Monoclonal anti-cardiolipin 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 F1 (NZB/W F1) mouse, were studied to investigate the pathogenicity of anti-cardiolipin Abs (aCL). Four of eighteen 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 domain of 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 cardiolipin (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 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, 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.
Haruta
K
K
Research Laboratory, Zenyaku Kogyo Co. Ltd., Tokyo, Japan.
Kobayashi
S
S
Hirose
S
S
Horiai
A
A
Ohyanagi
M
M
Tanaka
M
M
Kawano
T
T
Shirai
T
T
Takasaki
Y
Y
Hashimoto
H
H
D000818:Animals; D017153:Antibodies, Anticardiolipin / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000918:Antibody Specificity; D001667:Binding, Competitive; D002308:Cardiolipins / Q000276:immunology*; D003429:Cross Reactions; D006023:Glycoproteins / Q000276:immunology; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D051379:Mice; D013917:Thrombin / Q000494:pharmacology; D018180:Thrombomodulin / Q000276:immunology*; D053482:beta 2-Glycoprotein I
D017153:Antibodies, Anticardiolipin; D000911:Antibodies, Monoclonal; D002308:Cardiolipins; D006023:Glycoproteins; D007141:Immunoglobulin Fc Fragments; D018180:Thrombomodulin; D053482:beta 2-Glycoprotein I; D013917:Thrombin