CN114966059A - 一种新自身抗体抗Septin9抗体的检测及应用 - Google Patents
一种新自身抗体抗Septin9抗体的检测及应用 Download PDFInfo
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Abstract
本发明提供了一种新自身抗体抗Septin9抗体的检测及应用，涉及生物医药技术领域。本发明提供了一种检测抗Septin9自身抗体的试剂在制备诊断和/或治疗神经系统自身免疫疾病的工具中的应用，以从患有神经系统疾病的患者血清中发现的新的Septin9自身抗体，并以Septin9自身抗体作为神经系统自身免疫疾病相关的靶向分子标志物，抗Septin9抗体是神经系统自身免疫疾病的一个新的自身抗体。通过检测该自身抗体，为神经系统自身免疫疾病的诊断和治疗提供依据，并且可通过检测该自身抗体的滴度变化监测患者病情程度和治疗效果。
Description
技术领域
本发明属于生物医药技术领域，具体涉及一种新自身抗体抗Septin9抗体的检测及应用。
背景技术
神经系统自身免疫性疾病是神经病学领域中的一大类重要疾病。神经系统自身抗体是介导神经系统免疫疾病的重要分子。神经系统自身抗体是最为复杂的抗体系统，根据其靶抗原的分布部位，神经系统自身抗体大致分为周围神经系统抗体和中枢神经系统抗体；按照靶抗原在神经细胞内的定位，又可分为抗神经元胞内抗原抗体和神经元表面抗原抗体，其中amphiphysin、Ma2、Ri、Yo、Hu、CV2、GAD等分布于神经元胞内，多与神经系统副肿瘤疾病相关，而NMDAR、Gly、mGluR、LGI1、Caspr2、GABA、AMPA等神经元表面抗原抗体则常诱发自身免疫性脑炎。
神经系统自身免疫性疾病可发生在中枢神经系统、周围神经系统以及神经-肌肉接头处。神经系统自身抗体种类繁多，NMDAR、AMPA1/2R、GABABR、LGI1、CASPR2、DPPX、IgLON5、GlyR、mGluR1、mGluR5、Dopamine(D2)等自身免疫性脑炎(AE)相关抗体，AQP4、MOG、MBP等视神经脊髓炎谱系病相关抗体，GAD、Amphiphysin、GlyR等僵人综合征(SPS)相关抗体，GM1、GM2、GM3、GD1a、GD1b、GT1b、GQ1b免疫介导的周围神经病相关抗体，AchR、骨骼肌Musk、Titin、SOX-1(AGAN)、VGCC等免疫介导的神经肌肉接头病相关抗体均为常见的神经系统自身免疫性疾病。
神经系统自身抗体致病机理复杂，引起的临床表现各不相同。随着科技进步，人们对神经系统自身抗体认知不断加深，越来越多的神经系统自身抗体被发现。由于神经系统疾病的复杂性，很少与独特的临床表征相关联，所以很难仅仅通过对患者的观察或检查做出准确的诊断。神经系统自身免疫疾病抗体纷繁复杂，一种抗体又可能介导了不同部位的神经损害表现，如Hu抗体与副肿瘤性脑脊髓炎、边缘叶脑炎、感觉神经元病和亚急性小脑变性等多种神经功能障碍有关，使临床表现呈现多水平、多病灶、且易于重叠的复杂特点。有些抗体具有明显的致病性，有些抗体参与疾病的发生与发展，为疾病的诊断提供依据，辅助分型和预后判断。因此，神经系统自身抗体的检测对疾病的机制研究、诊断和治疗以及预后判断具有非常重要的意义。
发明内容
有鉴于此，本发明的目的在于提供一种新自身抗体抗Septin9抗体的检测及应用，尤其提供抗Septin9自身抗体的试剂在制备诊断和/或治疗神经系统自身免疫疾病的试剂盒中的应用，本发明提供的新的自身抗体，用于神经系统自身免疫性疾病的诊断，抗Septin9自身抗体的试剂能够实现神经系统自身免疫疾病的高效诊断和/或治疗。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了一种检测抗Septin9自身抗体的试剂在制备诊断和/或治疗神经系统自身免疫疾病的工具中的应用。
