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Factor VIII bypasses CD91/LRP for endocytosis by dendritic cells leading to T-cell activation

¹ Unité 872, Institut National de la Santé et de la Recherche Médicale, Paris, France
² Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche-Santé 872, Paris, France
³ Unité Mixte de Recherche-Santé 872, Université Paris Descartes, Paris, France
⁴ Laboratoire d’Hématologie, Université de Caen, France
⁵ Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA
⁶ Hemophilia Center, APHP Bicêtre University Hospital, Le Kremlin-Bicêtre, France and
⁷ Center for Molecular and Vascular Biology, University of Leuven, Belgium

Correspondence: Sebastien Lacroix-Desmazes, INSERM UMRS 872, Equipe 16, Centre de Recherche des Cordeliers, 15 rue de l’Ecole de Médecine, 75006 Paris, France. E-mail: sebastien.lacroix-des-mazes{at}crc.jussieu.fr

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, 2-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.

Key words: hemophilia, factor VIII, inhibitors, dendritic cells, T-cell clone, CD91/LRP.

This article has been cited by other articles:

				S. Lacroix-Desmazes, A.-M. Navarrete, S. Andre, J. Bayry, S. V. Kaveri, and S. Dasgupta Dynamics of factor VIII interactions determine its immunologic fate in hemophilia A Blood, July 15, 2008; 112(2): 240 - 249. [Abstract] [Full Text] [PDF]