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; Ellen A. M. Turenhout; Paul H. P. Kaijen; Mascha J. Greuter; Wouter Pos; Jan A. van Mourik; Rob Fijnheer; Jan Voorberg

doi:10.1160/TH06-03-0135

Thrombosis and Haemostasis, Table of Contents

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

¹Department of Plasma Proteins, Sanquin Research and AMC Landsteiner Laboratory, Amsterdam, The Netherlands

,

Ellen A. M. Turenhout

¹Department of Plasma Proteins, Sanquin Research and AMC Landsteiner Laboratory, Amsterdam, The Netherlands

,

Paul H. P. Kaijen

¹Department of Plasma Proteins, Sanquin Research and AMC Landsteiner Laboratory, Amsterdam, The Netherlands

,

Mascha J. Greuter

¹Department of Plasma Proteins, Sanquin Research and AMC Landsteiner Laboratory, Amsterdam, The Netherlands

,

Wouter Pos

¹Department of Plasma Proteins, Sanquin Research and AMC Landsteiner Laboratory, Amsterdam, The Netherlands

,

Jan A. van Mourik

¹Department of Plasma Proteins, Sanquin Research and AMC Landsteiner Laboratory, Amsterdam, The Netherlands

³Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

,

Rob Fijnheer

²Department of Hematology, University Medical Center, Utrecht, The Netherlands

,

Jan Voorberg

¹Department of Plasma Proteins, Sanquin Research and AMC Landsteiner Laboratory, Amsterdam, The Netherlands

