MONOCLONAL ANTICARDIOLIPIN ANTIBODIES FROM NEW-ZEALAND BLACK X NEW-ZEALAND WHITE F1-MICE REACT TO THROMBOMODULIN

The reactivity with and affinity for thrombomodulin (TM) of monoclonal anti-cardiolipin Abs (MoaCL), derived from a New Zealand Black x New Zealand White F-1 (NZB/W F-1) mouse, were studied to investigate the p athogenicity of anti-cardiolipin Abs (aCL). Four of eighteen MoaCL wer e 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 domain of human TM, a binding site for thrombin. Th e reaction with TM of these four MoaCL was inhibited by bovine thrombi n. When the affinity for TM of the MoaCL was determined, the dissociat ion constants (K-d) ranged from 4.8 x 10(-9) to 4.7 x 10(-8) M. By con trast, examination of the affinity for cardiolipin (CL) gave values fr om 8.3 x 10(-6) to 7.4 X 10(-5) M. Thus, these MoaCL reacted to TM wit h a higher affinity than to CL. Moreover, these MoaCL also bound to TM on 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 acti vated protein C and protein S show anticoagulatory activity. Thus, the 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.