏糖醇的NuPage LDS样品缓冲液(ThermoFisher Scientific,Schwerte,Germany)在70℃洗脱10分钟。在SDS-PAGE(NuPAGE,ThermoFisher Scientific,Schwerte,Germany)之前,用59mM碘乙酰胺(Bio-Rad,Hamburg,Germany)进行脲甲基化。用考马斯亮蓝(G-250)(Merck)显现分离的蛋白质,并通过质谱分析鉴定。
质谱法
从经考马斯亮蓝G-250染色的凝胶上切下可见的蛋白质条带。在脱色和胰蛋白酶消化后,提取肽并与α-氰基-4-羟基肉桂酸一起点样至MTP AnchorChip TM 384TF靶上。
使用flexControl 3.4软件,用Autoflex III smartbeam TOF/TOF200系统进行MALDI-TOF/TOF测量。肽质量指纹图谱(PMF)的MS光谱以具有4000-10000次照射并且质量范围为600Da至4000Da的正离子反射器模式记录。用商购可得的Peptide CalibrationStandard II进行外部校准光谱,用flexAnalysis 3.4处理,用BioTools 3.2分析峰列表。
Mascot搜索引擎Mascot Server 2.3(Matrix Science,London,UK)通过对仅限于哺乳动物的NCBI或SwissProt数据库进行搜索用于蛋白质鉴定。搜索参数如下:质量耐受设定为80ppm,接受一个错过的切割位点,并且半胱氨酸残基的脲甲基化以及甲硫氨酸残基的氧化分别设定为固定和可变修饰。为了评估蛋白质命中,选择显著性阈值p<0.05。
为了进一步确认PMF命中,选择每种鉴定的蛋白质的2至5个肽使用BioTools的WARP反馈机制进行MS/MS测量。分别用400和1000次射击记录母体和碎片质量。按如上所述处理和分析光谱,片段质量耐受性为0.7Da。
DAGLA在HEK293中的重组表达
编码人DAGLA的cDNA(SEQ ID NO 1)作为克隆IRATp970E05140D从SourceBioScience UK Limited获得。使用有义DAGLA(SEQ ID NO 2)和反义DAGLA(SEQ ID NO 3)引物通过PCR扩增编码序列。用BsmBI消化扩增产物,并与经NcoI和XhoI线性化的pTriEx-1(Merck,Darmstadt,Germany)连接。得到的构建体编码SEQ ID NO 4。
按照制造商的说明书(Biomol GmbH,Hamburg,Germany),在PEI介导的转染(Exgene 500)后,在人细胞系HEK293中瞬时表达DAGLA。转染后5天收获细胞并通过超声裂解。将裂解物以等分试样储存在-80℃直至进一步使用。
DAGLA-片段在大肠杆菌中的重组表达
对于跨越氨基酸残基1至22、44至60、81至101和123至136的DAGLA片段的表达,通过寡脱氧核苷酸有义DAGLA[1-22]和反义DAGLA[1-22](SEQ ID NO 5和6)、有义DAGLA[44-60]和反义DAGLA[44-60](SEQ ID NO 7和8)、有义DAGLA[81-101]和反义DAGLA[81-101](SEQ ID NO 9和10)以及有义DAGLA[123-136]和反义DAGLA[123-136](SEQ ID NO 11和12)的杂交产生编码序列。
通过连接到经修饰的pET24d(Merck,Darmstadt,Germany)质粒载体将接头片段与八组氨酸(H8)标签和谷胱甘肽S-转移酶(GST)标签编码序列进行融合。这些构建体分别编码H8-GST-DAGLA[1-22](SEQ ID NO 13)、H8-GST-DAGLA[44-60](SEQ ID NO 14)、H8-GST-DAGLA[81-101](SEQ ID NO 15)和H8-GST-DAGLA[123-136](SEQ ID NO 16)。
分别使用人DAGLA cDNA(SEQ ID NO 1)和DNA寡核苷酸有义DAGLA[158-598]和反义DAGLA[158-598](SEQ ID NO 17和18)以及有义DAGLA[583-1042]和反义DAGLA[583-1042](SEQ ID NO 19和20)PCR扩增DAGLA[158-598]和DAGLA[583-1042]编码序列。用BsmBI消化扩增产物并插入至编码H8-DAGLA[158-598]和H8-DAGLA[583-1042](八组氨酸标签,H8)(分别为SEQ ID NO 21和22)的NcoI XhoI线性化的pET24d-N(Exp Dermatol.2007Sep;16(9):770-7)中。
细菌表达基本上按在pET系统手册(Merck,Darmstadt,Germany)中所描述的使用大肠杆菌菌株RosettaBlue(DE3)pLacI(Merck,Darmstadt,Germany)进行。通过加入2mM异丙基β-D-硫代半乳糖苷(IPTG)在37℃下3小时诱导蛋白质表达。
纯化:
裂解细菌细胞,并将蛋白质溶解在尿素缓冲液中,并按照如在C.Probst,W.Schlumberger,W.Stocker等人,“Development of ELISA for the specifcdetermination of autoantibodies against envoplakin and periplakin inparaneoplastic pemphigus,”Clinica Chimica Acta,vol.410,no.1-2,pp.13–18,2009.中的实验步骤,通过Ni2+-亲和层析进行纯化。将蛋白质以等分试样储存在-80℃直至进一步使用。
患者的自身抗体的表征
使用大鼠和灵长类动物小脑的透化冷冻切片对血清P1至P5进行的间接免疫荧光试验(IFA)显示出分子层的颗粒状染色(图1)。用表达30种神经自身抗原(Hu、Yo、Ri、CV2、PNMA2、SOX1、ITPR1、Homer 3、CARP VIII、ARHGAP26、ZIC4、DNER/Tr、GAD65、GAD67、双载蛋白、恢复蛋白、GABAB受体、甘氨酸受体、DPPX、IgLON5、谷氨酸受体(NMDA、AMPA、mGluR1、mGluR5、GLURD2型)、LGI1、CASPR2、AQP4(M1和M23)、MOG、ATP1A3和NCDN)的重组HEK293细胞进行进一步的单特异性分析。没有观察到特异性反应。
DAGLA作为靶神经自身抗原的鉴定
将用P1至P5获得的来自匀浆大鼠小脑的免疫沉淀物进行蛋白质印迹分析。与用于免疫沉淀的相同血清一起孵育后,观察到大约115kDa的特异性反应,其在对照血清的免疫沉淀物中不存在(图2,A1)。在考马斯染色的SDS-PAGE中,可以在115kDa处检测到轻微的条带(图2,A2)。使用MALDI-TOF MS,蛋白质被鉴定为DAGLA(UNIPROT acc.#Q5YLM1)。作为正确抗原鉴定的证据,使用针对DAGLA的抗体通过蛋白质印迹测试免疫沉淀物。如115kDa条带所示,患者的血清的免疫沉淀物包含DAGLA(图2,A3)。此外,使用表达DAGLA(SEQ ID NO 4)的经转染的HEK293细胞通过IFA测试患者的样品。患者的血清与表达DAGLA的细胞反应(图2B1)。与此相反,经模拟物转染的细胞未显示出任何特异性抗体结合(图2B2)。
通过与包含DAGLA(SEQ ID NO 4)的HEK293裂解物预孵育,可以消除患者自身抗体对组织的反应(图3A)。当使用来自经模拟物转染的HEK293细胞的相应级分时,抗体结合不受影响。
使用患者血清和特异性多克隆抗-DAGLA的抗体(Sigma-Aldrich,Germany)对大鼠和灵长类动物小脑组织进行的IIFT显示了分子层染色的精确重叠(图3B)。
抗-DAGLA自身抗体的特异性
来自51名健康对照和40名患有各种神经性自身抗体相关的神经系统综合征(3x抗-CASPR2、5x抗-NMDAR、5x抗-LGI1、5x抗-Hu、2x抗-Hu/抗-Ri 3x抗-Ri、2x抗-Yo/抗-Ri、3x抗-Yo、5x抗-AQP4、5x抗-GAD65、2x抗-GABAB受体)患者的血清与患者样品平行地用HEK293-DAGLA通过IFA进行分析。疾病对照或健康对照血清均未显示出与HEK293-DAGLA细胞的阳性反应。
用DAGLA片段检测自身抗体的免疫测定法
将96-孔平板(Nunc,Germany)用100μl在PBS中浓度为2.5μg/ml的重组蛋白在25℃下包被2小时,用洗涤缓冲液(在PBS中0.05%[wt/vol]吐温20)洗涤3次,然后用封闭缓冲液(在PBS中0.1%[wt/vol]的酪蛋白)封闭1小时。通过与1:2000稀释的鼠单克隆抗六组氨酸标签抗体(Sigma-Aldrich,Germany)孵育来证实抗原固定成功。将实验血清样品以1:100稀释在样品缓冲液(在PBS中1%[wt/vol]酪蛋白、0.05%[wt/vol]吐温20)中,并在室温下孵育30分钟。洗涤三次后,通过与在样品缓冲液中以1:16000稀释的抗小鼠IgG-HRP缀合物(Jackson Research,UK)或未稀释的抗人IgG-POD(Euroimmun,Germany)孵育30分钟,如上所述进行洗涤,并与四甲基联苯胺(TMB)底物(Euroimmun,Germany)孵育15分钟,检测结合的抗体。所有的孵育步骤在室温下进行。使用自动分光光度计(Tecan,Germany)读取450nm处的光密度(OD)。
