Anti-ADAMTS13 Autoantibodies against Cryptic Epitopes in Immune-Mediated Thrombotic Thrombocytopenic Purpura

Elien Roose, Gestur Vidarsson, Kadri Kangro, Onno J.H.M. Verhagen, Ilaria Mancini, Linda Desender, Inge Pareyn, Nele Vandeputte, Aline Vandenbulcke, Chiara Vendramin, An Sofie Schelpe, Jan Voorberg, Marie Agnès Azerad, Laurent Gilardin, Marie Scully, Daan Dierickx, Hans Deckmyn, Simon F. De Meyer, Flora Peyvandi, Karen Vanhoorelbeke

Research output: Contribution to journalArticle

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Abstract

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by severe ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) deficiency, the presence of anti-ADAMTS13 autoantibodies and an open ADAMTS13 conformation with a cryptic epitope in the spacer domain exposed. A detailed knowledge of anti-ADAMTS13 autoantibodies will help identifying pathogenic antibodies and elucidating the cause of ADAMTS13 deficiency. We aimed at cloning anti-ADAMTS13 autoantibodies from iTTP patients to study their epitopes and inhibitory characteristics. We sorted anti-ADAMTS13 autoantibody expressing B cells from peripheral blood mononuclear cells of 13 iTTP patients to isolate anti-ADAMTS13 autoantibody sequences. Ninety-six B cell clones producing anti-ADAMTS13 autoantibodies were identified from which 30 immunoglobulin M (IgM) and 5 IgG sequences were obtained. For this study, we only cloned, expressed and purified the five IgG antibodies. In vitro characterization revealed that three of the five cloned IgG antibodies, TTP73-1, ELH2-1 and TR8C11, indeed recognize ADAMTS13. Epitope mapping showed that antibodies TTP73-1 and TR8C11 bind to the cysteine-spacer domains, while the antibody ELH2-1 recognizes the T2-T3 domains in ADAMTS13. None of the antibodies inhibited ADAMTS13 activity. Given the recent findings regarding the open ADAMTS13 conformation during acute iTTP, we studied if the cloned antibodies could recognize cryptic epitopes in ADAMTS13. Interestingly, all three antibodies recognize cryptic epitopes. In conclusion, we cloned three anti-ADAMTS13 autoantibodies from iTTP patients that recognize cryptic epitopes. Hence, these data nicely fit our recent finding that the conformation of ADAMTS13 is open during acute iTTP.

Original languageEnglish
Pages (from-to)1729-1742
Number of pages14
JournalThrombosis and Haemostasis
Volume118
Issue number10
DOIs
Publication statusPublished - Oct 1 2018

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Thrombotic Thrombocytopenic Purpura
Autoantibodies
Epitopes
Antibodies
Immunoglobulin G
B-Lymphocytes
Thrombospondin 1
Epitope Mapping
Disintegrins
Metalloproteases
Cysteine
Immunoglobulin M
Organism Cloning
Blood Cells
Clone Cells

ASJC Scopus subject areas

  • Hematology

Cite this

Roose, E., Vidarsson, G., Kangro, K., Verhagen, O. J. H. M., Mancini, I., Desender, L., ... Vanhoorelbeke, K. (2018). Anti-ADAMTS13 Autoantibodies against Cryptic Epitopes in Immune-Mediated Thrombotic Thrombocytopenic Purpura. Thrombosis and Haemostasis, 118(10), 1729-1742. https://doi.org/10.1055/s-0038-1669459

Anti-ADAMTS13 Autoantibodies against Cryptic Epitopes in Immune-Mediated Thrombotic Thrombocytopenic Purpura. / Roose, Elien; Vidarsson, Gestur; Kangro, Kadri; Verhagen, Onno J.H.M.; Mancini, Ilaria; Desender, Linda; Pareyn, Inge; Vandeputte, Nele; Vandenbulcke, Aline; Vendramin, Chiara; Schelpe, An Sofie; Voorberg, Jan; Azerad, Marie Agnès; Gilardin, Laurent; Scully, Marie; Dierickx, Daan; Deckmyn, Hans; De Meyer, Simon F.; Peyvandi, Flora; Vanhoorelbeke, Karen.

In: Thrombosis and Haemostasis, Vol. 118, No. 10, 01.10.2018, p. 1729-1742.

Research output: Contribution to journalArticle

Roose, E, Vidarsson, G, Kangro, K, Verhagen, OJHM, Mancini, I, Desender, L, Pareyn, I, Vandeputte, N, Vandenbulcke, A, Vendramin, C, Schelpe, AS, Voorberg, J, Azerad, MA, Gilardin, L, Scully, M, Dierickx, D, Deckmyn, H, De Meyer, SF, Peyvandi, F & Vanhoorelbeke, K 2018, 'Anti-ADAMTS13 Autoantibodies against Cryptic Epitopes in Immune-Mediated Thrombotic Thrombocytopenic Purpura', Thrombosis and Haemostasis, vol. 118, no. 10, pp. 1729-1742. https://doi.org/10.1055/s-0038-1669459
Roose, Elien ; Vidarsson, Gestur ; Kangro, Kadri ; Verhagen, Onno J.H.M. ; Mancini, Ilaria ; Desender, Linda ; Pareyn, Inge ; Vandeputte, Nele ; Vandenbulcke, Aline ; Vendramin, Chiara ; Schelpe, An Sofie ; Voorberg, Jan ; Azerad, Marie Agnès ; Gilardin, Laurent ; Scully, Marie ; Dierickx, Daan ; Deckmyn, Hans ; De Meyer, Simon F. ; Peyvandi, Flora ; Vanhoorelbeke, Karen. / Anti-ADAMTS13 Autoantibodies against Cryptic Epitopes in Immune-Mediated Thrombotic Thrombocytopenic Purpura. In: Thrombosis and Haemostasis. 2018 ; Vol. 118, No. 10. pp. 1729-1742.
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AU - Verhagen, Onno J.H.M.

AU - Mancini, Ilaria

AU - Desender, Linda

AU - Pareyn, Inge

AU - Vandeputte, Nele

AU - Vandenbulcke, Aline

AU - Vendramin, Chiara

AU - Schelpe, An Sofie

AU - Voorberg, Jan

AU - Azerad, Marie Agnès

AU - Gilardin, Laurent

AU - Scully, Marie

AU - Dierickx, Daan

AU - Deckmyn, Hans

AU - De Meyer, Simon F.

AU - Peyvandi, Flora

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