优选的，所述抗Septin9自身抗体的试剂包括Septin9蛋白，或能够表达所述Septin9蛋白的载体或细胞，或含所述Septin9蛋白的组织。
优选的，所述Septin9蛋白的氨基酸序列包括SEQ ID NO.1所示的氨基酸序列，或对SEQ ID NO.1所示的氨基酸序列进行改造和/或修饰后的序列。
优选的，所述改造包括：对SEQ ID NO.1所示的氨基酸序列经过替换、添加或缺失一个或几个氨基酸且具有与Septin9自身抗体结合功能的多肽或衍生的蛋白质，或对SEQID NO.1所示氨基酸序列上经修饰后且具有与Septin9自身抗体结合功能的蛋白质，或对SEQ ID NO.1所示氨基酸序列上经剪切后获得的具有与Septin9自身抗体结合功能的剪切变体；
所述修饰包括磷酸化修饰、糖基化修饰、乙酰化修饰或泛素化修饰。
优选的，所述Septin9蛋白包括利用表达系统表达得到的重组蛋白，或过表达细胞裂解物，或哺乳动物组织。
优选的，所述表达系统包括：原核表达系统、真核表达系统或昆虫表达系统。
优选的，所述检测抗Septin9自身抗体的方法包括：CBA、TBA、ELISA、免疫胶体金法、免疫印迹、免疫斑点、膜条法、化学发光、放射免疫法、液相芯片法、侧向层析和流式细胞中的至少一种。
本发明还提供了一种检测Septin9自身抗体的试剂盒，所述试剂盒包括抗Septin9自身抗体的试剂。
优选的，所述试剂盒还包括反应缓冲液、阳性对照、阴性对照、样品稀释液和标记的抗体；
所述标记的抗体经荧光基团、碱性磷酸酶标记基团、辣根过氧化酶、胶体金、生物素或放射性同位素标记。
本发明还提供了一种神经系统自身免疫疾病的诊断试剂盒，所述试剂盒包括用于检测Septin9自身抗体的固化的多肽；
所述固化的多肽的介质包括玻片、免疫磁珠、免疫孔板、硝酸纤维素膜或芯片。
有益效果：本发明提供了一种检测抗Septin9自身抗体的试剂在制备诊断和/或治疗神经系统自身免疫疾病的工具中的应用，以从患有神经系统疾病的患者血清中发现的新的Septin9自身抗体，并以Septin9自身抗体作为神经系统自身免疫疾病相关的靶向分子标志物，抗Septin9抗体是神经系统自身免疫疾病的一个新的自身抗体。通过筛查多例其它神经系统疾病患者血清和健康受试者血清和脑脊液，发现健康受试者均为阴性结果，其它神经系统疾病患者有少数为该抗体阳性。通过检测该自身抗体，为神经系统自身免疫疾病的诊断和治疗提供依据，并且可通过检测该自身抗体的滴度变化监测患者病情程度和治疗效果。
附图说明
图1为患者血清和健康受试者血清在大鼠原代神经元细胞的免疫荧光结果；
图2为血清免疫沉淀结果，M：marker；1：健康受试者血清；2：患者血清；
图3为患者血清免疫沉淀物的WB鉴定结果，M：marker；1：患者血清免疫沉淀物；2：健康受试者血清免疫沉淀物；
图4为患者血清与Septin9抗体在原代神经元细胞上的免疫荧光结果；
图5为患者血清和健康受试者血清在猴脑组织的免疫组化染色结果；
图6为中和实验验证猴脑组织上Septin9信号；
图7为鼠脑原代细胞Septin9信号鉴定，(a)：免疫印迹结果；(b)：血清中和实验验证原代细胞Septin9信号；
图8为HEK293细胞的免疫荧光法检测抗Septin9自身抗体，(a)：过表达免疫荧光结果；(b)：抗体和血清共同免疫荧光染色结果；(c)：血清中和实验验证HEK293细胞Septin9信号；
图9为Western Blot验证过表达HEK293细胞Septin9信号；