在RC-IFA中与HEK293-DAGLA显示阳性反应的8名患者的血清和20名健康对照血清使用人DAGLA蛋白的六个不同片段(SEQ ID NO 13、14、15、16、21、22)通过ELISA进行分析(图4)。患者血清或对照血清均未显示与包括AA 1-22(SEQ ID NO 23)、44-60(SEQ ID NO24)、81-101(SEQ ID NO 25)和158-589(SEQ ID NO 27)的片段的阳性反应。7名患者血清显示与c-末端细胞内片段AA 583-1042(SEQ ID NO 28)有阳性反应,而所有的对照血清均为阴性。另有两名患者血清显示与细胞外片段123-136(SEQ ID NO 26)有阳性反应,其在对照血清中未观察到。
序列表
<110> EUROIMMUN Medizinische Labordiagnostika AG
<120> 神经自身免疫性疾病的诊断
<130> 18PP110EP
<160> 28
<170> PatentIn version 3.5
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<212> DNA
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<223> 编码人DAGLA的cDNA
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atgcccggga tcgtggtgtt ccggcggcgc tggtctgtgg gcagtgatga cctcgtccta 60
ccagccatct tcctctttct cctgcatacc acctggtttg tgatcctgtc cgtggtgctc 120
ttcggcctgg tctataaccc gcacgaggcc tgctccctga acctggtgga ccacggccgc 180
ggctacctgg gcatcctgct gagctgcatg atcgctgaga tggccatcat ctggctgagc 240
atgcgcgggg gcatcctcta cacggagccc cgtgactcca tgcagtacgt gctctacgtg 300
cgcctggcca tcctggtgat cgagttcatc tacgccatcg tgggcatcgt ctggctcact 360
cagtactaca cctcctgcaa cgacctcact gccaagaatg tcaccctcgg aatggttgtc 420
tgcaactggg tagtcatcct cagtgtgtgc atcactgtcc tctgcgtctt cgaccccacg 480
ggccgcacct ttgtcaagct gagagccacc aagaggaggc agcgtaacct gcggacctac 540
aacctgcggc accgcttaga ggagggtcaa gccaccagct ggtcgcgccg gctcaaagtg 600
ttcctctgct gcacgcggac gaaggactcc cagtcagatg cctactcaga aatcgcctac 660
ctctttgcgg agttcttccg ggaccttgac attgtgccat ccgacatcat tgctggcctg 720
gtgctgctcc ggcagcggca gcgggccaag cgcaacgccg tgctggacga ggcaaacaat 780
gacatcttgg ccttcctgtc tgggatgccg gtgaccagaa acaccaagta cctcgacctc 840
aagaattcac aagagatgct ccgctacaaa gaggtctgct actacatgct ctttgccctg 900
gctgcctacg ggtggcccat gtacctgatg cggaagcccg cctgcggcct ctgccaactg 960
gctcggtcct gctcgtgttg cctgtgtcct gcgaggccgc ggttcgcccc tggagtcacc 1020
atcgaggaag acaactgctg tggctgtaat gccattgcca tccggcgcca cttcctggac 1080
gagaacatga ctgcggtgga catcgtctat acctcctgcc atgatgcggt ctatgaaacg 1140
cccttctacg tggcggtgga ccatgacaag aagaaagtgg tgatcagtat ccgggggacc 1200
ctgtccccca aggatgccct gactgacctg acgggtgatg ctgagcgcct ccccgtggag 1260
gggcaccacg gcacctggct gggccacaag ggtatggtcc tctcagctga gtacatcaag 1320
aagaaactgg agcaggagat ggtcctgtcc caggcctttg ggcgagacct gggccgcgga 1380
accaaacact acggcctgat tgtggtgggc cactccctgg gcgcgggcac tgctgccatc 1440
ctctccttcc ttctgcgccc acagtatccg accctcaagt gctttgccta ctccccgcca 1500
gggggcctgc tgagtgagga tgcaatggag tattccaagg agttcgtgac tgctgtggtt 1560
ctgggcaaag acctcgtccc caggattggc ctctctcagc tggaaggctt ccgcagacag 1620
ctcctggatg tcctgcagcg aagcaccaag cccaaatggc ggatcatcgt gggggccacc 1680
aaatgcatcc ccaagtcgga gctgcctgag gaggtagagg tgaccaccct ggccagcacg 1740
cggctctgga cccaccccag cgacctaact atagccctct cagccagcac tccactctac 1800
ccgcccggcc gcatcatcca cgtggtccac aaccaccctg cagagcagtg ctgctgctgt 1860
gagcaggagg agcccacata ctttgccatc tggggcgaca acaaggcctt caatgaggtg 1920
atcatctcgc cagccatgct gcatgagcac ctgccctatg tggtcatgga ggggctcaac 1980
aaggtgctgg agaactacaa caaggggaag accgctctgc tctctgcagc caaggtcatg 2040
gtgagcccta ccgaggtgga cctgactcct gagctcatct tccagcagca gccactcccc 2100
acggggccgc ccatgcccac tggccttgcc ctggagctgc cgactgcaga ccaccgcaac 2160
agcagcgtca ggagcaagtc ccagtctgag atgagcctgg agggcttctc ggaggggcgg 2220
ctgctgtcgc cagtggttgc ggcggcggcc cgccaggacc cggtggagct gctgctgctg 2280
tctacccagg agcggctggc ggcggagctg caggcccggc gggcaccact ggccaccatg 2340
gagagcctct cggacactga gtccctgtac agcttcgact cgcgccgctc ctcaggcttc 2400
cgcagcatcc ggggctcccc cagcctccac gctgtgctgg agcgtgatga aggccacctc 2460
ttctacattg accctgccat ccccgaggaa aacccatccc tgagctcgcg cactgagctg 2520
ctggcggccg acagcctgtc caagcactca caggacacgc agcccctgga ggcggccctg 2580
ggcagtggcg gcgtcactcc tgagcggccc cccagtgctg cggccaatga cgaggaggaa 2640
gaggttggcg gtgggggtgg cgggccggcc tcccgcgggg agctggcgct gcacaatggg 2700
cgcctggggg actcgcccag tcctcaggtg ctggaattcg ccgagttcat cgacagcctc 2760
ttcaacctgg acagcaagag cagctccttc caagacctct actgcatggt ggtgcccgag 2820
