In vivo inhibition of antiphospholipid antibody-induced pathogenicity utilizing the antigenic target peptide domain I of β2-glycoprotein I: proof of concept
In vivo inhibition of antiphospholipid antibody-induced pathogenicity utilizing the antigenic target peptide domain I of β2-glycoprotein I: proof of concept
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DOI：
10.1111/j.1538-7836.2009.03316.x
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发表时间：
2009-05-01
影响因子：
10.4
通讯作者：
Pierangeli, S.
中科院分区：
文献类型：
--
作者：
Ioannou, Y.;Romay-Penabad, Z.;Pierangeli, S.
目的：在抗磷脂综合征（APS）中，大多数循环致病性抗磷脂抗体（api）的免疫显性表位是β(2)-糖蛋白I的n -末端结构域I（DI）。我们之前已经证明重组DI在液相中抑制api与固定的天然抗原的结合，并且这种抑制作用在DI（D8S/D9G）突变体中更大，而在DI（R39S）突变体中不存在。因此，我们假设DI和DI（D8S/D9G）在体内可以抑制apl诱导的致病性。方法：C57BL/6小鼠（每组5只）分别注射APS患者纯化IgG （IgG-APS, 500 μ g）或正常血清IgG （IgG- nhs）和重组DI、DI（R39S）、DI（D8S/D9G）或无关对照肽（10-40 μ g）。测量的结果变量是治疗组和对照组在标准化血管损伤后的股静脉血栓动力学，主动脉内皮表面血管细胞粘附分子-1 （VCAM-1）的表达，以及小鼠巨噬细胞的组织因子（TF）活性。结果：与IgG-NHS相比，IgG-APS显著增加血栓大小。重组DI (P)预处理小鼠，IgG-APS增强血栓的作用被消除
Objectives: In the antiphospholipid syndrome (APS), the immunodominant epitope for the majority of circulating pathogenic antiphospholipid antibodies (aPLs) is the N-terminal domain I (DI) of beta(2)-glycoprotein I. We have previously shown that recombinant DI inhibits the binding of aPLs in fluid phase to immobilized native antigen, and that this inhibition is greater with the DI(D8S/D9G) mutant and absent with the DI(R39S) mutant. Hence, we hypothesized that DI and DI(D8S/D9G) would inhibit aPL-induced pathogenicity in vivo. Methods: C57BL/6 mice (n = 5, each group) were injected with purified IgG derived from APS patients (IgG-APS, 500 mu g) or IgG from normal healthy serum (IgG-NHS) and either recombinant DI, DI(R39S), DI(D8S/D9G), or an irrelevant control peptide (at 10-40 mu g). Outcome variables measured were femoral vein thrombus dynamics in treated and control groups following standardized vessel injury, expression of vascular cell adhesion molecule-1 (VCAM-1) on the aortic endothelial surface, and tissue factor (TF) activity in murine macrophages. Results: IgG-APS significantly increased thrombus size as compared with IgG-NHS. The IgG-APS thrombus enhancement effect was abolished in mice pretreated with recombinant DI (P