VH1-69 germline encoded antibodies directed towards ADAMTS13 in patients with acquired thrombotic thrombocytopenic purpura |
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Authors: | W POS B M LUKEN J A KREMER HOVINGA† E A M TURENHOUT F SCHEIFLINGER‡ J-F DONG§ R FIJNHEER¶ J VOORBERG |
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Institution: | Department of Plasma Proteins, Sanquin-AMC Landsteiner Laboratory, Amsterdam, The Netherlands;;Department of Haematology and Central Haematology Laboratory, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland;;Department of Discovery Research and Technical Assessment, Baxter Bioscience, Vienna, Austria;;Thrombosis Research Section, Baylor College of Medicine, Houston, TX, USA;;and Department of Haematology, University Medical Centre Utrecht, Utrecht, the Netherlands |
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Abstract: | Summary. Background: Autoantibodies directed towards ADAMTS13 are present in the majority of patients with acquired thrombotic thrombocytopenic purpura (TTP). Analysis of a set of antibodies derived from two patients with acquired TTP revealed frequent use of the VH1-69 heavy chain gene segment for the assembly of anti-ADAMTS13 antibodies. Objective: We explored the ability of two VH1-69 germline gene-encoded antibodies to inhibit the von Willebrand factor (VWF)-processing activity of ADAMTS13 under different experimental conditions. Furthermore, the presence of VH1-69 encoded anti-ADAMTS13 antibodies in 40 patients with acquired TTP was monitored using monoclonal antibody G8, which specifically reacts with an idiotype expressed on VH1-69 encoded antibodies. Methods and Results: Binding of the two VH1-69 encoded monoclonal antibodies was dependent on the presence of the spacer domain. Both antibodies inhibited ADAMTS13 activity under static conditions, as measured by cleavage of FRETS-VWF73 substrate and cleavage of VWF multimers. The recombinant antibodies were also capable of inhibiting the processing of UL-VWF strings on the surface of endothelial cells. G8-reactive antibodies directed towards ADAMTS13 were present in plasma of all patients containing anti ADAMTS13 antibodies. Conclusions: These results suggest that VH1-69 derived antibodies directed towards ADAMTS13 develop in the majority of patients with acquired TTP. |
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Keywords: | ADAMTS13 anti-idiotypic antibodies autoantibodies G8 thrombotic thrombocytopenic purpura VH1-69 |
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