Pathophysiology of adhesion molecules for induction of antiphospholipid antibodies and occurrence of thrombosis in antiphospholipid syndrome: Analysis of those mechanisms using adhesion-molecules knock out mice.

抗磷脂综合征（APS）是一种自身免疫性疾病，临床特征是血栓复发和妊娠发病率，以及抗磷脂抗体（aPL）阳性，包括抗心磷脂抗体（αCL）和狼疮抗凝剂（LA）。为了确定哪些粘附分子在诱导aPL中是必需的，我们尝试在缺乏l -选择素、p -选择素、e -选择素、ICAM-1和l -选择素/ICAM-1等粘附分子的小鼠中诱导APS，并评估小鼠的aPL生成和血栓形成情况。用弗氏佐剂每隔3周向C57BL/6小鼠脚垫注射纯化的β2-糖蛋白I (β2-GPI) 20 μg。第一次注射β2-GPI后6周，野生型小鼠出现血小板减少、APTT延长、aCL滴度升高，而仅注射弗氏佐剂小鼠未出现这些变化（p <0.005、<0.005、< 0.01）。注射5 mg/kg脂多糖（LPS）后，APS小鼠肾小球纤维蛋白沉积百分比（%GFD）显著高于对照组（p < 0.01）。除e -选择素KO小鼠外，所有粘附分子KO小鼠在反复注射β2-GPI后均出现血小板减少、APTT延长、高aCL滴度和aPL阳性，但与对照小鼠相比，这些小鼠的%GFD没有显著增加。相比之下，注射62-GPI后，e -select - ko小鼠的血小板计数、APTT、aCL滴度和%GFD未发生任何变化。这些发现表明，尽管多种粘附分子可能参与aps模型小鼠血栓形成的发展，但E-selectin在诱导aPL中起关键作用。

Antiphospholipid syndrome (APS) is an autoimmune disorder clinically characterized by recurrent thromboses and pregnant morbidity as well as positive for antiphospholipid antibodies (aPL) including anticardiolipin antibody (αCL) and lupus anticoagulant (LA). To determine which adhesion molecules are essential in the induction of aPL, we attempted to induce APS in the mice deficient of several kinds of adhesion molecules including L-selectin, P-selectin, E-selection, ICAM-1, and L-selectin/ICAM-1, and evaluated aPL production and thrombogenesity in the mice. C57BL/6 mice were injected with purified 20 μg of β2-glycoprotein I (β2-GPI) to pedal pad twice at a 3 week interval with Freund's adjuvant. Six weeks after the first injection of β2-GPI, wild-type mice developed thrombocytopenia, prolongation of APTT, and elevation of aCL titer, while the mice injected only with Freund's adjuvant did not show these changes (p < 0.005, <0.005, and < 0.01, respectively). The percentage of glomerular fibrin deposit (%GFD) induced by the injection of 5 mg/kg of lipopolysaccharide (LPS) increased significantly in the APS mice compared to the control mice (p < 0.01). All adhesion-molecule KO mice except for E-selectin KO mice developed thrombocytopenia, APTT prolongation, high aCL titers, and positivity for aPL after repeated injection of β2-GPI, though %GFD did not increase significantly in these mice compared to control mice. In contrast, E-selectin-KO mice did not develop any changes in platelet counts, APTT, aCL titer, and %GFD after injection of 62-GPI. These findings indicated that, although several adhesion molecules may be involved in the development of thrombosis in APS-model mice, E-selectin has a key role in the induction of aPL.