Targeting the complement system in neuromyelitis optica spectrum disorder.
Targeting the complement system in neuromyelitis optica spectrum disorder.
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在视神经肌萎缩症谱系障碍中靶向补体系统。
DOI：
10.1080/14712598.2021.1884223
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发表时间：
2021-08
影响因子：
4.6
通讯作者：
Verkman AS
中科院分区：
文献类型：
--
作者：
Asavapanumas N;Tradtrantip L;Verkman AS
视神经脊髓炎谱系障碍（NMOSD）以中枢神经系统炎症和脱髓鞘为特征。在AQP4-IgG血清阳性的NMOSD中，针对星形细胞水通道水通道蛋白-4 （AQP4）的循环免疫球蛋白G （IgG）自身抗体引起组织损伤。令人信服的证据支持AQP4- igg结合AQP4后补体活化的致病作用。临床研究支持eculizumab（一种C5切割抑制剂）在AQP4-IgG血清阳性NMOSD中的批准。本文综述了AQP4-IgG血清阳性NMOSD中补体依赖性和补体非依赖性组织损伤的体外、动物模型和人证据。本文讨论了补体靶点，包括补体蛋白、调节因子和过敏毒素受体，以及相应的候选药物。尽管临床前数据支持补体激活在AQP4-IgG血清阳性NMOSD中的核心致病作用，但它们并没有解决补体依赖性与补体非依赖性疾病机制的相对贡献，如抗体依赖性细胞毒性、T细胞效应机制和直接AQP4-IgG诱导的细胞损伤。补体依赖性机制在AQP4-IgG血清阳性NMOSD中占主导地位的最佳证据来自于eculizumab的临床数据。针对不同补体效应机制的各种候选药物可能提供更高的安全性和有效性。然而，尽管补体抑制在AQP4-IgG血清阳性NMOSD中已被证明有效，但鉴于多种药物选择和其他作用机制，补体抑制的最终利基尚不清楚。
Neuromyelitis optica spectrum disorder (NMOSD) is characterized by central nervous system inflammation and demyelination. In AQP4-IgG seropositive NMOSD, circulating immunoglobulin G (IgG) autoantibodies against astrocyte water channel aquaporin-4 (AQP4) cause tissue injury. Compelling evidence supports a pathogenic role for complement activation following AQP4-IgG binding to AQP4. Clinical studies supported the approval of eculizumab, an inhibitor of C5 cleavage, in AQP4-IgG seropositive NMOSD. This review covers in vitro, animal models and human evidence for complement-dependent and complement-independent tissue injury in AQP4-IgG seropositive NMOSD. Complement targets are discussed, including complement proteins, regulators and anaphylatoxin receptors, and corresponding drug candidates. Though preclinical data support a central pathogenic role of complement activation in AQP4-IgG seropositive NMOSD, they do not resolve the relative contributions of complement-dependent vs. complement-independent disease mechanisms such as antibody-dependent cellular cytotoxicity, T cell effector mechanisms, and direct AQP4-IgG-induced cellular injury. The best evidence that complement-dependent mechanisms predominate in AQP4-IgG seropositive NMOSD comes from eculizumab clinical data. Various drug candidates targeting distinct complement effector mechanisms may offer improved safety and efficacy. However, notwithstanding the demonstrated efficacy of complement inhibition in AQP4-IgG seropositive NMOSD, the ultimate niche for complement inhibition is not clear given multiple drug options with alternative mechanisms of action.
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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
神经霉素炎患者Optica患者的Aquaporin-4结合自身抗体通过下调EAAT2损害谷氨酸的转运。
影响因子：
15.3
作者：
Hinson, Shannon R.;Roemer, Shanu F.;Lucchinetti, Claudia F.;Fryer, James P.;Kryzer, Thomas J.;Chamberlain, Jayne L.;Howe, Charles L.;Pittock, Sean J.;Lennon, Vanda A.
通讯作者：
Lennon, Vanda A.
影响因子：
7.1
作者：
Jones MV;Huang H;Calabresi PA;Levy M
通讯作者：
Levy M
影响因子：
2.6
作者：
Campbell, WD;Lazoura, E;Okada, H
通讯作者：
Okada, H
影响因子：
9.3
作者：
Felix CM;Levin MH;Verkman AS
通讯作者：
Verkman AS