Glucose-regulated protein 78 autoantibody associates with blood-brain barrier disruption in neuromyelitis optica.
Glucose-regulated protein 78 autoantibody associates with blood-brain barrier disruption in neuromyelitis optica.
复制标题
DOI：
10.1126/scitranslmed.aai9111
复制
发表时间：
2017-07-05
影响因子：
17.1
通讯作者：
Bennett JL
中科院分区：
文献类型：
--
作者：
Shimizu F;Schaller KL;Owens GP;Cotleur AC;Kellner D;Takeshita Y;Obermeier B;Kryzer TJ;Sano Y;Kanda T;Lennon VA;Ransohoff RM;Bennett JL
视神经肌萎缩症（NMO）是一种由水通道蛋白4（AQP 4）抗体介导的炎症性疾病，在疾病的急性期具有显著的血脑屏障（BBB）破坏。抗AQP 4抗体主要在外周产生，但它们靶向BBB后面的星形胶质细胞血管周围末端。我们推断，内皮细胞靶向自身抗体可能促进AQP 4抗体的BBB转运，并促进NMO攻击。使用来自NMO患者的单克隆重组抗体（rAbs），我们鉴定了两种与脑微血管内皮细胞（BMEC）强烈结合的抗体。BMEC暴露于这些rAb导致核因子κB p65的核转位，减少claudin-5蛋白表达，并增强大分子转运。无偏膜蛋白质组学鉴定葡萄糖调节蛋白78（GRP 78）为rAb靶标。使用固定的GRP 78从50名NMO患者的合并的总免疫球蛋白G（IgG）（NMO-IgG）中去除GRP 78抗体降低了NMO-IgG对BMEC的生物学效应。GRP 78在体内表达于鼠BMEC的表面上，并且重复施用GRP 78特异性rAb引起血清白蛋白、IgG和纤维蛋白原外渗到小鼠脑中。我们的研究结果确定GRP 78抗体作为NMO发病机制的潜在组成部分和GRP 78作为促进治疗性抗体的中枢神经系统转运的候选靶标。
Neuromyelitis optica (NMO) is an inflammatory disorder mediated by antibodies to aquaporin-4 (AQP4) with prominent blood-brain barrier (BBB) breakdown in the acute phase of the disease. Anti-AQP4 antibodies are produced mainly in the periphery, yet they target the astrocyte perivascular end feet behind the BBB. We reasoned that an endothelial cell–targeted autoantibody might promote BBB transit of AQP4 antibodies and facilitate NMO attacks. Using monoclonal recombinant antibodies (rAbs) from patients with NMO, we identified two that strongly bound to the brain microvascular endothelial cells (BMECs). Exposure of BMECs to these rAbs resulted in nuclear translocation of nuclear factor κB p65, decreased claudin-5 protein expression, and enhanced transit of macromolecules. Unbiased membrane proteomics identified glucose-regulated protein 78 (GRP78) as the rAb target. Using immobilized GRP78 to deplete GRP78 antibodies from pooled total immunoglobulin G (IgG) of 50 NMO patients (NMO-IgG) reduced the biological effect of NMO-IgG on BMECs. GRP78 was expressed on the surface of murine BMECs in vivo, and repeated administration of a GRP78-specific rAb caused extravasation of serum albumin, IgG, and fibrinogen into mouse brains. Our results identify GRP78 antibodies as a potential component of NMO pathogenesis and GRP78 as a candidate target for promoting central nervous system transit of therapeutic antibodies.
登录
查看更多内容
影响因子：
11.2
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
通讯作者：
Hemmer, Bernhard
影响因子：
9.3
作者：
Jarius S;Franciotta D;Paul F;Ruprecht K;Bergamaschi R;Rommer PS;Reuss R;Probst C;Kristoferitsch W;Wandinger KP;Wildemann B
通讯作者：
Wildemann B
影响因子：
5.8
作者：
Jarius, S.;Wildemann, B.
通讯作者：
Wildemann, B.
DOI：
10.1212/nxi.0000000000000231
发表时间：
2016-06
期刊：
Neurology(R) neuroimmunology & neuroinflammation
影响因子：
--
作者：
Majed M;Fryer JP;McKeon A;Lennon VA;Pittock SJ
通讯作者：
Pittock SJ
影响因子：
3.3
作者：
Burgoon, MP;Williamson, RA;Gilden, DH
通讯作者：
Gilden, DH