agccccacca gtgactacgc tgagggcccc aagtccccca gccagcaaga gatcctgctc 2880
cgtgcccagt tcgagcccaa cctggtgccc aagcccccac ggctctttgc cggctcagcc 2940
gacccctcct cgggcatctc actctcgccc tccttcccgc tcagctcctc gggtgagctc 3000
atggacctga cgcccacggg cctcagtagc caggaatgcc tggcggctga caagatccgg 3060
acttctaccc ccactggcca cggagccagc cccgccaagc aagatgagct ggtcatctca 3120
gcacgctag 3129
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<213> 人工序列
<220>
<223> 用于扩增cDNA的有义DAGLA引物
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<223> 用于扩增cDNA的反义DAGLA-Stop引物
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atacgtctcc tcgagctagc gtgctgagat gaccagctc 39
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<213> 人工序列
<220>
<223> HEK293中表达的DAGLA
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Met Pro Gly Ile Val Val Phe Arg Arg Arg Trp Ser Val Gly Ser Asp
1 5 10 15
Asp Leu Val Leu Pro Ala Ile Phe Leu Phe Leu Leu His Thr Thr Trp
20 25 30
Phe Val Ile Leu Ser Val Val Leu Phe Gly Leu Val Tyr Asn Pro His
35 40 45
Glu Ala Cys Ser Leu Asn Leu Val Asp His Gly Arg Gly Tyr Leu Gly
50 55 60
Ile Leu Leu Ser Cys Met Ile Ala Glu Met Ala Ile Ile Trp Leu Ser
65 70 75 80
Met Arg Gly Gly Ile Leu Tyr Thr Glu Pro Arg Asp Ser Met Gln Tyr
85 90 95
Val Leu Tyr Val Arg Leu Ala Ile Leu Val Ile Glu Phe Ile Tyr Ala
100 105 110
Ile Val Gly Ile Val Trp Leu Thr Gln Tyr Tyr Thr Ser Cys Asn Asp
115 120 125
Leu Thr Ala Lys Asn Val Thr Leu Gly Met Val Val Cys Asn Trp Val
130 135 140
Val Ile Leu Ser Val Cys Ile Thr Val Leu Cys Val Phe Asp Pro Thr
145 150 155 160
Gly Arg Thr Phe Val Lys Leu Arg Ala Thr Lys Arg Arg Gln Arg Asn
165 170 175
Leu Arg Thr Tyr Asn Leu Arg His Arg Leu Glu Glu Gly Gln Ala Thr
180 185 190
Ser Trp Ser Arg Arg Leu Lys Val Phe Leu Cys Cys Thr Arg Thr Lys
195 200 205
Asp Ser Gln Ser Asp Ala Tyr Ser Glu Ile Ala Tyr Leu Phe Ala Glu
210 215 220
Phe Phe Arg Asp Leu Asp Ile Val Pro Ser Asp Ile Ile Ala Gly Leu
225 230 235 240
Val Leu Leu Arg Gln Arg Gln Arg Ala Lys Arg Asn Ala Val Leu Asp
245 250 255
Glu Ala Asn Asn Asp Ile Leu Ala Phe Leu Ser Gly Met Pro Val Thr
260 265 270
Arg Asn Thr Lys Tyr Leu Asp Leu Lys Asn Ser Gln Glu Met Leu Arg
275 280 285
Tyr Lys Glu Val Cys Tyr Tyr Met Leu Phe Ala Leu Ala Ala Tyr Gly
290 295 300
Trp Pro Met Tyr Leu Met Arg Lys Pro Ala Cys Gly Leu Cys Gln Leu
305 310 315 320
Ala Arg Ser Cys Ser Cys Cys Leu Cys Pro Ala Arg Pro Arg Phe Ala
325 330 335
Pro Gly Val Thr Ile Glu Glu Asp Asn Cys Cys Gly Cys Asn Ala Ile
340 345 350
Ala Ile Arg Arg His Phe Leu Asp Glu Asn Met Thr Ala Val Asp Ile
355 360 365
Val Tyr Thr Ser Cys His Asp Ala Val Tyr Glu Thr Pro Phe Tyr Val
370 375 380
Ala Val Asp His Asp Lys Lys Lys Val Val Ile Ser Ile Arg Gly Thr
385 390 395 400
Leu Ser Pro Lys Asp Ala Leu Thr Asp Leu Thr Gly Asp Ala Glu Arg
405 410 415
Leu Pro Val Glu Gly His His Gly Thr Trp Leu Gly His Lys Gly Met
420 425 430
Val Leu Ser Ala Glu Tyr Ile Lys Lys Lys Leu Glu Gln Glu Met Val
435 440 445
Leu Ser Gln Ala Phe Gly Arg Asp Leu Gly Arg Gly Thr Lys His Tyr
450 455 460
Gly Leu Ile Val Val Gly His Ser Leu Gly Ala Gly Thr Ala Ala Ile
465 470 475 480
Leu Ser Phe Leu Leu Arg Pro Gln Tyr Pro Thr Leu Lys Cys Phe Ala
485 490 495
Tyr Ser Pro Pro Gly Gly Leu Leu Ser Glu Asp Ala Met Glu Tyr Ser
500 505 510
Lys Glu Phe Val Thr Ala Val Val Leu Gly Lys Asp Leu Val Pro Arg
515 520 525
Ile Gly Leu Ser Gln Leu Glu Gly Phe Arg Arg Gln Leu Leu Asp Val
530 535 540
Leu Gln Arg Ser Thr Lys Pro Lys Trp Arg Ile Ile Val Gly Ala Thr
545 550 555 560
Lys Cys Ile Pro Lys Ser Glu Leu Pro Glu Glu Val Glu Val Thr Thr
565 570 575
Leu Ala Ser Thr Arg Leu Trp Thr His Pro Ser Asp Leu Thr Ile Ala
580 585 590
Leu Ser Ala Ser Thr Pro Leu Tyr Pro Pro Gly Arg Ile Ile His Val
595 600 605
Val His Asn His Pro Ala Glu Gln Cys Cys Cys Cys Glu Gln Glu Glu
610 615 620
Pro Thr Tyr Phe Ala Ile Trp Gly Asp Asn Lys Ala Phe Asn Glu Val
625 630 635 640
Ile Ile Ser Pro Ala Met Leu His Glu His Leu Pro Tyr Val Val Met
645 650 655
Glu Gly Leu Asn Lys Val Leu Glu Asn Tyr Asn Lys Gly Lys Thr Ala
660 665 670
