Anti-cysteine/spacer antibodies that open ADAMTS13 are a common feature in iTTP
2021
de Waele, Laure | Curie, Alexandre | Kangro, Kadri | Tellier, Edwige | Kaplanski, Gilles | Männik, Andres | Tersteeg, Claudia | Joly, Bérangère | Coppo, Paul | Veyradier, Agnès | de Meyer, Simon | Roose, Elien | Vanhoorelbeke, Karen | Laboratory for Thrombosis Research, Interdisciplinary Research Center ; Catholic University of Leuven | Service de Néphrologie [Rouen] ; CHU Rouen ; Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN) ; Normandie Université (NU) | Icosagen [Tartumaa, Estonia] | Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN) ; Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) | Hôpital de la Conception [CHU - APHM] (LA CONCEPTION) | Service d’Hématologie Biologique [CHU Lariboisière] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP) | Recherche clinique appliquée à l'hématologie (URP_3518) ; Université Paris Cité (UPCité) | CHU Saint-Antoine [AP-HP] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
International audience
Mostrar más [+] Menos [-]Inglés. Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by an autoantibody-mediated deficiency in ADAMTS13. In healthy individuals, ADAMTS13 has a folded conformation in which the central spacer (S) domain interacts with the C-terminal CUB domains. We recently showed that ADAMTS13 adopts an open conformation in iTTP and that patient immunoglobulin G antibodies (IgGs) can open ADAMTS13. Anti-ADAMTS13 autoantibodies in patients with iTTP are directed against the different ADAMTS13 domains, but almost all patients have autoantibodies binding to the cysteine/spacer (CS) domains. In this study, we investigated whether the autoantibodies against the CS and CUB domains can disrupt the S-CUB interaction of folded ADAMTS13, thereby opening ADAMTS13. To this end, we purified anti-CS and anti-CUB autoantibodies from 13 patients with acute iTTP by affinity chromatography. The successfully purified anti-CS (10/13 patients) and anti-CUB (4/13 patients) autoantibody fractions were tested further in our ADAMTS13 conformation enzyme-linked immunosorbent assay to study whether they could open ADAMTS13. Interestingly, all purified anti-CS fractions (10/10 patients) were able to open ADAMTS13. On the other hand, only half of the purified anti-CUB fractions (2/4 patients) opened ADAMTS13. Our finding highlights that anti-CS autoantibodies that open ADAMTS13 are a common feature of the autoimmune response in iTTP.
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