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Editorials
Figure 1. Effect of variants in the exosite 3 region of the spacer domain of ADAMTS13 and their impact on ADAMTS13 autoantibody binding and von Willebrand factor cleavage. The effect of wild-type (WT) ADAMTS13, with 100% ADAMTS13 autoantibody binding involving the amino acid configuration RFRRY, compared to the most productive variants (RARAA and AAAAA), which can reduce ADAMTS13 autoantibody binding but still retain von Willebrand factor (VWF) cleavage activity.
The three aromatic residues rather than the two argi- nine residues of exosite 3 in the spacer domain appear to have greater importance in ADAMTS 13 antibody bind- ing. The greatest influence was noted with cumulative mutations of the aromatic residues, demonstrating the maximum effect in preventing ADAMTS13 autoantibody binding, which is achieved by re-presenting epitope loops, lowering the surface charge and reducing surface size.9
Current therapy for TTP aims to replace ADAMTS13, via plasma exchange and immunosuppression to remove autoantibodies to ADAMTS13. The main therapeutic modalities used are steroids and rituximab. Their role in reducing IgG antibody levels has been well described in both the treatment of acute TTP12 and as prophylaxis,13,14 usually resulting in normalization of ADAMTS13 activi- ty. The importance of the work by Graca et al. is the detailed demonstration and confirmation that develop- ment of ADAMTS13 variants could be used to overcome the antibody response in iTTP, preventing autoantibodies to ADAMTS13 from binding to exosite 3 of the spacer domain but ensuring residual ADAMTS13 cleavage activ- ity. There may be a role for these variants in future care of patients, conquering the immunological consequence of ADAMTS13 antibodies.
References
1.Furlan M, Lammle B. Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. Best Pract Res Clin Haematol. 2001;14(2):437-454.
2. Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving pro- tease in acute thrombotic thrombocytopenic purpura. N Engl J Med. 1998;339(22):1585-1594.
3.Klaus C, Plaimauer B, Studt JD, et al. Epitope mapping of ADAMTS13 autoantibodies in acquired thrombotic thrombocy- topenic purpura. Blood. 2004;103(12):4514-4519.
4.Luken BM, Kaijen PH, Turenhout EA, et al. Multiple B-cell clones producing antibodies directed to the spacer and disintegrin/throm- bospondin type-1 repeat 1 (TSP1) of ADAMTS13 in a patient with acquired thrombotic thrombocytopenic purpura. J Thromb Haemost. 2006;4(11):2355-2364.
5.Zheng XL, Wu HM, Shang D, et al. Multiple domains of ADAMTS13 are targeted by autoantibodies against ADAMTS13 in patients with acquired idiopathic thrombotic thrombocytopenic purpura. Haematologica. 2010;95(9):1555-1562.
6. Yamaguchi Y, Moriki T, Igari A, et al. Epitope analysis of autoanti- bodies to ADAMTS13 in patients with acquired thrombotic throm- bocytopenic purpura. Thromb Res. 2011;128(2):169-173.
7. Pos W, Crawley JT, Fijnheer R, Voorberg J, Lane DA, Luken BM. An autoantibody epitope comprising residues R660, Y661, and Y665 in the ADAMTS13 spacer domain identifies a binding site for the A2 domain of VWF. Blood. 2010;115(8):1640-1649.
8. Thomas MR, de Groot R, Scully MA, Crawley JT. Pathogenicity of anti-ADAMTS13 autoantibodies in acquired thrombotic thrombo- cytopenic purpura. EBioMedicine. 2015;2(8):940-950.
9.Graça NGA, Ercig B, Velásquez Pereira LC, et al. Modifying ADAMTS13 to modulate binding of pathogenic autoantibodies of patients with acquired thrombotic thrombocytopenic purpura. Haematologica. 2020;105(11):2619-2630.
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