title: Factor VIII bypasses CD91/LRP for endocytosis by dendritic cells leading to T-cell activation.
abstract: 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.
  
  
  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.
authors.affiliation: Unité 872, Institut National de la Santé et de la Recherche Médicale, Paris, France.
authors.forename: Suryasarathi
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Navarrete
authors.forename: Sebastien
authors.initials: S
authors.lastname: André
authors.forename: Bharath
authors.initials: B
authors.lastname: Wootla
authors.forename: Sandrine
authors.initials: S
authors.lastname: Delignat
authors.forename: Yohann
authors.initials: Y
authors.lastname: Repessé
authors.forename: Jagadeesh
authors.initials: J
authors.lastname: Bayry
authors.forename: Antonino
authors.initials: A
authors.lastname: Nicoletti
authors.forename: Evgueni L
authors.initials: EL
authors.lastname: Saenko
authors.forename: Roseline
authors.initials: R
authors.lastname: d'Oiron
authors.forename: Marc
authors.initials: M
authors.lastname: Jacquemin
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Saint-Remy
authors.forename: Srini V
authors.initials: SV
authors.lastname: Kaveri
authors.forename: Sebastien
authors.initials: S
authors.lastname: Lacroix-Desmazes
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D002469:Cell Separation; D003713:Dendritic Cells / Q000166:cytology*; D004705:Endocytosis; D005169:Factor VIII / Q000096:biosynthesis* / Q000378:metabolism; D006467:Hemophilia A / Q000235:genetics; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008213:Lymphocyte Activation; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology*
chemical_list: D015703:Antigens, CD; C475476:LRP1 protein, human; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C078147:F8 protein, human; D005169:Factor VIII