Leu Leu Ser Ala Ala Lys Val Met Val Ser Pro Thr Glu Val Asp Leu
675 680 685
Thr Pro Glu Leu Ile Phe Gln Gln Gln Pro Leu Pro Thr Gly Pro Pro
690 695 700
Met Pro Thr Gly Leu Ala Leu Glu Leu Pro Thr Ala Asp His Arg Asn
705 710 715 720
Ser Ser Val Arg Ser Lys Ser Gln Ser Glu Met Ser Leu Glu Gly Phe
725 730 735
Ser Glu Gly Arg Leu Leu Ser Pro Val Val Ala Ala Ala Ala Arg Gln
740 745 750
Asp Pro Val Glu Leu Leu Leu Leu Ser Thr Gln Glu Arg Leu Ala Ala
755 760 765
Glu Leu Gln Ala Arg Arg Ala Pro Leu Ala Thr Met Glu Ser Leu Ser
770 775 780
Asp Thr Glu Ser Leu Tyr Ser Phe Asp Ser Arg Arg Ser Ser Gly Phe
785 790 795 800
Arg Ser Ile Arg Gly Ser Pro Ser Leu His Ala Val Leu Glu Arg Asp
805 810 815
Glu Gly His Leu Phe Tyr Ile Asp Pro Ala Ile Pro Glu Glu Asn Pro
820 825 830
Ser Leu Ser Ser Arg Thr Glu Leu Leu Ala Ala Asp Ser Leu Ser Lys
835 840 845
His Ser Gln Asp Thr Gln Pro Leu Glu Ala Ala Leu Gly Ser Gly Gly
850 855 860
Val Thr Pro Glu Arg Pro Pro Ser Ala Ala Ala Asn Asp Glu Glu Glu
865 870 875 880
Glu Val Gly Gly Gly Gly Gly Gly Pro Ala Ser Arg Gly Glu Leu Ala
885 890 895
Leu His Asn Gly Arg Leu Gly Asp Ser Pro Ser Pro Gln Val Leu Glu
900 905 910
Phe Ala Glu Phe Ile Asp Ser Leu Phe Asn Leu Asp Ser Lys Ser Ser
915 920 925
Ser Phe Gln Asp Leu Tyr Cys Met Val Val Pro Glu Ser Pro Thr Ser
930 935 940
Asp Tyr Ala Glu Gly Pro Lys Ser Pro Ser Gln Gln Glu Ile Leu Leu
945 950 955 960
Arg Ala Gln Phe Glu Pro Asn Leu Val Pro Lys Pro Pro Arg Leu Phe
965 970 975
Ala Gly Ser Ala Asp Pro Ser Ser Gly Ile Ser Leu Ser Pro Ser Phe
980 985 990
Pro Leu Ser Ser Ser Gly Glu Leu Met Asp Leu Thr Pro Thr Gly Leu
995 1000 1005
Ser Ser Gln Glu Cys Leu Ala Ala Asp Lys Ile Arg Thr Ser Thr
1010 1015 1020
Pro Thr Gly His Gly Ala Ser Pro Ala Lys Gln Asp Glu Leu Val
1025 1030 1035
Ile Ser Ala Arg
1040
<210> 5
<211> 73
<212> DNA
<213> 人工序列
<220>
<223> 用于扩增DAGLA片段的有义DAGLA[1-22]引物
<400> 5
catgcccggg atcgtggtgt tccggcggcg ctggtctgtg ggcagtgatg acctcgtcct 60
accagcctaa tga 73
<210> 6
<211> 73
<212> DNA
<213> 人工序列
<220>
<223> 用于扩增DAGLA片段的反义DAGLA[1-22]引物
<400> 6
tcgatcatta ggctggtagg acgaggtcat cactgcccac agaccagcgc cgccggaaca 60
ccacgatccc ggg 73
<210> 7
<211> 61
<212> DNA
<213> 人工序列
<220>
<223> 用于扩增DAGLA片段的有义DAGLA[44-60]引物
<400> 7
catggtctat aacccgcacg aggcctgctc cctgaacctg gtggaccacg gccgctaatg 60
a 61
<210> 8
<211> 61
<212> DNA
<213> 人工序列
<220>
<223> 用于扩增DAGLA片段的反义DAGLA[44-60]引物
<400> 8
tcgatcatta gcggccgtgg tccaccaggt tcagggagca ggcctcgtgc gggttataga 60
c 61
<210> 9
<211> 70
<212> DNA
<213> 人工序列
<220>
<223> 用于扩增DAGLA片段的有义DAGLA[81-101]引物
<400> 9
catgcgcggg ggcatcctct acacggagcc ccgtgactcc atgcagtacg tgctctacgt 60
gcgctaatga 70
<210> 10
<211> 70
<212> DNA
<213> 人工序列
<220>
<223> 用于扩增DAGLA片段的反义DAGLA[81-101]引物
<400> 10
tcgatcatta gcgcacgtag agcacgtact gcatggagtc acggggctcc gtgtagagga 60
tgcccccgcg 70
<210> 11
<211> 52
<212> DNA
<213> 人工序列
<220>
<223> 用于扩增DAGLA片段的有义DAGLA[123-136]引物
<400> 11
catgtacacc tcctgcaacg acctcactgc caagaatgtc accctctaat ga 52
<210> 12
<211> 52
<212> DNA
<213> 人工序列
<220>
<223> 用于扩增DAGLA片段的反义DAGLA[123-136]引物
<400> 12
tcgatcatta gagggtgaca ttcttggcag tgaggtcgtt gcaggaggtg ta 52
<210> 13
<211> 259
<212> PRT
<213> 人工序列
<220>
<223> H8-GST-DAGLA[1-22]
<400> 13
Met Ser His His His His His His His His Met Ser Pro Ile Leu Gly
1 5 10 15
Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro Thr Arg Leu Leu Leu Glu
20 25 30
Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu Tyr Glu Arg Asp Glu Gly
35 40 45
Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu Gly Leu Glu Phe Pro Asn
50 55 60
Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys Leu Thr Gln Ser Met Ala
65 70 75 80
Ile Ile Arg Tyr Ile Ala Asp Lys His Asn Met Leu Gly Gly Cys Pro
85 90 95
Lys Glu Arg Ala Glu Ile Ser Met Leu Glu Gly Ala Val Leu Asp Ile
100 105 110
Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser Lys Asp Phe Glu Thr Leu
115 120 125
Lys Val Asp Phe Leu Ser Lys Leu Pro Glu Met Leu Lys Met Phe Glu
130 135 140
Asp Arg Leu Cys His Lys Thr Tyr Leu Asn Gly Asp His Val Thr His
145 150 155 160
Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp Val Val Leu Tyr Met Asp
