Factor VIII bypasses CD91/LRP for endocytosis by dendritic cells leading to T-cell activation
| Autor: | Suryasarathi Dasgupta, Ana Maria Navarrete, Sebastien André, Bharath Wootla, Sandrine Delignat, Yohann Repessé, Jagadeesh Bayry, Antonino Nicoletti, Evgueni L. Saenko, Roseline d’Oiron, Marc Jacquemin, Jean-Marie Saint-Remy, Srini V. Kaveri, Sebastien Lacroix-Desmazes |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: | |
| Zdroj: | Haematologica, Vol 93, Iss 1 (2008) |
| Druh dokumentu: | article |
| ISSN: | 0390-6078 1592-8721 |
| DOI: | 10.3324/haematol.11535 |
| Popis: | Background The development of factor VIII (FVIII) inhibitors remains the major hurdle in the clinical management of patients with hemophilia A. FVIII uptake by professional antigen-presenting cells (APC) is the first step involved in initiation of immune responses to FVIII. Studies on FVIII catabolism have highlighted the role played by CD91/LRP as a potential target for increasing FVIII half-life in patients and prolonging treatment efficiency. We investigated the involvement of CD91 in FVIII endocytosis by human dendritic cells (DC), a model of professional APC.Design and Methods Immature DC were generated from circulating monocytes from healthy donors. Surface expression of CD91 was assessed by flow cytometry. Uptake of fluoroscein isothiocyanate-conjugated ligands by immature DC was studied in the presence of various blocking agents.Results CD91 was expressed on approximately 20% of DC and mediated the internalization of its model ligand, α2-macroglobulin. DC internalized FVIII and activated a human FVIII-specific T-cell clone in a dose-dependent manner. FVIII uptake by DC and subsequent T-cell activation were not inhibited by receptor-associated protein.Conclusions Our results indicate that CD91 and other members of the LDL receptor family are not strongly implicated in FVIII internalization by monocyte-derived DC, and suggest the involvement of alternative divalent ion-dependent endocytic receptors. |
| Databáze: | Directory of Open Access Journals |
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