Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica.
Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica.
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DOI：
10.1002/ana.21802
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发表时间：
2009-11
影响因子：
11.2
通讯作者：
Hemmer, Bernhard
中科院分区：
文献类型：
--
作者：
Bennett, Jeffrey L.;Lam, Chiwah;Kalluri, Sudhakar Reddy;Saikali, Philippe;Bautista, Katherine;Dupree, Cecily;Glogowska, Magdalena;Case, David;Antel, Jack P.;Owens, Gregory P.;Gilden, Don;Nessler, Stefan;Stadelmann, Christine;Hemmer, Bernhard
大多数视神经脊髓炎（NMO）患者的血清中含有针对水通道蛋白 - 4（AQP4）水通道的自身抗体（NMO - IgGs），该水通道位于大脑血管周围和软膜下区域的星形胶质细胞足突上。我们的目的是确定中枢神经系统（CNS）中NMO - IgGs的来源及其在疾病发病机制中的作用。
采用荧光激活细胞分选和单细胞逆转录酶PCR技术，在一名NMO患者首次临床发作后的脑脊液（CSF）中鉴定出过度表达的浆细胞免疫球蛋白（Ig）序列。从配对的重链和轻链序列产生单克隆重组抗体（rAbs），并测试其靶标特异性和Fc效应功能。通过将单一rAbs给予实验性自身免疫性脑脊髓炎（EAE）大鼠，研究CSF rAbs对中枢神经系统免疫病理学的影响。
抗体库分析显示出一个动态的、克隆性扩增的浆细胞群，具有抗原靶向反应的特征。通过多种独立的检测方法，从CSF浆细胞克隆产生的11种rAbs中有6种特异性结合AQP4。AQP4特异性rAbs识别构象表位，并介导AQP4导向的抗体依赖性细胞毒性和补体介导的裂解。当给予EAE大鼠时，一种AQP4特异性的NMO CSF rAb诱导了NMO免疫病理学改变：血管周围星形胶质细胞缺失、髓鞘溶解以及补体和Ig沉积。
对一名早期NMO患者的CSF浆细胞抗体库进行分子特征分析表明，AQP4特异性Ig在疾病发作时在鞘内合成，并直接导致中枢神经系统病理改变。AQP4现在是人类脱髓鞘疾病中第一个被确认的抗原靶点。
The serum of most neuromyelitis optica (NMO) patients contains autoantibodies (NMO-IgGs) directed against the aquaporin-4 (AQP4) water channel located on astrocyte foot processes in the perivessel and subpial areas of the brain. Our objectives were to determine the source of central nervous system (CNS) NMO-IgGs and their role in disease pathogenesis. Fluorescence activated cell sorting and single-cell reverse transcriptase PCR were used to identify overrepresented plasma cell immunoglobulin (Ig) sequences in the cerebrospinal fluid (CSF) of an NMO patient after a first clinical attack. Monoclonal recombinant antibodies (rAbs) were generated from the paired heavy and light chain sequences and tested for target specificity and Fc effector function. The effect of CSF rAbs on CNS immunopathology was investigated by delivering single rAbs to rats with experimental autoimmune encephalomyelitis (EAE). Repertoire analysis revealed a dynamic, clonally expanded plasma cell population with features of an antigen-targeted response. Using multiple independent assays, 6 of 11 rAbs generated from CSF plasma cell clones specifically bound to AQP4. AQP4-specific rAbs recognized conformational epitopes and mediated both AQP4-directed antibody-dependent cellular cytotoxicity and complement-mediated lysis. When administered to rats with EAE, an AQP4-specific NMO CSF rAb induced NMO immunopathology: perivascular astrocyte depletion, myelinolysis and complement and Ig deposition. Molecular characterization of the CSF plasma cell repertoire in an early NMO patient demonstrates that AQP4-specfic Ig is synthesized intrathecally at disease onset and directly contributes to CNS pathology. AQP4 is now the first confirmed antigenic target in human demyelinating disease.
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DOI：
10.1073/pnas.0607242103
发表时间：
2006-12-12
影响因子：
11.1
作者：
Zhou, Dun;Srivastava, Rajneesh;Hemmer, Bernhard
通讯作者：
Hemmer, Bernhard
影响因子：
9.9
作者：
Wingerchuk, D. M.;Lennon, V. A.;Weinshenker, B. G.
通讯作者：
Weinshenker, B. G.
影响因子：
14.5
作者：
Takahashi, Toshiyuki;Fujihara, Kazuo;Itoyama, Yasuto
通讯作者：
Itoyama, Yasuto
DOI：
10.1073/pnas.0502323102
发表时间：
2005-05-17
影响因子：
11.1
作者：
Burgoon, MP;Keays, KM;Gilden, DH
通讯作者：
Gilden, DH
影响因子：
1.9
作者：
Beyer, Anja-Maria;Wandinger, Klaus-Peter;Klehmet, Juliane
通讯作者：
Klehmet, Juliane