To serve and protect: The modulatory role of von Willebrand factor on factor VIII immunogenicity

Autor: Jan Voorberg, Robin B. Hartholt, Anja ten Brinke, Alice S. van Velzen, Ivan Peyron, Karin Fijnvandraat
Rok vydání: 2017
Předmět:
0301 basic medicine
congenital
hereditary
and neonatal diseases and abnormalities
animal diseases
media_common.quotation_subject
Antigen-Presenting Cells
030204 cardiovascular system & hematology
Hemophilia A
Immunoglobulin light chain
Blood coagulation factor VIII
law.invention
Immunomodulation
03 medical and health sciences
0302 clinical medicine
Sulfation
Von Willebrand factor
Isoantibodies
law
hemic and lymphatic diseases
von Willebrand Factor
Animals
Humans
Medicine
Protein Interaction Domains and Motifs
Internalization
Antigen-presenting cell
media_common
Factor VIII
Blood Coagulation Factor Inhibitors
biology
business.industry
Research
Immunogenicity
Dendritic Cells
Hematology
Endocytosis
Recombinant Proteins
030104 developmental biology
Oncology
Immunology
Recombinant DNA
biology.protein
business
Protein Binding
Zdroj: Blood Reviews. 31:339-347
ISSN: 0268-960X
DOI: 10.1016/j.blre.2017.07.001
Popis: Hemophilia A is a bleeding disorder characterized by the absence or dysfunction of blood coagulation factor VIII (FVIII). Patients are treated with regular infusions of FVIII concentrate. In response to treatment, approximately 30% of patients with severe hemophilia A develop inhibitory antibodies targeting FVIII. Both patient and treatment related risk factors for inhibitor development have been described. Multiple studies comparing the immunogenicity of recombinant and plasma-derived FVIII have yielded conflicting results. The randomized controlled SIPPET (Survey of Inhibitors in Plasma-Product Exposed Toddlers) trial demonstrated an increased risk of inhibitor development of recombinant FVIII when compared to von Willebrand factor (VWF)-containing plasma-derived FVIII. Presently, it is unclear which mechanism underlies the reduced immunogenicity of plasma-derived FVIII. In this review we address the potential role of VWF on FVIII immunogenicity and we discuss how VWF affects the immune recognition, processing and presentation of FVIII. We also briefly discuss the potential impact of glycan-composition on FVIII immunogenicity. It is well established that VWF shields the uptake of FVIII by antigen presenting cells. We have recently shown that VWF binds to the surface of dendritic cells. Here, we present a novel model in which surface bound FVIII-VWF complexes regulate the internalization of FVIII. Binding of FVIII to VWF is critically dependent on sulfation of Tyr1699 (HVGS numbering) in the light chain of FVIII. Incomplete sulfation of Tyr1699 has been suggested to occur in several recombinant FVIII products resulting in a loss of VWF binding. We hypothesize that this results in alternative pathways of FVIII internalization by antigen presenting cells which are not regulated by VWF. This hypothetical mechanism may explain the reduced immunogenicity of VWF containing plasma-derived FVIII concentrates as found in the SIPPET study.
Databáze: OpenAIRE
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