图10为Septin9与BFRF3信号相互验证，(a)：BFRF3过表达免疫荧光信号；(b)：Western Blot验证过表达BFRF3信号；(c)：血清中和实验验证Septin9信号不受BFRF3影响。
具体实施方式
本发明提供了一种检测抗Septin9自身抗体的试剂在制备诊断和/或治疗神经系统自身免疫疾病的工具中的应用。
本发明提供抗Septin9抗体作为神经系统自身免疫疾病的一种新的自身抗体，该自身抗体为患者神经系统疾病的诊断提供依据。本发明所述抗Septin9自身抗体的试剂优选包括Septin9蛋白，或能够表达所述Septin9蛋白的载体或细胞，或含所述Septin9蛋白的组织。本发明所述Septin9蛋白的氨基酸序列包括SEQ ID NO.1所示的氨基酸序列，或对SEQID NO.1所示的氨基酸序列进行改造和/或修饰后的序列，在本发明中，SEQ ID NO.1所对应的核苷酸序列优选如SEQ ID NO.2所示，且基因登录号NM_001113491.2。本发明所述改造，优选包括：对SEQ ID NO.1所示的氨基酸序列经过替换、添加或缺失一个或几个氨基酸且具有与Septin9自身抗体结合功能的多肽或衍生的蛋白质，或对SEQ ID NO.1所示氨基酸序列上经修饰后且具有与Septin9自身抗体结合功能的蛋白质，或对SEQ ID NO.1所示氨基酸序列上经剪切后获得的具有与Septin9自身抗体结合功能的剪切变体。本发明优选还可以对所述Septin9蛋白或经过改造的具有与Septin9自身抗体结合功能的多肽或衍生的蛋白质进行一系列修饰，所述修饰优选包括磷酸化修饰、糖基化修饰、乙酰化修饰或泛素化修饰。
本发明对所述Septin9蛋白的来源并没有特殊限定，优选包括利用表达系统表达得到的重组蛋白，或过表达细胞裂解物，或哺乳动物组织。本发明所述表达系统优选包括：原核表达系统、真核表达系统或昆虫表达系统。在本发明中，所述真核表达系统所使用的真核细胞优选包括HEK293细胞、CHO、Cos7、Hela细胞、毕赤酵母或酿酒酵母；所述原核表达系统使用的原核表达菌优选包括BL21、BL21(DE3)、Rosetta、ArcticExpress(DE3)或OrigamiB。本发明所述哺乳动物组织优选包括脑组织。
本发明所述检测抗Septin9自身抗体的方法，优选包括：CBA、TBA、ELISA、免疫胶体金法、免疫印迹、免疫斑点、膜条法、化学发光、放射免疫法、液相芯片法、侧向层析和流式细胞中的至少一种。
在本发明中，存在与Septin9的自身抗体以及来自以下群组的症状相关的神经系统自身免疫疾病，所述症状包括胸闷头痛、身体疲惫、记忆力减退、麻木、睡眠障碍、反应迟缓、情绪低落等等。在本发明实施例中，发现患者体内存在Septin9自身抗体，而表现出上述症状，而健康受试者不存在该自身抗体，进一步表明Septin9自身抗体的存在可能破坏了Septin9及其调控的相关蛋白，对神经系统造成损害，从而引起相应的神经系统自身免疫疾病。
本发明还提供了一种检测Septin9自身抗体的试剂盒，所述试剂盒包括抗Septin9自身抗体的试剂。
本发明所述抗Septin9自身抗体的试剂优选与上述相同，在此不再赘述。本发明所述试剂盒优选还包括反应缓冲液、阳性对照、阴性对照、样品稀释液和标记的抗体；所述标记的抗体优选经荧光基团、碱性磷酸酶标记基团、辣根过氧化酶、胶体金、生物素或放射性同位素标记。本发明提供了一种神经系统自身免疫疾病的新的标志物靶点，即提供一种用于检测神经系统自身免疫疾病的新的自身抗体，本发明制备的试剂盒能够高效用于神经系统自身免疫疾病的诊断。
本发明还提供了一种神经系统自身免疫疾病的诊断试剂盒，所述试剂盒包括用于检测Septin9自身抗体的固化的多肽；
所述固化的多肽的介质包括玻片、免疫磁珠、免疫孔板、硝酸纤维素膜或芯片。
本发明所述抗体标记物，优选包括荧光基团、碱性磷酸酶标记基团、辣根过氧化酶、胶体金、生物素或放射性同位素。
