Impact of N-glycan mediated shielding of ADAMTS-13 on the binding of pathogenic antibodies in immune thrombotic thrombocytopenic purpura
Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:21 |
|---|---|
| Enthalten in: |
Journal of thrombosis and haemostasis : JTH - 21(2023), 12 vom: 10. Dez., Seite 3402-3413 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Postmus, Tim [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 27.11.2023 Date Revised 20.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.jtha.2023.08.017 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM361318081 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM361318081 | ||
| 003 | DE-627 | ||
| 005 | 20240320233359.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.jtha.2023.08.017 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1337.xml |
| 035 | |a (DE-627)NLM361318081 | ||
| 035 | |a (NLM)37633643 | ||
| 035 | |a (PII)S1538-7836(23)00645-1 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Postmus, Tim |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Impact of N-glycan mediated shielding of ADAMTS-13 on the binding of pathogenic antibodies in immune thrombotic thrombocytopenic purpura |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 27.11.2023 | ||
| 500 | |a Date Revised 20.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a ADAMTS-13 | |
| 650 | 4 | |a autoantibodies | |
| 650 | 4 | |a hemostasis | |
| 650 | 4 | |a thrombotic microangiopathies | |
| 650 | 4 | |a thrombotic thrombocytopenic purpura | |
| 650 | 7 | |a ADAMTS13 Protein |2 NLM | |
| 650 | 7 | |a EC 3.4.24.87 |2 NLM | |
| 650 | 7 | |a von Willebrand Factor |2 NLM | |
| 650 | 7 | |a Autoantibodies |2 NLM | |
| 700 | 1 | |a Graça, Nuno A G |e verfasserin |4 aut | |
| 700 | 1 | |a Ferreira de Santana, Juliana |e verfasserin |4 aut | |
| 700 | 1 | |a Ercig, Bogac |e verfasserin |4 aut | |
| 700 | 1 | |a Langerhorst, Pieter |e verfasserin |4 aut | |
| 700 | 1 | |a Luken, Brenda |e verfasserin |4 aut | |
| 700 | 1 | |a Joly, Bérangère S |e verfasserin |4 aut | |
| 700 | 1 | |a Vanhoorelbeke, Karen |e verfasserin |4 aut | |
| 700 | 1 | |a Veyradier, Agnès |e verfasserin |4 aut | |
| 700 | 1 | |a Coppo, Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Voorberg, Jan |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of thrombosis and haemostasis : JTH |d 2003 |g 21(2023), 12 vom: 10. Dez., Seite 3402-3413 |w (DE-627)NLM126285683 |x 1538-7836 |7 nnns |
| 773 | 1 | 8 | |g volume:21 |g year:2023 |g number:12 |g day:10 |g month:12 |g pages:3402-3413 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.jtha.2023.08.017 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 21 |j 2023 |e 12 |b 10 |c 12 |h 3402-3413 | ||