抗リン脂質抗体の誘導・発症に及ぼす接着分子の関与: 接着分子KOマウスを用いた検討

金沢大学医薬保健研究域医学系各種接着分子ノックアウト(KO)マウスを用いて実験的抗リン脂質抗体症候群(APS)モデルマウスの作成を試み,抗リン脂質抗体(aPL)発現,血栓発症におよぼす接着分子の関与について検討した.C57BL/2(wild-type)マウスにヒトβ_2-glycoprotein I(β_2GPI)を能動感作することにより,実験的APSモデルマウスを作成した.同様にICAM-1,P-selectin,E-selectin,L-selectin KOマウスにβ_2GPIを感作し実験的APSマウスが作成されるか検討した.これらのマウスにlipopolysaccharide(LPS)を腹腔内投与しFDP,TATおよび腎糸球体血栓頻度(%GFD)を測定し,本モデルにおける血栓傾向を解析した.Wild-typeマウスでは,β_2GPI感作8週後に有意の血小板減少,活性化部分トロンボプラスチン時間(APTT)の延長,β_2GPI依存性抗カルジオリピン抗体(acL/β_2GPI)価の上昇を認め,aPLの発現を確認した.ICAM-1,P-selectin,L-selectin KOマウスでも同様の変化が見られたのに対し,E-selectin KOマウスではいずれのパラメータについても有意の変化は認めなかった.LPSを腹腔内投与したところ,β_2GPI能動感作wild-typeマウスでは非感作wild-typeマウスと比較して有意のFDP,TATの上昇,%GFDの上昇を認めたものの,接着分子KOマウスではいずれのKOマウスにおいてもFDP,TAT,%GFDの有意の上昇は認めなかった.以上の結果より,抗リン脂質抗体の発現にはE-selectinが,血栓発症に鱒そのほかの接着分子の関与が明らかとなった.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\u27s 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\u27s 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.研究課題/領域番号:17590985, 研究期間(年度):2005 – 2006出典：研究課題「抗リン脂質抗体の誘導・発症に及ぼす接着分子の関与:接着分子KOマウスを用いた検討」課題番号17590985（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-17590985/175909852006kenkyu_seika_hokoku_gaiyo/）を加工して作