Impact of N-glycan mediated shielding of ADAMTS-13 on the binding of pathogenic antibodies in immune thrombotic thrombocytopenic purpura.

التفاصيل البيبلوغرافية
العنوان:	Impact of N-glycan mediated shielding of ADAMTS-13 on the binding of pathogenic antibodies in immune thrombotic thrombocytopenic purpura.
المؤلفون:	Postmus T; Department of Molecular Hematology, Sanquin-Academic Medical Center Landsteiner Laboratory, Amsterdam, The Netherlands., Graça NAG; Department of Molecular Hematology, Sanquin-Academic Medical Center Landsteiner Laboratory, Amsterdam, The Netherlands., Ferreira de Santana J; Department of Molecular Hematology, Sanquin-Academic Medical Center Landsteiner Laboratory, Amsterdam, The Netherlands., Ercig B; Division of Biochemistry and Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Langerhorst P; Department of Molecular Hematology, Sanquin-Academic Medical Center Landsteiner Laboratory, Amsterdam, The Netherlands., Luken B; Sanquinnovate, Amsterdam, The Netherlands., Joly BS; Centre National de Référence des Microangiopathies Thrombotiques, hôpital Saint-Antoine, AP-HP. Sorbonne Université, Paris, France; Service d'hématologie biologique, hôpital Lariboisière et EA3518 Institut de Recherche Saint-Louis, AP-HP. Nord, Université Paris Cité, Paris, France., Vanhoorelbeke K; Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium., Veyradier A; Centre National de Référence des Microangiopathies Thrombotiques, hôpital Saint-Antoine, AP-HP. Sorbonne Université, Paris, France; Service d'hématologie biologique, hôpital Lariboisière et EA3518 Institut de Recherche Saint-Louis, AP-HP. Nord, Université Paris Cité, Paris, France., Coppo P; Centre National de Référence des Microangiopathies Thrombotiques, hôpital Saint-Antoine, AP-HP. Sorbonne Université, Paris, France; Service d'hématologie biologique, hôpital Lariboisière et EA3518 Institut de Recherche Saint-Louis, AP-HP. Nord, Université Paris Cité, Paris, France., Voorberg J; Department of Molecular Hematology, Sanquin-Academic Medical Center Landsteiner Laboratory, Amsterdam, The Netherlands; Department of Experimental Vascular Medicine, Amsterdam UMC, Amsterdam, The Netherlands. Electronic address: j.voorberg@sanquin.nl.
المصدر:	Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2023 Dec; Vol. 21 (12), pp. 3402-3413. Date of Electronic Publication: 2023 Aug 25.
نوع المنشور:	Journal Article; Research Support, Non-U.S. Gov't
اللغة:	English
بيانات الدورية:	Publisher: Elsevier Country of Publication: England NLM ID: 101170508 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-7836 (Electronic) Linking ISSN: 15387836 NLM ISO Abbreviation: J Thromb Haemost Subsets: MEDLINE
أسماء مطبوعة:	Publication: 2023- : [New York] : Elsevier Original Publication: Oxford : Blackwell Pub.
مواضيع طبية MeSH:	Purpura, Thrombotic Thrombocytopenic* , Thrombosis* , Purpura, Thrombocytopenic, Idiopathic*, Humans ; ADAMTS13 Protein ; von Willebrand Factor/metabolism ; Blood Platelets/metabolism ; Autoantibodies
مستخلص:	Background: Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic disorder, with 1.5 to 6.0 cases per million per year. The majority of patients with TTP develop inhibitory autoantibodies that predominantly target the spacer domain of ADAMTS-13. ADAMTS-13 is responsible for cleaving von Willebrand factor (VWF) multimers, thereby regulating platelet adhesion at sites of high-vascular shear stress. Inhibition and/or clearance of ADAMTS-13 by pathogenic autoantibodies results in accumulation of VWF multimers that promotes the formation of platelet-rich microthrombi. Previously, we have shown that insertion of a single N-glycan (NGLY) in the spacer domain prevents the binding of antispacer domain antibodies. Objectives: To explore whether NGLY mediated shielding of the ADAMTS-13 spacer domain effectively prevents binding of pathogenic antispacer autoantibodies in patients with immune-mediated TTP (iTTP). Methods: We screened 5 NGLY-ADAMTS-13 variants (NGLY3, NGLY7, NGLY8, NGLY3+7, and NGLY3+8) for binding of autoantibodies and for their activity in the presence and absence of 50 samples derived from patients with iTTP. Results: NGLY variants showed greatly reduced antibody binding, down to 27% of wild-type (wt) ADAMTS-13 binding. Moreover, NGLY variants of ADAMTS-13 remained more active in FRETS-VWF73 assay in the presence of the plasma samples from these 50 patients with acute phase iTTP when compared with wtADAMTS-13. On average, wtADAMTS-13 activity was reduced to 37% of regular levels in the presence of plasma, while NGLY3 and NGLY3+7 remained 69% and 81% active, respectively. Conclusion: These results reinforce our previous findings that NGLYs shield ADAMTS-13 from antibody binding and hence restore ADAMTS-13 activity in the presence of autoantibodies. Competing Interests: Declaration of competing interests N.A.G.G., B.E., and J.V. are listed as inventors on a patent application for NGLY modified ADAMTS-13. At the time of the study N.A.G.G., J.F.d.S., and B.M.L. were employed by Sanquinnovate, which is fully owned by Sanquin Blood Supply Foundation, a not-for-profit organisation. K.V. is a member of the advisory board of Takeda. P.C. is a member of the clinical advisory board for Alexion, Sanofi, Shire, Takeda, and Janssen. A.V. is a member of the advisory boards for Sanofi, Takeda, and LFB biomedicaments. The other authors have no competing interests to disclose. (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
فهرسة مساهمة:	Keywords: ADAMTS-13; autoantibodies; hemostasis; thrombotic microangiopathies; thrombotic thrombocytopenic purpura
المشرفين على المادة:	EC 3.4.24.87 (ADAMTS13 Protein) 0 (von Willebrand Factor) 0 (Autoantibodies)
تواريخ الأحداث:	Date Created: 20230826 Date Completed: 20231127 Latest Revision: 20240320
رمز التحديث:	20240320
DOI:	10.1016/j.jtha.2023.08.017
PMID:	37633643
قاعدة البيانات:	MEDLINE

الوصف
تدمد:	1538-7836
DOI:	10.1016/j.jtha.2023.08.017