本发明还提供了一种自身抗体的探究方法，该方法基于抗原抗体相互结合的基本原理，利用患者血清通过免疫沉淀方法捕获目标抗原抗体。在本发明的实施例中，优选从大鼠脑组织分离出原代细胞，分别用患者血清和健康人血清孵育原代细胞，通过荧光二抗放大信号，实现目标抗体初步发现的过程。本发明还利用哺乳动物优选大鼠和猴脑组织免疫组织化学法实现目标抗体进一步发现过程。本发明通过将患者血清和健康受试者血清与原代神经细胞孵育，通过荧光二抗放大信号，发现只与患者血清有信号而健康受试者血清没有信号的目标抗原，进而通过蛋白质谱分析和免疫印迹实验确定目标抗原。本发明通过血清中和实验验证哺乳动物脑组织和过表达HEK293细胞中目标抗原信号的真实性和特异性。
EB病毒与多发性硬化症(MS)密切相关，EB病毒激发免疫系统攻击人体自身的神经系统而引发了多发性硬化症。研究发现在EB病毒引起的多发性硬化症患者体内，识别EB病毒蛋白BFRF3的抗体，也可以识别哺乳动物神经系统Septin9蛋白，即EB病毒蛋白BFRF3的抗体与Septin9存在交叉反应。本发明进行研究时，患者均未感染EB病毒和其他病毒。本发明还通过CBA和血清中和实验验证了患者Septin9抗体和EB病毒蛋白BFRF3不存在交叉反应，本发明患者体内的Septin9抗体不是由EB病毒蛋白BFRF3与Septin9交叉反应引起的抗体。
下面结合实施例对本发明提供的一种新自身抗体抗Septin9抗体的检测及应用，进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。
本发明实施例中的患者血清均为医院赠予，已经经过本人同意。患者信息如下：
患者1：女，60岁，精神疲惫，记忆力减退，睡眠质量差，易怒易躁，伴随胸闷头痛，情绪低落，医生诊断为患有神经系统疾病。自免性脑炎6项(NMDAR、AMPAR1、AMPAR2、LGI1、CASPR2、GABABR)自身抗体IgG检测为阴性，副肿瘤14项(Ri，Hu，Yo，CV2，Ma2，Amphiphysin、Titin、Ma1、PKCγ、Recoverin、GAD65、Zic4、SOX1、Tr)自身抗体IgG检测均为阴性。EB病毒抗体检测(VCA-IgG、VCA-IgM、EA-IgM、NA-IgG)以及病毒DNA检测结果均为阴性。未感染乙型脑炎病毒、脊髓灰质炎病毒、人类免疫缺陷病毒等。
患者2：男，64岁，三年前出现肢体疼痛，麻木，反应迟缓，睡眠障碍等症状，自免性脑炎和副肿瘤自身抗体IgG检测均为阴性，EB病毒等其它病毒检测均为阴性。
本发明实施例中所使用患者血清均为患者1，经验证患者2的实验结果与患者1结果一致。
实施例1大鼠脑组织原代细胞的免疫荧光法筛出患者血清
1、用大鼠的胎鼠脑组织制备原代细胞，分离出原代神经元细胞。培养原代细胞时培养皿中放有玻片。
2、将培养两周的大鼠神经元细胞爬片用4％PFA固定10min，HEPES洗2遍，再用1.25M的甘氨酸终止10min，用HEPES洗2遍；
3、用患者血清和健康受试者血清(1：10稀释)孵育上述制备好的爬片1h；用HEPES洗2遍，每次5min；再用绿色荧光(FITC)标记的二抗羊抗人IgG孵育30min；HEPES洗2遍，每次5min；DAPI对细胞核进行染色；显微镜下观察结果。
患者和健康受试者血清在大鼠脑组织原代细胞的免疫荧光结果如图1所示，患者血清出现阳性信号，而健康受试者的血清未检出信号，提示患者血清可能存在某种健康受试者没有的抗体。
实施例2免疫沉淀法获得目标抗原
1、取6皿大鼠神经元细胞，弃上清，PBS洗2遍，0.4％多聚甲醛固定10min，1×HEPES洗3次；
