Complement Activation and Thrombin Generation by MBL Bound to β2-Glycoprotein I
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| Název: | Complement Activation and Thrombin Generation by MBL Bound to β2-Glycoprotein I |
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| Autoři: | Paolo Durigutto, Paolo Macor, Nicola Pozzi, Chiara Agostinis, Fleur Bossi, Pier Luigi Meroni, Claudia Grossi, Maria O Borghi, William Planer, Peter Garred, Francesco Tedesco |
| Přispěvatelé: | Durigutto, P., Macor, P., Pozzi, N., Agostinis, C., Bossi, F., Meroni, P. L., Grossi, C., Borghi, M. O., Planer, W., Garred, P., Tedesco, F. |
| Zdroj: | The Journal of Immunology. 205:1385-1392 |
| Informace o vydavateli: | Oxford University Press (OUP), 2020. |
| Rok vydání: | 2020 |
| Témata: | 0301 basic medicine, Calcium/metabolism, Human Umbilical Vein Endothelial Cell, Mannose-Binding Lectin, Endothelium/immunology, Cell Line, 03 medical and health sciences, Human Umbilical Vein Endothelial Cells, Thrombosis/immunology, Humans, Endothelium, Complement Activation, Antiphospholipid Syndrome, Calcium, Endothelial Cells, Protein Binding, Thrombin, Thrombosis, Tumor Necrosis Factor-alpha, beta 2-Glycoprotein I, Endothelial Cell, 0303 health sciences, Protein Binding/immunology, Complement Activation/immunology, Antiphospholipid Syndrome/immunology, beta 2-Glycoprotein I/immunology, Endothelial Cells/immunology, Tumor Necrosis Factor-alpha/immunology, Thrombin/immunology, Thrombosi, Mannose-Binding Lectin/immunology, Human |
| Popis: | β2-Glycoprotein I (β2-GPI) is an abundant plasma glycoprotein with unknown physiological function and is currently recognized as the main target of antiphospholipid Abs responsible for complement activation and vascular thrombosis in patients with antiphospholipid syndrome (APS). In this study, we provide evidence that mannose-binding lectin (MBL) binds to β2-GPI in Ca++ and a dose-dependent manner and that this interaction activates complement and promotes complement-dependent thrombin generation. Surprisingly, a significant binding was observed between MBL and isolated domains II and IV of β2-GPI, whereas the carbohydrate chains, domain I and domain V, were not involved in the interaction, documenting a noncanonical binding mode between MBL and β2-GPI. Importantly, this interaction may occur on endothelial cells because binding of MBL to β2-GPI was detected on the surface of HUVECs, and colocalization of MBL with β2-GPI was observed on the endothelium of a biopsy specimen of a femoral artery from an APS patient. Because β2-GPI–mediated MBL-dependent thrombin generation was increased after priming the endothelium with TNF-α, our data suggests that this mechanism could play an important yet unrecognized role under physiological conditions and may be upregulated in pathological situations. Moreover, the complement activation and the procoagulant effects of the β2-GPI/MBL complex may contribute to amplify similar activities of anti–β2-GPI Abs in APS and possibly act independently of Abs, raising the issue of developing appropriate therapies to avoid recurrences and disability in patients at risk for these clinical conditions. |
| Druh dokumentu: | Article |
| Popis souboru: | application/pdf |
| Jazyk: | English |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.2000570 |
| Přístupová URL adresa: | https://www.jimmunol.org/content/jimmunol/205/5/1385.full.pdf https://pubmed.ncbi.nlm.nih.gov/32759297 https://www.jimmunol.org/content/205/5/1385 http://hdl.handle.net/11368/2992293 https://europepmc.org/articles/PMC7489996/ https://moh-it.pure.elsevier.com/en/publications/complement-activation-and-thrombin-generation-by-mbl-bound-to-b2--2 https://pubmed.ncbi.nlm.nih.gov/32759297/ https://www.ncbi.nlm.nih.gov/pubmed/32759297 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489996 https://www.jimmunol.org/content/205/5/1385 https://hdl.handle.net/11368/2992293 https://doi.org/10.4049/jimmunol.2000570 |
| Rights: | OUP Standard Publication Reuse |
| Přístupové číslo: | edsair.doi.dedup.....f2a9b4002525d5843a73dba7bb10ba09 |
| Databáze: | OpenAIRE |
Nájsť tento článok vo Web of Science | Abstrakt: | β2-Glycoprotein I (β2-GPI) is an abundant plasma glycoprotein with unknown physiological function and is currently recognized as the main target of antiphospholipid Abs responsible for complement activation and vascular thrombosis in patients with antiphospholipid syndrome (APS). In this study, we provide evidence that mannose-binding lectin (MBL) binds to β2-GPI in Ca++ and a dose-dependent manner and that this interaction activates complement and promotes complement-dependent thrombin generation. Surprisingly, a significant binding was observed between MBL and isolated domains II and IV of β2-GPI, whereas the carbohydrate chains, domain I and domain V, were not involved in the interaction, documenting a noncanonical binding mode between MBL and β2-GPI. Importantly, this interaction may occur on endothelial cells because binding of MBL to β2-GPI was detected on the surface of HUVECs, and colocalization of MBL with β2-GPI was observed on the endothelium of a biopsy specimen of a femoral artery from an APS patient. Because β2-GPI–mediated MBL-dependent thrombin generation was increased after priming the endothelium with TNF-α, our data suggests that this mechanism could play an important yet unrecognized role under physiological conditions and may be upregulated in pathological situations. Moreover, the complement activation and the procoagulant effects of the β2-GPI/MBL complex may contribute to amplify similar activities of anti–β2-GPI Abs in APS and possibly act independently of Abs, raising the issue of developing appropriate therapies to avoid recurrences and disability in patients at risk for these clinical conditions. |
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| ISSN: | 15506606 00221767 |
| DOI: | 10.4049/jimmunol.2000570 |