纤溶酶免疫优先在MRL/MpJ小鼠中诱导潜在促血栓形成的IgG抗心磷脂抗体。
Plasmin immunization preferentially induces potentially prothrombotic IgG anticardiolipin antibodies in MRL/MpJ mice.
作者信息
Ede Kaleo, Hwang Kwan-Ki, Wu Chen-Ching, Wu Meifang, Yang Yao-Hsu, Lin Wei-Shiang, Chien Daniel, Chen Pei-Chih, Tsao Betty P, McCurdy Deborah K, Chen Pojen P
机构信息
University of California, Los Angeles, Division of Pediatric Allergy, Immunology and Rheumatology, Los Angeles, CA 90095, USA.
出版信息
Arthritis Rheum. 2009 Oct;60(10):3108-17. doi: 10.1002/art.24818.
OBJECTIVE
To test the hypothesis, utilizing 2 experimental mouse models, that plasmin is an important autoantigen that drives the production of certain IgG anticardiolipin (aCL) antibodies in patients with the antiphospholipid syndrome.
METHODS
BALB/cJ and MRL/MpJ mice were immunized with Freund's complete adjuvant in the presence or absence of human plasmin. The mouse sera were analyzed for production of IgG antiplasmin, IgG aCL, and IgG anti-beta(2)-glycoprotein I (anti-beta(2)GPI) antibodies. IgG monoclonal antibodies (mAb) were generated from the plasmin-immunized MRL/MpJ mice with high titers of aCL, and these 10 mAb were studied for their binding properties and functional activity in vitro.
RESULTS
Plasmin-immunized BALB/cJ mice produced high titers of IgG antiplasmin only, while plasmin-immunized MRL/MpJ mice produced high titers of IgG antiplasmin, IgG aCL, and IgG anti-beta(2)GPI. Both strains of mice immunized with the adjuvant alone did not develop IgG antiplasmin or IgG aCL. All 10 of the IgG mAb bound to human plasmin and cardiolipin, while 4 of 10 bound to beta(2)GPI, 3 of 10 bound to thrombin, and 4 of 10 bound to the activated coagulation factor X (FXa). Functionally, 4 of the 10 IgG mAb inhibited plasmin activity, 1 of 10 hindered inactivation of thrombin by antithrombin III, and 2 of 10 inhibited inactivation of FXa by antithrombin III.
CONCLUSION
Plasmin immunization leads to production of IgG antiplasmin, aCL, and anti-beta(2)GPI in MRL/MpJ mice, but leads to production of only IgG antiplasmin in BALB/cJ mice. IgG mAb generated from plasmin-immunized MRL/MpJ mice bind to various antigens and exhibit procoagulant activity in vitro. These results suggest that plasmin may drive potentially prothrombotic aCL in genetically susceptible individuals.
目的
利用两种实验小鼠模型来验证纤溶酶是一种重要的自身抗原，它可驱动抗磷脂综合征患者体内某些IgG抗心磷脂（aCL）抗体产生这一假说。
方法
在有或无人类纤溶酶存在的情况下，用弗氏完全佐剂免疫BALB/cJ和MRL/MpJ小鼠。分析小鼠血清中IgG抗纤溶酶、IgG aCL和IgG抗β2糖蛋白I（抗β2GPI）抗体的产生情况。从aCL滴度高的经纤溶酶免疫的MRL/MpJ小鼠中制备IgG单克隆抗体（mAb），并研究这10种mAb在体外的结合特性和功能活性。
结果
经纤溶酶免疫的BALB/cJ小鼠仅产生高滴度的IgG抗纤溶酶，而经纤溶酶免疫的MRL/MpJ小鼠产生高滴度的IgG抗纤溶酶、IgG aCL和IgG抗β2GPI。仅用佐剂免疫的两种品系小鼠均未产生IgG抗纤溶酶或IgG aCL。所有10种IgG mAb均与人纤溶酶和心磷脂结合，10种中有4种与β2GPI结合，10种中有3种与凝血酶结合，10种中有4种与活化的凝血因子X（FXa）结合。在功能上，10种IgG mAb中有4种抑制纤溶酶活性，10种中有1种阻碍抗凝血酶III对凝血酶的灭活，10种中有2种抑制抗凝血酶III对FXa的灭活。
结论
纤溶酶免疫可使MRL/MpJ小鼠产生IgG抗纤溶酶、aCL和抗β2GPI，但仅使BALB/cJ小鼠产生IgG抗纤溶酶。经纤溶酶免疫的MRL/MpJ小鼠产生的IgG mAb可与多种抗原结合，并在体外表现出促凝活性。这些结果表明，纤溶酶可能在遗传易感个体中驱动潜在的促血栓形成性aCL产生。
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