2、血清孵育：分别取10μL患者血清和健康受试者血清加至10mL DMEM中(1:1000稀释)，使用0.22μm滤膜过滤后加入到固定好的细胞中，室温孵育2h；
3、取15μLproteinA(GE公司)加入到2mL管子中，平衡液洗3遍，用300μL4％BSA封闭2h；
4、将孵育好的细胞置于冰上，弃上清，PBS洗2遍，加入500μL裂解液(150mM NaCl，1mM EDTA，100mM Tris-HCl，0.5％脱氧胆酸钠，1％TritonX-100，0.1％SDS，pH7.5)，收集细胞，加入终浓度为1×的蛋白酶抑制剂，裂解30min，间隔震荡，15000rpm离心30min，取上清，测浓度；
5、将步骤4收集的上清加入到步骤3处理好的珠子中，4℃过夜旋转孵育；
6、用裂解液将所有孵育的珠子洗4次，用80μL 2×loading buffer洗脱；
7、样本处理：洗脱液中先加入5×SDS-PAGE loading buffer，再加入终浓度为0.01M的DTT，100℃加热10min，然后再加入终浓度为2％的碘乙酰胺，室温放置30min；
8、电泳：处理好的样品跑胶，使用考马斯亮蓝染色液染色。
血清免疫沉淀结果如图2所示，其中，M：marker；1：健康受试者血清；2：患者血清。在用患者血清获得的来自大鼠鼠脑原代细胞的免疫沉淀物中检出一种大约40～60KD的蛋白质(图2泳道2)，该蛋白质不存在于类似制备的对照中(图2泳道1)。
实施例3质谱法、免疫印迹法鉴定免疫沉淀复合物中包含的目的抗原为Septin9
步骤1.质谱法分析免疫沉淀复合物中包含有Septin9蛋白序列
从实施例2的步骤8的凝胶切下蛋白条带送去拜谱生物进行质谱法分析。
结果：靶抗原与患者1的血清首先进行免疫沉淀，然后通过SDS-PAGE电泳分离蛋白质，从凝胶上切下正常血清无而患者血清有的条带，进行质谱分析，所鉴定的蛋白质序列中包括Septin9序列。
步骤2.免疫印迹验证免疫沉淀复合物中包含的目的抗原为Septin9
电泳：取实施例2步骤7得到的样品进行SDS-PAGE；
转膜：电泳完成后，使用湿法转膜，转膜条件为200mA，90min；
封闭：使用5％的脱脂奶粉室温封闭1h；
一抗孵育：按照1:2000的比例孵育抗Septin9的多克隆抗体(抗体购自于Proteintech公司，后文称Septin9商业化抗体)，室温孵育2h；
洗涤：TBST洗3次，每次5min；
二抗孵育：加入HRP标记的二抗，室温孵育1h
洗涤TBST洗3次，每次5min；
显色：加入化学发光液，观察结果。
实验结果如图3所示，其中，M：marker；1：患者血清免疫沉淀物；2：健康受试者血清免疫沉淀物。用患者血清捕获到的免疫沉淀物中存在与Septin9抗体反应的条带，目的蛋白条带处于40～60KD之间，而健康受试者的免疫沉淀物中无条带出现，证明该患者体内存在与Septin9反应的抗体。
实施例4原代神经元细胞免疫荧光验证患者血清与Septin9抗体信号，以及Septin9在神经元中的定位
将患者血清(1：100稀释)孵育实施例1中制备好的神经元细胞爬片1h，设两组重复；HEPES洗2次，每次5min；绿色荧光(FITC)标记的二抗羊抗人IgG孵育30min；HEPES洗3次，每次5min；显微镜下观察结果。再分别用商业化Septin9抗体(1：200稀释)、神经元markerMAP2抗体孵育上述患者血清孵育过的爬片，HEPES洗2次，每次5min；红色荧光(AlexaFluor 594)标记的二抗羊抗兔IgG孵育30min；显微镜下观察结果。
结果见图4，患者血清与Septin9抗体信号重合，完全一致，进一步说明该患者体内存在Septin9抗体。患者血清信号与神经元marker共同染色结果显示Septin9表达于神经元。
实施例5猴脑组织的免疫组化及血清中和实验验证