165 170 175
Pro Met Cys Leu Asp Ala Phe Pro Lys Leu Val Cys Phe Lys Lys Arg
180 185 190
Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr Leu Lys Ser Ser Lys Tyr
195 200 205
Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala Thr Phe Gly Gly Gly Asp
210 215 220
His Pro Pro Lys Leu Glu Val Leu Phe Gln Gly Pro Ala Met Pro Gly
225 230 235 240
Ile Val Val Phe Arg Arg Arg Trp Ser Val Gly Ser Asp Asp Leu Val
245 250 255
Leu Pro Ala
<210> 14
<211> 255
<212> PRT
<213> 人工序列
<220>
<223> H8-GST-DAGLA[44-60]
<400> 14
Met Ser His His His His His His His His Met Ser Pro Ile Leu Gly
1 5 10 15
Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro Thr Arg Leu Leu Leu Glu
20 25 30
Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu Tyr Glu Arg Asp Glu Gly
35 40 45
Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu Gly Leu Glu Phe Pro Asn
50 55 60
Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys Leu Thr Gln Ser Met Ala
65 70 75 80
Ile Ile Arg Tyr Ile Ala Asp Lys His Asn Met Leu Gly Gly Cys Pro
85 90 95
Lys Glu Arg Ala Glu Ile Ser Met Leu Glu Gly Ala Val Leu Asp Ile
100 105 110
Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser Lys Asp Phe Glu Thr Leu
115 120 125
Lys Val Asp Phe Leu Ser Lys Leu Pro Glu Met Leu Lys Met Phe Glu
130 135 140
Asp Arg Leu Cys His Lys Thr Tyr Leu Asn Gly Asp His Val Thr His
145 150 155 160
Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp Val Val Leu Tyr Met Asp
165 170 175
Pro Met Cys Leu Asp Ala Phe Pro Lys Leu Val Cys Phe Lys Lys Arg
180 185 190
Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr Leu Lys Ser Ser Lys Tyr
195 200 205
Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala Thr Phe Gly Gly Gly Asp
210 215 220
His Pro Pro Lys Leu Glu Val Leu Phe Gln Gly Pro Ala Met Val Tyr
225 230 235 240
Asn Pro His Glu Ala Cys Ser Leu Asn Leu Val Asp His Gly Arg
245 250 255
<210> 15
<211> 258
<212> PRT
<213> 人工序列
<220>
<223> H8-GST-DAGLA[81-101]
<400> 15
Met Ser His His His His His His His His Met Ser Pro Ile Leu Gly
1 5 10 15
Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro Thr Arg Leu Leu Leu Glu
20 25 30
Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu Tyr Glu Arg Asp Glu Gly
35 40 45
Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu Gly Leu Glu Phe Pro Asn
50 55 60
Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys Leu Thr Gln Ser Met Ala
65 70 75 80
Ile Ile Arg Tyr Ile Ala Asp Lys His Asn Met Leu Gly Gly Cys Pro
85 90 95
Lys Glu Arg Ala Glu Ile Ser Met Leu Glu Gly Ala Val Leu Asp Ile
100 105 110
Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser Lys Asp Phe Glu Thr Leu
115 120 125
Lys Val Asp Phe Leu Ser Lys Leu Pro Glu Met Leu Lys Met Phe Glu
130 135 140
Asp Arg Leu Cys His Lys Thr Tyr Leu Asn Gly Asp His Val Thr His
145 150 155 160
Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp Val Val Leu Tyr Met Asp
165 170 175
Pro Met Cys Leu Asp Ala Phe Pro Lys Leu Val Cys Phe Lys Lys Arg
180 185 190
Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr Leu Lys Ser Ser Lys Tyr
195 200 205
Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala Thr Phe Gly Gly Gly Asp
210 215 220
His Pro Pro Lys Leu Glu Val Leu Phe Gln Gly Pro Ala Met Arg Gly
225 230 235 240
Gly Ile Leu Tyr Thr Glu Pro Arg Asp Ser Met Gln Tyr Val Leu Tyr
245 250 255
Val Arg
<210> 16
<211> 252
<212> PRT
<213> 人工序列
<220>
<223> H8-GST-DAGLA[123-136]
<400> 16
Met Ser His His His His His His His His Met Ser Pro Ile Leu Gly
1 5 10 15
Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro Thr Arg Leu Leu Leu Glu
20 25 30
Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu Tyr Glu Arg Asp Glu Gly
35 40 45
Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu Gly Leu Glu Phe Pro Asn
50 55 60
Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys Leu Thr Gln Ser Met Ala
65 70 75 80
Ile Ile Arg Tyr Ile Ala Asp Lys His Asn Met Leu Gly Gly Cys Pro
85 90 95
Lys Glu Arg Ala Glu Ile Ser Met Leu Glu Gly Ala Val Leu Asp Ile
100 105 110
Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser Lys Asp Phe Glu Thr Leu
