Enhanced uptake of blood coagulation factor VIII containing immune complexes by antigen presenting cells

Autor: J. S. Verbeek, T. Rispens, Jan Voorberg, Aleksandra Wroblewska, Falk Nimmerjahn, A. ten Brinke, Ivan Peyron, J. W. Claassens, Robin B. Hartholt, Eszter Herczenik, Edith Slot, Martijn A. Nolte
Přispěvatelé: AII - Inflammatory diseases, Landsteiner Laboratory, ACS - Microcirculation
Rok vydání: 2016
Předmět:
congenital
hereditary
and neonatal diseases and abnormalities
immune complex
media_common.quotation_subject
animal diseases
Molecular Conformation
Antigen-Presenting Cells
Bone Marrow Cells
Antigen-Antibody Complex
030204 cardiovascular system & hematology
Immune complex formation
Hemophilia A
Immune tolerance
03 medical and health sciences
Mice
0302 clinical medicine
Immune system
hemic and lymphatic diseases
Immune Tolerance
Medicine
Animals
Humans
Receptor
Antigen-presenting cell
Internalization
Blood Coagulation
media_common
Mice
Knockout
Factor VIII
Microscopy
Confocal
biology
business.industry
Receptors
IgG
Antibodies
Monoclonal
Hematology
Dendritic Cells
Immune complex
Endocytosis
Recombinant Proteins
Rats
Mice
Inbred C57BL
Immunoglobulin G
Immunology
Fc gamma receptors
biology.protein
Antibody
business
030215 immunology
Zdroj: Journal of thrombosis and haemostasis, 15(2), 329-340. Wiley-Blackwell
Journal of Thrombosis and Haemostasis, 15(2), 329-340
ISSN: 1538-7836
1538-7933
Popis: Essentials Anti-factor (F) VIII antibody formation is a major complication in the treatment of hemophilia A. We investigated uptake of FVIII and FVIII immune complex by bone marrow derived dendritic cells. Immune complex formation increased uptake of FVIII 3-4 fold in a Fcγ receptor dependent manner. FVIII immune complex binding to Fcγ receptors may modulate immune tolerance induction. SummaryBackground A major complication in the treatment of hemophilia A is the development of inhibitory antibodies targeting coagulation factor VIII (FVIII). Eradication of these inhibitors can be established by immune tolerance induction (ITI), which consists of daily administration of high dosages of FVIII. FVIII immune complexes (FVIII-IC) could be formed following FVIII infusion in patients with pre-existing anti-FVIII antibodies. Objectives Here we studied endocytosis of FVIII-IC by bone marrow-derived dendritic cells (BMDCs). Methods BMDCs were pulsed with FVIII/FVIII-IC and uptake was assessed by flow cytometry and confocal imaging. Results BMDCs were able to efficiently internalize FVIII-IC in a dose-dependent manner, 3–4-fold more efficiently when compared with equimolar concentrations of non-complexed FVIII. Uptake of FVIII-IC, but not FVIII alone, could be inhibited with anti-Fcγ receptor (FcγR) antibody 2.4G2, indicating functional involvement of FcγR. No internalization of FVIII-IC was observed in BMDCs lacking FcγRI, FcγRIIb, FcγRIII and FcγRIV. Genetic ablation of FcγRIIb, FcγRIII or FcγRIV individually did not affect the ability of anti-FVIII IgG to promote the uptake of FVIII. BMDCs lacking FcγRI showed lower FVIII-IC uptake levels when compared with other single FcγR null BMDCs. Expression of the inhibitory FcγRIIb alone was sufficient to internalize FVIII-IC more efficiently than FVIII. Conclusions FcγR are critical in the internalization of FVIII-IC by BMDCs and multiple FcγR can contribute independently to this process. Our findings provide a basis for future studies to address whether the outcome of ITI is dependent on the interplay between FVIII-IC and inhibitory and activating FcγR.
Databáze: OpenAIRE
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