步骤1猴脑组织免疫荧光染色
取制备好的猴脑组织片进行免疫组化染色，具体步骤如下：
一抗孵育：按照1:100的比例孵育患者血清，室温孵育1h；洗涤：PBST洗3次，每次5min；二抗孵育：加入荧光标记的二抗，室温孵育1h；洗涤：PBST洗3次，每次5min；显微镜下观察结果拍照。
猴脑组织免疫组化结果，由图5可以看出，与健康受试者血清染色结果相比，患者血清在猴脑组织上有明显的信号。
步骤2血清中和实验验证猴脑组织上的信号
1、中和蛋白的制备：收集过表达Septin9蛋白的HEK293细胞1皿(10cm皿)，对照细胞为转入空载pcDNA3.1的细胞，加入200μLPBS，超声破碎(破碎条件为：15％功率，破3s，停6s，共超声3次)，得到的样品即为Septin9中和蛋白和对照蛋白；
2、中和实验：
按照1：100的比例用PBST稀释患者血清，稀释好的血清中分别加入20μL Septin9中和蛋白及对照蛋白，室温孵育10min；一抗孵育：将上述孵育好的样本加至猴脑组织爬片上，室温孵育1h；PBST洗3次，每次5min；二抗孵育：加入FITC标记的二抗，室温孵育1h；洗涤：PBST洗3次，每次5min，显微镜下观察结果。
商业化Septin9抗体中和实验同患者血清中和实验，按照1：200的比例用PBST稀释商业化Septin9抗体，二抗选用红色荧光Alexa Fluor 594标记。
猴脑组织上表达的抗Septin9抗原的特异性信号如图6所示，Septin9中和蛋白明显的封闭了该患者血清在猴脑组织上出现的信号，而对照蛋白未封闭住组织上出现的信号(图6中(a))；同样的Septin9中和蛋白也封闭了商业化抗体在猴脑组织上的信号(图6中(b))。
实施例6免疫印迹以及血清中和实验验证大鼠神经元细胞Septin9抗原
步骤1原代神经元细胞免疫印记迹
1、取一皿大鼠神经元细胞，弃上清，PBS洗2遍，加入500μL裂解液(150mM NaCl，1mMEDTA，100mM Tris-HCl，0.5％脱氧胆酸钠，1％TritonX-100，0.1％SDS，pH7.5)，收集细胞，加入终浓度为1×的蛋白酶抑制剂，裂解30min，间隔震荡，15000rpm离心30min，取上清，测浓度；
2、电泳：取上一步得到的样品进行SDS-PAGE电泳；
3、转膜：电泳完成后，使用湿法转膜，转膜条件为200mA，90min；
4、封闭：使用5％的脱脂奶粉室温封闭1h；
一抗孵育：按照1:2000的比例孵育商业化Septin9抗体(抗体购自于Proteintech公司)，患者血清1:500稀释，室温孵育2h；
5、洗涤：TBST洗3次，每次5min；
6、二抗孵育：加入HRP标记的二抗，室温孵育1h；
7、洗涤TBST洗3次，每次5min；
显色：加入化学发光液，观察结果。
步骤2神经元细胞免疫印记迹血清中和实验
中和实验与步骤1不同之处在于第4步一抗孵育，患者血清分别用Septin9中和蛋白和对照蛋白封闭，中和蛋白和对照蛋白制备方法同实施例5步骤2。
实验结果如图7所示，在鼠脑原代神经元细胞中，Septin9商业化抗体和患者血清均可以检出Septin9抗原信号(图7中(a))。血清中和实验验证了信号的真实性，患者血清经过Septin9中和蛋白封闭后，信号消失，而对照蛋白封闭后信号依然存在，表明实验中Septin9信号真实(图7中(b))，鼠脑原代细胞中存在与Septin9抗体结合的Septin9蛋白。
实施例7 HEK293细胞的免疫荧光法检测抗Septin9自身抗体
1、重组载体的构建
将Septin9基因通过分子克隆方法连至pcDNA3.1上，得到重组载体pcDNA3.1-Septin9，构建好的重组载体经测序正确后大提备用；
2、细胞转染
