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Thromb Haemost 2006; 96(03): 295-301
DOI: 10.1160/TH06-03-0135
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Amino acid regions 572–579 and 657–666 of the spacer domain of ADAMTS13 provide a common antigenic core required for binding of antibodies in patients with acquired TTP

Brenda M. Luken
1   Department of Plasma Proteins, Sanquin Research and AMC Landsteiner Laboratory, Amsterdam, The Netherlands
,
Ellen A. M. Turenhout
1   Department of Plasma Proteins, Sanquin Research and AMC Landsteiner Laboratory, Amsterdam, The Netherlands
,
Paul H. P. Kaijen
1   Department of Plasma Proteins, Sanquin Research and AMC Landsteiner Laboratory, Amsterdam, The Netherlands
,
Mascha J. Greuter
1   Department of Plasma Proteins, Sanquin Research and AMC Landsteiner Laboratory, Amsterdam, The Netherlands
,
Wouter Pos
1   Department of Plasma Proteins, Sanquin Research and AMC Landsteiner Laboratory, Amsterdam, The Netherlands
,
Jan A. van Mourik
1   Department of Plasma Proteins, Sanquin Research and AMC Landsteiner Laboratory, Amsterdam, The Netherlands
3   Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
,
Rob Fijnheer
2   Department of Hematology, University Medical Center, Utrecht, The Netherlands
,
Jan Voorberg
1   Department of Plasma Proteins, Sanquin Research and AMC Landsteiner Laboratory, Amsterdam, The Netherlands
› Author AffiliationsFinancial support: This study was supported by research funding from the Landsteiner Foundation of Blood Transfusion Research (grants 01.14/05.28) and the Dutch Thrombosis Foundation (grant 2004.003).
Further Information

Publication History

Received 06 March 2006

Accepted after revision 31 July 2006

Publication Date:
30 November 2017 (online)

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Summary

Antibodies directed against ADAMTS13 have been detected in the majority of patients with acquired thrombotic thrombocytopenic purpura (TTP). We have previously localized a major antigenic determinant within the spacer domain of ADAMTS13. To identify the amino acid residues of the spacer domain that are involved in binding of anti-ADAMTS13 antibodies, we constructed a series of fifteen hybrids (designated A-O) in which 5–10 amino acids of the spacer domain were exchanged for the corresponding region of ADAMTS1. Plasma from six patients with antibodies directed against the spacer domain was analyzed for reactivity with the ADAMTS13/ADAMTS1 chimeras. Exchange of amino acid residues 572–579 (hybrid C) and 657–666 (hybrid M) completely abolished the binding of antibodies from all six patients analyzed. Regions 580–587 (D), 602–620 (G, H), 629–638 (J), and 667–767 (N) contributed to binding of antibodies from patients 2, 4, and 5 (epitope present within regions CDGHJMN). Antibodies derived from patient 1 required region 602–620 (G, H) for binding (CGHM-epitope). For antibodies of patient 3, residues 564–571 (B), 580–587 (D), and 629–638 (J) were required (BCDJM-epitope), whereas replacement of residues 602–610 (G) and 629–638 (J) greatly diminished binding of antibodies from patient 6 (CGJM-epitope). Despite the presumably polyclonal origin of the antibodies present in plasma of patients, our results suggest that residues 572–579 (C) and 657–666 (M) comprise a common antigenic core region that is crucial for binding of anti-ADAMTS13 antibodies. Other regions that spatially surround this antigenic core further modulate binding of antibodies to the spacer domain.

Keywords

ADAMS/ADAMTS 13 - autoantibodies - thrombotic thrombocytopenic purpura - TTP - HUS
 

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