与β2糖蛋白I结合的抗β2糖蛋白I抗体可通过糖蛋白Ib-IX-V以失调的方式激活血小板。
Anti-beta2-glycoprotein I antibodies in complex with beta2-glycoprotein I can activate platelets in a dysregulated manner via glycoprotein Ib-IX-V.
作者信息
Shi Tong, Giannakopoulos Bill, Yan Xiaokai, Yu Pei, Berndt Michael C, Andrews Robert K, Rivera Juan, Iverson G Michael, Cockerill Keith A, Linnik Matthew D, Krilis Steven A
机构信息
St. George Hospital, University of New South Wales, Sydney, New South Wales, Australia.
出版信息
Arthritis Rheum. 2006 Aug;54(8):2558-67. doi: 10.1002/art.21968.
OBJECTIVE
Results of previous studies suggest that anti-beta2-glycoprotein I (anti-beta2GPI) antibodies in complex with beta2GPI activate platelets in a dysregulated manner, potentially contributing to the prothrombotic tendency associated with the antiphospholipid syndrome (APS). We undertook this study to investigate the possible contribution of the GPIb-IX-V receptor to platelet activation mediated by the anti-beta2GPI antibody-beta2GPI complex.
METHODS
In vitro methods were used in the present study. The interaction between beta2GPI and the GPIbalpha subunit of the GPIb-IX-V receptor was delineated using direct binding and competitive inhibition assays. The interaction between the anti-beta2GPI antibody-beta2GPI complex and platelets was studied using a novel method in which the Fc portion of the antibody was immobilized using protein A coated onto a microtiter plate. Platelet activation was assessed by two methods; one involved measuring thromboxane B2 production and the other involved assessment of the activation of the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta intracellular signaling pathway. The contribution of the GPIbalpha receptor to platelet activation induced by the anti-beta2GPI antibody-beta2GPI complex was assessed by observing the influence of 2 anti-GPIbalpha antibodies (AK2 and SZ2) directed against distinct epitopes.
RESULTS
This study showed that beta(2)GPI could bind to the GPIbalpha receptor. The anti-beta2GPI antibody-beta2GPI complex was able to activate platelets, and this effect was inhibited by anti-GPIbalpha antibody directed against epitope Leu-36-Gln-59, but not by anti-GPIbalpha antibody directed against residues Tyr-276-Glu-282.
CONCLUSION
Our findings show that inappropriate platelet activation by the anti-beta2GPI antibody-beta2GPI complex via the GPIbalpha receptor may contribute to the prothrombotic tendency associated with APS.
目的
先前研究结果表明，抗β2糖蛋白I（抗β2GPI）抗体与β2GPI形成的复合物会以失调的方式激活血小板，这可能是抗磷脂综合征（APS）相关血栓形成倾向的原因之一。我们开展这项研究，旨在探讨糖蛋白Ib-IX-V受体（GPIb-IX-V）在抗β2GPI抗体-β2GPI复合物介导的血小板激活过程中可能发挥的作用。
方法
本研究采用体外实验方法。通过直接结合和竞争性抑制实验，明确β2GPI与GPIb-IX-V受体的GPIbalpha亚基之间的相互作用。利用一种新方法研究抗β2GPI抗体-β2GPI复合物与血小板之间的相互作用，该方法是将包被有蛋白A的微孔板用于固定抗体的Fc部分。通过两种方法评估血小板激活情况；一种方法是检测血栓素B2的生成，另一种方法是评估磷脂酰肌醇3激酶/蛋白激酶B/糖原合成酶激酶3β细胞内信号通路的激活情况。通过观察两种针对不同表位的抗GPIbalpha抗体（AK2和SZ2）的影响，评估GPIbalpha受体在抗β2GPI抗体-β2GPI复合物诱导的血小板激活过程中的作用。
结果
本研究表明β2GPI能够与GPIbalpha受体结合。抗β2GPI抗体-β2GPI复合物能够激活血小板，针对表位Leu-36-Gln-59的抗GPIbalpha抗体可抑制这种作用，而针对残基Tyr-276-Glu-282的抗GPIbalpha抗体则无此作用。
结论
我们的研究结果表明，抗β2GPI抗体-β2GPI复合物通过GPIbalpha受体不适当激活血小板，可能是APS相关血栓形成倾向的原因之一。
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