(1)293T细胞培养：DMEM高糖培养基与FBS按9:1比例配制成10％FBS-DMEM高糖培养基，待细胞铺满时按1:5～1:6传代，传代的培养皿中放有玻片，置于37℃，5％CO2的细胞培养箱中过夜培养；
(2)待细胞密度为30％～40％时，将pcDNA3.1-Septin9和对照质粒pcDNA3.1转入细胞中，置于37℃，5％CO2的细胞培养箱中培养；
3、爬片固定
(1)洗涤：将转染48h的细胞用PBS洗涤2次；
(2)固定：加入丙酮固定30min；
(3)洗涤：丙酮固定后的爬片用PBS洗涤2次，干燥后备用。
4、免疫荧光检测信号
分别用商业化Septin9抗体(1：200稀释)、患者血清(1：100稀释)、健康受试者(1：10稀释)孵育上述制备好的爬片1h；PBST洗3次，每次5min；荧光标记的二抗孵育30min；PBST洗3次，每次5min；显微镜下观察结果，结果见图8中(a)。
5、商业化Septin9抗体和患者血清共同免疫荧光染色：先用患者血清孵育固定好的爬片，做免疫荧光染色，再用抗体孵育患者血清孵育过的爬片，做免疫荧光染色，显微镜下观察结果，结果见图8中(b)。
6、血清中和实验验证HEK293细胞爬片上的信号
(1)按照1:100的比例用PBST稀释患者血清，稀释好的血清分别加入20μL Septin9中和蛋白及对照蛋白，室温孵育10min；
(2)一抗孵育：将上述孵育好的样本加至制备好的细胞爬片上，室温孵育1h；PBST洗涤3次，每次5min；
(3)二抗孵育：加入FITC标记的二抗，室温孵育1h；PBST洗涤3次，每次5min；显微镜下观察结果，结果见图8中(c)。
中和蛋白的制备同实施例5步骤2。
实验结果：由图8中(a)可以看出，与健康受试者血清染色结果相比，商业化Septin9抗体和患者血清在表达Septin9抗原的细胞爬片上有明显的信号。图8中(b)显示抗体信号和患者血清信号重叠，高度一致。图8中(c)显示过表达Septin9抗原的细胞爬片经过中和蛋白封闭的患者血清孵育后，信号明显降低，而经过对照蛋白封闭的患者血清依然有明显的信号，说明Septin9中和蛋白明显的封闭了该患者血清在细胞爬片上出现的信号，而对照蛋白未封闭住细胞爬片上出现的信号。实验结果表明患者血清中存在Septin9抗体。实验进一步验证了爬片信号的真实性和特异性，可用于Septin9自身抗体的检测。
实施例8免疫印迹验证HEK293细胞Septin9过表达信号
转染pcDNA3.1-Septin9和对照质粒pcDNA3.1至HEK293细胞，培养48h后收集细胞，超声破碎，离心，收集上清，作为Western Blot实验上样样品。具体步骤同中和蛋白制备方法。
免疫印迹实验同实施例3步骤2。一抗孵育：分别孵育商业化Septin9抗体(抗体购自于Proteintech公司)和患者血清。
实验结果如图9所示，过表达Septin9的HEK293细胞，商业化Septin9抗体和患者血清均能检测到信号，进一步验证了信号的真实性。
实施例9验证Septin9抗体与EB病毒蛋白BFRF3不存在交叉反应
1、重组载体的构建
将BFRF3基因融合flag标签通过分子克隆方法连至pcDNA3.1上，得到重组载体BFRF3-flag，构建好的重组载体经测序正确后大提备用；所述BFRF3氨基酸序列如SEQ IDNO.3所示，所述BFRF3(基因登录号NC_009334.1)核苷酸序列如SEQ ID NO.4所示。
2、转染BFRF3-flag和对照质粒pcDNA3.1至HEK293细胞，培养48h后，丙酮固定，flag标签抗体、Septin9抗体、患者血清免疫荧光鉴定BFRF3信号，实验结果见图10中(a)；