115 120 125
Lys Val Asp Phe Leu Ser Lys Leu Pro Glu Met Leu Lys Met Phe Glu
130 135 140
Asp Arg Leu Cys His Lys Thr Tyr Leu Asn Gly Asp His Val Thr His
145 150 155 160
Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp Val Val Leu Tyr Met Asp
165 170 175
Pro Met Cys Leu Asp Ala Phe Pro Lys Leu Val Cys Phe Lys Lys Arg
180 185 190
Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr Leu Lys Ser Ser Lys Tyr
195 200 205
Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala Thr Phe Gly Gly Gly Asp
210 215 220
His Pro Pro Lys Leu Glu Val Leu Phe Gln Gly Pro Ala Met Tyr Thr
225 230 235 240
Ser Cys Asn Asp Leu Thr Ala Lys Asn Val Thr Leu
245 250
<210> 17
<211> 41
<212> DNA
<213> 人工序列
<220>
<223> 有义DAGLA[158-598]
<400> 17
atacgtctcg catggacccc acgggccgca cctttgtcaa g 41
<210> 18
<211> 46
<212> DNA
<213> 人工序列
<220>
<223> 反义DAGLA[158-598]
<400> 18
tatcgtctcg tcgatcatta tggagtgctg gctgagaggg ctatag 46
<210> 19
<211> 43
<212> DNA
<213> 人工序列
<220>
<223> 有义DAGLA[583-1042]
<400> 19
atacgtctcg catgtggacc caccccagcg acctaactat agc 43
<210> 20
<211> 47
<212> DNA
<213> 人工序列
<220>
<223> 反义DAGLA[583-1042]
<400> 20
tatcgtctcg tcgatcatta gcgtgctgag atgaccagct catcttg 47
<210> 21
<211> 453
<212> PRT
<213> 人工序列
<220>
<223> H8-DAGLA[158-598]
<400> 21
Met Ser His His His His His His His His Ser Met Asp Pro Thr Gly
1 5 10 15
Arg Thr Phe Val Lys Leu Arg Ala Thr Lys Arg Arg Gln Arg Asn Leu
20 25 30
Arg Thr Tyr Asn Leu Arg His Arg Leu Glu Glu Gly Gln Ala Thr Ser
35 40 45
Trp Ser Arg Arg Leu Lys Val Phe Leu Cys Cys Thr Arg Thr Lys Asp
50 55 60
Ser Gln Ser Asp Ala Tyr Ser Glu Ile Ala Tyr Leu Phe Ala Glu Phe
65 70 75 80
Phe Arg Asp Leu Asp Ile Val Pro Ser Asp Ile Ile Ala Gly Leu Val
85 90 95
Leu Leu Arg Gln Arg Gln Arg Ala Lys Arg Asn Ala Val Leu Asp Glu
100 105 110
Ala Asn Asn Asp Ile Leu Ala Phe Leu Ser Gly Met Pro Val Thr Arg
115 120 125
Asn Thr Lys Tyr Leu Asp Leu Lys Asn Ser Gln Glu Met Leu Arg Tyr
130 135 140
Lys Glu Val Cys Tyr Tyr Met Leu Phe Ala Leu Ala Ala Tyr Gly Trp
145 150 155 160
Pro Met Tyr Leu Met Arg Lys Pro Ala Cys Gly Leu Cys Gln Leu Ala
165 170 175
Arg Ser Cys Ser Cys Cys Leu Cys Pro Ala Arg Pro Arg Phe Ala Pro
180 185 190
Gly Val Thr Ile Glu Glu Asp Asn Cys Cys Gly Cys Asn Ala Ile Ala
195 200 205
Ile Arg Arg His Phe Leu Asp Glu Asn Met Thr Ala Val Asp Ile Val
210 215 220
Tyr Thr Ser Cys His Asp Ala Val Tyr Glu Thr Pro Phe Tyr Val Ala
225 230 235 240
Val Asp His Asp Lys Lys Lys Val Val Ile Ser Ile Arg Gly Thr Leu
245 250 255
Ser Pro Lys Asp Ala Leu Thr Asp Leu Thr Gly Asp Ala Glu Arg Leu
260 265 270
Pro Val Glu Gly His His Gly Thr Trp Leu Gly His Lys Gly Met Val
275 280 285
Leu Ser Ala Glu Tyr Ile Lys Lys Lys Leu Glu Gln Glu Met Val Leu
290 295 300
Ser Gln Ala Phe Gly Arg Asp Leu Gly Arg Gly Thr Lys His Tyr Gly
305 310 315 320
Leu Ile Val Val Gly His Ser Leu Gly Ala Gly Thr Ala Ala Ile Leu
325 330 335
Ser Phe Leu Leu Arg Pro Gln Tyr Pro Thr Leu Lys Cys Phe Ala Tyr
340 345 350
Ser Pro Pro Gly Gly Leu Leu Ser Glu Asp Ala Met Glu Tyr Ser Lys
355 360 365
Glu Phe Val Thr Ala Val Val Leu Gly Lys Asp Leu Val Pro Arg Ile
370 375 380
Gly Leu Ser Gln Leu Glu Gly Phe Arg Arg Gln Leu Leu Asp Val Leu
385 390 395 400
Gln Arg Ser Thr Lys Pro Lys Trp Arg Ile Ile Val Gly Ala Thr Lys
405 410 415
Cys Ile Pro Lys Ser Glu Leu Pro Glu Glu Val Glu Val Thr Thr Leu
420 425 430
Ala Ser Thr Arg Leu Trp Thr His Pro Ser Asp Leu Thr Ile Ala Leu
435 440 445
Ser Ala Ser Thr Pro
450
<210> 22
<211> 472
<212> PRT
<213> 人工序列
<220>
<223> H8-DAGLA[583-1042]
<400> 22
Met Ser His His His His His His His His Ser Met Trp Thr His Pro
1 5 10 15
Ser Asp Leu Thr Ile Ala Leu Ser Ala Ser Thr Pro Leu Tyr Pro Pro
20 25 30
Gly Arg Ile Ile His Val Val His Asn His Pro Ala Glu Gln Cys Cys
35 40 45
Cys Cys Glu Gln Glu Glu Pro Thr Tyr Phe Ala Ile Trp Gly Asp Asn
50 55 60
Lys Ala Phe Asn Glu Val Ile Ile Ser Pro Ala Met Leu His Glu His
65 70 75 80
Leu Pro Tyr Val Val Met Glu Gly Leu Asn Lys Val Leu Glu Asn Tyr
85 90 95
Asn Lys Gly Lys Thr Ala Leu Leu Ser Ala Ala Lys Val Met Val Ser
