Pathogenic natural antibodies propagate cerebral injury following ischemic stroke in mice.
Pathogenic natural antibodies propagate cerebral injury following ischemic stroke in mice.
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DOI：
10.4049/jimmunol.1102132
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发表时间：
2012-02-01
期刊：
影响因子：
--
通讯作者：
Tomlinson S
中科院分区：
文献类型：
--
作者：
Elvington A;Atkinson C;Kulik L;Zhu H;Yu J;Kindy MS;Holers VM;Tomlinson S
自身反应性天然抗体在某些组织缺血和再灌注后引发损伤，但它们在缺血性中风中的作用尚不清楚。我们研究了缺血后大脑中新表位的表达，以及天然抗体在识别这些表位和介导补体依赖性损伤中的作用。识别磷脂子集的新型 IgM mAb (C2) 和先前表征的抗膜联蛋白 IV mAb (B4) 用于在大脑中动脉闭塞和再灌注 60 分钟后重建和表征抗体缺陷 Rag1−/− 小鼠的损伤。在其他受保护的 Rag1−/− 小鼠中用 C2 或 B4 mAb 重建可恢复野生型小鼠的损伤，如梗塞体积、脱髓鞘和神经评分所证明的那样。在野生型小鼠和重建的 Rag1−/− 小鼠中都证实了 IgM 沉积，并且在 B4 mAb 重建后，IgM 与补体激活片段 C3d 共定位。此外，重组膜联蛋白 IV 显着减少了野生型小鼠和给予正常小鼠血清的 Rag1−/− 小鼠的梗塞体积，表明单一抗体反应性足以在整个天然抗体库的背景下发生脑缺血再灌注损伤。最后，C2 和 B4 mAb 在体外与缺氧但不正常含氧的人内皮细胞结合。因此，致病性天然 IgM 与缺血后新表位的结合会在小鼠脑缺血和再灌注后引发补体依赖性损伤，并且根据先前研究人血清中 IgM 反应性的数据，小鼠和人似乎都存在类似的识别系统。
Self-reactive natural antibodies initiate injury following ischemia and reperfusion of certain tissues, but their role in ischemic stroke is unknown. We investigated neoepitope expression in the post-ischemic brain, and the role of natural antibodies in recognizing these epitopes and mediating complement-dependent injury. A novel IgM mAb recognizing a subset of phospholipids (C2) and a previously characterized anti-annexin IV mAb (B4) were used to reconstitute and characterize injury in antibody deficient Rag1−/− mice after 60 minutes of middle cerebral artery occlusion and reperfusion. Reconstitution with C2 or B4 mAb in otherwise protected Rag1−/− mice restored injury to that seen in wild-type mice, as demonstrated by infarct volume, demyelination and neurological scoring. IgM deposition was demonstrated in both wild-type mice and reconstituted Rag1−/− mice, and IgM co-localized with the complement activation fragment, C3d, following B4 mAb reconstitution. Further, recombinant annexin IV significantly reduced infarct volumes in wild-type mice and in Rag1−/− mice administered normal mouse serum, demonstrating that a single antibody reactivity is sufficient to develop cerebral ischemia reperfusion injury in the context of an entire natural antibody repertoire. Finally, C2 and B4 mAbs bound to hypoxic, but not normoxic, human endothelial cells in vitro. Thus, the binding of pathogenic natural IgM to post-ischemic neoepitopes initiates complement-dependent injury following murine cerebral ischemia and reperfusion and, based also on previous data investigating IgM reactivity in human serum, there appears to be a similar recognition system in both mouse and man.
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影响因子：
6.9
作者：
Ducruet, Andrew F.;Sosunov, Sergey A.;Zacharia, Brad E.;Gorski, Justin;Yeh, Mason L.;DeRosa, Peter;Cohen, Gregory;Gigante, Paul R.;Connolly, E. Sander, Jr.
通讯作者：
Connolly, E. Sander, Jr.
与凋亡相关决定因素的IgM抗体募集C1Q并增强凋亡细胞的树突状细胞吞噬作用。
DOI：
10.4049/jimmunol.0804191
发表时间：
2009-05-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chen Y;Park YB;Patel E;Silverman GJ
通讯作者：
Silverman GJ
DOI：
10.4049/jimmunol.0803980
发表时间：
2009-05-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kulik L;Fleming SD;Moratz C;Reuter JW;Novikov A;Chen K;Andrews KA;Markaryan A;Quigg RJ;Silverman GJ;Tsokos GC;Holers VM
通讯作者：
Holers VM
DOI：
10.1084/jem.20031763
发表时间：
2004-12-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chang MK;Binder CJ;Miller YI;Subbanagounder G;Silverman GJ;Berliner JA;Witztum JL
通讯作者：
Witztum JL
影响因子：
4.4
作者：
Fleming, SD;Egan, RP;Tsokos, GC
通讯作者：
Tsokos, GC