› Author Affiliations

Abstract

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

Full Text

References

References
1 Moake JL, Rudy CK, Troll JH. et al. Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 1982; 307: 1432-5.
2 Moake JL, Turner NA, Stathopoulos NA. et al. Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stress-induced platelet aggregation. J Clin Invest 1986; 78: 1456-61.
3 Federici AB, Bader R, Pagani S. et al. Binding of von Willebrand factor to glycoproteins Ib and IIb/IIIa complex: affinity is related to multimeric size. Br J Haematol 1989; 73: 93-9.
4 Arya M, Anvari B, Romo GM. et al. Ultralarge multimers of von Willebrand factor form spontaneous high-strength bonds with the platelet glycoprotein Ib-IX complex: studies using optical tweezers. Blood 2002; 99: 3971-7.
5 Moake JL. Thrombotic microangiopathies. N Engl J Med 2002; 347: 589-600.
6 Levy GG, Nichols WC, Lian EC. et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001; 413: 488-94.
7 Kokame K, Matsumoto M, Soejima K. et al. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci USA 2002; 99: 11902-7.
8 Matsumoto M, Kokame K, Soejima K. et al. Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome. Blood 2004; 103: 1305-10.
9 Uchida T, Wada H, Mizutani M. et al. Identification of novel mutations in ADAMTS13 in an adult patient with congenital thrombotic thrombocytopenic purpura. Blood 2004; 104: 2081-3.
10 Allford SL, Hunt BJ, Rose P. et al. Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias. Br J Haematol 2003; 120: 556-73.
11 Lämmle B, Kremer-Hovinga JA, Alberio L. Thrombotic thrombocytopenic purpura. J Thromb Haemost 2005; 03: 1663-75.
12 Veyradier A, Obert B, Houllier A. et al. Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. Blood 2001; 98: 1765-72.
13 Vesely SK, George JN, Lämmle B. et al. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood 2003; 102: 60-8.
14 Kremer-Hovinga JA, Studt JD, Alberio L. et al. Von Willebrand factor-cleaving protease (ADAMTS-13) activity determination in the diagnosis of thrombotic microangiopathies: the Swiss experience. Semin Hematol 2004; 41: 75-82.
15 Zheng XL, Kaufman RM, Goodnough LT. et al. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Blood 2004; 103: 4043-9.
16 Furlan M, Robles R, Solenthaler M. et al. Acquired deficiency of von Willebrand factor-cleaving protease in a patient with thrombotic thrombocytopenic purpura. Blood 1998; 91: 2839-46.
17 Furlan M, Robles R, Galbusera M. et al. Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 1998; 339: 1578-84.
18 Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339: 1585-94.
19 Scheiflinger F, Knöbl P, Trattner B. et al. Nonneutralizing IgM and IgG antibodies to von Willebrand factor-cleaving protease (ADAMTS-13) in a patient with thrombotic thrombocytopenic purpura. Blood 2003; 102: 3241-43.
20 Rieger M, Mannucci PM, Kremer-Hovinga JA. et al. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Blood 2005; 106: 1262-7.
21 Soejima K, Matsumoto M, Kokame K. et al. ADAMTS-13 cysteine-rich/spacer domains are functionally essential for von Willebrand factor cleavage. Blood 2003; 102: 3232-7.
22 Klaus C, Plaimauer B, Studt JD. et al. Epitope mapping of ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura. Blood 2004; 103: 4514-9.
23 Luken BM, Turenhout EA, Hulstein JJ. et al. The spacer domain of ADAMTS13 contains a major binding site for antibodies in patients with thrombotic thrombocytopenic purpura. Thromb Haemost 2005; 93: 267-74.
24 Zhou W, Dong L, Ginsburg D. et al. Enzymaticallyactive ADAMTS13 variants are not inhibited by anti-ADAMTS13 autoantibodies-A novel therapeutic strategy?. J Biol Chem 2005; 280: 39934-41.
25 Zheng X, Nishio K, Majerus EM. et al. Cleavage of von Willebrand factor requires the spacer domain of the metalloprotease ADAMTS13. J Biol Chem 2003; 278: 30136-41.
26 Ai J, Smith P, Wang S. et al. The proximal carboxylterminal domains of ADAMTS13 determine substrate specificity and are all required for cleavage of von Willebrand factor. J Biol Chem 2005; 280: 29428-34.
27 Majerus EM, Anderson PJ, Sadler JE. Binding of ADAMTS13 to von Willebrand factor. J Biol Chem 2005; 280: 21773-8.
28 Kuno K, Kanada N, Nakashima E. et al. Molecular cloning of a gene encoding a new type of metalloproteinase-disintegrin family protein with thrombospondin motifs as an inflammation associated gene. J Biol Chem 1997; 272: 556-62.
29 Vázquez F, Hastings G, Ortega MA. et al. METH-1, a human ortholog of ADAMTS-1, and METH-2 are members of a new family of proteins with angio-inhibitory activity. J. Biol Chem 1999; 274: 23349-57.
30 Kokame K, Nobe Y, Kokubo Y. et al. FRETSVWF73, a first fluorogenic substrate for ADAMTS13 assay. BrJ Haematol 2005; 129: 93-100.
31 Bruno K, Völkel D, Plaimauer B. et al. Cloning, expression and functional characterization of the fulllength murine ADAMTS13. J Thromb Haemost 2005; 03: 1064-73.
32 Zheng X, Chung D, Takayama TK. et al. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem 2001; 276: 41059-63.
33 Nicholson AC, Malik SB, Logsdon Jr JM. et al. Functional evolution of ADAMTS genes: evidence from analyses of phylogeny and gene organization. BMC Evol Biol 2005; 05: 11.
34 Andreini C, Banci L, Bertini I. et al. Comparative analysis of the ADAM and ADAMTS families. J Proteome Res 2005; 04: 881-8.
35 Kokame K, Matsumoto M, Fujimura Y. et al. VWF73, a region from D1596 to R1668 of von Willebrand factor, provides a minimal substrate for ADAMTS-13. Blood 2004; 103: 607-12.
36 Tao Z, Wang Y, Choi H. et al. Cleavage of ultralarge multimers of von Willebrand factor by C-terminaltruncated mutants of ADAMTS-13 under flow. Blood 2005; 106: 141-3.
37 Dong JF, Moake JL, Bernardo A. et al. ADAMTS-13 metalloprotease interacts with the endothelial cell-derived ultra-large von Willebrand factor. J Biol Chem 2003; 278: 29633-9.
38 Tao Z, Peng Y, Nolasco L. et al. Recombinant CUB-1 domain polypeptide inhibits the cleavage of ULVWF strings by ADAMTS-13 under flow conditions. Blood 2005; 106: 4139-45.