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Brenda M. Luken, Ellen A. M. Turenhout, Paul H. P. Kaijen, Mascha J. Greuter, Wouter Pos, Jan A. van Mourik, Rob Fijnheer, Jan Voorberg
Amino acid regions 572579 and 657666 of the spacer domain of ADAMTS13 provide a common antigenic core required for binding of antibodies in patients with acquired TTP
Keywords: ADAMS/ADAMTS 13, autoantibodies, thrombotic thrombocytopenic purpura, TTP, HUS
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 510 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 572579 (hybrid C) and 657666 (hybrid M) completely abolished the binding of antibodies from all six patients analyzed. Regions 580587 (D), 602620 (G, H), 629638 (J), and 667767 (N) contributed to binding of antibodies from patients 2, 4, and 5 (epitope present within regions CDGHJMN). Antibodies derived from patient 1 required region 602620 (G, H) for binding (CGHM-epitope). For antibodies of patient 3, residues 564571 (B), 580587 (D), and 629638 (J) were required (BCDJM-epitope), whereas replacement of residues 602610 (G) and 629638 (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 572579 (C) and 657666 (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.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 96, 09/2006
Pages: 295 - 301