Pathogenity of anti-cardiolipin antibodies : Reactivity to thrombomodulin

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The reactivity with and affinity for thrombomodulin (TM) of monoclonal anticardiolipin antibodies (MoaCL), derived from a NZB x NZW (NZB/W) F1 mouse, were studied to investigate the pathogenicity of anticardiolipin antibodies (aCL). Four of 18 MoaCL were found to react with rabbit TM when examined using ELISA.These four MoaCL also reacted with synthetic peptide that included the epidermal growth factor-like (EGF-like) domain to human TM,a binding site for thrombin. The reaction with TM of these four MoaCL was inhibited by bovine thrombin. When the affinity for TM of the MoaCL was determined, the dissociation constants (Kd) ranged from 4.8 x 10-9 to 4.7 x 10-8 M.By contrast, examination of the affinity for CL gave values from 8.3 x 10-6 to 7.4 x 10-5 M.Thus, these MoaCL reacted to TM with a higher affinity than to CL.Moreover, these MoaCL also bound to TM on human umbilical vein endothelial cells (HUVEC) and down-regulated the expression level of TM on the surface of HUVEC,due to internalization of TM.The binding of thrombin to TM is known to initiate rapid protein C activation and complexes of activated protein C and protein S show anticoagulatory activity. Thus, present studies suggest that certain pathogenic aCL cross-react with TM and induce down-regulation of TM on endothelial cells, followed by induction of thrombosis.