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Some Plasmin-Induced Antibodies Bind to Cardiolipin, Display Lupus Anticoagulant Activity and Induce Fetal Loss in Mice¹

Xiao-Xiang Chen^*, Yue-Ying Gu^*, Shu-Jie Li^*, Jie Qian^*, Kwan-Ki Hwang, Pojen P. Chen, Shun-Le Chen^* and Cheng-De Yang^2,*

^* Department of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; and Department of Medicine, Division of Rheumatology, University of California, Los Angeles, CA 90095

The combined presence of anti-phospholipid Ab (aPL), thrombosis, and/or fetal loss is recognized as the antiphospholipid syndrome (APS). aPL include anti-cardiolipin Ab (aCL) and/or lupus anticoagulants (LAC, detected as Ig that prolong certain in vitro phospholipid (PL)-restricted blood clotting tests); both aCL and LAC are the diagnostic Ab for APS. Studies show that aPL represent a heterogeneous group of Ab, which recognize various PL, PL-binding plasma proteins, and/or PL-protein complexes. Recently, we found that five of seven patient-derived IgG monoclonal aCL react with thrombin, activated protein C, and plasmin. All three proteins are trypsin-like serine proteases (SP), and are highly homologous in their catalytic domains. Importantly, among these SP autoantigens, the reactive aCL bind to plasmin with the highest affinity, suggesting that plasmin may serve as a major driving autoantigen for some aCL in 30% of APS patients who are positive for IgG anti-plasmin Ab. To test this hypothesis, we immunized BALB/c mice with human plasmin and analyzed immune sera for aCL activity and reactivity with relevant SP. We found that some immune sera displayed aCL activity and/or bound to test SP. Subsequently, eight mAb were obtained and studied. The results revealed that one mAb displayed the aCL and the LAC activities and induced fetal loss when injected into pregnant mice. Immunohistological analyses of placentas revealed extensive deposits of activated C3 components. Combined, these data demonstrate that plasmin may serve as a driving Ag for some pathogenic aPL.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Research Grant 30371332 from the National Natural Science Foundation of China; Research Grant 03JC14039 from Shanghai Science and Technical Committee, China; and by Research Grant AR42506 from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Cheng-De Yang, Department of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, 145 Shan Dong Zhong Road, Shanghai, China. E-mail address: yangchengde{at}hotmail.com

³ Abbreviations used in this paper: APS, antiphospholipid syndrome; aCL, anti-cardiolipin Ab; aPL, anti-phospholipid Ab; CL, cardiolipin; LAC, lupus anticoagulant; PL, phospholipid; SP, serine proteases.

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