Rahgozar Soheila, Yang Qiuxia, Giannakopoulos Bill, Yan Xiaokai, Miyakis Spiros, Krilis Steven A
St George Hospital, University of New South Wales, Sydney, New South Wales, Australia.
Arthritis Rheum. 2007 Feb;56(2):605-13. doi: 10.1002/art.22367.
Beta(2)-glycoprotein I (beta(2)GPI) is a dominant antigenic target in antiphospholipid syndrome (APS). Beta(2)-glycoprotein I may bind to factor XI and serve a physiologic function as a regulator of factor XI activation by thrombin. We undertook this study to investigate the possible interactions of beta(2)GPI with thrombin in beta(2)GPI-regulated factor XI activation by thrombin and to evaluate the effect of anti-beta(2)GPI antibodies on this system.
The beta(2)GPI interaction with thrombin was investigated in direct and competitive assays using beta(2)GPI domain mutants and thrombin-binding exosite oligonucleotides. Beta(2)-glycoprotein I inhibition of thrombin-mediated factor XI activation was assessed in the presence of 8 anti-beta(2)GPI monoclonal antibodies (mAb) directed against domain I.
Domain V of beta(2)GPI was involved in direct binding to thrombin, and exosite I and exosite II on thrombin took part in this interaction. Anti-beta(2)GPI mAb produced a >70% inhibition of thrombin-mediated factor XI activation in the presence of beta(2)GPI.
We demonstrate that beta(2)GPI interacts with thrombin exosites I and II. This novel finding necessitates a reinterpretation of previous studies from which the detection of anti-human thrombin antibodies in APS has been reported. We also show that anti-beta(2)GPI antibodies potentiate the inhibitory effect of beta(2)GPI on thrombin-mediated factor XIa generation.
β2糖蛋白I（β2GPI）是抗磷脂综合征（APS）中的主要抗原靶点。β2糖蛋白I可能与因子XI结合，并作为凝血酶激活因子XI的调节剂发挥生理功能。我们进行这项研究，以探讨在β2GPI调节凝血酶激活因子XI的过程中β2GPI与凝血酶之间可能存在的相互作用，并评估抗β2GPI抗体对该系统的影响。
使用β2GPI结构域突变体和凝血酶结合外位点寡核苷酸，通过直接和竞争性试验研究β2GPI与凝血酶的相互作用。在8种针对结构域I的抗β2GPI单克隆抗体（mAb）存在的情况下，评估β2糖蛋白I对凝血酶介导的因子XI激活的抑制作用。
β2GPI的结构域V参与与凝血酶的直接结合，凝血酶上的外位点I和外位点II参与了这种相互作用。在存在β2GPI的情况下，抗β2GPI mAb对凝血酶介导的因子XI激活产生了>70%的抑制作用。
我们证明β2GPI与凝血酶的外位点I和II相互作用。这一新发现需要重新解释先前报道在APS中检测到抗人凝血酶抗体的研究。我们还表明，抗β2GPI抗体增强了β2GPI对凝血酶介导的因子XIa生成的抑制作用。
