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Published on: September 1, 2015
Factor VIII bypasses CD91/LRP for endocytosis by dendritic cells leading to T-cell activation
Suryasarathi Dasgupta1, Ana Maria Navarrete, Sebastien André
1Unité 872, Institut National de la Santé et de la Recherche Médicale, Paris, France.
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 fluorescein 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, alpha2-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.
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