100 105 110
Pro Thr Glu Val Asp Leu Thr Pro Glu Leu Ile Phe Gln Gln Gln Pro
115 120 125
Leu Pro Thr Gly Pro Pro Met Pro Thr Gly Leu Ala Leu Glu Leu Pro
130 135 140
Thr Ala Asp His Arg Asn Ser Ser Val Arg Ser Lys Ser Gln Ser Glu
145 150 155 160
Met Ser Leu Glu Gly Phe Ser Glu Gly Arg Leu Leu Ser Pro Val Val
165 170 175
Ala Ala Ala Ala Arg Gln Asp Pro Val Glu Leu Leu Leu Leu Ser Thr
180 185 190
Gln Glu Arg Leu Ala Ala Glu Leu Gln Ala Arg Arg Ala Pro Leu Ala
195 200 205
Thr Met Glu Ser Leu Ser Asp Thr Glu Ser Leu Tyr Ser Phe Asp Ser
210 215 220
Arg Arg Ser Ser Gly Phe Arg Ser Ile Arg Gly Ser Pro Ser Leu His
225 230 235 240
Ala Val Leu Glu Arg Asp Glu Gly His Leu Phe Tyr Ile Asp Pro Ala
245 250 255
Ile Pro Glu Glu Asn Pro Ser Leu Ser Ser Arg Thr Glu Leu Leu Ala
260 265 270
Ala Asp Ser Leu Ser Lys His Ser Gln Asp Thr Gln Pro Leu Glu Ala
275 280 285
Ala Leu Gly Ser Gly Gly Val Thr Pro Glu Arg Pro Pro Ser Ala Ala
290 295 300
Ala Asn Asp Glu Glu Glu Glu Val Gly Gly Gly Gly Gly Gly Pro Ala
305 310 315 320
Ser Arg Gly Glu Leu Ala Leu His Asn Gly Arg Leu Gly Asp Ser Pro
325 330 335
Ser Pro Gln Val Leu Glu Phe Ala Glu Phe Ile Asp Ser Leu Phe Asn
340 345 350
Leu Asp Ser Lys Ser Ser Ser Phe Gln Asp Leu Tyr Cys Met Val Val
355 360 365
Pro Glu Ser Pro Thr Ser Asp Tyr Ala Glu Gly Pro Lys Ser Pro Ser
370 375 380
Gln Gln Glu Ile Leu Leu Arg Ala Gln Phe Glu Pro Asn Leu Val Pro
385 390 395 400
Lys Pro Pro Arg Leu Phe Ala Gly Ser Ala Asp Pro Ser Ser Gly Ile
405 410 415
Ser Leu Ser Pro Ser Phe Pro Leu Ser Ser Ser Gly Glu Leu Met Asp
420 425 430
Leu Thr Pro Thr Gly Leu Ser Ser Gln Glu Cys Leu Ala Ala Asp Lys
435 440 445
Ile Arg Thr Ser Thr Pro Thr Gly His Gly Ala Ser Pro Ala Lys Gln
450 455 460
Asp Glu Leu Val Ile Ser Ala Arg
465 470
<210> 23
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> H8-GST-DAGLA[1-22]
<400> 23
Met Pro Gly Ile Val Val Phe Arg Arg Arg Trp Ser Val Gly Ser Asp
1 5 10 15
Asp Leu Val Leu Pro Ala
20
<210> 24
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> H8-GST-DAGLA[44-60]
<400> 24
Val Tyr Asn Pro His Glu Ala Cys Ser Leu Asn Leu Val Asp His Gly
1 5 10 15
Arg
<210> 25
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> H8-GST-DAGLA[81-101]
<400> 25
Met Arg Gly Gly Ile Leu Tyr Thr Glu Pro Arg Asp Ser Met Gln Tyr
1 5 10 15
Val Leu Tyr Val Arg
20
<210> 26
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> H8-GST-DAGLA[123-136], 与患者血清有反应性
<400> 26
Tyr Thr Ser Cys Asn Asp Leu Thr Ala Lys Asn Val Thr Leu
1 5 10
<210> 27
<211> 441
<212> PRT
<213> 人工序列
<220>
<223> DAGLA[158-598]
<400> 27
Thr Gly Arg Thr Phe Val Lys Leu Arg Ala Thr Lys Arg Arg Gln Arg
1 5 10 15
Asn Leu Arg Thr Tyr Asn Leu Arg His Arg Leu Glu Glu Gly Gln Ala
20 25 30
Thr Ser Trp Ser Arg Arg Leu Lys Val Phe Leu Cys Cys Thr Arg Thr
35 40 45
Lys Asp Ser Gln Ser Asp Ala Tyr Ser Glu Ile Ala Tyr Leu Phe Ala
50 55 60
Glu Phe Phe Arg Asp Leu Asp Ile Val Pro Ser Asp Ile Ile Ala Gly
65 70 75 80
Leu Val Leu Leu Arg Gln Arg Gln Arg Ala Lys Arg Asn Ala Val Leu
85 90 95
Asp Glu Ala Asn Asn Asp Ile Leu Ala Phe Leu Ser Gly Met Pro Val
100 105 110
Thr Arg Asn Thr Lys Tyr Leu Asp Leu Lys Asn Ser Gln Glu Met Leu
115 120 125
Arg Tyr Lys Glu Val Cys Tyr Tyr Met Leu Phe Ala Leu Ala Ala Tyr
130 135 140
Gly Trp Pro Met Tyr Leu Met Arg Lys Pro Ala Cys Gly Leu Cys Gln
145 150 155 160
Leu Ala Arg Ser Cys Ser Cys Cys Leu Cys Pro Ala Arg Pro Arg Phe
165 170 175
Ala Pro Gly Val Thr Ile Glu Glu Asp Asn Cys Cys Gly Cys Asn Ala
180 185 190
Ile Ala Ile Arg Arg His Phe Leu Asp Glu Asn Met Thr Ala Val Asp
195 200 205
Ile Val Tyr Thr Ser Cys His Asp Ala Val Tyr Glu Thr Pro Phe Tyr
210 215 220
Val Ala Val Asp His Asp Lys Lys Lys Val Val Ile Ser Ile Arg Gly
225 230 235 240
Thr Leu Ser Pro Lys Asp Ala Leu Thr Asp Leu Thr Gly Asp Ala Glu
245 250 255
Arg Leu Pro Val Glu Gly His His Gly Thr Trp Leu Gly His Lys Gly
260 265 270
Met Val Leu Ser Ala Glu Tyr Ile Lys Lys Lys Leu Glu Gln Glu Met
275 280 285
Val Leu Ser Gln Ala Phe Gly Arg Asp Leu Gly Arg Gly Thr Lys His
290 295 300
Tyr Gly Leu Ile Val Val Gly His Ser Leu Gly Ala Gly Thr Ala Ala