3、转染BFRF3-flag和对照质粒pcDNA3.1至HEK293细胞，培养48h后收集细胞，超声破碎，离心，收集上清，作为Western Blot实验上样样品。具体步骤同中和蛋白制备方法。flag标签抗体鉴定BFRF3表达情况，实验结果见图10中(b)；
4、转染pcDNA3.1-Septin9至HEK293细胞，制备免疫荧光细胞爬片；转染BFRF3-flag和对照质粒pcDNA3.1至HEK293细胞，制备BFRF3中和蛋白和对照蛋白，中和蛋白和对照蛋白制备方法同实施例5步骤2。通过血清中和实验探索BFRF3中和蛋白是否能够封闭掉Septin9信号。
图10中(a)和图10中(b)结果显示BFRF3过表达细胞均可以检测出BFRF3信号，而Septin9抗体和患者血清均未检测出BFRF3信号，说明Septin9抗体不识别BFRF3蛋白。血清中和实验图10中(c)结果显示BFRF3中和蛋白未能封闭掉Septin9信号，进一步说明Septin9抗体不识别BFRF3蛋白，即Septin9抗体与BFRF3没有交叉反应，患者血清中的Septin9抗体不是由BFRF3引起的。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
序列表
<110> 陕西脉元生物科技有限公司
<120> 一种新自身抗体抗Septin9抗体的检测及应用
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Claims (10)
1.一种检测抗Septin9自身抗体的试剂在制备诊断和/或治疗神经系统自身免疫疾病的工具中的应用。
2.根据权利要求1所述应用，其特征在于，所述抗Septin9自身抗体的试剂包括Septin9蛋白，或能够表达所述Septin9蛋白的载体或细胞，或含所述Septin9蛋白的组织。
3.根据权利要求2所述应用，其特征在于，所述Septin9蛋白的氨基酸序列包括SEQ IDNO.1所示的氨基酸序列，或对SEQ ID NO.1所示的氨基酸序列进行改造和/或修饰后的序列。
4.根据权利要求3所述应用，其特征在于，所述改造包括：对SEQ ID NO.1所示的氨基酸序列经过替换、添加或缺失一个或几个氨基酸且具有与Septin9自身抗体结合功能的多肽或衍生的蛋白质，或对SEQ ID NO.1所示氨基酸序列上经修饰后且具有与Septin9自身抗体结合功能的蛋白质，或对SEQ ID NO.1所示氨基酸序列上经剪切后获得的具有与Septin9自身抗体结合功能的剪切变体；
所述修饰包括磷酸化修饰、糖基化修饰、乙酰化修饰或泛素化修饰。
5.根据权利要求2或3所述应用，其特征在于，所述Septin9蛋白包括利用表达系统表达得到的重组蛋白，或过表达细胞裂解物，或哺乳动物组织。
6.根据权利要求5所述应用，其特征在于，所述表达系统包括：原核表达系统、真核表达系统或昆虫表达系统。
7.根据权利要求1所述应用，其特征在于，所述检测抗Septin9自身抗体的方法包括：CBA、TBA、ELISA、免疫胶体金法、免疫印迹、免疫斑点、膜条法、化学发光、放射免疫法、液相芯片法、侧向层析和流式细胞中的至少一种。
8.一种检测Septin9自身抗体的试剂盒，其特征在于，所述试剂盒包括抗Septin9自身抗体的试剂。
9.根据权利要求8所述试剂盒，其特征在于，所述试剂盒还包括反应缓冲液、阳性对照、阴性对照、样品稀释液和标记的抗体；
所述标记的抗体经荧光基团、碱性磷酸酶标记基团、辣根过氧化酶、胶体金、生物素或放射性同位素标记。
10.一种神经系统自身免疫疾病的诊断试剂盒，其特征在于，所述试剂盒包括用于检测Septin9自身抗体的固化的多肽；
所述固化的多肽的介质包括玻片、免疫磁珠、免疫孔板、硝酸纤维素膜或芯片。
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