305 310 315 320
Ile Leu Ser Phe Leu Leu Arg Pro Gln Tyr Pro Thr Leu Lys Cys Phe
325 330 335
Ala Tyr Ser Pro Pro Gly Gly Leu Leu Ser Glu Asp Ala Met Glu Tyr
340 345 350
Ser Lys Glu Phe Val Thr Ala Val Val Leu Gly Lys Asp Leu Val Pro
355 360 365
Arg Ile Gly Leu Ser Gln Leu Glu Gly Phe Arg Arg Gln Leu Leu Asp
370 375 380
Val Leu Gln Arg Ser Thr Lys Pro Lys Trp Arg Ile Ile Val Gly Ala
385 390 395 400
Thr Lys Cys Ile Pro Lys Ser Glu Leu Pro Glu Glu Val Glu Val Thr
405 410 415
Thr Leu Ala Ser Thr Arg Leu Trp Thr His Pro Ser Asp Leu Thr Ile
420 425 430
Ala Leu Ser Ala Ser Thr Pro Pro Asp
435 440
<210> 28
<211> 460
<212> PRT
<213> 人工序列
<220>
<223> DAGLA[583-1042], 与患者血清有反应性
<400> 28
Trp Thr His Pro Ser Asp Leu Thr Ile Ala Leu Ser Ala Ser Thr Pro
1 5 10 15
Leu Tyr Pro Pro Gly Arg Ile Ile His Val Val His Asn His Pro Ala
20 25 30
Glu Gln Cys Cys Cys Cys Glu Gln Glu Glu Pro Thr Tyr Phe Ala Ile
35 40 45
Trp Gly Asp Asn Lys Ala Phe Asn Glu Val Ile Ile Ser Pro Ala Met
50 55 60
Leu His Glu His Leu Pro Tyr Val Val Met Glu Gly Leu Asn Lys Val
65 70 75 80
Leu Glu Asn Tyr Asn Lys Gly Lys Thr Ala Leu Leu Ser Ala Ala Lys
85 90 95
Val Met Val Ser Pro Thr Glu Val Asp Leu Thr Pro Glu Leu Ile Phe
100 105 110
Gln Gln Gln Pro Leu Pro Thr Gly Pro Pro Met Pro Thr Gly Leu Ala
115 120 125
Leu Glu Leu Pro Thr Ala Asp His Arg Asn Ser Ser Val Arg Ser Lys
130 135 140
Ser Gln Ser Glu Met Ser Leu Glu Gly Phe Ser Glu Gly Arg Leu Leu
145 150 155 160
Ser Pro Val Val Ala Ala Ala Ala Arg Gln Asp Pro Val Glu Leu Leu
165 170 175
Leu Leu Ser Thr Gln Glu Arg Leu Ala Ala Glu Leu Gln Ala Arg Arg
180 185 190
Ala Pro Leu Ala Thr Met Glu Ser Leu Ser Asp Thr Glu Ser Leu Tyr
195 200 205
Ser Phe Asp Ser Arg Arg Ser Ser Gly Phe Arg Ser Ile Arg Gly Ser
210 215 220
Pro Ser Leu His Ala Val Leu Glu Arg Asp Glu Gly His Leu Phe Tyr
225 230 235 240
Ile Asp Pro Ala Ile Pro Glu Glu Asn Pro Ser Leu Ser Ser Arg Thr
245 250 255
Glu Leu Leu Ala Ala Asp Ser Leu Ser Lys His Ser Gln Asp Thr Gln
260 265 270
Pro Leu Glu Ala Ala Leu Gly Ser Gly Gly Val Thr Pro Glu Arg Pro
275 280 285
Pro Ser Ala Ala Ala Asn Asp Glu Glu Glu Glu Val Gly Gly Gly Gly
290 295 300
Gly Gly Pro Ala Ser Arg Gly Glu Leu Ala Leu His Asn Gly Arg Leu
305 310 315 320
Gly Asp Ser Pro Ser Pro Gln Val Leu Glu Phe Ala Glu Phe Ile Asp
325 330 335
Ser Leu Phe Asn Leu Asp Ser Lys Ser Ser Ser Phe Gln Asp Leu Tyr
340 345 350
Cys Met Val Val Pro Glu Ser Pro Thr Ser Asp Tyr Ala Glu Gly Pro
355 360 365
Lys Ser Pro Ser Gln Gln Glu Ile Leu Leu Arg Ala Gln Phe Glu Pro
370 375 380
Asn Leu Val Pro Lys Pro Pro Arg Leu Phe Ala Gly Ser Ala Asp Pro
385 390 395 400
Ser Ser Gly Ile Ser Leu Ser Pro Ser Phe Pro Leu Ser Ser Ser Gly
405 410 415
Glu Leu Met Asp Leu Thr Pro Thr Gly Leu Ser Ser Gln Glu Cys Leu
420 425 430
Ala Ala Asp Lys Ile Arg Thr Ser Thr Pro Thr Gly His Gly Ala Ser
435 440 445
Pro Ala Lys Gln Asp Glu Leu Val Ile Ser Ala Arg
450 455 460
Claims (15)
1.一种诊断疾病的方法,其包括在来自患者的样品中检测与DAGLA结合的自身抗体的步骤。
2.包含DAGLA或其变体的固定化多肽。
3.包含DAGLA或其变体的多肽用于疾病诊断的用途,优选包括在样品中检测与DAGLA结合的自身抗体的步骤。
4.包含DAGLA或其变体的多肽用于疾病治疗。
5.经分离的针对DAGLA的自身抗体。
6.根据权利要求5所述的自身抗体在疾病诊断中的用途。
7.一种分离与DAGLA结合的自身抗体的方法,包括步骤
a)在与复合物形成相容的条件下将含有所述自身抗体的样品与包含DAGLA或其变体的多肽接触,其中所述自身抗体与所述多肽结合,
b)分离在步骤a)中形成的复合物,
c1)检测在步骤a)形成的复合物或c2)解离在步骤b)中分离的复合物并将所述自身抗体与述多肽分离。
8.药物组合物,其含有包含DAGLA或其变体的多肽。
9.医疗装置,优选诊断装置,其包括包含DAGLA或其变体的多肽。
10.用于疾病诊断的试剂盒,所述试剂盒包括包含DAGLA或其变体的多肽或包括包含DAGLA或其变体的多肽的医疗装置,
其中所述试剂盒优选另外包括用于检测包含所述多肽和与DAGLA结合的抗体,优选与DAGLA结合的自身抗体的复合物的工具,
其中所述试剂盒优选还包括包含DAGLA或其变体的阳性对照。
11.含有DAGLA或其变体的多肽或结合DAGLA的自身抗体或包括含有DAGLA或其变体的多肽的医疗装置在制备用于疾病诊断的试剂盒或医疗装置,优选诊断装置中的用途。
12.根据权利要求1、3、4、6、10和11中任一项所述的方法、多肽、用途、自身抗体、药物组合物、医疗装置或试剂盒,
其中所述疾病为PNS、小脑炎、癫痫、硬化和肿瘤。
13.根据权利要求1、3、7和12中任一项所述的方法或用途,其中所述样品为包含抗体的体液,其优选选自包括全血、血浆、血清、脑脊髓液和唾液的组。
14.根据权利要求1、3、6、7和10至13中任一项所述的方法、用途或试剂盒,其中使用选自下述的技术检测所述自身抗体或复合物:免疫扩散技术、免疫电泳技术、光散射免疫测定、凝集技术、标记免疫测定,例如选自下述的组中的那些:放射性标记的免疫测定、酶免疫测定(更优选为ELISA)、化学发光免疫测定(优选电化学发光免疫测定)和免疫荧光(优选间接免疫荧光)。
15.根据权利要求9至14中任一项所述的医疗装置或试剂盒,其中所述医疗装置选自玻璃载玻片(优选用于显微镜检查)、生物芯片、微量滴定板、侧向流动装置、测试条、膜(优选线印迹)、层析柱和珠(优选磁珠或荧光珠)。
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